Podcasts about neuropeptide

In dieser Der Schmerzcode-Podcast-Folge tauchen Jan-Peer und Marco tief in die komplexe Welt des Schmerzes ein. Sie reflektieren über vergangene Informationen, betonen die Fortsetzung der Reise durch den Schmerz. Heute planen sie, die Signalumschaltung vom ersten zum zweiten Neuron im Rückenmark zu untersuchen und die Bahnen zu betrachten, die letztendlich zum Thalamus führen. Die Gastgeber diskutieren die komplexe Modulation des Schmerzsignals zwischen den Neuronen, heben schmerzhemmende Mechanismen hervor und tauchen tief in die Anatomie des Rückenmarks ein. Die Rolle der Interneurone, die das Schmerzsignal beeinflussen, wird erläutert, ebenso wie die Projektionsbahn im Rückenmark zum Thalamus. Jan-Peer und Marco diskutieren die sensorisch-diskriminativen Komponenten und affektiven Aspekte des Schmerzes sowie die Weiterleitung vegetativer Komponenten wie Schwitzen und Erbrechen über separate Bahnen im Rückenmark. Die komplexe Mechanik der Schmerzweiterleitung im Rückenmark wird betont und die Verarbeitung von Schmerzinformationen im Gehirn beleuchtet. Im weiteren Verlauf des Podcasts wird detailliert über die Verschaltungsebenen vom Rückenmark zum Mittelhirn gesprochen. Die schnelle Reaktion des Wegziehreflexes bei Schmerzreizen wird erklärt und Mechanismen der schmerzhemmenden Effekte sowie segmentale Schmerzhemmung auf spinaler Ebene werden diskutiert. Die Verarbeitung von Signalen im Gehirn zur Schmerzregulierung und -modulation wird erörtert, einschließlich der Bedeutung von Opiatrezeptoren und Neurotransmittern wie Serotonin und Noradrenalin. Therapeutische Ansätze wie Akupunktur, Kryotherapie und Taping, die auf der Stimulierung von Interneuronen basieren, werden beleuchtet. Die Interaktion verschiedener Neurotransmittertypen zur Regulierung von Schmerzsignalen wird beschrieben und potenzielle weitere Untersuchungen zu Mechanismen der Schmerzmodulation in zukünftigen Folgen angedeutet. Der Podcast schließt mit einem Ausblick auf kommende Folgen, in denen das dritte Neuron und die zentrale Schmerzmatrix behandelt werden sollen, sowie einer Betonung der Bedeutung von fundiertem Wissen bei der Schmerzdiagnose und -behandlung.

Dr. Doug Brackmann is here to share his remarkable story of long-term sobriety, a psychedelic journey, and an unexpected relapse after 36 years. Doug is a clinical psychologist and dual PhD holder. He's renowned for his work in harnessing the power of thought and action.  Through his counseling techniques and use of meditation, he assists "hunters", highly driven individuals, in navigating their gifts and ambitions. Doug is also the celebrated author of the best-selling book, Driven: Understanding and Harnessing the Genetic Gifts Shared by Entrepreneurs, Navy SEALs, Pro Athletes, and Maybe YOU. We don't talk about his book today, our conversation takes a different turn as we explore Doug's encounter with psychedelics and the surprising outcome. He had a relapse after more than three decades of abstinence. He takes us on a journey from when he was living in his car in 1986 to a house fire that almost had devastating consequences, but led to his second quest for sobriety.  We also talk about healing trauma, addictive personalities, boundaries, and staying sober. With mounting evidence supporting the use of psychedelics like ketamine, psilocybin, and MDMA for mental and substance use disorder recovery, Doug's story offers unique insights. Get ready for a deeply enlightening discussion.  [04:45] Doug became sober on April 22nd of 1986. He was a high school dropout living in a car. He was a true alcoholic. When he began drinking, things became unpredictable. [05:56] He went to three or four meetings a week for 20 years. He loved being sober. [06:20] When he tried psychedelics, it opened the door to THC.  [08:14] He was a clinical psychologist and had patients interested in plant medicine. Doug figured he had everything under control, and decided to try psilocybin and mescaline. It was an amazing experience, and opened his eyes to the potential of trauma healing. [10:33] This opened the door to experimenting with MDMA. [15:55] Doug and Tim discuss the different forms of addiction and questions that surround it.  [18:50] Three or four months later, Doug tried MDMA with psilocybin. This opened the door to trying other psychedelics like ayahuasca. [22:46] During this experience, he felt like his soul left his body and when it entered again all of his PTSD came out at once. [23:28] Integration work is trauma healing. [25:40] Complications from life led to THC gummies which led to his relapse. Doug feels that the psychedelics opened the door to the gummies which led to his relapse. [30:11] Doug shares how his house caught on fire. November 19th 2022 was when he decided to go back to being sober. [33:35] He began going to meetings again, and it's great to be sober.  [35:47] Psychedelics are an interesting tool for people who know how to use them properly. [39:44] Doug's advice is once you reach 20 years of sobriety, maintain it. [41:09] Doug's advice is to pursue trauma healing before pursuing medicine healing. The practices of moving energy through the body are more important than the medicine. [42:53] Doug shares a website to find a trauma healing practitioner.  [45:37] It's important to go to meetings.  [47:16] Anything medicine will give you, you can find in the 12 steps or meditation or other ways. Look at powerful trauma healing techniques that don't have a relapse potential. [50:19] Choose your addictions wisely and put boundaries around them. [51:14] Doug talks about his book Driven. He talks about genetics around boredom and the difference between farmers and hunters.  [55:03] Neuropeptide y serves us as hunters and entrepreneurs. [57:18] Driven is synonymous with an addictive personality.   Links mentioned in this episode: Camelback Recovery I Love Being Sober YouTube Dr. Doug Brackmann LinkedIn Driven Driven: Understanding and Harnessing the Genetic Gifts Shared by Entrepreneurs, Navy SEALs, Pro Athletes, and Maybe YOU Somatic Experiencing International

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.07.11.548551v1?rss=1 Authors: Zhang, S. X., Kim, A., Madara, J. C., Zhu, P. K., Christenson, L. F., Lutas, A., Kalugin, P. N., Jin, Y., Paul, A., Tian, L., Lowell, B. B., Andermann, M. L. Abstract: We investigated how transmission of hunger- and satiety-promoting neuropeptides, NPY and alpha MSH, is integrated at the level of intracellular signaling to control feeding. Receptors for these peptides use the second messenger cAMP, but the messenger's spatiotemporal dynamics and role in energy balance are controversial. We show that AgRP axon stimulation in the paraventricular hypothalamus evokes probabilistic and spatially restricted NPY release that triggers stochastic cAMP decrements in downstream MC4R-expressing neurons (PVHMC4R). Meanwhile, POMC axon stimulation triggers stochastic, alpha MSH-dependent cAMP increments. NPY and alpha MSH competitively control cAMP, as reflected by hunger-state-dependent differences in the amplitude and persistence of cAMP transients evoked by each peptide. During feeding bouts, elevated alpha MSH release and suppressed NPY release cooperatively sustain elevated cAMP in PVH MC4R neurons, thereby potentiating feeding-related excitatory inputs and promoting satiation across minutes. Our findings highlight how state-dependent integration of opposing, quantal peptidergic events by a common biochemical target calibrates energy intake. 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/2023.07.03.547448v1?rss=1 Authors: Thiel, D., Yanez-Guerra, L. A., Kieswetter, A., Cole, A. G., Temmerman, L., Technau, U., Jekely, G. Abstract: Neuropeptides are ancient signaling molecules in animals but only few peptide receptors are known outside bilaterians. Cnidarians possess a large number of G protein-coupled receptors (GPCRs), the most common receptors of bilaterian neuropeptides, but most of these remain orphan with no known ligands. We searched for neuropeptides in the sea anemone Nematostella vectensis and created a library of 64 peptides derived from 33 precursors. In a large-scale pharmacological screen with these peptides and 161 N. vectensis GPCRs, we identified 31 receptors specifically activated by one of 14 peptides. Mapping GPCR and neuropeptide expression to single-cell sequencing data revealed how cnidarian tissues are extensively wired by multilayer peptidergic networks. Phylogenetic analysis identified no direct orthology to bilaterian peptidergic systems and supports the independent expansion of neuropeptide signaling in cnidarians from a few ancestral peptide-receptor pairs. 