Podcasts about Gabaa

PMDS, premenstruellt dyforiskt syndrom, är den svåraste formen av PMS och ger symtom som djup nedstämdhet, ångest, irritabilitet, trötthet, sömnproblem med mera under fasen mellan ägglossning och menstruation. Cirka 3-5% av de som har menstruationer drabbas, och tillståndet kan ha mycket stor påverkan på livskvalitet, relationer, arbete och studier. Vi gästas i avsnittet av Dr Louise Stiernman från Umeå universitet. Hon har nyligen presenterat och försvarat sin doktorsavhandling om PMDS och mätbara förändringar i hjärnan : "Premenstruellt dysforiskt syndrom: Hjärnans struktur och funktion, GABAA-aktiva neurosteroider och GABAA-receptorplasticitet."Hör om PMDS och vad som orsakar tillståndet, vad Louise och hennes kollegor upptäckt när de undersökt aktiviteten i hjärnan hos individer med PMDS, och vad det här kan ha för betydelse för vidare forskning och behandling! TUNE IN för ett ännu ett viktigt avsnitt.Avsnittet är i samarbete med MAM och Frida Baby Hosted on Acast. See acast.com/privacy for more information.

Neuroscientist Nazanin Azarinejad Mohammadi discusses her research on epilepsy genetics, the clinical and functional characterisation of GABAA-receptor related disorders, and how mutations in the GABAA-receptor subunits can lead to epilepsy and morbidities. Nazanin also highlights the variability in symptoms among individuals with the same mutation and the need for further research to understand the factors that contribute to this variability. Plus, emphasised is the importance of genetic testing and personalised treatment for patients with these mutations. ----------------------------------------- Paper: “Clinical and functional characterization of GABAA-receptor related disorders: translating genetic diagnostics into personalized treatment”

RespireRx Pharmaceuticals Inc CEO Arnold Lippa joined Steve Darling from Proactive to unveil exciting developments within the company. Lippa shared the groundbreaking news that RespireRx's lead GABAA receptor potentiator, KRM-II-81, has ascended to the next phase of evaluation within the esteemed NIH HEAL Initiative® Preclinical Screening Platform for Pain program. The NIH HEAL Initiative, an integral component in combatting the national opioid public health crisis, stands as a collaborative and resolute effort aimed at accelerating scientific solutions. Launched in April 2018, this initiative is dedicated to advancing prevention and treatment strategies for opioid misuse and addiction, while concurrently enhancing pain management protocols. Lippa elaborated on the significant progress made with KRM-II-81, citing emerging data that showcased its efficacy in mitigating pain-like behaviors in rats. Remarkably, these effects were observed at doses demonstrating minimal or no detectable side effects, underscoring the compound's potential for therapeutic success. These promising results were witnessed across both male and female rats, across two distinct measures, including models of post-incision pain and spinal nerve ligation-induced persistent neuropathic pain. This latest research builds upon prior observations made by RespireRx Pharmaceuticals Inc and other laboratories, affirming KRM-II-81's effectiveness in alleviating acute, chronic, and neuropathic pain across various experimental models. Importantly, these benefits were achieved without the development of tolerance or sedation, highlighting the compound's favorable safety profile and therapeutic potential. As a result of these compelling findings, KRM-II-81 has progressed within the NIH PSPP program, where it will undergo further evaluation across additional disease-specific pain models. With promising clinical validation on the horizon, RespireRx Pharmaceuticals Inc firmly believes that KRM-II-81 holds the potential to emerge as a groundbreaking medication not only for pain management but also for the treatment of epilepsy and other neuropsychiatric disorders. This remarkable advancement underscores the company's commitment to pioneering innovative solutions that address critical medical needs and improve patient outcomes. #proactiveinvestors #respirerxpharmaceuticalsinc #otc #rspi #CAREM281, #Analgesic, #NonAddictive, #OpioidAlternative, #PainReliefInnovation, #GABAAgonist, #PharmaNews, #DrugDevelopment, #HEALInitiative, #NeurologicalDisorders, #MedicalBreakthrough, #AddictionFree, #ChronicPainSolution, #NeuropathicPain, #AcutePain, #OpioidEpidemicSolution, #HealthcareInnovation, #Pharmaceuticals, #ClinicalResearch, #PainManagement, #ScienceNews, #Biotech, #MedicalResearch, #PharmaTech #invest #investing #investment #investor #stockmarket #stocks #stock #stockmarketnews

CME credits: 0.50 Valid until: 05-12-2024 Claim your CME credit at https://reachmd.com/programs/cme/postpartum-depression-a-significant-burden-and-a-novel-approach-to-treatment/15685/ The recent development and approval of two neuroactive steroids is likely to change the treatment paradigm for moderate to severe postpartum depression (PPD). These agents have a quick onset and function as GABAA positive allosteric modulators. Join Drs. Shulman and Deligiannidis as they address the burdens and impacts of PPD on mothers, babies, and partners, and deep dive into the pathophysiologic role and clinical findings associated with the use of neuroactive steroids in the management of PPD. =

Contributor: Travis Barlock MD Educational Pearls: Alcohol binds the GABA receptor, which produces an inhibitory response, hence the “depressive” effects of ethanol beverages. Over time, alcohol downregulates the GABA receptors, leading to unopposed glutamate activity. Given that glutamate is excitatory, this can lead to seizures. Alcohol also suppresses REM sleep; in patients with chronically suppressed REM sleep, the brain starves for dream sleep and it spills over into the wakeful state, inducing a dream-like state when someone is awake. The awake dream-like state of delirium tremens (DT) differs from alcohol hallucinosis Alcohol hallucinosis presents with visual hallucinations in a wakeful state DT presents with a generalized clouding of the sensorium and a dream-like state Treatment for DT is better achieved with phenobarbital due to predictable pharmacology Phenobarbital acts on GABA and NMDA receptors References 1. Davies M. The role of GABAA receptors in mediating the effects of alcohol in the central nervous system. J Psychiatry Neurosci. 2003;28(4):263-274. 2. Fujimoto J, Lou JJ, Pessegueiro AM. Use of Phenobarbital in Delirium Tremens. J Investig Med High Impact Case Reports. 2017;5(4):4-6. doi:10.1177/2324709617742166 3. Walker, M. Chapter 13: iPads, Factory Whistles, and Nightcaps In: Walker, M, Why We Sleep. Scribner; 2017, pg. 272.  4. Zarcone V. Alcoholism and sleep. Adv Biosci. 1978;21:29-38. Summarized & Edited by Jorge Chalit, OMSII  

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.07.18.549465v1?rss=1 Authors: Alfonsa, H., Vyazovskiy, V. V., Akerman, C. Abstract: Neural plasticity varies depending on the time of day and preceding sleep-wake history. It is unclear however, how diurnal changes in cellular physiology modulate a neuron's propensity to exhibit synaptic plasticity. Recently it has been shown that cortical pyramidal neurons exhibit diurnal changes in their transmembrane chloride gradients, which shift the equilibrium potential for GABAA receptors (EGABAA). Here we demonstrate that diurnal EGABAA affects membrane potential dynamics and glutamatergic long-term potentiation (LTP) elicited by high-frequency spiking activity in pyramidal neurons of mouse cortex. More depolarized EGABAA values associated with the active period facilitate LTP induction by promoting residual depolarization during synaptically-evoked spiking. Diurnal differences in LTP can be reversed by switching the EGABAA-dependent effects on membrane potential dynamics, either by direct current injection or pharmacologically altering EGABAA. These findings identify EGABAA as a metaplastic regulator of glutamatergic synaptic potentiation, which has implications for understanding synaptic plasticity during waking and sleep. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.07.13.547220v1?rss=1 Authors: Arias-Hervert, E. R., Birdsong, W. T. Abstract: Activation of opioid receptors in the anterior cingulate cortex (ACC) mediates aspects of analgesia induced by both exogenous and endogenous opioids. We have previously shown that opioids signaling disrupts both afferent excitatory and indirect inhibitory synaptic transmission from the medial thalamus (MThal) to the ACC, but the effects of endogenous opioids within this circuit remain poorly understood. The goal of the current study was to understand how the endogenous opioid, [Met]5-enkephalin (ME), modulates thalamic-driven excitatory and inhibitory synaptic transmission onto layer V pyramidal neurons in the ACC. We used pharmacology, brain slice electrophysiology and optogenetic stimulation to study opioid-mediated modulation of optically evoked glutamatergic and GABAergic transmission. The results revealed that ME inhibited both AMPA-mediated excitatory and GABA-mediated inhibitory synaptic transmission in the ACC. However, inhibitory transmission was more potently inhibited than excitatory transmission by ME. This preferential reduction in GABAA-mediated synaptic transmission was primarily due to the activation of delta opioid receptors by ME and resulted in a net disinhibition of MThal-ACC excitatory pathway. These results suggest that moderate concentrations of ME can lead to net excitation of ACC circuitry and that analgesia may be associated with disinhibition rather than inhibition of ACC subcircuits. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.07.06.547738v1?rss=1 Authors: Ahmed, M., Campbell, S. A. Abstract: Objective: Childhood absence epilepsy (CAE) is a paediatric generalized epilepsy disorder with a confounding feature of resolving in adolescence in a majority of cases. In this study, we modelled how the small-scale (synapse-level) effect of progesterone metabolite allopregnanolone induces a large-scale (network-level) effect on a thalamocortical circuit associated with this disorder. In particular, our goal was to understand the role of sex steroid hormones in the spontaneous remission of CAE. Methods: The conductance-based computational model consisted of single-compartment cortical pyramidal, cortical interneurons, thalamic reticular and thalamocortical relay neurons, each described by a set of ordinary differential equations. Excitatory and inhibitory synapses were mediated by AMPA, GABAa and GABAb receptors. The model was implemented using the NetPyne modelling tool and the NEURON simulator. Results: The action of allopregnanolone on individual GABAa-receptor mediated synapses has an ameliorating effect on spike-wave discharges (SWDs) associated with absence seizures. This effect is region-specific and most significant in the thalamus, particularly the synapses between thalamic reticular neurons.Significance: The remedying effect of allopregnanolone on SWDs may possibly be true only for individuals that are predisposed to remission due to intrinsic connectivity differences or differences in tonic inhibition. These results are a useful first-step and prescribe directions for further investigation into the role of ALLO together with these differences to distinguish between models for CAE-remitting and non-remitting individuals. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.07.04.547710v1?rss=1 Authors: Evans-Strong, A., Walton, N., Roper, A., Donaldson, S. T., Lewis, M., Maguire, J. Abstract: Neurosteroids have been implicated in the pathophysiology of post-traumatic stress disorder (PTSD). Allopregnanolone is reduced in subsets of individuals with PTSD and has been explored as a novel treatment strategy. Both direct trauma exposure and witnessed trauma are risk factors for PTSD; however, the role of neurosteroids in the behavioral outcomes of these unique experiences has not been explored. Here we investigate whether observational fear is associated with a reduced capacity for endogenous neurosteroidogenesis and the relationship with behavioral outcomes. We demonstrate that both mice directly subjected to the threat (foot shocks) and those witnessing the threat have decreased plasma levels of allopregnanolone. The expression of a key enzyme involved in endogenous neurosteroid synthesis, 5-reductase type 2, is decreased in the basolateral amygdala (BLA), which is a major emotional processing hub implicated in PTSD. We demonstrate that knockdown of 5-reductase type 2 exaggerates the behavioral expression of fear in response to witnessed trauma, whereas treatment with an exogenous, synthetic neuroactive steroid GABAA receptor PAM with molecular pharmacology similar to allopregnanolone (SGE-516 [tool compound]) decreases the behavioral response to observational fear. These data implicate impaired endogenous neurosteroidogenesis in the pathophysiology of threat exposure, both direct and witnessed. Further, these data suggest that treatment with exogenous 5-reduced neurosteroids or targeting endogenous neurosteroidogenesis may be beneficial for the treatment of individuals with PTSD, whether resulting from direct or witnessed trauma. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.07.03.547522v1?rss=1 Authors: Bryson, M., Kloefkorn, H., Idlett-Ali, S., Garraway, S. M., Hochman, S., Martin, K. Abstract: Spinal cord injury (SCI) leads to hyperexcitability and dysfunction in spinal sensory processing. As hyperexcitable circuits can become epileptiform we explored whether such activity emerges in a thoracic SCI contusion model of neuropathic pain. Recordings from spinal sensory axons in multiple below-lesion segmental dorsal roots (DRs) demonstrated that SCI facilitated the emergence of spontaneous ectopic burst spiking in afferent axons, which synchronized across multiple adjacent DRs. Burst frequency correlated with behavioral mechanosensitivity. The same bursting events were recruited by afferent stimulation, and timing interactions with ongoing spontaneous bursts revealed that recruitment was limited by a prolonged post-burst refractory period. Ectopic bursting in afferent axons was driven by GABAA receptor activation, presumably via conversion of subthreshold GABAergic interneuronal presynaptic axoaxonic inhibitory actions to suprathreshold spiking. Collectively, the emergence of stereotyped bursting circuitry with hypersynchrony, sensory input activation, post-burst refractory period, and reorganization of connectivity represent defining features of epileptiform network. Indeed, these same features were reproduced in naive animals with the convulsant 4-aminopyridine (4-AP). We conclude that SCI promotes the emergence of epileptiform activity in spinal sensory networks that promote profound corruption of sensory signaling. This includes sensory circuit hypoexcitability during the refractory period and ectopic hyperexcitability during bursting via spiking in afferent axons that propagate bidirectionally via reentrant central and peripheral projections. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.06.26.546410v1?rss=1 Authors: Neyama, H., Wu, Y., Nakaya, Y., Kato, S., Shimizu, T., Tahara, T., Shigeta, M., Inoue, M., Miyamichi, K., Matsushita, N., Mashimo, T., Miyasaka, Y., Watanabe, Y., Kobayashi, M., Kobayashi, K., Cui, Y. Abstract: Placebo analgesia is caused by inactive treatment, implicating endogenous brain function involvement. However, the underlying neurobiological mechanisms remain unclear. We found that -opioid signals in the medial prefrontal cortex (mPFC) activate the descending pain inhibitory system to initiate placebo analgesia in neuropathic pain rats. Chemogenetic manipulation demonstrated that specific activation of -opioid receptor-positive (MOR+) neurons in the mPFC or suppression of the mPFC-ventrolateral periaqueductal gray (vlPAG) circuit inhibited placebo analgesia in rats. MOR+ neurons in the mPFC are monosynaptically connected and directly inhibit L5 pyramidal neurons that project to the vlPAG via GABAA receptors. Thus, intrinsic opioid signaling in the mPFC disinhibits excitatory outflow to the vlPAG by suppressing MOR+ neurons, leading to descending pain inhibitory system activation that initiates placebo analgesia. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

En este episodio, Hugo nos habla de la investigación que realizó durante su doctorado sintetizando una molécula que existe en la naturaleza y haciendo que otra molécula se pudiera activar y desactivar en respuesta a la luz. Notas:Redes sociales:Puedes seguirnos en Twitter, Instagram y Facebook para estar al tanto de cualquier novedad.Si quieres aprender más sobre Neurociencia, puedes seguir a Clara en su canal de YouTube “Cerebrotes”, donde sube vídeos semanales hablando de Neurociencia y Psicología. También la puedes encontrar en Twitter, Instagram y Facebook con el nombre artístico de Cerebrotes. A Hugo puedes encontrarle en Twitter como @Hugovalentes.Nuestro contenido y opiniones no representan a nuestros empleadores. -Referencias:Biomimetic synthesis of (−)-PF-1018 and development of photoswitchable GABAA receptor potentiators (uni-muenchen.de)-Fe de errores:Dijimos para el experimento del propofol que se había ensayado en peces cebra y fue en renacuajos:https://onlinelibrary.wiley.com/action/downloadSupplement?doi=10.1002%2Fanie.201205475&file=anie_201205475_sm_video.m4v

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.04.18.537383v1?rss=1 Authors: Wang, Y.-J., Seibert, H., Ahn, L. Y., Schaffer, A. E., Mu, T.-W. Abstract: Recent advances in genetic diagnosis identified variants in genes encoding GABAA receptors as causative for genetic epilepsy. Here, we selected eight disease-associated variants in the alpha1 subunit of GABAA receptors causing mild to severe clinical phenotypes and showed that they are loss of function, mainly by reducing the folding and surface trafficking of the alpha1 protein. Furthermore, we sought client protein-specific pharmacological chaperones to restore the function of pathogenic receptors. Applications of positive allosteric modulators, including Hispidulin and TP003, increase the functional surface expression of the alpha1 variants. Mechanism of action study demonstrated that they enhance the folding and assembly and reduce the degradation of GABAA variants without activating the unfolded protein response in HEK293T cells and human iPSC-derived neurons. Since these compounds cross the blood-brain barrier, such a pharmacological chaperoning strategy holds great promise to treat genetic epilepsy in a GABAA receptor-specific manner. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.04.16.537084v1?rss=1 Authors: Lipkin, A. M., Bender, K. J. Abstract: Neurons are remarkably polarized structures: dendrites spread and branch to receive synaptic inputs while a single axon extends and transmits action potentials to downstream targets. Neuronal polarity is maintained by the axon initial segment (AIS), a region between the soma and axon proper that is also the site of action potential (AP) generation. This polarization between dendrites and axons extends to inhibitory neurotransmission. In adulthood, the neurotransmitter GABA hyperpolarizes dendrites but instead depolarizes axons. These differences in function collide at the AIS. Multiple studies have shown that GABAergic signaling in this region can share properties of either the mature axon or mature dendrite, and that these properties evolve over a protracted period encompassing periadolescent development. Here, we explored how developmental changes in GABAergic signaling affect AP initiation. We show that GABA at the axon initial segment inhibits action potential initiation in Layer 2/3 pyramidal neurons in prefrontal cortex from mice of either sex across GABA reversal potentials observed in periadolescence. These actions occur largely through current shunts generated by GABAA receptors and changes in voltage-gated channel properties that affected the number of channels that could be recruited for AP electrogenesis. These results suggest that GABAergic neurons targeting the axon initial segment provide an inhibitory "veto" across the range of GABA polarity observed in normal adolescent development, regardless of GABAergic synapse reversal potential. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Episode Highlights With MattHow he was shot in a robberyHe spent $45k on sleep and these are his main lessonsInexpensive things related to sleep that anyone can do: light, sleep environment, temperature, food timingHow temperature drastically affects sleepWays to improve deep sleepWhy one hour of sleep is worth two hours (with some nuance)The reason when you work your body you tend to get more deep sleep and when you work your brain you tend to get more REM (and this is a good thing)During daylight savings, when we lose an hour of sleep, heart attacks go up by 24% and when we gain an hour, it goes down by 21%Why night shift work is classified as a carcinogenHow not getting enough sleep leads to weight gain or loss of muscle massLack of sleep directly impacts hunger, willpower and moreHow blood sugar response changes from just one night of impaired sleepHis top supplements for sleep: L-Theanine (in evening), magnesium, glycine, potassium, GABAA reason to consider taking potassium at night and how it can help minimize bathroom trips at nightWhat to know about wearables and trackables for sleepHRV- what to know and understand and ways to improve it with float tanks, breathwork, and movementWhy he sets an alarm for his sleep supplements and his bedtimeA simple rule: 8 hours plus an hour for every hour of exerciseWhy sleep quality trumps sleep quantityResources We MentionBiOptimizersBon Charge red bulbsEssentia Mattress - Use code wellnessmama15 for discountSleep.me - ChiliPadEight Sleep - Use code Mama150 for a discountOura RingLevelsNanoViPower Sleep : The Revolutionary Program That Prepares Your Mind for Peak Performance by James MaasThe Body Keeps the Score: Brain, Mind, and Body in the Healing of Trauma by Bessel van der Kolk M.D.Power vs. Force: The Hidden Determinants of Human Behavior by Dr. David R. Hawkins