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/2023.04.29.538817v1?rss=1 Authors: Kalienkova, V., Dandamudi, M., Paulino, C., Lynagh, T. Abstract: 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/2023.03.29.534505v1?rss=1 Authors: Hiraki-Kajiyama, T., Miyasaka, N., Ando, R., Wakisaka, N., Itoga, H., Onami, S., Yoshihara, Y. Abstract: Zebrafish is a useful model organism in neuroscience; however, its gene expression atlas in the adult brain is not well developed. In the present study, we examined the expression of 38 neuropeptides, and glutamatergic neuron marker gene mix (slc17a6a, slc17a6b, slc17a7a, and slc17a7b) in the adult zebrafish brain using in situ hybridization. The results are summarized as an expression atlas in 19 coronal planes of the forebrain. Furthermore, the scan data of all sections were made publicly available as a database. Based on these data, we performed detailed neuroanatomical analyses of the hypothalamus. By scrutinizing and comparing the expression patterns of neuropeptides, we found that several regions described as one nucleus in the reference zebrafish brain atlas contain two or more subregions with significantly different neuropeptide/neurotransmitter expression profiles, and we proposed them as novel subnuclei. Subsequently, the expression data obtained in this study were compared with those in mice, and a cluster analysis was performed to examine the similarities. As a result, several nuclei in zebrafish and mice were clustered in close vicinity: zebrafish ventral part of the anterior part of the parvocellular preoptic nucleus (PPav)/magnocellular preoptic nucleus (PM) and mouse paraventricular hypothalamic nucleus (Pa), zebrafish posterior part of the parvocellular preoptic nucleus (PPp) and mouse medial preoptic area (MPA), zebrafish dorsal part of the ventral zone of periventricular hypothalamus (Hvd)/anterior tuberal nucleus (ATN) and mouse ventromedial hypothalamic nucleus (VMN). The present expression atlas, database, and anatomical findings will contribute to future neuroscientific research using zebrafish. 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/2023.02.28.530282v1?rss=1 Authors: Kuang, D., Hanchate, N. K., Lee, C.-Y., Heck, A., Ye, X., Erdenebileg, M., Buck, L. B. Abstract: The sense of smell has potent effects on appetite, but the underlying neural mechanisms are largely a mystery. The hypothalamic arcuate nucleus contains two subsets of neurons linked to appetite: AgRP (agouti-related peptide) neurons, which enhance appetite, and POMC (pro-opiomelanocortin) neurons, which suppress appetite. Here, we find that AgRP and POMC neurons receive indirect inputs from partially overlapping areas of the olfactory cortex, thus identifying their sources of odor signals. We also find neurons directly upstream of AgRP or POMC neurons in numerous other areas, identifying potential relays between the olfactory cortex and AgRP or POMC neurons. Transcriptome profiling of individual AgRP neurons reveals differential expression of receptors for multiple neuromodulators. Notably, known ligands of the receptors define subsets of neurons directly upstream of AgRP neurons in specific brain areas. Together, these findings indicate that higher olfactory areas can differentially influence AgRP and POMC appetite neurons, that subsets of AgRP neurons can be regulated by different neuromodulators, and that subsets of neurons upstream of AgRP neurons in specific brain areas use different neuromodulators, together or in distinct combinations to modulate AgRP neurons and thus appetite. 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/2023.02.10.528013v1?rss=1 Authors: Boyle, K. A., Polgar, E., Gutierrez-Mecinas, M., Dickie, A. C., Cooper, A. H., Bell, A. M., Jumolea, E., Casas-Benito, A., Watanabe, M., Hughes, D. I., Weir, G., Riddell, J., Todd, A. J. Abstract: Somatosensory information is processed by a complex network of interneurons in the spinal dorsal horn. It has been reported that inhibitory interneurons that express neuropeptide Y (NPY), either permanently or during development, suppress mechanical itch, with no effect on pain. Here we investigate the role of interneurons that continue to express NPY (NPY-INs) in adulthood. We find that chemogenetic activation of NPY-INs reduces behaviours associated with acute pain and pruritogen evoked itch, whereas silencing them causes exaggerated itch responses that depend on cells expressing the gastrin-releasing peptide receptor. As predicted by our previous studies, silencing of another population of inhibitory interneurons (those expressing dynorphin) also increases itch, but to a lesser extent. Importantly, NPY IN activation also reduces behavioural signs of inflammatory and neuropathic pain. These results demonstrate that NPY-INs gate pain and itch transmission at the spinal level, and therefore represent a potential treatment target for pathological pain and itch. 