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.04.02.535293v1?rss=1 Authors: Zimbelman, A. R., Wong, B., Murray, C. H., Wolf, M. E., Stefanik, M. T. Abstract: Protein translation is essential for some forms of synaptic plasticity. We used nucleus accumbens (NAc) medium spiny neurons (MSN), co-cultured with cortical neurons to restore excitatory synapses, to examine whether dopamine modulates protein translation in NAc MSN. FUNCAT was used to measure translation in MSNs under basal conditions and after disinhibiting excitatory transmission using the GABAA receptor antagonist bicuculline (2 hr). Under basal conditions, translation was not altered by the D1-class receptor (D1R) agonist SKF81297 or the D2-class receptor (D2R) agonist quinpirole. Bicuculline alone robustly increased translation. This was reversed by quinpirole but not SKF81297. It was also reversed by co-incubation with the D1R antagonist SCH23390, but not the D2R antagonist eticlopride, suggesting dopaminergic tone at D1Rs. This was surprising because no dopamine neurons are present. An alternative explanation is that bicuculline activates translation by increasing glutamate tone at NMDA receptors (NMDAR) within D1R/NMDAR heteromers, which have been described in other cell types. Supporting this, immunocytochemistry and proximity ligation assays revealed D1/NMDAR heteromers on NAc cells both in vitro and in vivo. Further, bicuculline's effect was reversed to the same extent by SCH23390 alone, the NMDAR antagonist APV alone, or SCH23390+APV. These results suggest that: 1) excitatory synaptic transmission stimulates translation in NAc MSNs, 2) this is opposed when glutamate activates D1R/NMDAR heteromers, even in the absence of dopamine, and 3) antagonist occupation of D1Rs within the heteromers prevents their activation. Our study is the first to suggest a role for D2 receptors and D1R/NMDAR heteromers in regulating protein translation. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.03.20.533578v1?rss=1 Authors: Gu, L., Liu, L., Shao, W., Gu, J., Xu, Q., Wang, Y., Yu, Q., Lian, X., Zhang, H. Abstract: Generation of the unconsciousness associated with arousal during the initial stage of anesthesia by midazolam is critical for general anesthesia, however, the exact mechanism remains unknown. Here, firstly, we found that the destruction of noradrenergic neurons in the locus coeruleus (LCNE) could prolong the emergence time of midazolam-induced anesthesia. Secondly, the same results were found by activation of the noradrenergic pathway between the LC and the ventrolateral preoptic nucleus (VLPO) using optogenetics and chemogenetics approaches, respectively. Thirdly, this effect was mediated by alpha 1 and beta adrenergic receptors rather than alpha2 adrenergic receptors in the VLPO. Moreover, the noradrenergic pathway to modulate the arousal between the LC and VLPO was controlled by GABAA receptors in the LC and VLPO in our models. Our data demonstrate that activation of the NEergic pathway between the LC and VLPO can promote arousal to prevent delayed recovery from midazolam-induced anesthesia. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.03.16.532906v1?rss=1 Authors: Hamel, R., Pearson, J., Sifi, L., Patel, D., Hinder, M. R., Jenkinson, N., Galea, J. Abstract: Monetary rewards and punishments enhance motor performance and are associated with corticospinal excitability (CSE) increases within the motor cortex (M1) during movement preparation. However, such CSE changes have unclear origins; they could stem from increased glutamatergic (GLUTergic) facilitation and/or decreased type A gamma-aminobutyric acid (GABAA)-mediated inhibition within M1. To investigate this, paired-pulse transcranial magnetic stimulation was used to assess GLUTergic facilitation and GABAA inhibition within M1 whilst participants prepared to execute 4-element finger-press sequences. Behaviourally, rewards and punishments enhanced both reaction and movement times. Neurochemically, regardless of rewards or punishments, a digit-specific increase in GLUTergic facilitation and digit-unspecific decrease in GABAA inhibition occurred during preparation as movement onset approached. In parallel, both rewards and punishments non-specifically increased GLUTergic facilitation, but only rewards non-specifically decreased GABAA inhibition during preparation. This suggests that, to enhance performance, rewards both increase GLUTergic facilitation and decrease GABAA inhibition whilst punishments selectively increase GLUTergic facilitation. A control experiment revealed that such changes were not observed post-movement as participants processed reward and punishment feedback, indicating they were selective to movement preparation. Collectively, these results map the neurochemical changes in M1 by which incentives enhance motor performance. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.03.14.532627v1?rss=1 Authors: Day, M., Belal, M., Surmeier, C., Melendez-Zaidi, A., Tkatch, T., Clarke, V. R. J., Surmeier, D. J. Abstract: Synaptic transmission mediated by GABAA receptors (GABAARs) in adult, principal striatal spiny projection neurons (SPNs) can suppress ongoing spiking, but its effect on synaptic integration at sub-threshold membrane potentials is less well characterized, particularly those near the resting down-state. To fill this gap, a combination of molecular, optogenetic, optical and electrophysiological approaches were used to study SPNs in mouse ex vivo brain slices, and computational tools were used to model somatodendritic synaptic integration. Activation of GABAARs, either by uncaging of GABA or by optogenetic stimulation of GABAergic synapses, evoked currents with a reversal potential near -60 mV in perforated patch recordings from both juvenile and adult SPNs. Molecular profiling of SPNs suggested that this relatively positive reversal potential was not attributable to NKCC1 expression, but rather to a dynamic equilibrium between KCC2 and Cl-/HCO3- cotransporters. Regardless, from down-state potentials, optogenetic activation of dendritic GABAergic synapses depolarized SPNs. This GABAAR-mediated depolarization summed with trailing ionotropic glutamate receptor (iGluR) stimulation, promoting dendritic spikes and increasing somatic depolarization. Simulations revealed that a diffuse dendritic GABAergic input to SPNs effectively enhanced the response to coincident glutamatergic input. Taken together, our results demonstrate that GABAARs can work in concert with iGluRs to excite adult SPNs when they are in the resting down-state, suggesting that their inhibitory role is limited to brief periods near spike threshold. This state-dependence calls for a reformulation of the role intrastriatal GABAergic circuits. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.03.02.530499v1?rss=1 Authors: Barbour, A. J., Gourmaud, S., Li, X., Stewart, D. A., Irwin, D. J., Talos, D. M., Jensen, F. E. Abstract: Increasing evidence indicates a bidirectional relationship between epilepsy and Alzheimer's disease (AD) with 22% of AD patients additionally suffering from seizures, which may be a targetable component of disease progression. Since epileptogenesis is associated with changes in excitatory: inhibitory (E:I) balance, we examined postmortem AD brain tissue from patients with and without seizure history and five times familial AD (5XFAD) mice for changes in several markers of E:I balance, including the inhibitory GABAA receptor, the chloride cotransporters, sodium potassium chloride cotransporter 1 (NKCC1) and potassium chloride cotransporter 2 (KCC2), and the excitatory NMDA and AMPA type glutamate receptors. We hypothesized that seizure history in AD patients would be associated with greater E:I imbalances, and that such changes would also be observed in the 5XFAD mice following pentylenetetrazol (PTZ) kindling. We found that seizures in AD patients were associated with alterations in NKCC1 and KCC2 expression, indicative of depolarizing GABA, and exacerbated cognitive deficits. Seizures also significantly contributed to E:I imbalance in the 5XFAD mouse model, as similar changes in NKCC1 and KCC2 expression were found in PTZ treated 5XFAD mice, along with altered AMPA receptor protein expression indicative of calcium permeable-AMPA receptors. In addition, we found that chronic treatment with the mTOR inhibitor rapamycin at doses we have previously shown to attenuate seizure-induced {beta}-amyloid pathology and cognitive deficits in 5XFAD mice, can mitigate the dysregulation of markers of E:I balance in this model. These data suggest that mTOR activation plays a role in modifying the E:I imbalance and network hyperexcitability in AD and that the FDA-approved mTOR inhibitors such as rapamycin may have potential for therapy in AD patients with a seizure history. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.02.26.530150v1?rss=1 Authors: Craft, M. F., Barreiro, A. K., Hari Gautam, S., Shew, W., Ly, C. Abstract: Odor perception is the impetus for important animal behaviors, most obviously for feeding but also for mating and communication. There are two predominate modes of odor processing: odors pass through the front of the nose (orthonasal) while inhaling and sniffing, or through the rear (retronasal) during exhalation and while eating. Despite the importance of olfaction for an animal's well-being and specifically that ortho and retro naturally occur, it is unknown how the modality (ortho versus retro) is even transmitted to cortical brain regions, which could significantly affect how odors are processed and perceived. We show mitral cell neurons in the rat olfactory bulb reliably transmit ortho versus retro food odor stimuli. Drug manipulations affecting GABAA that control synaptic inhibition lead to worse decoding of ortho/retro, independent of whether overall inhibition increases or decreases, suggesting that the olfactory bulb circuit is naturally structured to encode this important aspect of odors. Detailed data analysis paired with a firing rate model to capture population trends in spiking statistics shows how this circuit with baseline inhibition can encode odor modality. We have not only shown that ortho versus retro information is encoded to downstream brain regions, but models and analyses reveal the network dynamics that promotes this encoding. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.02.23.529740v1?rss=1 Authors: Pradhan, A. K., Neumueller, T., Klug, C., Fuchs, S., Schlegel, M., Ballmann, M., Tartler, K. J., Pianos, A., Garcia-Sanchez, M., Liere, P., Schumacher, M., Kreutzer, M., Rupprecht, R., Rammes, G. Abstract: Alzheimer's disease (AD) is characterized by the accumulation of {beta}-amyloid peptide (A{beta}). There is increasing evidence that depression may precede AD and may be an early manifestation of dementia, suggesting common mechanisms underlying both diseases. Ligands targeting the mitochondrial translocator protein (18 kDa) (TSPO), promote neurosteroidogenesis and may be neuroprotective. Moreover, TSPO is upregulated in AD. To study whether the TSPO ligand XBD173 may exert early neuroprotective effects in AD pathology we investigated the impact of XBD173 on amyloid toxicity and neuroplasticity in mouse models. We show that XBD173 (emapunil), via neurosteroid-mediated signaling via delta subunit-containing GABAA receptors, prevents the neurotoxic effect of A{beta} on long-term potentiation (CA1-LTP) in the hippocampus and prevents the loss of spines. Chronic but not acute administration of XBD173 ameliorates spatial learning deficits in transgenic AD mice with arctic mutation (ArcA{beta}) mice. The heterozygous TSPO-knockout crossed with the transgenic arctic mutation model of AD mice (het TSPOKO X ArcA{beta}) treated with XBD173 does not show this improvement in spatial learning suggesting TSPO is needed for procognitive effects of XBD173. The neuroprotective profile of XBD173 in AD pathology is further supported by a reduction in plaques and soluble A{beta} levels in the cortex, increased synthesis of neurosteroids, rescued spine density, reduction of complement protein C1q deposits, and reduced astrocytic phagocytosis of functional synapses both in the hippocampus and cortex. Our findings suggest that XBD173 may exert therapeutic effects via TSPO in a mouse model of AD. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.02.22.529541v1?rss=1 Authors: Guet-McCreight, A., Moradi-Chameh, H., Mazza, F., Prevot, T. D., Valiante, T. A., Sibille, E., Hay, E. Abstract: Reduced inhibition by somatostatin-expressing interneurons is associated with depression. Administration of positive allosteric modulators of 5 subunit-containing GABAA receptor (5-PAM) that selectively target this lost inhibition exhibit antidepressant and pro-cognitive effects in rodent models of chronic stress. However, the functional effects of 5-PAM on the human brain in vivo are unknown, and currently cannot be assessed experimentally. We modeled the effects of 5-PAM on tonic inhibition as measured in human neurons, and tested in silico 5-PAM effects on detailed models of human cortical microcircuits in health and depression. We found that 5-PAM effectively recovered impaired cortical processing as quantified by stimulus detection metrics, and also recovered the power spectral density profile of the microcircuit EEG signals. We performed an 5-PAM dose response and identified simulated EEG biomarkers. Our results serve to de-risk and facilitate 5-PAM translation and provide biomarkers in non-invasive brain signals for monitoring target engagement and drug efficacy. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.02.16.528867v1?rss=1 Authors: Sun, C., Zhu, H., Clark, S. A., Gouaux, E. Abstract: Type A GABA receptors (GABAARs) are the principal inhibitory receptors in the brain and the target of a wide range of clinical agents, including anesthetics, sedatives, hypnotics, and antidepressants. However, our understanding of GABAAR pharmacology has been hindered by the vast number of pentameric assemblies that can be derived from a total 19 different subunits and the lack of structural knowledge of clinically relevant receptors. Here, we isolate native murine GABAAR assemblies containing the widely expressed 1 subunit, and elucidate their structures in complex with drugs used to treat insomnia (zolpidem and flurazepam) and postpartum depression (the neurosteroid allopregnanolone). Using cryo-EM analysis and single-molecule photobleaching experiments, we uncover only three structural populations in the brain: the canonical 1{beta}2{gamma}2 receptor containing two 1 subunits and two unanticipated assemblies containing one 1 and either an 2, 3 or 5 subunit. Both of the noncanonical assemblies feature a more compact arrangement between the transmembrane and extracellular domains. Interestingly, allopregnanolone is bound at the transmembrane /{beta} subunit interface, even when not added to the sample, revealing an important role for endogenous neurosteroids in modulating native GABAARs. Together with structurally engaged lipids, neurosteroids produce global conformational changes throughout the receptor that modify both the pore diameter and binding environments for GABA and insomnia medications. Together, our data reveal that GABAAR assembly is a strictly regulated process that yields a small number of structurally distinct complexes, defining a structural landscape from which subtype-specific drugs can be developed. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.02.09.527837v1?rss=1 Authors: Yelhekar, T. D., Kuznetsova, T., Malinina, E., Ponimaskin, E., Dityatev, A., Druzin, M., Johansson, S. Abstract: The neuronal intracellular chloride concentration [Cl-]i is critical for {gamma}-aminobutyric acid type A (GABAA) receptor-mediated transmission. Degradation of the extracellular matrix (ECM) is associated with raised [Cl-]i but neither the mechanisms underlying this effect nor the consequences for GABA-mediated transmission are well understood. Hitherto it has been unclear how to reconcile the effect of the ECM on [Cl-]i with the established role of cation-chloride cotransporters in setting [Cl-]i. In the present work we clarify the role of the ECM in the control of neuronal [Cl-]i. By measuring [Cl-]i in central neurons from male rats we show that the ECM affects basal [Cl-]i as well as the rate of Cl- extrusion after a high load. The mechanism is not via impermeant anions but through regulation of K+-Cl--cotransporter 2 (KCC2). ECM degradation is accompanied by an N-type Ca2+-channel- and calpain-dependent reduction in the amount of KCC2 protein, increased basal [Cl-]i, reduced Cl- extrusion capacity as well as by reduced inhibitory, or even an excitatory, effect of intense GABAA-receptor mediated trans mission. This implies a previously unrecognized pathway for the control of neuronal [Cl-]i and excitability by the ECM. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.01.25.525544v1?rss=1 Authors: Mabuchi, Y., Cui, X., Xie, L., Kim, H., Jiang, T., Yapici, N. Abstract: Vision is critical for the regulation of mating behaviors in many species. Here, we discovered that the Drosophila ortholog of human GABAA-receptor-associated protein (GABARAP) is required to fine-tune male courtship by modulating the activity of visual feedback neurons, lamina tangential cells (Lat). GABARAP is a ubiquitin-like protein that regulates cell-surface levels of GABAA receptors. Knocking down GABARAP or GABAA receptors in Lat neurons or hyperactivating them induces male courtship toward other males. Inhibiting Lat neurons, on the other hand, delays copulation by impairing the ability of males to follow females. Remarkably, the human ortholog of Drosophila GABARAP restores function in Lat neurons. Using in vivo two-photon imaging and optogenetics, we show that Lat neurons are functionally connected to neural circuits that mediate visually-guided courtship pursuits in males. Our work reveals a novel physiological role for GABARAP in fine-tuning the activity of a visual circuit that tracks a mating partner during courtship. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.01.10.523440v1?rss=1 Authors: Masri, S., Fair, R., Mowery, T. M., Sanes, D. H. Abstract: Even transient periods of developmental hearing loss during the developmental critical period have been linked to long-lasting deficits in auditory perception, including temporal and spectral processing, which correlate with speech perception and educational attainment. In gerbils, hearing loss-induced perceptual deficits are correlated with a reduction of both ionotropic GABAA and metabotropic GABAB receptor-mediated synaptic inhibition in auditory cortex, but most research on critical period plasticity has focused on GABAA receptors. We developed viral vectors to express both endogenous GABAA or GABAB receptor subunits in auditory cortex and tested their capacity to restore perception of temporal and spectral auditory cues following critical period hearing loss in the Mongolian gerbil. HL significantly impaired perception of both temporal and spectral auditory cues. While both vectors similarly increased IPSCs in auditory cortex, only overexpression of GABAB receptors improved perceptual thresholds after HL to be similar to those of animals without developmental hearing loss. These findings identify the GABAB receptor as an important regulator of sensory perception in cortex and point to potential therapeutic targets for developmental sensory disorders. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.12.28.522113v1?rss=1 Authors: Normoyle, K. P., Staley, K. J. Abstract: GABA is the primary inhibitory neurotransmitter. Membrane currents evoked by GABAA receptor activation have uniquely small driving forces: their reversal potential (EGABA) is very close to the resting membrane potential. As a consequence, GABAA currents can flow in either direction, depending on both the membrane potential and the local intra and extracellular concentrations of the primary permeant ion, chloride (Cl). Cytoplasmic Cl concentrations vary widely due to displacement of mobile Cl ions by relatively immobile anions. Here we describe new reporters of extracellular chloride (Cl-o) and demonstrate that Cl is displaced in the extracellular space by high and spatially heterogenous concentrations of sulfated glycosaminoglycans. The mean Cl-o is only half the canonical concentration, i.e. the Cl concentration in the cerebrospinal fluid. Cl-o microdomains provide a mechanism to link the highly stable distribution of GAGs in the brain extracellular space to neuronal signal processing via the effects on the amplitude and direction of GABAA transmembrane Cl currents. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.12.14.520067v1?rss=1 Authors: RIONDEL, P., JURCIC, N., TROUSLARD, J., WANAVERBECQ, N., SEDDIK, R. Abstract: Spinal cerebrospinal fluid-contacting neurons (CSF-cNs) form an evolutionary conserved bipolar cells population localized around the central canal of all vertebrates. CSF-cNs were shown to express molecular markers of neuronal immaturity into adulthood, however the functional relevance of their incomplete maturation remains unknown. Neuronal maturation is classically associated with the expression of the K+-Cl- cotransporter 2 (KCC2), allowing chloride (Cl-) extrusion and hyperpolarising GABA transmission. Here, we show no detectable expression of KCC2 in CSF-cNs of adult mouse spinal cord. Accordingly, lack of KCC2 expression results in low Cl- extrusion capacity in CSF-cNs under high Cl- load in whole-cell patch-clamp. Using cell-attached recordings, we found that activation of ionotropic GABAA receptors induced a dominant depolarising effect in 70% of CSF-cNs recorded with intact intracellular chloride concentration. Moreover, in these cells, depolarising GABA-responses can drive action potentials as well as intracellular calcium elevations by activating voltage-gated calcium channels. CSF-cNs express the Na+-K+-Cl- cotransporter 1 (NKCC1) involved in Cl- uptake and its inhibition by bumetanide blocked the GABA-induced calcium transients in CSF-cNs. Finally, we show that activation of metabotropic GABAB receptors did not mediate hyperpolarisation in spinal CSF-cNs, presumably due to the lack of expression of G protein-coupled inwardly rectifying potassium (GIRK) channels. Together, these findings outline CSF-cNs as a unique neuronal population in adult spinal cord with immature Cl- homeostasis and no hyperpolarising GABAergic signalling but rather generation of excitation and intracellular calcium modulation. GABA may therefore promote CSF-cNs maturation and integration into the existing spinal circuit. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.12.11.519958v1?rss=1 Authors: Come, E., Blachier, S., Gouhier, J., Russeau, M., LEVI, S. Abstract: An upregulation of the Na+-K+-2Cl- co-transporter NKCC1, the main chloride importer in mature neurons, can lead to depolarizing/excitatory responses mediated by GABAA receptors and thus to hyperactivity. Understanding the regulatory mechanisms of NKCC1 would help prevent intra-neuronal chloride accumulation that occurs in pathologies with defective inhibition. The cellular and molecular regulatory mechanisms of NKCC1 are poorly understood. Here, we report in mature hippocampal neurons that GABAergic activity controls the membrane diffusion and clustering of NKCC1 via the chloride-sensitive WNK1 kinase and the downstream SPAK kinase that directly phosphorylates NKCC1 on key threonine residues. At rest, this signaling pathway has little effect on intracellular Cl- concentration but it participates to the elevation of intraneuronal Cl- concentration in hyperactivity condition associated with an up-regulation of NKCC1. The fact that the chloride exporter KCC2 is also regulated in mature neurons by the WNK1 pathway indicates that this pathway will be a target of choice in the pathology. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

233 Sobrevolando la Biblia - Jueces 20 Todo Israel se reúne en Mizpa para ver qué hacer por lo del asunto de la mujer descuartizada. Los hombres perversos de Gabaa no se entregan y su tribu, Benjamín, los defiende. Irrumpe una guerra civil. Benjamín, aunque tiene soldados muy diestros con sus hondas, es una minoría. A pesar de sufrir una baja de considerable en sus tropas, Israel tiene a Dios de su lado y Él les da la victoria. Sólo sobrevive un pequeño remanente de Benjamín. Otra expresión de la gracia de Dios: Saúl, de Gabaa, fue el primer rey de Israel; Saulo de Tarso, era benjamita, poderoso apóstol usado por Dios al principio de la era cristiana. www.revistabalsamo.com www.soloporfe.com www.graciamasgracia.com  