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/2023.02.03.527010v1?rss=1 Authors: Selten, M., Bernard, C., Hamid, F., Hanusz-Godoy, A., Oozeer, F., Zimmer, C., Marin, O. Abstract: Neuronal activity is regulated in a narrow permissive band for the proper operation of neural networks. Changes in synaptic connectivity and network activity, for example, during learning, might disturb this balance, eliciting compensatory mechanisms to maintain network function. In the neocortex, excitatory pyramidal cells and inhibitory interneurons exhibit robust forms of stabilising plasticity. However, while neuronal plasticity has been thoroughly studied in pyramidal cells, little is known about how interneurons adapt to persistent changes in their activity. Here we uncover the critical cellular and molecular mechanisms through which cortical parvalbumin-expressing (PV+) interneurons adapt to changes in their activity levels. We found that changes in the activity of PV+ interneurons drive cell-autonomous, bi-directional compensatory adjustments of the number and strength of inhibitory synapses received by these cells, specifically from other PV+ interneurons. High-throughput profiling of ribosome-associated mRNA revealed that increasing the activity of PV+ interneurons leads to the cell-autonomous upregulation of two genes encoding multiple secreted neuropeptides, Vgf and Scg2. Functional experiments demonstrated that VGF is critically required for the activity-dependent scaling of inhibitory PV+ synapses onto PV+ interneurons. Our findings reveal an instructive role for neuropeptide-encoding genes in regulating synaptic connections among PV+ interneurons in the adult mouse neocortex. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

To watch this as a video Download it and play it from the Downloads section in the Castbox app on your device.MEMOPROVE® is an innovative European Nootropic that, as its name implies, enhances memory and cognition. Whether you're a grad student, a hardworking professional, or just sick of forgetting where you left your keys - Neuropeptides can give you an edge. The active peptide in this Nootropic is N-PEP-12™.Read Review

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.12.12.520095v1?rss=1 Authors: Francisco, A. P., Tastekin, I., Fernandes, A. B., Ezra-Nevo, G., Deplancke, B., Oliveira-Maia, A. J., Gontijo, A. M., Ribeiro, C. Abstract: Neuropeptides play a key role in regulating physiology and behavior, including feeding. While animals modify their food choices to respond to the lack of specific nutrients, the mechanisms mediating nutrient-specific appetites remain unclear. Here, we identified marmite (mmt), a previously uncharacterized Drosophila melanogaster gene encoding a secreted peptide that controls feeding decisions. We show that both mmt mutants and neuronal knockdown of mmt specifically increased the intake of proteinaceous food, whereas neuronal mmt overexpression reduced protein appetite. mmt expression is also higher in animals maintained on amino acid rich food, suggesting that mmt encodes a protein-specific satiety signal. Mmt is expressed in a small number of neurons in the adult nervous system, with a single pair of neurons modulating protein appetite. Finally, sequence and phylogenetic analysis showed that mmt is part of an ancient and conserved family of neuropeptides, including the poorly understood vertebrate neuropeptides B and W genes. Functional experiments showed that mmt and vertebrate NPB and NPW modulate food intake in both flies and mice. Therefore, we discovered an ancient family of neuropeptides involved in controlling feeding across phyla. 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/2022.11.15.516679v1?rss=1 Authors: Lee, J. I., Lee, T. Y., Yoon, K.-h., Chang, E. Abstract: The ability for animals to adapt their behaviors to specific environments is imperative to increase their evolutionary success. This is particularly true for behaviors such as parental behaviors that directly affect reproductive fitness. Here, we identified an oviposition behavior in the nematode C. elegans that increases the survival of the young. In standard laboratory culture, the bacterivorous hermaphrodite mothers lay eggs across a 2D E. coli lawn with no discernable pattern. However, in 3D culture they display a stereotypical behavior in which they temporarily leave the bacteria to lay eggs far away from the E. coli colony, resulting in a scattered ring of eggs located outside the bacteria. This oviposition behavior requires low oxygen levels and is regulated by the neuropeptide FLP-17 and its cognate receptor EGL-6. We confirm that a circuitry involving the oxygen-sensing BAG neurons and the vulva muscle-controlling HSN motor neurons regulates oviposition behavior. We show that loss of proper oviposition behavior results in lower reproductive fitness for the mothers and embryonic lethality for the eggs laid in bacteria under hypoxic conditions. Finally, we show that the degree of oviposition behavior varies among wild strains of C. elegans found in nature. The ability for C. elegans mothers to sense their environments and adjust their behaviors in adverse conditions is likely an adaptation that has allowed the worm to thrive in diverse and often hazardous habitats. 