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.11.08.515720v1?rss=1 Authors: Barron, T., Yalcin, B., Mochizuki, A., Cantor, E., Shamardani, K., Tlais, D., Franson, A., Lyons, S., Mehta, V., Maleki Jahan, S., Taylor, K. R., Keough, M. B., Xu, H., Su, M., Quezada, M. A., Woo, P. J., Fisher, P. G., Campen, C. J., Partap, S., Koschmann, C., Monje, M. Abstract: Pediatric high-grade gliomas are the leading cause of brain cancer-related death in children. High-grade gliomas include clinically and molecularly distinct subtypes that stratify by anatomical location into diffuse midline gliomas (DMG) such as diffuse intrinsic pontine glioma (DIPG) and hemispheric high-grade gliomas. Neuronal activity drives high-grade glioma progression both through paracrine signaling(1,2) and direct neuron-to-glioma synapses(3-5). Glutamatergic, AMPA receptor-dependent synapses between neurons and malignant glioma cells have been demonstrated in both pediatric(3) and adult high-grade gliomas(4), but neuron-to-glioma synapses mediated by other neurotransmitters remain largely unexplored. Using whole-cell patch clamp electrophysiology, in vivo optogenetics and patient-derived glioma xenograft models, we have now identified functional, tumor-promoting GABAergic neuron-to-glioma synapses mediated by GABAA receptors in DMGs. GABAergic input has a depolarizing effect on DMG cells due to NKCC1 expression and consequently elevated intracellular chloride concentration in DMG tumor cells. As membrane depolarization increases glioma proliferation(3), we find that the activity of GABAergic interneurons promotes DMG proliferation in vivo. Increasing GABA signaling with the benzodiazepine lorazepam, a positive allosteric modulator of GABAA receptors commonly administered to children with DMG for nausea or anxiety, increases GABAA receptor conductance and increases glioma proliferation in orthotopic xenograft models of DMG. Conversely, levetiracetam, an anti-epileptic drug that attenuates GABAergic neuron-to-glioma synaptic currents, reduces glioma proliferation in patient-derived DMG xenografts and extends survival of mice bearing DMG xenografts. Concordant with gene expression patterns of GABAA receptor subunit genes across subtypes of glioma, depolarizing GABAergic currents were not found in hemispheric high-grade gliomas. Accordingly, neither lorazepam nor levetiracetam influenced the growth rate of hemispheric high-grade glioma patient-derived xenograft models. Retrospective real-world clinical data are consistent with these conclusions and should be replicated in future prospective clinical studies. Taken together, these findings uncover GABAergic synaptic communication between GABAergic interneurons and diffuse midline glioma cells, underscoring a tumor subtype-specific mechanism of brain cancer neurophysiology with important potential implications for commonly used drugs in this disease context. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.26.513964v1?rss=1 Authors: Nagarajan, R., Lyu, J., Kambali, M., Wang, M., Pearce, R. A., Rudolph, U. Abstract: Background: Postoperative neurocognitive disorder (poNCD), previously also referred to as postoperative cognitive dysfunction (POCD) following surgery and anesthesia, is a significant public health problem in patients over 60 years. Propofol is the most commonly used intravenous anesthetic, acting primarily via GABAA receptors. However, it has also been shown to have apparent neuroprotective effects in aged mice and mouse models of Alzheimer s disease. Therefore, we postulated that chronic intermittent propofol would attenuate the development of postoperative cognitive deficits in aged mice. Methods: Abdominal surgery was performed under isoflurane anesthesia in 21-24 months-old mice. Animals received either chronic intermittent propofol (CIP, 75 mg/kg i.p.) or vehicle (IntralipidR) every 5th day throughout the experiment, starting 17 days before surgery. The levels of alpha5 GABAA receptors on cell surface membranes, as well as behavioral or biochemical manifestations of poNCD were studied. Results: CIP led to a sustained redistribution of the GABAA receptor alpha5-subunit to the cell surface membranes. Laparotomy impaired learning and memory functions, as determined using a behavioral test battery that included Y maze alternation, novel object recognition, water maze learning and reversal learning, and cued and contextual fear conditioning, compared to no surgery controls. Strikingly, CIP strongly attenuated the surgery-induced memory impairment. Western blots on hippocampal tissues showed increased expression of the pro-apoptotic markers cleaved caspase-3, cleaved caspase-9, and Bax, indicating that abdominal surgery promoted apoptosis. Moreover, surgery increased expression of Iba-1, a marker of microglial activation. Chronic intermittent propofol prevented this proapoptotic and microglial activation. Conclusions: Our results suggest that propofol - via mechanisms not fully understood, potentially via the sustained increased availability of alpha5-GABAA receptors on cell surface membranes - improves cognitive function by attenuating surgery-induced neuroinflammation and caspase activation and/or independently of this by rebalancing neuronal inhibition in aged mice. These findings support a therapeutic potential of perioperative propofol or of other compounds leading to a sustained redistribution of alpha5-GABAA receptors to the cell surface membranes in the perioperative period for reducing the risk of surgery-induced cognitive decline in aged individuals. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.24.513629v1?rss=1 Authors: Wang, Y.-J., Di, X.-J., Han, D.-Y., Nashmi, R., Henderson, B. J., Moss, F. J., Mu, T.-W. Abstract: Protein homeostasis (proteostasis) deficiency is recognized as a contributing factor to many neurodegenerative, neurological, and metabolic diseases. However, how the proteostasis network orchestrates the folding and assembly of multi-subunit membrane proteins is not completely understood. In this investigation, we focus on characterizing the biogenesis pathway of a multi-subunit neuroreceptor, the gamma-aminobutyric acid type A (GABAA) receptor. Previous proteomics studies identified Hsp47 (Gene: SERPINH1), a heat shock protein in the endoplasmic reticulum lumen, as the most enriched GABAA receptor-interacting chaperone. Here, we show that Hsp47 enhances neuronal GABAA receptor functional surface expression, acting after Binding immunoglobulin Protein (BiP), to preferentially bind the folded conformation of GABAA receptors. Therefore, Hsp47 promotes the subunit-subunit interaction, the receptor assembly process, and the anterograde trafficking of GABAA receptors. These Hsp47 properties are also extended to other Cys-loop receptors, including nicotinic acetylcholine receptors. Therefore, in addition to its known function as a collagen chaperone, this work establishes that Hsp47 also plays a critical and general role in the maturation of multi-subunit neuroreceptors. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Jueces 20: Saca tu viga primero.Jueces 20:23-‬29 RVA2015:Entonces subieron todos los hijos de Israel y todo el pueblo, y fueron a Betel. Lloraron, permanecieron allí delante del SEÑOR, ayunaron aquel día hasta el atardecer y ofrecieron holocaustos y sacrificios de paz delante del SEÑOR. Los hijos de Israel consultaron al SEÑOR. (El arca del pacto de Dios estaba allí en aquellos días; y Fineas hijo de Eleazar, hijo de Aarón, servía delante de ella en aquellos días). Ellos preguntaron: —¿Volveremos a salir a la batalla contra los hijos de Benjamín, nuestros hermanos, o desistiremos? Y el SEÑOR respondió: —Suban, porque mañana yo los entregaré en su mano. Entonces Israel puso gente emboscada alrededor de Gabaa.---------En este capítulo podemos ver el punto más bajo de Israel en la época de los jueces. Sin Dios, sin ley, y cada día degradándose más, alejados de Dios. En un suceso trágico donde los israelitas cometieron toda clase de abusos y vejámenes contra sus propios hermanos, y cayendo en un lugar de inmoralidad y criminalidad extrema, los israelitas tocaron fondo y reaccionaron indignados ante ese acto repugnante. Qué triste es decidir tomar una acción de cambio, buscando enmendar los errores cuando ocurre una tragedia primero. Ellos se levantaron para ir a atacar a la tribu de Benjamín y tratar de hacer justicia y juicio sobre los criminales. Aquí podemos ver que, aunque era una acción necesaria, ellos no consultaron a Dios primero. Solo le "informaron" y pidieron dirección sobre quién iría primero.Dios permitió que fueran y sufrieron pérdida. La segunda vez también preguntaron a Dios si subían otra vez y Dios les dijo que si eso querían, pues que subieran. Después de otra derrota, ellos cayeron en cuenta que debían acercarse a Dios debidamente, trayendo las ofrendas debidas y humillando su corazón en ayuno y oración.Esta es una gran lección para los cristianos que desean hacer la voluntad de Dios pero olvidando el orden que Dios quiere que lo hagamos; debemos primero vivir conforme a Su voluntad antes de juzgar y pretender enseñarles a otros cómo hacer justicia y en verdad.Esto me recuerda a la vida de David cuando él estaba en pecado y había cometido una de las más graves faltas de su vida que aprenderás más adelante. Cuando escuchó de un rico injusto que arrebató una oveja a su vecino pobre, se enojó y mandó a castigar al rico. El problema fue que esa era una ilustración de su propia vida, siendo injusto con otros pero quería hacer justicia entre el rico y el pobre. ¡Él era el rico injusto!Después que Israel se acercó al Señor con todo el corazón, haciendo los respectivos sacrificios y ofrendas para hacer las paces con Dios, y se humillaron delante de Dios sacando el tiempo para hacer ayunos y oraciones, entonces clamaron y pidieron la voluntad de Dios, y esperaron la confirmación si debían atacar o no. Ahora no estaban pidiendo que Dios aprobara la voluntad de ellos sino que Dios hiciera Su divina voluntad.Entonces, Dios no solo le respondió que subieran, sino que también les afirmó que Él iba a entregar a los benjaminitas en sus manos para que ellos fueran castigados y enjuiciados por sus actos malévolos. Tanto las tribus de Israel como la tribu de Benjamín habían fallado a Dios por muchos años, pero cuando las tribus de Israel se humillaron y vinieron correctamente delante de Dios, el Señor los perdonó y aprobó su intención de purificar al pueblo eliminando a los criminales que no se habían arrepentido. Es por eso que Jesucristo nos enseñó que primero debemos sacar la viga que hay en nuestro ojo antes de sacar la del vecino. Primero arreglar nuestra casa antes de pretender arreglar otras casas ajenas. Si no, podríamos caer en hipocresía y apariencias falsas de piedad y pretensiones.La arrogancia, altivez y maldad de Benjamín les trajo consecuencias dolorosas. Sus propios pecados hicieron que muchos murieran. Este es un final agridulce del tiempo donde una tribu casi queda eliminada y muchos de las otras tribus como unos cuarenta mil guerreros murieron. Cuando una familia abre las puertas al pecado, se alejan del Señor y ninguno va a vivir una vida plena en Dios; todos pierden.Evitemos descuidarnos, bajando la guardia del ayuno y la oración. Haz tu mayor esfuerzo de escuchar mensajes de la Palabra de Dios que te animen a seguir al Señor, busca dirección espiritual de personas que pueden ser de gran apoyo y pueden brindarte un buen consejo basado en la Palabra de Dios para que vivas una vida espiritual triunfante. Y no olvides escuchar siembre este devocional.Soy Eduardo Rodríguez.

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.06.511115v1?rss=1 Authors: Wierenga, C. J., Herstel, L. J., Peerboom, C., Uijtewaal, S., Selemangel, D., Karst, H. Abstract: Intraneuronal chloride concentrations ([Cl-]i) decrease during development resulting in a shift from depolarizing to hyperpolarizing {gamma}-aminobutyric acid (GABA) responses via chloride-permeable GABAA receptors. This GABA shift plays a pivotal role in postnatal brain development, and can be strongly influenced by early life experience. Here, we assessed the applicability of the recently developed fluorescent SuperClomeleon (SClm) sensor to examine changes in [Cl-]i using two-photon microscopy in brain slices. We used SClm mice of both sexes to monitor the developmental decrease in neuronal chloride levels in organotypic hippocampal cultures. We could discern a clear reduction in [Cl-]i between DIV3 and DIV9 (equivalent to the second postnatal week in vivo) and a further decrease in some cells until DIV22. In addition, we assessed alterations in [Cl-]i in the medial prefrontal cortex (mPFC) of P9 male SClm mouse pups after early life stress (ELS). ELS was induced by limiting nesting material between P2 and P9. ELS induced a shift towards higher (i.e. immature) chloride levels in layer 2/3 cells in the mPFC. Although conversion from SClm fluorescence to absolute chloride concentrations proved difficult, our study underscores that the SClm sensor is a powerful tool to measure physiological changes in [Cl-]i in brain slices. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.06.511220v1?rss=1 Authors: Mudd, D. B., Juvale, P., Shree, N., Pallas, S. L. Abstract: Refinement of developing visual projections is reported to depend on visual experience in rats, cats, ferrets, and monkeys. Visual deprivation in these species delays visual pathway development, reportedly maintaining a juvenile condition and prolonging the critical period for plasticity. Deprivation has been associated with retention of immature NMDA and GABAA receptors and a juvenile state of chloride transporters. In contrast, receptive fields (RFs) in superior colliculus (SC) and visual cortex (V1) of Syrian hamsters refine normally with spontaneous activity alone, requiring visual experience only to maintain refined RFs in adulthood. Continued visual deprivation into adulthood leads to RF enlargement. This failure to maintain refined RFs and thus preserve high acuity vision in visually deprived adult SC is associated with a loss of GABA and GAD, caused at least in part by a reduction in BDNF-TrkB signaling. In order to explore the postsynaptic mechanism, we examined GABAA receptor expression levels, location, and subunit composition using Western blotting. In addition, we assayed the GABAA receptor anchoring protein gephyrin and expression levels of the chloride transporters KCC2 and NKCC2. To test the alternate hypothesis that RFs enlarge in adulthood as a result of immature postsynaptic NMDA receptors, we examined NR2A/2B ratios and levels of the anchoring protein PSD-95. We found no evidence supporting visual deprivation-related postsynaptic alterations in receptors, chloride transporters, or anchoring proteins in adult hamsters. Thus, we argue that visual deprivation continued past puberty reveals a new form of maladaptive, inhibitory plasticity in which, rather than retaining juvenile features and extending the critical period, continued lack of inhibition in adulthood reopens the critical period, reversing the refinement of receptive fields to the detriment of visual acuity. These results suggest that attempts to increase plasticity in adulthood for purposes of rehabilitation or recovery from injury should consider the possibility of unintended negative consequences. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.09.10.507343v1?rss=1 Authors: Godavarthi, S. K., Hiramoto, M., Ignatyev, Y., Levin, J. B., Li, H., Pratelli, M., Borchardt, J., Czajkowski, C. M., Borodinsky, L. N., Sweeney, L., Cline, H. T., Spitzer, N. C. Abstract: Alteration of the electrical activity of the nervous system causes plasticity in neural circuits. Many of the changes occur at synapses. For example, neurotransmitter switching involves changes in the identity of presynaptic neurotransmitters and corresponding changes in postsynaptic transmitter receptors, thereby achieving a match between the transmitter and its cognate receptor. However, it is unknown whether changes in postsynaptic receptors can regulate presynaptic transmitters. Here we address this question at the developing neuromuscular junction. We find that blockade of endogenous postsynaptic acetylcholine receptors leads to loss of the cholinergic phenotype in motor neurons and the reappearance and stabilization of an earlier, developmentally transient glutamatergic phenotype. In addition, exogenous postsynaptic expression of GABAA receptors leads to the appearance and stabilization of an earlier, transient GABAergic motor neuron phenotype. Thus, acetylcholine receptors are necessary to stabilize acetylcholine as a transmitter, and GABAA receptors are sufficient to stabilize GABA as a transmitter. GARLH4 links the GABAA receptor to neuroligin, and Lrp4 links the acetylcholine receptor to dystroglycan through rapsyn and MUSK. Both neuroligin and dystroglycan bind to neurexin, which in turn binds to forms of the CASK transcription factor in motor neurons. Knock down of GARLH4 or Lrp4 postsynaptically or CASK presynaptically blocks stabilization of the GABAergic and cholinergic phenotypes. These results implicate transsynaptic bridges in establishing receptor-dependent stability of the cognate neurotransmitters. Our findings provide opportunities to investigate a role for dysfunctional transmitter receptors in neurological disorders that involve the loss of the presynaptic transmitter. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.08.25.505296v1?rss=1 Authors: Vandrey, B., Armstrong, J., Brown, C. M., Garden, D. L. F., Nolan, M. F. Abstract: Standard models for spatial and episodic memory suggest that the lateral entorhinal cortex (LEC) and medial entorhinal cortex (MEC) send parallel independent inputs to the hippocampus, each carrying different types of information. Here, we evaluate the possibility that information is integrated between divisions of the entorhinal cortex prior to reaching the hippocampus. We demonstrate that fan cells in layer 2 (L2) of LEC that receive neocortical inputs, and that project to the hippocampal dentate gyrus, also send axon collaterals to layer 1 (L1) of the MEC. Activation of fan cell inputs evokes monosynaptic glutamatergic excitation of stellate and pyramidal cells in L2 of the MEC, typically followed by inhibition that contains fast and slow components mediated by GABAA and GABAB receptors, respectively. Fan cell inputs also directly activate interneurons in L1 and L2 of MEC, with synaptic connections from L1 interneurons accounting for slow feedforward inhibition of L2 principal cell populations. The relative strength of excitation and inhibition following fan cell activation differs substantially between neurons and is largely independent of anatomical location. Our results demonstrate that the LEC, in addition to directly influencing the hippocampus, can activate or inhibit major hippocampal inputs arising from the MEC. Thus, local circuits in the superficial MEC may combine spatial information with sensory and higher order signals from the LEC, providing a substrate for integration of what and where components of episodic memories. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer

En este episodio te detallo cómo funcionan las benzodiazepinas en tus receptores GABAA, por qué desarrollamos una tolerancia hacia ellas y por qué no recomiendo usarlas. Este tipo de fármacos actúa directamente como un "tapón" sobre el problema y no tratando la causa del mismo, te dejo mi opinión, mis tips y consejos para reducir su uso o eliminarlo con el tiempo, a través del estilo de vida, suplementación y nutrición. Mi curso Ayuno Experto - El curso MÁS COMPLETO de Ayuno Intermitente en español: https://philhugo.com/producto/ayuno-experto/ Las gafas de luz que te recomiendo en el episodio con 15% de descuento: BonCharge https://bit.ly/3NzfVB8 MIS OTROS CURSOS Y PROGRAMAS:

Dr. Justin Abbatemarco discusses the features of anti-γ-aminobutyric acid type A (anti-GABAA) receptor encephalitis. 

En su reposo. 08/01/2022. T11. E20. “Entonces subieron todos los hijos de Israel, y todo el pueblo, y vinieron a la casa de Dios; y lloraron, y se sentaron allí en presencia de Jehová, y ayunaron aquel día hasta la noche; y ofrecieron holocaustos y ofrendas de paz delante de Jehová”. ‭‭Jueces‬ ‭20:26‬ Reacción ante la crisis La unidad de la nación por causa del oprobio de los de Gabaa, y su amplia ventaja numérica contra la tribu de Benjamín parecía garantizar una victoria aplastante y un castigo seguro contra aquellos perversos hombres. Incluso, tuvieron la precaución de consultar a Dios en este tema y el Señor les autorizó el proceso a seguir. Todo parecía estar en orden. Sin embargo, no fue una vez si dos ocasiones las que fueron derrotados por los guerreros benjamitas, que destacaban por su habilidad y destreza en el arte de la guerra. ¿Cómo es posible eso, si su motivo es justo, son mayoría y además tenían la autorización divina? No parece tener sentido lo que les ocurrió. Cualquier podría sentirse olvidado por Dios o sin ánimos para seguir intentándolo. Es normal que reaccionemos así ante la adversidad. Pero la reacción del pueblo de Israel en este capítulo es digna de reconocer e imitar. No solo las acciones sino la actitud tras esas acciones es lo que destaca de la nación. Fueron ante Dios. Lloraron. Permanecieron ante Dios. Ayunaron Ofrecieron holocaustos y ofrendas. No recriminaron ni se alejaron de Dios. No criticaron los resultados ni se dividieron entre ellos las culpas. Ante los problemas que enfrentamos, la respuesta que ha de esperarse de un hijo de Dios es acercarse todavía más al Señor. Reconocer nuestra necesidad y nuestra dependencia de su ayuda. Justo cuando los problemas parecen infranqueables. Cuando todo está aparentemente perdido, cuando hemos fracasado una y otra vez, es el momento adecuado para ir ante el Señor con todavía mayor entrega y disposición. La victoria finalmente llegó para Israel y pudieron hacer justicia ante la perversidad cometida. El Señor traerá el triunfo a nuestras vidas en el tiempo perfecto. Su poder se manifestará y veremos su gloria llevándonos a experimentar el cumplimiento de todas sus promesas. Que sin importar qué tan derrotados estemos, o que tan fracasados nos sintamos, hoy sea un día para buscar más al Señor. Él está presto para recibirnos. Isaí Rodríguez Ruiz

“Entonces los filisteos se juntaron para pelear contra Israel, treinta mil carros, seis mil hombres de a caballo, y pueblo numeroso como la arena que está a la orilla del mar; y subieron y acamparon en Micmas, al oriente de Bet-avén. Cuando los hombres de Israel vieron que estaban en estrecho (porque el pueblo estaba en aprieto), se escondieron en cuevas, en fosos, en peñascos, en rocas y en cisternas. Y algunos de los hebreos pasaron el Jordán a la tierra de Gad y de Galaad; pero Saúl permanecía aún en Gilgal, y todo el pueblo iba tras él temblando. Y él esperó siete días, conforme al plazo que Samuel había dicho; pero Samuel no venía a Gilgal, y el pueblo se le desertaba. Entonces dijo Saúl: Traedme holocausto y ofrendas de paz. Y ofreció el holocausto. Y cuando él acababa de ofrecer el holocausto, he aquí Samuel que venía; y Saúl salió a recibirle, para saludarle. Entonces Samuel dijo: ¿Qué has hecho? Y Saúl respondió: Porque vi que el pueblo se me desertaba, y que tú no venías dentro del plazo señalado, y que los filisteos estaban reunidos en Micmas, me dije: Ahora descenderán los filisteos contra mí a Gilgal, y yo no he implorado el favor de Jehová. Me esforcé, pues, y ofrecí holocausto. Entonces Samuel dijo a Saúl: Locamente has hecho; no guardaste el mandamiento de Jehová tu Dios que él te había ordenado; pues ahora Jehová hubiera confirmado tu reino sobre Israel para siempre. Mas ahora tu reino no será duradero. Jehová se ha buscado un varón conforme a su corazón, al cual Jehová ha designado para que sea príncipe sobre su pueblo, por cuanto tú no has guardado lo que Jehová te mandó. Y levantándose Samuel, subió de Gilgal a Gabaa de Benjamín.” (1 Samuel 13: 5-15).

1 SAMUEL 11: 1 Después subió Nahas amonita, y acampó contra Jabes de Galaad. Y todos los de Jabes dijeron a Nahas: Haz alianza con nosotros, y te serviremos. 2 Y Nahas amonita les respondió: Con esta condición haré alianza con vosotros, que a cada uno de todos vosotros saque el ojo derecho, y ponga esta afrenta sobre todo Israel. 3 Entonces los ancianos de Jabes le dijeron: Danos siete días, para que enviemos mensajeros por todo el territorio de Israel; y si no hay nadie que nos defienda, saldremos a ti. 4 Llegando los mensajeros a Gabaa de Saúl, dijeron estas palabras en oídos del pueblo; y todo el pueblo alzó su voz y lloró. 5 Y he aquí Saúl que venía del campo, tras los bueyes; y dijo Saúl: ¿Qué tiene el pueblo, que llora? Y le contaron las palabras de los hombres de Jabes. 6 Al oír Saúl estas palabras, el Espíritu de Dios vino sobre él con poder; y él se encendió en ira en gran manera.

This is part 2 of our 3-part series on "Breaking Addictions" where we cover one of the most dangerous types of addiction....alcohol. In this episode, we dive into the addictive properties of alcohol, how to tell if you've developed a dependency on alcohol, and some of the long-term detriments of frequent alcohol consumption. We also share our personal experience with drinking and Andy shares why he decided to give up alcohol for a full year.  Subscribe to the Rat Pack NewsletterRate the show on Apple PodcastFollow along on InstagramTry the cleanest, most effective electrolyte drink on the market: Drink LMNTResourcesCDC excessive alcohol intakeAlcohol and DopamineSex Differences in Striatal Dopamine Release in Young Adults After Oral Alcohol ChallengeThe role of GABAA receptors in mediating the effects of alcohol in the central nervous systemCriteria for Alcohol Use DisorderAgrp neuron activity is required for alcohol-induced overeatingAlcohol and fertility: how much is too much?Alcohol and Health: 15 Effects of Excess Alcohol Intake and 4 Benefits of Moderate DrinkingWhy People DrinkChanges in Adult Alcohol Use and Consequences During the COVID-19 Pandemic in the USHelp for Alcohol & Drug DependenceAlcohol and Drug Helpline: 800-527-5344National Council on Alcoholism and Drug Dependence, Inc.: 800-622-2255Local Alcoholics Anonymous (AA) groupDisclaimerThis podcast is not intended to provide medical advice, diagnosis, or treatment. The products, information, services, and other content provided on and through this podcast, including information that may be provided in the show notes (directly or via linking to third-party sites), are provided for informational purposes only. Please consult with your physician or other healthcare professionals regarding any medical or health-related diagnosis or treatment options.

LIBRO PRIMERA DE SAMUEL BIBLIA ZOÉ CAPÍTULO 26 DAVID SIGUE EL CAMINO PREPARADO POR DIOS Y ELOHIM  PRUEBA SU CORAZÓN POR MEDIO DEL REY SAÚL 1 Vinieron los zifeos a Saúl en Gabaa, diciendo: No está David escondido en el collado de Haquila, al oriente del desierto? SAÚL VUELVE A BUSCAR LA MUERTE DE DAVID 2 Saúl entonces se levantó y descendió al desierto de Zif, llevando consigo tres mil hombres escogidos de Israel, para buscar a David en el desierto de Zif DAVID Y SAÚL EN EL DESIERTO 3 Y acampó Saúl en el collado de Haquila, que está al oriente del desierto, junto al camino. Y estaba David en el desierto, y entendió que Saúl le seguía en el desierto 4 David, por tanto, envió espías, y supo con certeza que Saúl había venido DAVID VISITA EL CAMPAMENTO DE SAÚL 5 Y se levantó David, y vino al sitio donde Saúl había acampado; y miró David el lugar donde dormían Saúl y Abner hijo de Ner, general de su ejército. Y estaba Saúl durmiendo en el campamento, y el pueblo estaba acampado en derredor de él 6 Entonces David dijo a Ahimelec heteo y a Abisai hijo de Sarvia, hermano de Joáb: Quién descenderá conmigo a Saúl en el campamento? Y dijo Abisai: Yo descenderé contigo 7 David, pues, y Abisai fueron de noche al ejército; y he aquí que Saúl estaba tendido durmiendo en el campamento, y su lanza clavada en tierra a su cabecera; y Abner y el ejército estaban tendidos alrededor de él. DAVID PROHÍBE MATAR A SAÚL 8 Entonces dijo Abisai a David: Hoy ha entregado Dios a tu enemigo en tu mano; ahora, pues, déjame que le hiera con la lanza, y lo enclavaré en la tierra de un golpe, y no le daré segundo golpe 9 Y David respondió a Abisai: No le mates; porque ¿quién extenderá su mano contra el ungido de Jehová, y será inocente? 10 Dijo además David: Vive Jehová, que si Jehová no lo hiriere, o su día llegue para que muera, o descendiendo en batalla perezca, DAVID TIENE TEMOR DE JEHOVÁ Y  PERDÓNA LA VIDA A SAÚL 11Guárdeme Jehová de extender mi mano contra el ungido de Jehová. Pero toma ahora la lanza que está a su cabecera, y la vasija de agua, y vámonos. JEHOVÁ ENVÍA SUEÑO A LOS HOMBRES DE SAÚL 12 Se llevó, pues, David la lanza y la vasija de agua de la cabecera de Saúl, y se fueron; y no hubo nadie que viese, ni entendiese, ni velase, pues todos dormían; porque un profundo sueño enviado de Jehová había caído sobre ellos. LOS MONTES OPUESTOS 13 Entonces pasó David al lado opuesto, y se puso en la cumbre del monte a lo lejos, habiendo gran distancia entre ellos. DAVID PREGUNTA A ABNER JEFE DEL EJÉRCITO DE SAÚL 14 Y dio voces David al pueblo, y a Abner hijo de Ner, diciendo: ¿No respondes, Abner? Entonces Abner respondió y dijo: ¿Quién eres tú que gritas al rey? 15 Y dijo David a Abner: ¿No eres tú un hombre? ¿y quién hay como tú en Israel? ¿Por qué, pues, no has guardado al rey tu señor? Porque uno del pueblo ha entrado a matar a tu señor el rey. 16 Esto que has hecho no está bien. Vive Jehová, que sois dignos de muerte, porque no habéis guardado a vuestro señor, al ungido de Jehová. Mira pues, ahora, dónde está la lanza del rey, y la vasija de agua que estaba a su cabecera. SAÚL RECONOCE LA VOZ DE DAVID 17 Y conociendo Saúl la voz de David, dijo: ¿No es ésta tu voz, hijo mío David? Y David respondió: Mi voz es, rey señor mío. 18 Y dijo: Porqué persigue así mi señor a su siervo? Qué he hecho? Qué mal hay en mi mano? DAVID OFRECE SU VIDA , SI JEHOVÁ LA QUIERE POR MANO DE  SAÚL 19 Ruego, pues, que el rey mi señor oiga ahora las palabras de su siervo : Si Jehová te incita contra mí, acepte él la ofrenda DAVID NO ENTREGARÁ SU VIDA SÍ ES VOLUNTAD DE HOMBRES Más si fueren hijos de hombres, malditos sean ellos en presencia de Jehová, Porque me han arrojado hoy para que no tenga parte en la heredad de Jehová, diciendo: Ve y sirve a dioses ajenos. 20 No caiga, pues, ahora mi sangre en tierra delante de Jehová, 21 Entonces dijo Saúl: He pecado.... FUNDACIÓN VIDA ZOE EDITADO LIVEMAN DEE 2021

Jueces 19 relata una terrible historia que nos recuerda lo que sucede cuando el hombre pone a un lado a Dios y sus principios.

LIBRO PRIMERA DE SAMUEL BIBLIA ZOÉ CAPÍTULO 22 LOS VALIENTES DE DAVID DAVID Y SUS HERMANOS 1 Yéndose luego David de allí, huyó a la cueva de Adulam; y cuando sus hermanos y toda la casa de su padre lo supieron, vinieron allí a él. A DAVID SE JUNTAN LOS AFLIGIDOS, ENDEUDADOS, Y AMARGADOS DE ESPÍRITU 2 Y se juntaron con él todos los afligidos, y todo el que estaba endeudado, y todos los que se hallaban en amargura de espíritu, y fue hecho jefe de ellos; y tuvo consigo como cuatrocientos hombres. DAVID PROTEJE LA VIDA DE SUS PADRES 2 Y se fue David de allí a Mizpa de Moab, y dijo al rey de Moab: Yo te ruego que mi padre y mi madre estén con vosotros, hasta que sepa lo que Dios hará de mí. 3 Los trajo, pues, a la presencia del rey de Moab, y habitaron con él todo el tiempo que David estuvo en el lugar fuerte. GAD EL PROFETA ADVIERTE A DAVID 4 Pero el profeta Gad dijo a David: No te estés en este lugar fuerte; anda y vete a tierra de Judá. Y David se fue, y vino al bosque de Haret. 5 Oyó Saúl que se sabía de David y de los que estaban con él. Y Saúl estaba sentado en Gabaa, debajo de un tamarisco sobre un alto; y tenía su lanza en su mano, y todos sus siervos estaban alrededor de él. 6 Y dijo Saúl a sus siervos que estaban alrededor de él: Oíd ahora, hijos de Benjamín: ¿Os dará también a todos vosotros el hijo de Isaí tierras y viñas, y os hará a todos vosotros jefes de millares y jefes de centenas, SAÚL COSECHA LO QUE SEMBRÓ 7 Para que todos vosotros hayáis conspirado contra mí, y no haya quien me descubra al oído cómo mi hijo ha hecho alianza con el hijo de Isaí, ni alguno de vosotros que se duela de mí y me descubra cómo mi hijo, Él ha levantado a mi siervo contra mí para que me aceche, tal como lo hace hoy? DOEG TRAICIONA A DAVID 8 Entonces Doeg edomita, que era el principal de los siervos de Saúl, respondió y dijo: Yo vi al hijo de Isaí que vino a Nob, a Ahimelec hijo de Ahitob, 9 Él cual consultó por él a Jehová y le dio provisiones, y también le dio la espada de Goliat el filisteo. 10 Y el rey envió por el sacerdote Ahimelec hijo de Ahitob, y por toda la casa de su padre, los sacerdotes que estaban en Nob; y todos vinieron al rey. SAÚL MATA A LOS SACERDOTES DE NOB 11 Y Saúl le dijo: Oye ahora, hijo de Ahitob. Y él dijo: Heme aquí, señor mío. 12 Y le dijo Saúl: ¿Por qué habéis conspirado contra mí, tú y el hijo de Isaí, cuando le diste pan y espada, y consultaste por él a Dios, para que se levantase contra mí y me acechase, como lo hace hoy día? Ahimelec declara a Saúl los hechos de David y busca respuesta de Jehová 13 Entonces Ahimelec respondió al rey, y dijo: ¿Y quién entre todos tus siervos es tan fiel como David, yerno también del rey, que sirve a tus órdenes y es ilustre en tu casa? 14 ¿He comenzado yo desde hoy a consultar por él a Dios? Lejos sea esto de mí; y no culpe el rey de cosa alguna a su siervo, ni a toda la casa de mi padre; porque tu siervo ninguna cosa sabe de este asunto, grande ni pequeña. LOS HOMBRES DE SAÚL DESOBEDECEN AL VER LAS INJUSTICIAS EN SAÚL 15 Y el rey dijo: Sin duda morirás, Ahimelec, tú y toda la casa de tu padre. 16 Entonces dijo el rey a la gente de su guardia que estaba alrededor de él: Volveos y matad a los sacerdotes de Jehová; porque también la mano de ellos está con David, pues sabiendo ellos que huía, no me lo descubrieron. Pero los siervos del rey no quisieron extender sus manos para matar a los sacerdotes de Jehová. 17 Doeg mata a los Sacerdotes y a todo habitante así como destruye todo lo existente en la ciudad de Nob. 18 Entonces dijo el rey a Doeg: Vuelve tú, y arremete contra los sacerdotes. Y se volvió Doeg el edomita y acometió a los sacerdotes, y mató en aquel día a ochenta y cinco varones que vestían efod de lino. 19 Y a Nob, ciudad de los sacerdotes, hirió a filo de espada; así a hombres como a mujeres, niños hasta los de pecho, bueyes, asnos y ovejas, todo lo hirió a filo de espada... FUNDACIÓN VIDA ZOE EDITADO LIVEMAN DEE 2021

Vinieron los zifeos a Saúl en Gabaa, diciendo: ¿No está David escondido en el collado de Haquila, al oriente del desierto? Saúl entonces se levantó y descendió al desierto de Zif, llevando consigo tres mil hombres escogidos de Israel, para buscar a David en el desierto de Zif. Y acampó Saúl en el collado de Haquila, que está al oriente del desierto, junto al camino. Y estaba David en el desierto, y entendió que Saúl le seguía en el desierto. David, por tanto, envió espías, y supo con certeza que Saúl había venido. Y se levantó David, y vino al sitio donde Saúl había acampado; y miró David el lugar donde dormían Saúl y Abner hijo de Ner, general de su ejército. Y estaba Saúl durmiendo en el campamento, y el pueblo estaba acampado en derredor de él. Entonces David dijo a Ahimelec heteo y a Abisai hijo de Sarvia, hermano de Joab: ¿Quién descenderá conmigo a Saúl en el campamento? Y dijo Abisai: Yo descenderé contigo.

LIBRO PRIMERA DE SAMUEL BIBLIA ZOE CAPÍTULO 14 1 AL 52 JEHOVÁ ESTABA CON JONATÁN 1 Aconteció un día, que Jonatán hijo de Saul,  dijo a su criado que le traía las armas: Ven y pasemos a la guarnición de los filisteos, que está de aquel lado. Y no lo hizo saber a su padre. 2 Y Saul se hallaba al extremo de Gabaa, debajo de un granado que hay en Migrón, y la gente que estaba con él era como seiscientos hombres. 3 Y Ahías hijo de Ahitob, hermano de Icabod, hijo de Finees, hijo de Elí, sacerdote de Jehová en Silo, llevaba el efod; y no sabía el pueblo que Jonatán se hubiese ido. 4 Y entre los desfiladeros por donde Jonatán procuraba pasar a la guarnición de los filisteos, había un peñasco agudo de un lado, y otro del otro lado; el uno se llamaba Boses, y el otro Sene. 5 Uno de los peñascos estaba situado al norte, hacia Micmas, y el otro al sur, hacia Gabaa. JONATÁN DECLARA SU FE EN JEHOVÁ 6 Dijo, pues, Jonatán a su paje de armas: Ven, pasemos a la guarnición de estos incircuncisos; quizá haga algo Jehová por nosotros, pues no es difícil para Jehová salvar con muchos o con pocos. 7 Y su paje de armas le respondió: Haz todo lo que tienes en tu corazón; ve, pues aquí estoy contigo a tu voluntad. 8 Dijo entonces Jonatán: Vamos a pasar a esos hombres, y nos mostraremos a ellos. 9 Si nos dijeren así: Esperad hasta que lleguemos a vosotros, entonces nos estaremos en nuestro lugar, y no subiremos a ellos. 10 Mas si nos dijeren así: Subid a nosotros, entonces subiremos, porque Jehová los ha entregado en nuestra mano; y esto nos será por señal. 11 Se mostraron, pues, ambos a la guarnición de los filisteos, y los filisteos dijeron: He aquí los hebreos, que salen de las cavernas donde se habían escondido. 12 Y los hombres de la guarnición respondieron a Jonatán y a su paje de armas, y dijeron: Subid a nosotros, y os haremos saber una cosa. Entonces Jonatán dijo a su paje de armas: Sube tras de  mí, porque Jehová los ha entregado en manos de Israel. 13 Y subió Jonatán trepando con sus manos y sus pies, y tras él su paje de armas; y a los que caían delante de Jonatán, su paje de armas que iba tras él los mataba. 14 Y fue esta primera matanza que hicieron Jonatán y su paje de armas, como veinte hombres, en el espacio de una media yugada de tierra. 15 Y hubo pánico en el campamento y por el campo, y entre toda la gente de la guarnición; y los que habían ido a merodear, también ellos tuvieron pánico, y la tierra tembló; hubo, pues, gran consternación. 16 Y los centinelas de Saul vieron desde Gabaa de Benjamín cómo la multitud estaba turbada, e iba de un lado a otro y era deshecha. 17 Entonces Saul dijo al pueblo que estaba con él: Pasad ahora revista, y ved quién se haya ido de los nuestros. Pasaron revista, y he aquí que faltaba Jonatán y su paje de armas. 18 Y Saul dijo a Ahías: Trae el arca de Dios. Porque el arca de Dios estaba entonces con los hijos de Israel. 19 Pero aconteció que mientras aún hablaba Saul con el sacerdote, el alboroto que había en el campamento de los filisteos aumentaba, e iba creciendo en gran manera. Entonces dijo Saul al sacerdote: Detén tu mano. 20 Y juntando Saul a todo el pueblo que con él estaba, llegaron hasta el lugar de la batalla; y he aquí que la espada de cada uno estaba vuelta contra su compañero, y había gran confusión. 21 Y los hebreos que habían estado con los filisteos de tiempo atrás, y habían venido con ellos de los alrededores al campamento, se pusieron también del lado de los israelitas que estaban con Saul y con Jonatán. 22 Asimismo todos los israelitas que se habían escondido en el monte de Efraín, oyendo que los filisteos huían, también ellos los persiguieron en aquella batalla. 23 Así salvó Jehová a Israel aquel día. Y llegó la batalla hasta Bet-avén. 24 Pero los hombres de Israel fueron puestos en apuro aquel día; porque Saúl había juramentado al pueblo, se ha maldito el que pruebe pan antes de caerla noche.... FUNDACIÓN VIDA ZOE EDITADO LIVEMAN DEE 2021

LIBRO PRIMERA DE SAMUEL BIBLIA ZOE CAPÍTULO 13 GUERRA CONTRA LOS FILISTEOS Había ya reinado Saul un año; y cuando hubo reinado dos años sobre Israel, escogió luego a tres mil hombres de Israel, de los cuales estaban con Saul 2000 mil en Micmas y en el monte de Betel, y 1000 estaban con Jonatán en Gabaa de Benjamín; y envió al resto del pueblo cada uno a sus tiendas. Y Jonatán atacó a la guarnición de los filisteos que había en el collado, y lo oyeron los filisteos. E hizo Saul tocar trompeta por todo el país, diciendo: Oigan los hebreos. Israel abominable a los Filisteos !! Y todo Israel oyó que se decía: Saul ha atacado a la guarnición de los filisteos; y también que Israel se había hecho abominable a los filisteos. Y se juntó el pueblo en pos de Saul en Gilgal. Entonces los filisteos se juntaron para pelear contra Israel, treinta mil carros, seis mil hombres de a caballo, y pueblo numeroso como la arena que está a la orilla del mar; y subieron y acamparon en Micmas, al oriente de Bet-avén. El miedo en Israel !!! Cuando los hombres de Israel vieron que estaban en estrecho (porque el pueblo estaba en aprieto), se escondieron en cuevas, en fosos, en peñascos, en rocas y en cisternas. Y algunos de los hebreos pasaron el Jordán a la tierra de Gad y de Galaad; pero Saul permanecía aún en Gilgal, y todo el pueblo iban tras él, temblando. Los Hebreos comienzan a desertar a Saul, !! Y él esperó siete días, conforme al plazo que Samuel había dicho; pero Samuel no venía a Gilgal, y el pueblo se le desertaba. Saul decide por si mismo no esperar más a Samuel y hace lo que le es prohibido, hacer sacrificio. !! Entonces dijo Saul: Traedme holocausto y ofrendas de paz. Y ofreció el holocausto. Y cuando él acababa de ofrecer el holocausto, he aquí Samuel que venía; y Saul salió a recibirle, para saludarle. Los ojos y la razón traicionan a Saul !! Entonces Samuel dijo: ¿Qué has hecho? Y Saul respondió: Porque vi que el pueblo se me desertaba, y que tú no venías dentro del plazo señalado, y que los filisteos estaban reunidos en Micmas, me dije: Ahora descenderán los filisteos contra mí a Gilgal, y yo no he implorado el favor de Jehová. Me esforcé, pues, y ofrecí holocausto. Saul pierde su reinado por desobedecer !! Entonces Samuel dijo a Saul : Locamente has hecho; no guardaste el mandamiento de Jehová tu Dios que él te había ordenado; pues ahora Jehová hubiera confirmado tu reino sobre Israel para siempre. Mas ahora tu reino no será duradero. Jehová se ha buscado un varón conforme a su corazón, al cual Jehová ha designado para que sea príncipe sobre su pueblo, por cuanto tú no has guardado lo que Jehová te mandó. Y levantándose Samuel, subió de Gilgal a Gabaa de Benjamín. Y Saul contó la gente que se hallaba con él, como seiscientos hombres. Saul, pues, y Jonatán su hijo, y el pueblo que con ellos se hallaba, se quedaron en Gabaa de Benjamín; pero los filisteos habían acampado en Micmas. Y salieron merodeadores del campamento de los filisteos en tres escuadrones; un escuadrón marchaba por el camino de Ofra hacia la tierra de Sual, otro escuadrón marchaba hacia Bet-horón, y el tercer escuadrón marchaba hacia la región que mira al valle de Zeboim, hacia el desierto. Los Filisteos engañan a los hebreos !! Y en toda la tierra de Israel no se hallaba herrero; porque los filisteos habían dicho: Para que los hebreos no hagan espada o lanza. Por lo cual todos los de Israel tenían que descender a los filisteos para afilar cada uno la reja de su arado, su azadón, su hacha o su hoz. Y el precio era un pim por las rejas de arado y por los azadones, y la tercera parte de un siclo por afilar las hachas y por componer las aguijadas. Saul y Jonatán unicos con espada y lanza!! Así aconteció que en el día de la batalla no se halló espada ni lanza en mano de ninguno del pueblo que estaba con Saúl y con Jonatán, excepto Saul y Jonatán su hijo, que las tenían.... FUNDACIÓN VIDA ZOE EDITADO LIVEMAN DEE 2021

PRIMERA DE SAMUEL BIBLIA ZOE CAPÍTULO 11 1 AL 15 SAÚL DERROTA A LOS AMONITAS 1 Después subió Nahas amonita, y acampó contra Jabes de Galaad. Y todos los de Jabes dijeron a Nahas: Haz alianza con nosotros, y te serviremos. LA INPIEDAD DE LOS AMONITAS 2 Y Nahas amonita les respondió: Con esta condición haré alianza con vosotros, que a cada uno de todos vosotros saque el ojo derecho, y ponga esta afrenta sobre todo Israel. 3 Entonces los ancianos de Jabes le dijeron: Danos siete días, para que enviemos mensajeros por todo el territorio de Israel; y si no hay nadie que nos defienda, saldremos a ti. 4 Llegando los mensajeros de Gabaa a Saul, dijeron estas palabras en oídos del pueblo; y todo el pueblo alzó su voz y lloró. EL ESPÍRITU DE JEHOVÁ VIENE EN PODER Y TEMOR SOBRE SAÚL Y ISRAEL 5 Y he aquí Saul que venía del campo, tras los bueyes; y dijo Saul: ¿Qué tiene el pueblo, que llora? Y le contaron las palabras de los hombres de Jabes. 6 Al oír Saul estas palabras, el Espíritu de Dios vino sobre él con poder; y él se encendió en ira en gran manera. 7 Y tomando un par de bueyes, los cortó en trozos y los envió por todo el territorio de Israel por medio de mensajeros, diciendo: Así se hará con los bueyes del que no saliere en pos de Saul y en pos de Samuel. Y cayó temor de Jehová sobre el pueblo, y salieron como un solo hombre. 8 Y los contó en Bezec; y fueron los hijos de Israel trescientos mil, y treinta mil los hombres de Judá. 9 Y respondieron a los mensajeros que habían venido: Así diréis a los de Jabes de Galaad: Mañana al calentar el sol, seréis librados. Y vinieron los mensajeros y lo anunciaron a los de Jabes, los cuales se alegraron. 10 Y los de Jabes dijeron a los enemigos: Mañana saldremos a vosotros, para que hagáis con nosotros todo lo que bien os pareciere. 11 Aconteció que al día siguiente dispuso Saul al pueblo en tres compañías, y entraron en medio del campamento a la vigilia de la mañana, e hirieron a los amonitas hasta que el día calentó; y los que quedaron fueron dispersos, de tal manera que no quedaron dos de ellos juntos. SAMUEL Y SAÚL , VAN A GILGAL A DECLARAR FE EN JEHOVÁ 12 El pueblo entonces dijo a Samuel: ¿Quiénes son los que decían: Ha de reinar Saul sobre nosotros? Dadnos esos hombres, y los mataremos. 13 Y Saul dijo: No morirá hoy ninguno, porque hoy Jehová ha dado salvación en Israel. 14 Mas Samuel dijo al pueblo: Venid, vamos a Gilgal para que renovemos allí el reino. 15 Y fue todo el pueblo a Gilgal, e invistieron allí a Saul por rey delante de Jehová en Gilgal. Y sacrificaron allí ofrendas de paz delante de Jehová, y se alegraron mucho allí Saul y todos los de Israel. FUNDACIÓN VIDA ZOE EDITADO LIVEMAN DEE 2021

Benzodiazepines do not mainly impact the uptake or metabolism of biogenic amines, although they enhance the activity of gamma-aminobutyric acid (GABA). The antidepressant efficacy of benzodiazepines, which are GABAA receptor agonists, is compatible with the GABA depression theory.https://recoverypartnernetwork.com/drug/benzodiazepine/benzodiazepine-addiction

Bad news/good news: Grand mal got run over by a reindeer, BUT we got new microphones! In addition to learning what science does and doesn’t know about brain lightning storms (seizures), hear Libby’s seasonal reflections on the Little Drummer Boy. Key Words absence, amygdala, anticonvulsant, apoptosis, atonic, aura, benzodiazepine, carbamazepine (Tegretol), cellular signaling cascade, clonic, complex, cortex, cyanotic, diazepam (Valium), electroencephalogram (EEG), epilepsy, excitotoxicity, GABA, GABAA receptor, generalized, glucose, glutamate, grand mal, hippocampus, inhibitory surround, kindling, limbic, lorazepam (Ativan), magnetic resonance imaging (MRI), metabolism, motor, myoclonic, necrosis, negative symptom, occipital, oxygen, partial (focal), petit mal, phenytoin (Dilantin), piloerection, plasticity, positive symptom, positron emission tomography (PET), postictal, primary, secondary, seizure, sensory, simple, single photon emission computed tomography (SPECT), status epilepticus, symptomatic epilepsy, tonic, tonic-clonic, visual 54 key terms! Old West Words of the Day (Gap Junction Almanac) vum vaultinghouse References and Resources Textbooks Principles of Neural Science, Kandel, Schwartz, and Jessell, 4th Edition Vander’s Human Physiology, 13th Edition   Connect with us! FB @HeadshakeShow T @HeadshakeShow ‘Sta @HeadshakeNinja Site headshake.show OR headshake.ninja Music Bushwick Tarantella by Kevin MacLeod is licensed under a Creative Commons Attribution license (https://creativecommons.org/licenses/by/4.0/) Source: http://incompetech.com/music/royalty-free/index.html?isrc=USUAN1300002 Artist: http://incompetech.com/ Modified from original with volume fading and cuts   Disclaimer This podcast is for entertainment and education only. Neither of the hosts is a medical doctor, and nothing they say is medical advice. Please consult with your medical provider before making decisions about your health.

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.11.14.381749v1?rss=1 Authors: Sullivan, B. J., Kipnis, P. A., Ammanuel, S. G., Kadam, S. D. Abstract: Objective: SYNGAP1 encephalopathy is a developmental and epileptic encephalopathy caused by pathogenic loss of function variants. Syngap1-heterozygous (Het+/-) mice demonstrate progressive epilepsy with multiple seizure phenotypes in adulthood. Here, we investigate early-life seizures in Het+/- pups and explore of Syngap1 encephalopathy during development. Methods: Post-natal day 7 (P7) and P12 mice were investigated by tethered video-electroencephalographic (vEEG). The effects of GABAergic drugs phenobarbital (PB) and pentylenetetrazol (PTZ) were investigated at P7 and P12, respectively. 24h tethered vEEG was performed at P24, and telemetric 24h vEEG with 6h sleep deprivation was performed at P35. The effect of perampanel (PMP), an AMPA receptor antagonist, was investigated at P24. Results: Het+/- mice have spontaneous early-life seizures that lack an overt behavioral phenotype. These subclinical seizures are refractory to PB, but the GABAA receptor (GABAAR) antagonist PTZ significantly reduced seizure frequency suggesting that GABAergic signaling may promote seizure generation in Het+/- pups. At juvenile ages, Het+/- pups recapitulated the early emergence of high gamma (35-50Hz) during NREM and disruption of behavioral-state gamma homeostasis. This biomarker was significantly exacerbated in Het+/- pups after increasing sleep pressure with sleep deprivation. Significance: Seizures during development have adverse effects on cognitive function. Therefore, an improved understanding of the SYNGAP1 epilepsy during developmental ages is necessary to delineate the deleterious interactions between aberrant synaptic function and recurrent seizures. The development of evidence-based therapies for early-life intervention will benefit from these insights. Copy rights belong to original authors. Visit the link for more info

In this episode, we discuss the mechanisms of burning with propofol infusion and explore the evidence behind strategies like mixing lidocaine with propofol.  Our guest today is Dr. Stu Forman, Professor of Anesthesiology at Massachusetts General Hospital. He is an investigator on several NIH-sponsored basic research grants and co-director of the Harvard Anesthesia Research Training Fellowship. Connect with us @DepthAnesthesia on Twitter or email us at depthofanesthesia@gmail.com. Thanks for listening! Please rate us on iTunes and share with your colleagues.  Music by Stephen Campbell, MD.  -- References Bengalorkar GM, Bhuvana K, Sarala N, Kumar T. Fospropofol: clinical pharmacology. J Anaesthesiol Clin Pharmacol. 2011 Jan;27(1):79-83. PMID: 21804712; PMCID: PMC3146164. Dajun Song, Mohamed A. Hamza, Paul F. White, Stephanie I. Byerly, Stephanie B. Jones, Amy D. Macaluso; Comparison of a Lower-lipid Propofol Emulsion with the Standard Emulsion for Sedation during Monitored Anesthesia Care. Anesthesiology 2004; 100:1072–1075 doi: https://doi.org/10.1097/00000542-200405000-00007 Euasobhon P, Dej-Arkom S, Siriussawakul A, Muangman S, Sriraj W, Pattanittum P, Lumbiganon P. Lidocaine for reducing propofol-induced pain on induction of anaesthesia in adults. Cochrane Database Syst Rev. 2016 Feb 18;2(2):CD007874. doi: 10.1002/14651858.CD007874.pub2. PMID: 26888026; PMCID: PMC6463799. Fischer MJ, Leffler A, Niedermirtl F, Kistner K, Eberhardt M, Reeh PW, Nau C. The general anesthetic propofol excites nociceptors by activating TRPV1 and TRPA1 rather than GABAA receptors. J Biol Chem. 2010 Nov 5;285(45):34781-92. doi: 10.1074/jbc.M110.143958. Epub 2010 Sep 7. PMID: 20826794; PMCID: PMC2966094. Jalota L, Kalira V, George E, Shi YY, Hornuss C, Radke O, Pace NL, Apfel CC; Perioperative Clinical Research Core. Prevention of pain on injection of propofol: systematic review and meta-analysis. BMJ. 2011 Mar 15;342:d1110. doi: 10.1136/bmj.d1110. PMID: 21406529. Klement W, Arndt JO. Pain on i.v. injection of some anaesthetic agents is evoked by the unphysiological osmolality or pH of their formulations. Br J Anaesth. 1991 Feb;66(2):189-95. doi: 10.1093/bja/66.2.189. PMID: 1817619. Sahinovic MM, Struys MMRF, Absalom AR. Clinical Pharmacokinetics and Pharmacodynamics of Propofol. Clin Pharmacokinet. 2018;57(12):1539-1558. doi:10.1007/s40262-018-0672-3 Scott RP, Saunders DA, Norman J. Propofol: clinical strategies for preventing the pain of injection. Anaesthesia. 1988 Jun;43(6):492-4. doi: 10.1111/j.1365-2044.1988.tb06641.x. PMID: 3261547.

1 Samuel 11 Reina Valera 1960 1Después subió Nahas amonita, y acampó contra Jabes de Galaad. Y todos los de Jabes dijeron a Nahas: Haz alianza con nosotros, y te serviremos. 2Y Nahas amonita les respondió: Con esta condición haré alianza con vosotros, que a cada uno de todos vosotros saque el ojo derecho, y ponga esta afrenta sobre todo Israel. 3Entonces los ancianos de Jabes le dijeron: Danos siete días, para que enviemos mensajeros por todo el territorio de Israel; y si no hay nadie que nos defienda, saldremos a ti. 4Llegando los mensajeros a Gabaa de Saúl, dijeron estas palabras en oídos del pueblo; y todo el pueblo alzó su voz y lloró. 5Y he aquí Saúl que venía del campo, tras los bueyes; y dijo Saúl: ¿Qué tiene el pueblo, que llora? Y le contaron las palabras de los hombres de Jabes. 6Al oír Saúl estas palabras, el Espíritu de Dios vino sobre él con poder; y él se encendió en ira en gran manera. 7Y tomando un par de bueyes, los cortó en trozos y los envió por todo el territorio de Israel por medio de mensajeros, diciendo: Así se hará con los bueyes del que no saliere en pos de Saúl y en pos de Samuel. Y cayó temor de Jehová sobre el pueblo, y salieron como un solo hombre. 8Y los contó en Bezec; y fueron los hijos de Israel trescientos mil, y treinta mil los hombres de Judá. 9Y respondieron a los mensajeros que habían venido: Así diréis a los de Jabes de Galaad: Mañana al calentar el sol, seréis librados. Y vinieron los mensajeros y lo anunciaron a los de Jabes, los cuales se alegraron. 10Y los de Jabes dijeron a los enemigos: Mañana saldremos a vosotros, para que hagáis con nosotros todo lo que bien os pareciere. 11Aconteció que al día siguiente dispuso Saúl al pueblo en tres compañías, y entraron en medio del campamento a la vigilia de la mañana, e hirieron a los amonitas hasta que el día calentó; y los que quedaron fueron dispersos, de tal manera que no quedaron dos de ellos juntos. 12El pueblo entonces dijo a Samuel: ¿Quiénes son los que decían: ¿Ha de reinar Saúl sobre nosotros? Dadnos esos hombres, y los mataremos. 13Y Saúl dijo: No morirá hoy ninguno, porque hoy Jehová ha dado salvación en Israel. 14Mas Samuel dijo al pueblo: Venid, vamos a Gilgal para que renovemos allí el reino. 15Y fue todo el pueblo a Gilgal, e invistieron allí a Saúl por rey delante de Jehová en Gilgal. Y sacrificaron allí ofrendas de paz delante de Jehová, y se alegraron mucho allí Saúl y todos los de Israel

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.09.29.319715v1?rss=1 Authors: Inami, S., Sato, T., Suzuki, Y., Kitamoto, T., Sakai, T. Abstract: The LIM-homeodomain (LIM-HD) transcription factor Apterous (Ap) and its cofactor Chip (Chi) form a complex that regulates various developmental events in Drosophila. Although Ap continues to be expressed in the adult brain, the functions of the centrally expressed Ap remain incompletely understood. Here, we show that Ap and Chi in the Drosophila memory center, the mushroom bodies (MBs), are indispensable for long-term memory (LTM) maintenance, whereas Ap in a subset of clock neurons [large ventral-lateral neurons (l-LNvs)] plays a crucial role in memory consolidation in a Chi-independent manner. Ex vivo imaging revealed that Ap, but not Chi, in l-LNvs is essential for the appropriate Cl- responses to GABA. Furthermore, knockdown of GABAA receptor in l-LNvs compensated for the impairment of memory consolidation in ap null mutant flies. Our results indicate that Drosophila Ap functions differently in l-LNvs and MBs, and it contributes to the consolidation and maintenance of LTM. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.09.15.298711v1?rss=1 Authors: Hynd, M., Soh, C., Rangel, B., Wessel, J. R. Abstract: By stopping actions even after their initiation, humans can adapt their ongoing behavior rapidly to changing environmental circumstances. The neural processes underlying the implementation of rapid action-stopping are still controversially discussed. In the early 1990s, a fronto-central P3 event-related potential (ERP) was identified in the human EEG response following stop-signals in the classic stop-signal task, accompanied by the proposal that this ERP reflects the 'inhibitory' side of the purported horse-race underlying successful action-stopping. Later studies have lent support to this interpretation by finding that the amplitude and onset of the stop-signal P3 relate to both overt behavior and to movement-related EEG activity in ways predicted by the race model. However, such studies are limited by the ability of EEG to allow direct inferences about the presence (or absence) of true, physiologically inhibitory signaling at the neuronal level. To address this, we here present a cross-modal individual differences investigation of the relationship between the features stop-signal P3 ERP and GABAergic neurotransmission in primary motor cortex (M1, as measured by paired-pulse transcranial magnetic stimulation). Following recent work, we measured short-interval intracortical inhibition (SICI), a marker of inhibitory GABAa activity in M1, in a group of 41 human participants who also performed the stop-signal task while undergoing EEG recordings. In line with the P3-inhibition hypothesis, we found that subjects with stronger inhibitory GABA activity in M1 also showed both faster onsets and larger amplitudes of the stop-signal P3. This provides direct evidence linking the properties of this ERP to a true physiological index of motor system inhibition. We discuss these findings in the context of recent theoretical developments and empirical findings regarding the neural implementation of inhibitory control during action-stopping. Copy rights belong to original authors. Visit the link for more info

LIBRO DE JUECES CAPÍTULOS 19 AL 21 EXTRACTO CAPÍTULO 20 BIBLIA ZOE LA GUERRA CIVIL DENTRO DE ISRAEL LA GUERRA CONTRA BENJAMÍN Entonces salieron todos los hijos de Israel, y se reunió la congregación como un solo hombre, desde Dan hasta Beerseba y la tierra de Galaad, a Jehová en Mizpa. Y los jefes de todo el pueblo, de todas las tribus de Israel, se hallaron presentes en la reunión del pueblo de Dios, 400 mil hombres de a pie que sacaban espada. Y los hijos de Benjamín oyeron que los hijos de Israel habían subido a Mizpa. LA MALDAD DEL CORAZÓN DEL HOMBRE Y dijeron los hijos de Israel: Decid cómo fue esta maldad. Entonces el varón levita, marido de la mujer muerta, respondió y dijo: Yo llegué a Gabaa de Benjamín con mi concubina, para pasar allí la noche. Y levantándose contra mí los de Gabaa, rodearon contra mí la casa por la noche, con idea de matarme, y a mi concubina la 10  humillaron de tal manera que murió. Entonces tomando yo mi concubina, la corté en pedazos, y la envié por todo el territorio de la posesión de Israel, por cuanto han hecho maldad y crimen en Israel. EL HOMBRE DESDE LA CAÍDA SIEMPRE TRATA DE DAR SU OPINIÓN, CUANDO EL VERDADERO PARECER Y CONSEJO VIENE DE JEHOVA He aquí todos vosotros sois hijos de Israel; dad aquí vuestro parecer y consejo. Entonces todo el pueblo, como un solo hombre, se levantó, y dijeron: Ninguno de nosotros irá a su tienda, ni volverá ninguno de nosotros a su casa. LA GUERRA DENTRO DEL CORAZÓN DEL HOMBRE Mas esto es ahora lo que haremos a Gabaa: contra ella subiremos por sorteo. Tomaremos 10 hombres de cada ciento por todas las tribus de Israel, y ciento de cada mil, y 1000 de cada diez mil, que lleven víveres para el pueblo, para que yendo a Gabaa de Benjamín le hagan conforme a toda la abominación que ha cometido en Israel. Y se juntaron todos los hombres de Israel contra la ciudad, ligados como un solo hombre. Y las tribus de Israel enviaron varones por toda la tribu de Benjamín, diciendo: ¿Qué maldad es esta que ha sido hecha entre vosotros? Entregad, pues, ahora a aquellos hombres perversos que están en Gabaa, para que los matemos, y quitemos el mal de Israel. LA MALDAD DEL HOMBRE NATURAL NO PUEDE OÍR A SUS HERMANOS POR MANTENER SU OPINIÓN Mas los de Benjamín no quisieron oír la voz de sus hermanos los hijos de Israel, EL HOMBRE PREFIERE LA GUERRA QUE ESCUCHAR sino que los de Benjamín se juntaron de las ciudades en Gabaa, para salir a pelear contra los hijos de Israel. Y fueron contados en aquel tiempo los hijos de Benjamín de las ciudades, 26 mil hombres que sacaban espada, sin los que moraban en Gabaa, que fueron por cuenta setecientos hombres escogidos. De toda aquella gente había 700 hombres escogidos, que eran zurdos, Todos los cuales tiraban una piedra con la honda a un cabello, y no erraban. Y fueron contados los varones de Israel, fuera de Benjamín, 400 mil hombres que sacaban espada, todos estos hombres de guerra. DIOS PESA LAS ACCIONES DE SUS HIJOS Luego se levantaron los hijos de Israel, y subieron a la casa de Dios y consultaron a Dios, diciendo: ¿Quién subirá de nosotros el primero en la guerra contra los hijos de Benjamín? Y Jehová respondió: Judá será el primero. Se levantaron, pues, los hijos de Israel por la mañana, contra Gabaa. Y salieron los hijos de Israel a combatir contra Benjamín, y los varones de Israel ordenaron la batalla contra ellos junto a Gabaa. Saliendo entonces de Gabaa los hijos de Benjamín, derribaron por tierra aquel día 22 mil hombres de los hijos de Israel. Mas reanimándose el pueblo, los varones de Israel volvieron a ordenar la batalla en el mismo lugar donde la habían ordenado el primer día. LA ORACIÓN Y EL   LAMENTÓ, HERRAMIENTA PARA SABER EL CONSEJO DE JEHOVÁ Porque los hijos de Israel subieron y lloraron delante de Jehová hasta la noche, FUNDACIÓN VIDA ZOE EDITADO LIVEMAN DEE 2020

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.08.18.255323v1?rss=1 Authors: Lombardi, A., Jedlicka, P., Luhmann, H. J., Kilb, W. Abstract: The impact of GABAergic transmission on neuronal excitability depends on the Cl--gradient across membranes. However, the Cl--fluxes through GABAA receptors alter the intracellular Cl- concentration ([Cl-]i) and in turn attenuate GABAergic responses, a process termed ionic plasticity. Recently it has been shown that coincident glutamatergic inputs significantly affect ionic plasticity. Yet how the [Cl-]i changes depend on the properties of glutamatergic inputs and their spatiotemporal relation to GABAergic stimuli is unknown. To investigate this issue, we used compartmental biophysical models of Cl- dynamics simulating either a simple ball-and-stick topology or a reconstructed immature CA3 neuron. These computational experiments demonstrated that glutamatergic co-stimulation enhances GABA receptor-mediated Cl- influx at low and attenuates or reverses the Cl- efflux at high initial [Cl-]i. The size of glutamatergic influence on GABAergic Cl--fluxes depends on the conductance, decay kinetics, and localization of glutamatergic inputs. Surprisingly, the glutamatergic shift in GABAergic Cl--fluxes is invariant to latencies between GABAergic and glutamatergic inputs over a substantial interval. In agreement with experimental data, simulations in a reconstructed CA3 pyramidal neuron with physiological patterns of correlated activity revealed that coincident glutamatergic synaptic inputs contribute significantly to the activity-dependent [Cl-]i changes. Whereas the influence of spatial correlation between distributed glutamatergic and GABAergic inputs was negligible, their temporal correlation played a significant role. In summary, our results demonstrate that glutamatergic co-stimulation had a substantial impact on ionic plasticity of GABAergic responses, enhancing the destabilization of GABAergic inhibition in the mature nervous systems, but suppressing GABAergic [Cl-]i changes in the immature brain. Therefore, glutamatergic shift in GABAergic Cl--fluxes should be considered as a relevant factor of short term plasticity. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.08.14.250860v1?rss=1 Authors: Crestani, A. P., Lotz, F. N., Casagrande, M. A., Popik, B., Guerra, K. T. K., de Oliveira Alvares, L., Quillfeldt, J. A. Abstract: Systems consolidation is a time-dependent process in which the retrieval of contextual memories becomes progressively independent from the hippocampus and more reliant on cortical structures. One qualitative consequence, supposed to be causally related, is the progressive loss of memory precision. Memory generalization, however, is a much more complex phenomena, and may take place much faster in adult animals, for instance, in response to changes in the available levels of sex hormones. In this sense, females are known to display a generalized memory earlier than males. Sex differences might have an important role in the modulation of mnemonic processes, and despite being of paramount importance for the understanding of the cognitive dynamics of juveniles, it remains poorly investigated. Here, we studied adolescent rats (P42-49) of different sex comparing the natural time-course of systems consolidation as verified both by the hippocampus-dependency and the onset of memory generalization. Contextual fear discrimination was quantified at different time-points after learning (2, 7, 14, 21 and 28 days). Our results demonstrated that, contrary to what is observed in adults, memory generalization occurs earlier in adolescent males (14 days) than in females (28 days). During adolescence, females display a higher mean discrimination index at all time-points, suggesting that they retain a more detailed memory. Likewise, pre-test pharmacological inactivation of the hippocampus (with GABAA agonist muscimol) was able to impair memory retrieval in females, but not in males, 14 days after training. These results support a causal relationship between memory generalization and retrieval independence from the hippocampus in male adolescent rats. However, both aspects of the systems consolidation process appear to be distinctly modulated in animals of different sex, with males (and ovariectomized females) enduring an accelerated onset of both memory precision loss and the hippocampus independence compared to females, suggesting a clear role for gonadal hormones in this cognitive corticalization process. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.08.12.248294v1?rss=1 Authors: de Paiva, J. P. Q., Bueno, A. P. A., dos Santos Corrêa, M., Oliveira, M. G., Ferreira, T. L., Fornari, R. V. Abstract: The insular cortex (IC) is notably implicated in emotional and cognitive processing; however, little is known regarding to what extent its two main subregions play functionally distinct roles on memory consolidation of conditioned fear tasks. Here we verified the effects of temporary functional inactivation of the anterior (aIC) and posterior IC (pIC) on contextual and tone fear memory. Rats received post-training bilateral infusions of the GABAA receptor agonist muscimol into either the aIC or pIC and were tested 48 and 72 hours after the conditioning session to assess contextual (CFC) and tone (TFC) fear conditioning, respectively. Inactivation of the aIC during memory consolidation did not affect fear memory for CFC or TFC. On the other hand, post-training inactivation of the pIC impaired TFC but not CFC. Our findings indicate that the pIC is a necessary part of the neural circuitry related to the consolidation of cued-fear memories. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.08.05.238725v1?rss=1 Authors: Johnson, S. A., Zequeira, S., Turner, S. M., Maurer, A. P., Bizon, J. L., Burke, S. N. Abstract: Mnemonic similarity task performance, in which a known target stimulus must be distinguished from similar lures, is supported by the hippocampus and perirhinal cortex and is known to decline in advanced age. Interestingly, disrupting hippocampal activity leads to mnemonic discrimination impairments when lures are novel, but not when they are familiar. This observation suggests other brain structures can support discrimination abilities as stimuli are learned. The prefrontal cortex (PFC) is critical for retrieval of remote events and executive functions, such as working memory, and is also particularly vulnerable to dysfunction in aging. Importantly, the medial PFC is reciprocally connected to the perirhinal cortex and neuron firing in this region coordinates communication between lateral entorhinal and perirhinal cortices to presumably modulate hippocampal activity. This anatomical organization and function of the medial PFC suggests that it contributes to mnemonic discrimination; however, this notion has not been empirically tested. In the current study, young adult male and female F344 x Brown Norway F1 hybrid rats were trained on a rodent object-based mnemonic similarity task, and surgically implanted with guide cannulae targeting prelimbic and infralimbic regions of the medial PFC. Prior to mnemonic discrimination tests, rats received PFC infusions of the GABAA agonist muscimol. Analyses of expression of the neuronal activity-dependent immediate-early gene Arc in medial PFC and adjacent cortical regions confirmed muscimol infusions led to neuronal inactivation in the infralimbic and prelimbic cortices. Moreover, muscimol infusions in PFC impaired mnemonic discrimination performance relative to the vehicle control across all testing blocks when lures shared 50-90% feature overlap with the target. Thus, in contrast to prior results from rats given hippocampal muscimol infusions, PFC inactivation impaired target-lure discrimination regardless of the novelty or familiarity of the lures. These findings indicate the PFC plays a critical role in mnemonic similarity task performance, but the time course of PFC involvement is dissociable from that of the hippocampus. Copy rights belong to original authors. Visit the link for more info

Israel confronted Benjamin and demanded they produce the transgressors so they could be slain for their crime, but Benjamin refused throwing Israel into civil war. Israel lost the first two battles (the first two days), but on the third day, Israel nearly wiped out all of Benjamin, leaving a remnant hiding in the rocks of Remmon

While a stranger was sojourning in Gabaa, men came to the door of a house insisting that the owner let him out that they might know him. His concubine was sent out in his stead and the people of the city raped her until morning so that she died. He became so angry he divided her body into twelve parts and sent them throughout all Israel. And each of the twelve tribes came together to decide how to judge the matter.

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.07.22.216200v1?rss=1 Authors: Lodge, M., Hernandez, M.-C., Schulz, J. M., Bischofberger, J. Abstract: GABA can depolarize immature neurons close to the action potential (AP) threshold in development and adult neurogenesis. Nevertheless, GABAergic synapses effectively inhibit AP firing in newborn granule cells of the adult hippocampus as early as 2 weeks post mitosis. The underlying mechanisms are largely unclear. Here we analyzed GABAergic inputs in newborn 2- to 4-week-old hippocampal granule cells mediated by soma-targeting parvalbumin (PV) and dendrite-targeting somatostatin (SOM) interneurons. Surprisingly, both interneuron subtypes activate 5-subunit containing GABAA receptors (5-GABAARs) in young neurons, showing a nonlinear voltage dependence with increasing conductance around the AP threshold. By contrast, in mature cells, PV interneurons mediate linear GABAergic synaptic currents lacking 5-subunits, while SOM-interneurons continue to target nonlinear 5-GABAARs. Computational modelling shows that the voltage-dependent amplification of 5-GABAAR opening in young neurons is crucial for inhibition of AP firing to generate balanced and sparse firing activity, even with depolarized GABA reversal potentials. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.07.05.188821v1?rss=1 Authors: La Terra, D., Petryszyn, S., Rosier, M., Palmer, L. M. Abstract: The thalamus is the gateway to the cortex. Cortical encoding of sensory information can therefore only be understood by considering the influence of thalamic processing on sensory input. Despite modulating sensory processing, little is known about the role of the thalamus during sensory-based behavior, let alone goal-directed behavior. Here, we use two-photon Ca2+ imaging, patch-clamp electrophysiology and optogenetics to investigate the role of axonal projections from the posteromedial nucleus of the thalamus (POm) to the forepaw area of the primary somatosensory cortex (forepaw S1) during sensory processing and goal-directed behavior. We demonstrate that POm axons are active during tactile stimulus and increase activity specifically during the response and, to a lesser extent, reward epochs of a tactile goal-directed task. Furthermore, POm axons in forepaw S1 preferentially signaled correct behavior, with greatest activity during HIT responses. This activity is important for behavioral performance, as photoinhibition of archaerhodopsin-expressing neurons in the POm decreased overall behavioral success. Direct juxtacelluar recordings in the awake state illustrates POm neurons fire sustained action potentials during tactile stimulus. This tactile-evoked POm firing pattern was used during ChR2 photoactivation of POm axons in forepaw S1, revealing that action potentials in layer 2/3 (L2/3) pyramidal neurons are inhibited during sustained POm input. Taken together, POm axonal projections in forepaw S1 encode correct goal-directed active behavior, leading to GABAA-mediated inhibition of L2/3 pyramidal neurons. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.06.29.178160v1?rss=1 Authors: Rahmati, N., Normoyle, K. P., Glykys, J., Dzhala, V. I., Lillis, K. P., Kahle, K. T., Raiyyani, R., Jacob, T., Staley, K. J. Abstract: Developmental, cellular, and subcellular variations in the direction of neuronal Cl- currents elicited by GABAA receptor activation have been frequently reported, and we found a corresponding variance in the reversal potential (EGABA) for individual interneurons synapsing on a single pyramidal cell. These findings suggest a corresponding variance in the cytoplasmic concentration of Cl- ([Cl-i]). We determined [Cl-]i by: 1) two-photon imaging of the Cl- sensitive, ratiometric fluorescent protein SuperClomeleon (sCLM); 2) Fluorescence Lifetime IMaging (FLIM) of the Cl- sensitive fluorophore MEQ; and 3) electrophysiological measurements of EGABA. These methods collectively demonstrated stable [Cl-]i microdomains in individual neurons in vivo. Fluorometric and electrophysiological estimates of local [Cl-]i were highly correlated. [Cl-]i microdomains persisted after pharmacological inhibition of cation-chloride cotransporters (CCCs) but steadily decreased after inhibiting the polymerization of the anionic macromolecule actin. These studies highlight the existence of functionally significant neuronal Cl- microdomains that modify the impact of GABAergic inputs. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.06.29.176974v1?rss=1 Authors: Vinner, E., Matzner, A., Belelovsky, K., Bar-Gad, I. Abstract: Motor tics, the hallmark of Tourette syndrome, are modulated by different behavioral and environmental factors. A major modulating factor is the sleep-wake cycle in which tics are attenuated to a large extent during sleep. This study investigates the neural mechanisms underlying tic reduction during sleep in an animal model of chronic tic disorders. We recorded the neuronal activity during spontaneous sleep-wake cycles throughout continuous GABAA antagonist infusion into the striatum. Analysis of video streams and concurrent kinematic assessments indicated tic reduction during sleep in both frequency and intensity. Extracellular recordings in the striatum revealed a dissociation between motor tic expression and their macro-level neural correlates (LFP spikes) during the sleep-wake cycle. LFP spikes persisted during tic-free sleep and did not change their properties despite the reduced behavioral expression. Local, micro-level, activity near the infusion site was phase-locked to the LFP spikes during wakefulness but this locking decreased significantly during sleep. These results suggest that while LFP spikes, which are generated as a result of abnormal and focal disinhibition in the striatum, encode motor tic feasibility, the behavioral expression of tics requires local striatal neural activity entrained to the LFP spikes, leading to the propagation of the activity to downstream targets and consequently their motor expression. These findings point to a possible mechanism for the modulation of tic expression in TS patients during sleep and potentially during other behavioral states. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.06.16.155077v1?rss=1 Authors: Bird, C. W., Chavez, G. J., Barber, M. J., Valenzuela, C. F. Abstract: Prenatal ethanol exposure causes a variety of cognitive deficits that have a persistent impact on quality of life, some of which may be explained by ethanol-induced alterations in interneuron function. Studies from several laboratories, including our own, have demonstrated that a single binge-like ethanol exposure during the third-trimester equivalent of human pregnancy leads to acute apoptosis and long-term loss of interneurons in the rodent retrosplenial cortex (RSC). The RSC is interconnected with the hippocampus, thalamus, and other neocortical regions and plays distinct roles in visuospatial processing and storage and retrieval of hippocampal-dependent episodic memories. Here we used slice electrophysiology to characterize the acute effects of ethanol on GABAergic neurotransmission in neonates, as well as the long-term effects of neonatal ethanol exposure on parvalbumin-interneuron mediated neurotransmission in adolescent mice. Mice were exposed to ethanol using vapor inhalation chambers. In postnatal day (P) 7 mouse pups, ethanol unexpectedly failed to potentiate GABAA receptor-mediated synaptic transmission. Binge-like ethanol exposure of P7 mice expressing channel rhodopsin in parvalbumin-positive interneurons enhanced the peak amplitudes, total charge, decays, and decreased rise-times of optically-evoked GABAA receptor-mediated inhibitory postsynaptic currents in adolescent animals. These effects could partially explain learning and memory deficits caused by developmental ethanol exposure. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.06.15.152652v1?rss=1 Authors: Sylantyev, S., Savtchenko, L. P., O'Neill, N., Rusakov, D. A. Abstract: Coincidence detection of excitatory inputs by principal neurons underpins the rules of signal integration and Hebbian plasticity in the brain. In the hippocampal circuitry, detection fidelity is thought to depend on the GABAergic synaptic input through a feed-forward inhibitory circuit also involving the hyperpolarization-activated Ih current. However, afferent connections often bypass feed-forward circuitry, suggesting that a different GABAergic mechanism might control coincidence detection in such cases. To test whether fluctuations in the extracellular GABA concentration [GABA] could play a regulatory role here, we use a GABA 'sniffer' patch in acute hippocampal slices of the rat and document strong dependence of [GABA] on network activity. We find that blocking GABAergic signalling strongly reduces the coincidence detection window of direct excitatory inputs to pyramidal cells whereas increasing [GABA] through GABA uptake blockade expands it. The underlying mechanism involves membrane-shunting tonic GABAA receptor current; it does not have to rely on Ih but depends strongly on the neuronal GABA transporter GAT-1. We use dendrite-soma dual patch-clamp recordings to show that the strong effect of membrane shunting on coincidence detection relies on nonlinear amplification of changes in the decay of dendritic synaptic currents when they reach the soma. Our results suggest that, by dynamically regulating extracellular GABA, brain network activity can optimise signal integration rules in local excitatory circuits. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.06.06.137844v1?rss=1 Authors: Bernstein, H. L., Lu, Y.-L., Botterill, J. J., Duffy, A. M., LaFrancois, J. J., Scharfman, H. E. Abstract: Glutamatergic dentate gyrus (DG) mossy cells (MCs) innervate the primary cell type, granule cells (GCs), and GABAergic neurons which inhibit GCs. Prior studies suggest that the net effect of MCs is mainly to inhibit GCs, leading one to question why direct excitation of GCs is often missed. We hypothesized that MCs do have excitatory effects, but each GC is only excited weakly, at least under most experimental conditions. To address this hypothesis, MC axons were stimulated optogenetically in slices. A brief optogenetic stimulus to MC axons in the inner molecular layer (IML) led to a short-latency field EPSP (fEPSP) in the IML, suggesting there was a direct excitatory effect on GCs. Population spikes were negligible however, consistent with weak excitation. FEPSPs reflected AMPA/NMDA receptor-mediated EPSPs in GCs. EPSPs reached threshold after GC depolarization or facilitating NMDA receptors. GABAA and GABAB receptor-mediated IPSPs often followed EPSPs. At the network level, an optogenetic stimulus led to a brief, small facilitation of the PP-evoked population spike followed by a longer, greater inhibition. These data are consistent with rapid and selective GC firing by MCs (MC [->] GC) and disynaptic inhibition (MC [->] GABAergic neuron [->] GC). Notably, optogenetic excitation was evoked for both dorsal and ventral MCs, ipsilateral and contralateral MC axons, and two Cre lines. Together the results suggest a way to reconcile past studies and provide new insight into the balance of excitation and inhibition of GCs by MCs. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.06.02.128900v1?rss=1 Authors: Field, M., Thomas, P., Smart, T. Abstract: GABAA receptors (GABAARs) are pentameric ligand-gated ion channels distributed throughout the brain where they mediate synaptic and tonic inhibition. Following activation, these receptors undergo desensitization which involves entry into long-lived agonist-bound closed states. Although the kinetic effects of this state are recognised and its structural basis has been uncovered, the physiological impact of desensitization on inhibitory neurotransmission remains unknown. Here we describe an enduring new form of long-term potentiation at inhibitory synapses that elevates synaptic current amplitude for 24 hrs following desensitization of GABAARs in response to prolonged agonist exposure or allosteric modulation. Using receptor mutants and allosteric modulators we demonstrate that desensitization of GABAARs facilitates their phosphorylation by PKC, which increases the number of receptors at inhibitory synapses. These observations provide a new physiological relevance to the desensitized state of GABAARs, acting as a signal to regulate the efficacy of inhibitory synapses during prolonged periods of inhibitory neurotransmission. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.05.29.123034v1?rss=1 Authors: Schmerl, B., Gimber, N., Kuropka, B., Rentsch, J., Kunde, S.-A., Ewers, H., Freund, C., Schmoranzer, J., Rademacher, N., Shoichet, S. A. Abstract: Recent advances in imaging technology have highlighted that scaffold proteins and receptors are arranged in sub-synaptic nanodomains. The synaptic MAGUK scaffold protein MPP2 is a component of AMPA receptor-associated protein complexes and also binds to the synaptic cell adhesion molecule SynCAM1. Using super-resolution imaging, we now show that MPP2 and SynCAM1 are situated at the periphery of the postsynaptic density. In order to explore MPP2-associated protein complexes, we used a quantitative comparative mass spectrometry approach and identified multiple GABAA receptor subunits among the novel synaptic MPP2 interactors. We further show that GABAA receptors are found together with MPP2 in a subset of dendritic spines and thus highlight MPP2 as a scaffold molecule capable of acting as an adaptor molecule that links peripheral synaptic elements critical for inhibitory regulation to central structures at the PSD of glutamatergic synapses. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.05.25.114389v1?rss=1 Authors: Liu, J.-J., Tsien, R. W., Pang, Z. P. Abstract: Neuropeptide melanin-concentrating hormone (MCH) plays important roles in the brain including control of energy homeostasis, sleep, learning and memory. However, the synaptic and circuitry mechanisms underlying MCH-mediated regulations remain largely unknown. Here, we uncover that MCH modulates the hippocampo (HP)-dorsal lateral septum (dLS)-lateral hypothalamus neural circuit to facilitate spatial learning and memory. MCH achieves this function by enhancing both excitatory and inhibitory synaptic transmission via presynaptic mechanisms. The dLS neuronal spiking activity in response to HP CA3 excitatory inputs is strongly controlled by feed-forward inhibition (FFI) mediated by both GABAA and GABAB receptors. Endogenous MCH signaling enhances Signal/Noise (S/N) ratio of dLS neurons by increase the excitatory strengths, meanwhile decrease the overall dLS excitability by enhance inhibition which reduces dLS FFI, and consequentially enables dLS neurons to fire with high fidelity with HP synaptic inputs. Our data unravel the multifaceted synaptic mechanisms of MCH in the defined HP-dLS circuitry which may contribute to learning and memory. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.05.22.109413v1?rss=1 Authors: Rajkumar, R., Regio Brambilla, C., Veselinovic, T., Bierbrier, J., Wyss, C., Ramkiran, S., Orth, L., Lang, M., Rota Kops, E., Mauler, J., Scheins, J., Neumaier, B., Ermert, J., Herzog, H., Langen, K.-J., Binkofski, F. C., Lerche, C., Shah, N. J., Neuner, I. Abstract: The symbiosis of neuronal activities and glucose energy metabolism is reflected in the generation of functional magnetic resonance imaging (fMRI) and electroencephalography (EEG) signals. However, their association with the balance between neuronal excitation and inhibition (E/I-B), which is closely related to the activities of glutamate and GABA ({gamma} -aminobutyric acid) and the receptor availability (RA) of GABAA and mGluR5, remains unexplored. This study investigates these associations during the resting state (RS) condition using simultaneously recorded PET/MR/EEG (trimodal) data. Glucose metabolism and neuroreceptor binding availability (non-displaceable binding potential (BPND)) of GABAA and mGluR5 were found to be significantly higher and closely linked within core resting-state networks (RSNs). The neuronal generators of EEG microstates and the fMRI measures were most tightly associated with the BPND of GABAA relative to mGluR5 BPND and the glucose metabolism, emphasising a predominance of inhibitory processes within in the core RSNs at rest. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.05.10.087114v1?rss=1 Authors: Zhang, C.-Q., Catron, M. A., Ding, L., Hanna, C. M., Gallagher, M. J., Macdondald, R. L., Zhou, C. Abstract: Idiopathic generalized epilepsy(IGE) patients have genetic causes and their seizure onset mechanisms particularly during sleep remain elusive. Here we proposed that sleep-like slow-wave oscillations(0.5 Hz SWOs) potentiated excitatory or inhibitory synaptic currents in layer V cortical pyramidal neurons from wild-type(wt) mouse ex vivo brain slices. In contrast, SWOs potentiated excitatory, not inhibitory, currents in cortical neurons from heterozygous(het) knock-in(KI) IGE mice(GABAA receptor lower case Greek gamma2 subunit Gabrg2Q390X mutation), creating an imbalance between evoked excitatory and inhibitory currents to effectively prompt neuronal action potentials. Similarly, more physiologically similar up/down-state(present during slow-wave sleep) induction in cortical neurons could potentiate excitatory synaptic currents within slices from wt/het Gabrg2Q390X KI mice. Consequently, SWOs or up/down-state induction in vivo (using optogenetic method) could trigger epileptic spike-wave discharges(SWDs) in het Gabrg2Q390X KI mice. To our knowledge, this is the first operative mechanism to explain why epileptic SWDs preferentially happen during non-REM sleep or quiet-wakefulness in human IGE patients. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.05.11.087726v1?rss=1 Authors: Shaw, A. D., Chandler, H. L., Hamandi, K., Muthukumaraswamy, S. D., Hammers, A., Singh, K. D. Abstract: The non-invasive study of cortical oscillations provides a window onto neuronal processing. Temporal correlation of these oscillations between distinct anatomical regions is considered a marker of functional connectedness. As the most abundant inhibitory neurotransmitter in the mammalian brain, {gamma}-aminobutyric acid (GABA) is thought to play a crucial role in shaping the frequency and amplitude of oscillations, which thereby suggests a further role for GABA in shaping the topography of functional connectivity. This study explored the effects of pharmacologically blocking the reuptake of GABA (increasing local concentrations and availability) through oral administration of the GAT1-blocker tiagabine (15 mg). We show that the spatial distribution of connectivity effects corresponds to template maps of flumazenil PET maps of GABAA receptor distribution. In a placebo-controlled crossover design, we collected resting MEG recordings from 15 healthy male individuals prior to, and at 1-, 3- and 5- hours post, administration of tiagabine and placebo pill. Using amplitude envelope correlations (AECs) we quantified the functional connectivity in discrete frequency bands across the whole brain, using the 90-region Automatic Anatomical Labelling atlas (AAL90), as well as quantifying the average oscillatory activity at each region. Analysis of variance in connectivity using a drug-by-time (2x4) design revealed interaction effects, accompanied by main effects of drug and time. Post-hoc permutation testing of each post-drug recording against the respective pre-drug baseline revealed consistent reductions of a bilateral occipital network spanning theta, alpha and beta frequencies, and across 1- 3- and 5- hour recordings following tiagabine, but not placebo. The same analysis applied to the activity of each region also revealed a significant interaction, with post-hoc permutation testing signalling significant reductions in activity in middle occipital regions across delta, theta, alpha and beta frequency bands. Crucially, we show that the spatial distribution of both connectivity and activity changes with tiagabine overlaps significantly with template quantitative GABAA maps derived from flumazenil volume-of-distribution (FMZ-VT) PET, clearly demonstrating a mechanistic link between GABA availability, GABAA receptor distribution and low-frequency network oscillations. We therefore propose a utility for functional connectivity and activity measures as receptor-mapping tools in pharmacological imaging. Copy rights belong to original authors. Visit the link for more info

Greg Kirschen takes us through the treatment of postpartum depression and psychosis. feedback@obgyn.fm American Psychiatric Association. (2013). In Diagnostic and statistical manual of mental disorders (5th ed.). doi:10.1176/appi.books.9780890425596.744053 Tate G. 1830. “A Treatise on Hysteria.” London: S. Highley, 174 Fleet St & Webb St, Maze Pond, Borough. Smith TN. 1830. “Observations on hysteria.” The Boston Medical and Surgical Journal. 3(34): 540. Louden, I. 1988. Puerperal insanity in the 19thCentury. Journal of the Royal Society of Medicine. 81, p 76-79. Griffen W, Griffen D. 1829. Observations on Functional Disorders of the Spinal Cord, and Their Connexion with Hysterical, Nervous, and Other Diseases. Illustrated by Cases, Selected Chiefly from the Reports of the Pallas, Kenry, and Currah Dispensaries. London Medical and Physical Journal. 7(42) 477-489. Reid, J. 1848. Dr. Reid on Puerperal Insanity. Journal of Psychological and Medical Mental Pathology. 1(1): 128-151. Clark AC. 1887. Aetiology, Pathology, and Treatment of Puerperal Insanity. Journal of Mental Science. 33(142): 169-189. Donkin, AS. 1863. The Pathological Relation between Albuminuria and Puerperal Mania. Journal of Mental Science. 9(47): 401-405. Barkin V. 1929. Protein therapy in insanity of puerperal origin. British Medical Journal. 1(3549): 67. Earle P. 1854. Bloodletting in Mental Disorders. American Journal of Insanity. 10(4): 287-405. Mackenzie FW. 1851. Puerperal Insanity: Especially in Reference to Anaemia. London Journal of Medicine. 3(30): 504-521. Gordon HL. 1897. Sir James Young Simpson and Chloroform (1811-1870). Masters of Medicine. T. Fisher Unwin, for Great Britain and Longmans Green & Co. for the United States of America. Dunn, PM. 2002. Sir James Young Simpson (1811-1870) and obstetric anesthesia. Archives of Disease in Childhood-Fetal and Neonatal edition. 86(3): F207-F209. Koppanyi T, Dille JM, Linegar CR. 1936. Studies on Barbiturates: XVII. The Effect of Prolonged Chloroform Anesthesia on the Duration of Action of Barbiturates. The Journal of Pharmacology and Experimental Therapeutics. 119-127. Waters ATH. 1857. On the use of chloroform in the treatment of puerperal insanity. American Journal of Psychiatry. 13(4): 341-353. Ramachandran CT, Subramanyam N, Baker G, et al. 2011. Antidepressants: From MAOIs to SSRIs and more. Indian Journal of Psychiatry. 53(2): 180-182. Agin HV. 1963. Phenelzine in the treatment of depression. American Journal of Psychiatry. 119(12): 1173-1174. Blacker KH, Weinstein BJ, Ellman GL. 1962. Mother’s Milk and Chlorpromazine. 119(2): 178-179. Whalley LJ, Eagles JM, Bowler GMR, et al. 1987. Selective effects of ECT on hypothalamic-pituitary activity. Psychological Medicine. 17(2): 319-328. Williams RL, Barrera SE. 1950. Observations and opinions concerning complications and contraindications in electric convulsive therapy. Psychiatric Quarterly. 24(4): 800-809. Matthew JR, Constan E. 1964. Complications following ECT over a three year period in a state institution. American Journal of Psychiatry. 120(11)-1119-1120.  Sobel DE. 1960. Fetal Damage Due to ECT, Insulin Coma, Chlorpromazine, or Reserpine. AMA Archives of General Psychiatry. 2(6): 606-611. Langan RC, Goodbred AJ. 2016. Identification and Management of Peripartum Depression.American Family Physician. 93(10): 852-858.  Information from your family doctor: Postpartum depression. 2010. American Family Physician. 82(8): 939-940. Schiller CE, Schmidt PJ, Rubinow D. 2014. Allopregnanolone as a Mediator of Affective Switching in Reproductive Mood Disorders. Psychopharmacology. 231(17): 3557-3567. Bitran D, Hilvers RJ, Kellogg CK. 1991.Anxiolytic effects of 3α-hydroxy-5α[β]-pregnan-20-one:endogenous metabolites of progesterone that are active at the GABAA receptor. Brain Research. 561:157–161. Ottander U, Poromaa IS, Bjurulf E, et al. 2005. Allopregnanolone and pregnanolone are produced by the human corpus luteum. Molecular and Cellular Endocrinology. 239(1-2): 37-44. Meltzer-Brody S, Colquhoun H. Reisenberg R, et al. 2018. Brexanolone injection in post-partum depression: two multicentre, double-blind, randomised, placebo-controlled, phase 3 trials. The Lancet. 392(10152): 1058-1070.

Hay una historia horrible en el capítulo 19 de Jueces. Un levita, que vivía en un lugar remoto de Efraín tomó como concubina una mujer de Belén. Esta, por motivos que el texto no especifica, lo dejó y se volvió a casa de su padre a Belén. Este hombre levita salió a buscarla, y el padre de esta lo recibió con alegría y lo acogió unos días. Cuando por fin llegó el momento de marcharse, iniciaron su viaje un poco tarde, así que tuvieron que parar a hacer noche. Eligieron la ciudad israelita de Gabaa, en el territorio de Benjamín, pensando que así estarían más seguros. Ya de noche, nos narra el texto que los hombres del pueblo llegaron a la puerta de la casa donde estaban alojados, e insistían en que saliera el levita que estaba hospedado ahí para conocerlo. Estos hombres, nos da a entender el texto, querían abusar sexualmente del viajero. Este tipo de actividad vimos que se practicaba en Sodoma y Gomorra, donde algo similar ocurrió a los mensajeros que fueron a casa de Lot. Tal abominación estaba ocurriendo en las ciudades del pueblo de Dios. Este hombre levita, al ver la violencia e intenciones claras de estos hombres de Gabaa, les echó a su concubina, aquella a por la cual había venido a buscar amorosamente. ¿Cómo es posible? Me pregunto yo. ¿Qué tipo de hombre se defiende exponiendo a su amada?Estos hombres de Gabaa abusaron de ella de tal modo que a la madrugada ya, el levita abrió la puerta y la encontró ahí sin vida. La tomó, se fue a su casa, y denunció el horrendo crimen enviando partes de la víctima a cada tribu de Israel. Nos dice el texto en Jueces 20 que “Entonces todo el pueblo, como un solo hombre, se levantó, y dijeron: Ninguno de nosotros irá a su tienda, ni volverá ninguno de nosotros a su casa.”Las tribus indignadas, se levantaron a una para confrontar a la tribu de Benjamín y pedirles que les entregaran a los hombres que habían cometido tal aberración.Dice el texto: “se juntaron todos los hombres de Israel contra la ciudad, ligados como un solo hombre. Y las tribus de Israel enviaron varones por toda la tribu de Benjamín, diciendo: ¿Qué maldad es esta que ha sido hecha entre vosotros? Entregad, pues, ahora a aquellos hombres perversos que están en Gabaa”Pero Jueces 20:13 nos narra la triste reacción: “Mas los de Benjamín no quisieron oír la voz de sus hermanos los hijos de Israel,”Como los de Benjamín no trataron el problema, las otras tribus se unieron contra ellos. Esta fue la gota que colmó el vaso. Este fue el suceso que los de Israel no pudieron consentir. Cuando observo lo que está ocurriendo en la sociedad presente, me pregunto, como el salmista preguntaba: ¿Hasta cuándo, oh Señor?¿Cuán lejos hemos de llegar para calificar algo como “demasiado malo para consentir”? ¿Cuánta inmoralidad se puede permitir? ¿Cuánta violencia? ¿Cuánta injusticia? ¿Qué tendría que ocurrir para que la sociedad respondiera unánime contra la maldad en el mundo?Creo que se esperamos un suceso tan horrendo contra el cual todos respondan para demandar justicia y santidad, puede que tenga que ocurrir algo muy gordo. Pienso en la historia reciente, los genocidios, las guerras, los ataques terroristas, los millones de niños muertos, etc. ¿Tan lejos hay que llegar? La decadencia de la sociedad no ha tocado fondo. Pero ¿qué tal si lo pensamos a modo más reducido? Quizás lo podemos considerar individualmente. ¿Cuánto consiento yo en mi vida antes de darme cuenta de que estoy haciendo mal y que tengo que rectificar? ¿Hasta donde estoy dispuesta a llegar en el camino que me aleja de la santidad que Dios quiere de mí? ¿Consiento pecados que al compararme con otros parecen insignificantes? Quizás deba parar y compararme con la santidad de Dios, y no consentir pensamientos, actitudes ni actividades en mi vida que Dios considera impuros. “El salmista pedía: Examíname, oh Dios, y conoce mi corazón;
Pruébame y conoce mis pensamientos;Y ve si hay en mí camino de perversidad,
Y guíame en el camino eterno.”Salmo 139: 23-24Si nos juzgamos a nosotras mismas, y pedimos al Señor que nos examine y nos muestre aquellas cosas que debemos cambiar, no tendremos que preocuparnos por la gota que colmará el vaso. Mucho mejor disfrutar el ser llenas del Espíritu de Dios, porque la Palabra nos dice que contra la abundancia del fruto del Espíritu no hay ley.” (Gálatas 5:23-25)

In dieser 3. Podcast-Folge zum Thema Schlaf spricht Prof. Dr. med. Harald Schmidt über Schlafmittel. Da das Thema doch recht umfangreich ist geht es heute um die chemischen Substanzen und das große Problem von 2 Millionen Schlafmittelabhängigen in Deutschland In einer weiteren Folge um die Pflanzlichen. Der neueste Stand der Medizin, Evidenz-basiert und direkt umsetzbare praktische Impulse warten auf Sie. //   Vorbemerkungen //  Wann? //  Ich sag’s gleich, wie auch schon in der letzten Folge zur Schlafhygiene, ich bin kein Freund von Schlafmitteln. Ausnahmen sind zwei nachvollziehbare Gründe: Jetlag ein emotional stark bewegendes/belastenden Erlebnis. //   Wann nicht //  Schlaftabletten zu verwenden, um z.B. trotz der Nervosität vor einer Prüfung schlafen zu können, ist hingegen keine gute Idee. Fast alle Schlafmittel können bis in den Tag hineinwirken und die körperliche und geistige Leistungsfähigkeit stark einschränken. //   Abhängigkeit //  Schlafmittel sind in aller Regel nicht für die Selbstbehandlung geeignet. Das gilt vor allem für verschreibungspflichtige Schlafmittel wie Benzodiazepine, die schnell eine Abhängigkeit verursachen können. Sie können dann nicht mehr ohne Schlafmittel schlafen. Die Schlafmittel-Abhängigkeit wird zur Ursache Ihrer Schlafstörung oder Sie haben nun zwei Schlafstörungen. Aber auch nicht verschreibungspflichtige, aber apothekenpflichtige chemische sowie pflanzliche Schlafmittel können zumindest psychisch abhängig machen. Etwa die Hälfte der Benutzer von Schlafmitteln entwickelt nach Angaben der Deutschen Hauptstelle für Suchtgefahren eine Schlafmittel-Abhängigkeit. Das sind allein in Deutschland 400.000 Schlafmittel-Süchtige jedes Jahr. Insgesamt gelten etwa 2 Millionen Menschen als abhängig von Schlafmitteln. Etwa die Hälfte dieser Menschen konsumiert die häufig verschriebenen Benzodiazepine. Als besonders anfällig für Medikamentensucht und Schlafmittelmissbrauch gelten Frauen. Zahlreiche Studien legen nahe, dass Schlafmittel die Lebenserwartung deutlich verkürzen können. //   Nur kurzfristig! //  Schlafmittel sind nicht für den langfristigen Einsatz gedacht. Ohne ärztliche Weisung sollten Sie Schlafmittel nie länger als eine Woche anwenden. Sollte Ihr Arzt immer wieder ohne Nachfragen Schlafmittel-Rezepte ohne besondere Diagnose ausstellen, wenden Sie sich am besten an einen anderen Arzt, um ihre Schlafstörungen besser zu behandeln und wenden Sie die Tipps meiner vorherigen Podcast-Folge “Endlich besser schlafen” an. //   Das ideale Schlafmittel... //  … gibt es nicht. Es müsste einen Schlaf bewirken, der sich vom natürlichen Schlaf in nichts unterscheidet. Alle heute verwendeten Mittel verändern jedoch die Schlafstadien und die messbaren Hirnströme. GABAA //  Die meisten Schlafmittel wirken über einen Ionenkanal der durch den Neurotransmitter γ-Aminobuttersäure reguliert wird. γ-Aminobuttersäure = GABA und hiervon der Typ A also GABAA. Schlafmittel binden entweder an GABA Bindungsstelle oder an eine eigene. Dadurch kommt es zum Einstrom negativer Cl Ionen. Da Nervenzellen durch den Einstrom positiver Ionen aktiviert werden, hemmt dies also die Nervenzellen. GABAA. Ist dabei der wichtigste hemmende Rezeptor im zentralen Nervensystem. Dadurch wird zwar Schlaf induziert, aber auf Kosten des erholsamen REM- und Tiefschlafs. Nach Absetzen vieler Schlafmittel gibt es zunächst einen überschießenden REM-Schlaf während sich der Tiefschlaf nur langsam erholt. Übrigens, auch Alkohol bindet an diesen GABAA-Rezeptor wodurch sich dessen sedierende Wirkung erklärt; aber ich erwähnte unter Schlafstörungen dass Alkohol ein denkbar ungeeigneter Schlafförderer ist, da dessen Metabolite während der Nacht den Schlaf stören und Durchschlafen verhindern. //   Verschreibungspflichtige chemische Arzneimittel: //   Barbiturate  //  Nicht mehr als Schlafmittel,...

On this episode of the Healthy Wealthy and Smart Podcast, Dr. Cheryl Keller Capone joins me to discuss how she navigated her experience with chronic pain. Dr. Cheryl Keller Capone is an Associate Research Professor in Center for Comparative Genomics and Bioinformatics and Department of Biochemistry and Molecular Biology at Penn State University. She is currently using genomics and DNA sequencing technologies to study blood cell development with an overall research goal of understanding gene regulation in mammals. In total, she has over 23 years of scientific research experience in several different fields, including muscle development, neuroscience, and mitochondrial DNA forensics. She is also a certified personal trainer through the National Academy of Sports Medicine, and a recreational triathlete. In this episode, we discuss: -Cheryl’s long journey with chronic pain -The catalyst for Cheryl’s road to recovery -Implementing the biopsychosocial model and functional movement to combat persistent pain -Empowering advice for those experiencing persistent pain -And so much more!   Cheryl advises practitioners to remain humble about their ability to diagnosis and treat patients who suffer from persistent pain. From her experience, she states, “I wasn’t expecting any sort of specific diagnoses. In fact, I was very frustrated by the fact that individual providers were focusing on one thing or another and trying to pin it down to one particular structural cause.” After many disappointments, Dr. Keller Capone was exposed to a practitioner who effectively communicated his humility and willingness to try different treatments and she found that, “This was a very refreshing response to me.”   To those who are suffering from chronic pain, Cheryl recommends participating in activities you find joyful and meaningful. She found that making small improvements in these activities helped prove to herself that, “This is not permanent, changes can be made. It helped me with hope.”   The most empowering belief system that helped guide Cheryl was one of self-ownership, she stressed to herself, “I was going to have to own this. I was going to have to own my pain and own my recovery and be responsible.”   With persistent pain, it is important to remember that while the journey may have ups and downs, there are no barriers to your recovery. Cheryl advises, “There is most likely a path forward for everyone… Take ownership of your own path.”   For more information on Cheryl: Dr. Cheryl Keller Capone received her Ph.D. in Biochemistry and Molecular Biology from Penn State University in 1999. Her graduate research focused on muscle development and differentiation, and during this time was awarded the Paul Berg Prize in Molecular Biology, the Roberts Graduate Fellowship, and the Frederick J. Wedler Outstanding Doctoral Dissertation Award. After graduate school, she transitioned to the field of neuroscience where she studied the molecular biology of GABAA receptors in mammals, followed by a year in industry where she worked in the field of mitochondrial DNA forensics. In 2009, Cheryl returned to Penn State University, and is currently studying blood cell development with an overall research goal of understanding molecular mechanisms of gene regulation in mammals. She also has extensive experience in genomic technologies and methodologies, including DNA sequencing and data analysis. Outside of the lab, Cheryl is also a former collegiate runner, who became interested in strength training and movement following a long injury history and many years of chronic pain. This experience led to her interest in pain science as well as a certification as a personal trainer through the National Academy of Sports Medicine. When not in the lab or working with clients, Cheryl enjoys strength training, running, hiking, swimming, cycling and spending time with her husband and son in State College, PA.   Resources discussed on this show: Dr. Cheryl Keller Capone Twitter Dr. Cheryl Keller Capone Instagram Dr. Cheryl Keller Capone LinkedIn Dr. Cheryl Keller Capone Facebook Dr. Cheryl Keller Capone Blog   Thanks for listening and subscribing to the podcast! Make sure to connect with me on twitter, instagram and facebook to stay updated on all of the latest! Show your support for the show by leaving a rating and review on iTunes!   Have a great week and stay Healthy Wealthy and Smart!   Xo Karen    

hno. Sebastian Zamudio 1 Samuel 11Reina-Valera 1960 (RVR1960) Saúl derrota a los amonitas 11 Después subió Nahas amonita, y acampó contra Jabes de Galaad. Y todos los de Jabes dijeron a Nahas: Haz alianza con nosotros, y te serviremos. 2 Y Nahas amonita les respondió: Con esta condición haré alianza con vosotros, que a cada uno de todos vosotros saque el ojo derecho, y ponga esta afrenta sobre todo Israel. 3 Entonces los ancianos de Jabes le dijeron: Danos siete días, para que enviemos mensajeros por todo el territorio de Israel; y si no hay nadie que nos defienda, saldremos a ti. 4 Llegando los mensajeros a Gabaa de Saúl, dijeron estas palabras en oídos del pueblo; y todo el pueblo alzó su voz y lloró. 5 Y he aquí Saúl que venía del campo, tras los bueyes; y dijo Saúl: ¿Qué tiene el pueblo, que llora? Y le contaron las palabras de los hombres de Jabes. 6 Al oír Saúl estas palabras, el Espíritu de Dios vino sobre él con poder; y él se encendió en ira en gran manera. 7 Y tomando un par de bueyes, los cortó en trozos y los envió por todo el territorio de Israel por medio de mensajeros, diciendo: Así se hará con los bueyes del que no saliere en pos de Saúl y en pos de Samuel. Y cayó temor de Jehová sobre el pueblo, y salieron como un solo hombre. 8 Y los contó en Bezec; y fueron los hijos de Israel trescientos mil, y treinta mil los hombres de Judá. 9 Y respondieron a los mensajeros que habían venido: Así diréis a los de Jabes de Galaad: Mañana al calentar el sol, seréis librados. Y vinieron los mensajeros y lo anunciaron a los de Jabes, los cuales se alegraron. 10 Y los de Jabes dijeron a los enemigos: Mañana saldremos a vosotros, para que hagáis con nosotros todo lo que bien os pareciere. 11 Aconteció que al día siguiente dispuso Saúl al pueblo en tres compañías, y entraron en medio del campamento a la vigilia de la mañana, e hirieron a los amonitas hasta que el día calentó; y los que quedaron fueron dispersos, de tal manera que no quedaron dos de ellos juntos. 12 El pueblo entonces dijo a Samuel: ¿Quiénes son los que decían: ¿Ha de reinar Saúl sobre nosotros? Dadnos esos hombres, y los mataremos. 13 Y Saúl dijo: No morirá hoy ninguno, porque hoy Jehová ha dado salvación en Israel. 14 Mas Samuel dijo al pueblo: Venid, vamos a Gilgal para que renovemos allí el reino. 15 Y fue todo el pueblo a Gilgal, e invistieron allí a Saúl por rey delante de Jehová en Gilgal. Y sacrificaron allí ofrendas de paz delante de Jehová, y se alegraron mucho allí Saúl y todos los de Israel.

In dieser Arbeit wurde mittels einer fokal applizierten Penicillin-Lösung in den Subregionen CA1 und CA3 des Hippocampus eine lokale Hemmung der GABAA-vermittelten Inhibition zur Erzeugung begrenzter epileptischer Herde vorgenommen. Anhand der konventionellen Ableitung von Feldpotentialen sowie des optischen Registrierverfahrens mit Hilfe von spannungssensitiven Farbstoffen wurde die räumlich-zeitliche Erregungsausbreitung innerhalb der Nervenzellverbände analysiert. Die Erfassung der Erregungszustände definierter Neuronenpopulationen ergab, dass beim Auftreten epileptischer Aktivität nicht unbedingt eine gleichzeitige Depolarisation aller Neuronen innerhalb einer Population vorliegt. Weiterhin können ähnlich aussehende Feldpotentiale mit einem unterschiedlichen Ausmaß der neuronalen Depolarisation einhergehen. Außerdem unterliegt das Synchronisierungsverhalten der Nervenzellen bei epileptischen Entladungen vielfältigen Aktivitätsmustern.

1) Clinical and serological characterization of the antibodies to GABAA receptor a1 and y2 subunits and 2) Topic of the month: Stroke in systemic disease. This podcast for the Neurology Journal begins and closes with Dr. Robert Gross, Editor-in-Chief, briefly discussing highlighted articles from the print issue of Neurology. In the second segment Dr. Lara Marcuse interviews Dr. Angela Vincent about her paper on the clinical and serological characterization of the antibodies to GABAA receptor a1 and y2 subunits. Dr. James Addington is reading our e-Pearl of the week about navigating painful neuropathies. In the next part of the podcast Dr. Michelle Johansen interviews Dr. Steve Zeiler about the topic of stroke in the setting of CNS vasculitis. The participants had nothing to disclose except Drs. Vincent, Addington, Johansen and Zeiler.Dr. Vincent serves on the advisory editorial board Journal of Neurology; holds patent with Oxford University for LGI1/CASPR2 antibodies, licensed to Euroimmun AG, and for GABAAR antibodies, in negotiation with Euroimmun AG; was a consultant with Athena Diagnostics; occasional small honoraria, travel and speaker honoraria from Baxter International Inc. and Biogen Idec; receives royalties from Athena Diagnostics (MuSK assays), from Euroimmun AG (LGI1 and CASPR2 assays) Clinical Neuroimmunology (Blackwell Publishing, 2005) and Inflammatory and Autoimmune Disorders of the Nervous System in Children (Mac Keith Press 2010); and receives research support from the NIH.Dr. Addington serves on the editorial team for the Neurology® Resident and Fellow Section. Dr. Johansen serves as a scientific advisory member of Stroke and as a contributor to Blogging Stroke.Dr. Zeiler receives research support from Johns Hopkins Neurology and NIH; has provided expert legal testimony in 2013 and 2014.

The chloride concentration in neurons is in general established by the precise functional expression of the sodium-potassium-chloride cotransporter one (NKCC1) and the potassium-chloride cotransporter two (KCC2). NKCC1 raises the intracellular chloride concentration, while KCC2 extrudes chloride. The intracellular chloride concentration determines the strength and direction of γ-aminobutyric acid (GABA) receptor-mediated transmission. In general, the intracellular chloride concentration in neurons is low and causes GABA-mediated inhibition. However, the intracellular chloride concentration in immature neurons is high leading to GABAergic depolarization, which can cause excitation. The effects of excitatory GABA signaling in early development is still unclear. It has been speculated that excitatory GABA, causing general depolarization in neurons, has profound effects on neuronal activity and neuronal maturation. Therefore, I studied in collaboration with Carsten Pfeffer the development of the hippocampal network during the early phase of postnatal development under conditions when excitatory GABA action is abolished. Here, sodium-potassium-chloride cotransporter one (NKCC1) knockout mice (Nkcc1-/-) were used to reduce the intracellular chloride concentration in immature neurons. Young CA1 pyramidal neurons of Nkcc1-/- mice showed diminished GABAergic depolarization. I found that this reduction was sufficient to cause a delay in the maturation of glutamatergic and GABAergic synapses. This suggests that GABAergic excitation during early postnatal development, increasing the network activity, facilitates the maturation of synaptic networks. GABAergic depolarization in Nkcc1-/- mice was reduced but not completely abolished; suggesting that additional chloride loading mechanisms might exist. As the anionexchanger three (AE3) was proposed to contribute to chloride accumulation, AE3 knockout (Ae3-/-) mice were also studied. I could not detect any changes in intracellular chloride concentration after loss of AE3 at postnatal day one (P1). However at P5, the disruption of AE3 affected the early network activity pattern, indicating an effect of reduced intracellular chloride concentration. These data showed that NKCC1 establishes high intracellular chloride concentration in neurons providing the basis for GABAergic excitation. The role of AE3 is still not clear; it might contribute to the chloride accumulation in neurons. In addition to the function of chloride transporters, chloride conductive channels are likely to modulate the intracellular chloride concentration, and therefore could influence neuronal excitability. Especially ClC-2 has been suggested to contribute to chloride extrusion. I investigated the functional role of the voltage-gated chloride channel ClC-2. As specific blockers for ClC-2 are not available, I used ClC-2 knockout (Clcn2-/-) mice. It has been proposed that ClC-2 constitutes a pathway for chloride extrusion to maintain the inhibitory action of GABA in mature neurons. My data provide direct evidence that ClC-2 mediates fast chloride extrusion preventing chloride accumulation. Chloride extrusion by ClC-2 seemed to be important especially in adult hippocampal pyramidal neurons where GABAA receptor activation occurs in high frequency bursts. Interestingly, the chloride-conductance of ClC-2 occurs first in the second postnatal week of developing mice, suggesting that ClC-2 is important in fully developed neurons, but might not be important in immature neurons. Surprisingly, neurons in Clcn2-/- mice have a very high membrane resistance compared to WT animals, indicating that ClC-2 is active during the resting membrane potential. This might be a general feature of neurons, as I recorded the chloride conductance of ClC-2 in various neuron types. I showed that the resting conductance of ClC-2 affects resting membrane properties, which determine the neuronal excitability. As a consequence, the loss of ClC-2 increases the excitability of a neuron; however, it does not cause hyperexcitation of the hippocampal network. Even more, the network excitability is reduced in ClC-2 KO mice in comparison to the WT. This reduction is caused by an increased inhibition. I found that ClC-2 expressing interneurons increased their inhibitory action onto pyramidal cells after loss of ClC-2. Taken together, my data reveal that ClC-2 plays a dual role in adult neurons. First, ClC-2 contributes a fast mechanism to extrude chloride after chloride accumulation. Second, ClC-2 provides the chloride leak conductance under resting conditions. The loss of ClC-2 leads to a higher excitability of the neuron due to a strongly increased membrane resistance. Importantly, hyper-excitability of the neuronal network is circumvented by a parallel enhanced inhibition, which can explain the absence of an epileptic phenotype in mice.

The electrical activity of the brain is the result of a complex interaction between excitation and inhibition mediated by several types of neurotransmitters. As the majority of neurons in the brain utilize either the inhibitory neurotransmitter γ-aminobutyric acid (GABA) or the excitatory neurotransmitter glutamate, the interplay of these two neurotransmitters principally controls brain excitability and, hence, imbalance between these two neurotransmitters may cause severe pathological conditions. Inhibition of glutamic acid decarboxylase (GAD), the rate-limiting enzyme of GABA synthesis, is believed to change neuronal network activity caused by impaired GABAergic inhibition. Recordings of intrinsic optical signals (IOSs) and whole-cell patch-clamp measurements of GABAA receptor-mediated miniature postsynaptic currents (GABAA Minis) and spontaneous excitatory postsynaptic currents (sEPSCs) were performed in the motor cortex in acute brain slices to unveil the effects of GAD inhibitors at the network level. The first project of this PhD thesis was to prove the IOS technique for its capability of monitoring neuronal network activity over several hours. Concurrently, new software for the analysis of IOS data was developed, which facilitates and significantly accelerates data analysis. Afterwards, changes in neuronal network activity after impairing GAD activity with the well-known GAD inhibitor semicarbazide (SMC) were observed with the IOS technique. If compared to the values of sham-drug application, a stable and reversible increase in both signal intensity and signal area was observed after 2 h of 2 mM SMC application. Consistent with these findings of IOS recordings, patch-clamp measurements of GABAA Minis revealed an SMC-induced reduction in the strength of GABAergic inhibition. The results are in line with the assumption that SMC impairs GABA synthesis by blocking GAD activity. SMC application, however, did not alter spontaneous excitatory neuronal network activity. The final aim of this study was to investigate potential effects of Anti-GAD autoantibodies-containing immunoglobulin G (IgG) derived from patients with stiff-person syndrome (SPS-IgG) on motor cortical neuronal network activity. IOS recordings do not reveal differences in neuronal network activity during SPS-IgG application and control IgG application. However, run-down of IOSs was significantly decelerated during IgG application, which possibly indicates a diminished neuronal cell death caused by an unspecific IgG effect. Compared to brain slices preincubated with IgG-free artificial cerebrospinal fluid, control IgG did not affect GABAA Mini amplitude and frequency as well as sEPSC amplitude. The sEPSC frequency, however, was significantly reduced under these conditions. This decreased excitatory transmitter release might explain the beneficial effect of immunoglobulin treatment in some forms of epilepsy. Similar to SMC, patch-clamp measurements of GABAA Minis revealed a reduction in the strength of GABAergic inhibition after preincubation with SPS-IgG. Consistent with this finding, application of SPS-IgG enhanced sEPSC frequency. This shows that IgG of SPS patients is indeed capable of altering GABAergic synaptic transmission, thus further supporting the hypothesis of an autoimmune origin of the stiff-person syndrome.

In dieser Arbeit wurde das GABAerge System in Leydig-Zellen detailliert analysiert. Mehrere GABAA und GABAC Rezeptor Untereinheiten sowie das GABA synthetisierende Enzym GAD 67 und der vesikuläre GABA Transporter VIAAT konnten mit RT – PCR, Western Blot und Immunfluoreszenz-Experimenten in TM3, Leydig-Tumorzellen, und primären adulten Leydig-Zellen nachgewiesen werden. Es gelang molekulare Signaltransduktionswege von GABA aufzudecken: Gen Array, Western Blot und semiquantitative RT – PCR Experimente zeigten, dass GABA und der GABAA Rezeptor Agonist Isoguvacin den Transkriptionsfaktor egr-1 in TM3 und adulten Leydig-Zellen induzieren. Western Blot Experimente lassen schließen, dass GABA vermittelt über GABAA Rezeptoren die MAP – Kinasen ERK 1/2 in TM3 Zellen phosphoryliert und somit in den enzymatisch aktiven Zustand überführt. In primären adulten Leydig-Zellen konnte weiterhin gezeigt werden, dass GABA die Testosteron Produktion steigert. Elektrophysiologische Untersuchungen der TM3 und der primären adulten Leydig-Zellen zeigten schließlich, dass das initiale GABA Signal nicht über einen für GABAA Rezeptor typischen Cl--Strom vermittelt wird. Die RT – PCR Analyse von postnatalen Mäusehoden ergab ebenfalls, dass GAD 67, VIAAT und mehreren GABAA und GABAC Rezeptor Untereinheiten in dieser Entwicklungsphase des Hodens anwesend sind und lieferten ferner Hinweise dafür, dass sich insbesondere die Expression der Rezeptor Untereinheiten in der postnatalen Periode im Hoden ändert. Darüber hinaus konnte nachgewiesen werden, dass proliferierende interstitielle Zellen im postnatalen Rattenhoden immunopositiv für egr-1 sind. Somit ist eine physiologische Funktion von egr-1 in dieser Phase der Leydig-Zellentwicklung plausibel.

A. A fundamental property of hearing is the decomposition of complex sounds into perceptually distinct frequency components. Each receptor cell in the cochlea and most centrally located neurons respond only to a limited range of frequencies. The individual frequency channels are spatially organized on the cortical surface. This consistent topographical pattern provides a framework for the investigation of other functional organization principles, e.g., the functional properties of neurons in the six cortical layers and the responsiveness of neurons to complex sounds. The frequency specific features of inhibition should play an important role in shaping a neuron’s response to complex behaviorally relevant stimuli. Physiological and immunocytochemical evidence indicates a layer-dependent organization of inhibitory circuits in the neocortex. To investigate the contribution of GABAergic inhibition to frequency tuning in the different cortical layers, single and multi units were recorded in near-radial penetrations before and during iontophoretic application of the GABAA-receptor antagonist bicuculline in the auditory cortex of the lightly anaesthetized gerbil (Meriones unguiculatus). Bicuculline generally increased the spontaneous neuronal activity and enhanced and prolonged onset responses to sound. Application of bicuculline often resulted in a shift of the most sensitive frequency of the neurons’ receptive fields and a decrease of threshold (5.5 dB). A broadening of the frequency tuning evident by lower Q40dB values was observed in 63% of the units. In units with several peaks in their tuning curve or clearly separated response areas, bicuculline application removed inhibitory gaps in the receptive fields and created single-peaked tuning curves. The influence of bicuculline on the receptive field size was not significantly layer-specific but tended to be most pronounced in layers V and VI. In layer VI, "silent" neurons were frequently found that responded to sound only when GABAergic inhibition was antagonized. From the analysis of postembedding GABA immunocytochemistry, the proportion of GABAergic neurons was found to be maximal in layers I and V, and the number of GABAergic perisomatic puncta (axon terminals) on cell somata peaked in layer V. The influence of bicuculline was compared with the effects of two-tone suppression. It was found that in some units, the effects of suppression could be partially mediated by intracortical GABAergic inhibition. In some units in layers IV, V, and VI, additionally to the initial excitatory activity in response to stimulus onset, a second, long-lasting excitatory response occurred several hundred milliseconds after the stimulus. This late response was not dependent on stimulus duration and could be enhanced or elicited by GABAA blockade. The fact that several, rhythmically occurring late responses were elicited by the application of bicuculline suggests that recurrent excitatory networks can become entrained by small modifications of inhibition. B. In the natural environment, acoustic signals like animals’ communication sound or human speech is often masked by background noise. Amplitude fluctuations are often superimposed upon environmental sounds on their path of transmission which can lead to a distinct temporal structure of the sound. Furthermore, many natural background sounds are often temporally structured. Vertebrates have evolved mechanisms to exploit amplitude modulations in background noise to improve signal detection. Psychophysical and behavioral experiments have shown that amplitude-modulated background noise (comodulated noise) is less effective as a masker than unmodulated noise bands of the same bandwidth, a phenomenon called comodulation masking release (CMR). This phenomenon has been extensively studied in human psychoacoustics. However, the underlying neural mechanisms are still debated. Animal models in which a direct comparison of the neuronal response and the behaviorally measured performance is possible could increase our understanding of the underlying mechanisms. CMR could be demonstrated behaviorally and neurophysiologically in a songbird, however, models for mammals are still lacking. In behavioral experiments, Kittel et al. (2000) demonstrated CMR in the gerbil. In the present study, using acoustic stimuli that were identical with those of a behavioral experiment, a neural correlate of CMR was described in the auditory cortex of the gerbil and compared with the behavioral data. In this study of neural mechanisms of masking release in the primary auditory cortex of the anaesthetized gerbil, I determined neural detection thresholds for 200-ms test tones presented in a background of band-pass amplitude modulated (50 Hz) noise maskers of different bandwidth (between 50 and 3200 Hz). Neural release from masking caused by comodulated band-pass noise was evident at the level of the gerbil’s primary auditory cortex. On average, the largest masking release (median 6.9 dB) was found for a masker bandwidth of 3200 Hz. This is less than the median masking release of 15.7 dB observed in the behavioral study in the gerbil. For most masker bandwidths, however, a small fraction of the neurons exhibited a masking release that was close to or even larger than the behavioral masking release. The observation that the release from masking increased as a function of the masker bandwidth indicates that spectral components remote from the signal frequency enhance the signal detection. However, there was no correlation between the neurons’ filter bandwidths and the amount of masking release. Thus, neuronal masking release in the gerbil primary auditory cortex could be attributed to both signalmasker interactions across different frequency channels and also to mechanisms that act within a single frequency channel. The gerbil appears to be a suitable animal model for additional studies comparing behavioral and physiological performance in the same species. These studies could increase our understanding of the perceptual mechanisms that are useful for the analysis of auditory scenes.

This study investigated the representation of acoustic motion in different fields of auditory cortex of the rufous horseshoe bat, Rhinolophus rouxi. Motion in horizontal direction (azimuth) was simulated using successive stimuli with dynamically changing interaural intensity differences presented via earphones. The mechanisms underlying a specific sensitivity of neurons to the direction of motion were investigated using microiontophoretic application of γ-aminobutyric acid (GABA) and the GABAA receptor antagonist bicuculline methiodide (BMI). In the first part of the study, responses of a total of 152 neurons were recorded. Seventy-one percent of sampled neurons were motion-direction sensitive. Two types of responses could be distinguished. Thirty-four percent of neurons showed a directional preference exhibiting stronger responses to one direction of motion. Fifty-seven percent of neurons responded with a shift of spatial receptive field position depending on the direction of motion. Both effects could occur in the same neuron depending on the parameters of apparent motion. Most neurons with contralateral receptive fields exhibited directional preference only with motion entering the receptive field from the opposite direction (i.e. the ipsilateral part of the azimuth). Receptive field shifts were opposite to the direction of motion. Specific combinations of spatio-temporal parameters determined the motion-direction-sensitive responses. Velocity was not encoded as a specific parameter. Temporal parameters of motion and azimuthal position of the moving sound source were differentially encoded by neurons in different fields of auditory cortex. Neurons with a directional preference in the dorsal fields can encode motion with short interpulse intervals, whereas direction preferring neurons in the primary field can best encode motion with medium interpulse intervals. Furthermore, neurons with a directional preference in the dorsal fields are specialized for encoding motion in the midfield of azimuth, whereas direction preferring neurons in the primary field can encode motion in lateral positions. In the second part of the study, responses were recorded from additional 69 neurons. Microiontophoretic application of BMI influenced the motion-direction sensitivity of 53 % of neurons. In 21 % of neurons the motion-direction sensitivity was decreased by BMI by decreasing either directional preference or receptive field shift. In neurons with a directional preference, BMI increased the spike number for the preferred direction in about the same amount as for the non-preferred direction. Thus, inhibition was not direction specific. In contrast, BMI increased motion-direction sensitivity by either increasing directional preference or magnitude of receptive field shifts in 22 % of neurons. An additional 10 % of neurons changed their response from a receptive field shift to a directional preference under BMI. In these 32 % of neurons, the observed effects could often be better explained by adaptation of excitation than by inhibition. The results suggest, that motion information is differentially processed in different fields of the auditory cortex of the rufous horseshoe bat. Thus, functionally organized pathways for the processing of different parameters of auditory motion seem to exist. The fact that cortex specific GABAergic inhibition contributes to motion-direction sensitivity in at least a part of cortical neurons is supportive for the notion that the auditory cortex plays an important role in further processing the neural responses to apparent motion brought up from lower levels of the auditory pathway.

1. Adult rats and rats with a postnatal age of 3-29 days (PN 3-29) were used for the preparation of in vitro slices of the frontal neocortex. Epileptiform activity was induced by bath application of the gamma-aminobutyric acid-A (GABAA) receptor antagonists bicuculline or picrotoxin. 2. The voltage-sensitive dye RH 414 and a laser scanning microscope were used for multiple-site optical recordings of membrane potential changes associated with epileptiform activity. Optical signals were compared with simultaneously measured extra-cellular field potentials. 3. Optical signals could be reliably recorded for the duration of the experiments (2-4 h). Extracellular recordings of convulsant-induced paroxysmal depolarizing shifts (PDSs) in slices stained with RH 414 were comparable with those obtained in unstained slices. Changes in dye signals in response to reductions in extracellular calcium, addition of tetrodotoxin (TTX), or application of excitatory amino acid receptor antagonists indicate that the fluorescence changes correlate well with established electrophysiological measures of epileptiform activity. 4. In slices from adult animals, dye signals were observed at all recording sites. The response with the shortest latency occurred invariably at the site of stimulation, and activity spread rapidly in both vertical and horizontal directions. Spread was significantly faster in the vertical than in the horizontal direction. 5. Epileptiform activity was absent or only weakly expressed in slices from PN 3-9 animals. Activity was detectable predominantly in upper cortical layers. 6. Dye signals were observed at all measurement points in slices from PN 10-19 animals. In this age group, peak amplitude increased with spread of activity from lower to upper cortical layers. There was no significant difference between the speed of propagation in the vertical and in the horizontal directions. Spontaneous epileptiform activity occurred at a high rate in the PN 10-19 age group, and signals associated with spontaneous epileptiform events were largest in upper layers. 7. In the PN 10-19 age group, optical signals were characterized by the repetitive occurrence of PDS discharges superimposed on a sustained response. The amplitude of the sustained response decreased with increasing distance from the site of stimulation. Analysis of the latencies revealed that the superimposed PDS-like events were generated at multiple sites within the scanning area. Amplitude and rate of rise were largest in slices from PN 10-19 animals. These values declined with ongoing development.

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.04.10.035352v1?rss=1 Authors: Norgaard, M., Beliveau, V., Ganz, M., Svarer, C., Pinborg, L. H., Keller, S. H., Jensen, P. S., Greve, D. N., Knudsen, G. M. Abstract: Gamma-aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the human brain and plays a key role in several brain functions and neuropsychiatric disorders such as anxiety, epilepsy, and depression. The binding of benzodiazepines to the benzodiazepine receptor sites (BZR) located on GABAA receptors (GABAARs) potentiates the inhibitory effect of GABA leading to the anxiolytic, anticonvulsant and sedative effects used for treatment of those disorders. However, the function of GABAARs and the expression of BZR protein is determined by the GABAAR subunit stoichiometry (19 genes coding for individual subunits), and it remains to be established how the pentamer composition varies between brain regions and individuals. Here, we present a quantitative high-resolution in vivo atlas of the human brain BZRs, generated on the basis of [11C]flumazenil Positron Emission Tomography (PET) data. Next, based on autoradiography data, we transform the PET-generated atlas from binding values into BZR protein density. Finally, we examine the brain regional association with mRNA expression for the 19 subunits in the GABAAR, including an estimation of the minimally required expression of mRNA levels for each subunit to translate into BZR protein. This represents the first publicly available quantitative high-resolution in vivo atlas of the spatial distribution of BZR densities in the healthy human brain. The atlas provides a unique neuroscientific tool as well as novel insights into the association between mRNA expression for individual subunits in the GABAAR and the BZR density at each location in the brain. Copy rights belong to original authors. Visit the link for more info