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/2022.11.14.516160v1?rss=1 Authors: Li, M., Larsen, P. A. Abstract: Alzheimer's disease (AD) is a fatal neurodegenerative disease that involves early and significant neuropathological changes within the entorhinal cortex (EC). Many have reported on neuronal loss and synaptic dysfunction in the brains of AD patients and AD models. In parallel, abnormalities of neuropeptides (NPs) that play important roles in modulating neuronal activities are commonly observed in AD and other neurodegenerative diseases. However, the involvement of NPs has mostly been studied in the context of neurons; a cell type-specific examination of NP expression in AD brains is needed. Here, we aim to examine the NP networks in the EC of AD brains using single-nuclei and bulk transcriptomic data from other regions in the temporal cortex, focusing on the gene expression of NP and their cognate G-protein coupled receptors. We find that NP genes were expressed by all major cell types in the brain and there was a significant decrease in the quantity and the proportion of cells that express NPs in AD EC cells. On the contrary, the overall expression of GPCR genes showed an increase in AD cells, likely reflecting ongoing compensatory mechanisms in AD brains. In addition, we report that there was a disproportionate absence of cells expressing higher levels and greater diversity of NPs in AD brains. Finally, we established a negative correlation between age and the abundance of AD-associated NPs in the hippocampus, supporting that the disruption of the NP signaling network in the EC may contribute to the early pathogenesis of AD. In short, we report widespread disruption of the NP networks in AD brains at the single-cell level. In light of our results, we hypothesize that brain cells, especially neurons, that express high levels of NPs may exhibit selective vulnerability to AD. Moreover, it is likely AD brains undergo specific adaptive changes to fluctuating NP signaling, a process that can likely be targeted with therapeutic approaches aimed at stabilizing NP expression landscapes. Given that GPCRs are one of the most druggable targets for neurological diseases and disorders, we believe NP signaling pathways can be harnessed for future biomarkers and treatment strategies for AD. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

https://psychiatry.dev/wp-content/uploads/speaker/post-10741.mp3?cb=1668000847.mp3 Playback speed: 0.8x 1x 1.3x 1.6x 2x Download: A neuropeptide signal confers ethanol state dependency during olfactory learning in Caenorhabditis elegans – PubMed Jonathan H Lindsay et al. PNAS. 2022.Full EntryA neuropeptide signal confers ethanol state dependency during olfactory learning in Caenorhabditis elegans – PubMed

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.30.514428v1?rss=1 Authors: Beets, I., Zels, S., Vandewyer, E., Demeulemeester, J., Caers, J., Baytemur, E., Schafer, W. R., Vertes, P. E., Mirabeau, O., Schoofs, L. Abstract: Neuropeptides are ancient, widespread signaling molecules that underpin almost all brain functions. They constitute a broad ligand-receptor network, mainly by binding to G protein-coupled receptors (GPCRs). However, the organization of the peptidergic network and roles of many neuropeptides remain elusive, as our insight into neuropeptide-receptor interactions is limited and many peptide GPCRs in animal models and humans are still orphan receptors. Here we report a genome-wide neuropeptide-GPCR interaction map in C. elegans. By reverse pharmacology screening of over 55,384 possible interactions, we identify 461 cognate peptide-GPCR couples that uncover a broad signaling network with specific and complex combinatorial interactions encoded across and within single peptidergic genes. These interactions provide insights into neuropeptide functions and evolution. Combining our dataset with phylogenetic analysis supports peptide-receptor co-evolution and conservation of at least 14 bilaterian peptidergic systems in C. elegans. This resource lays a foundation for system-wide analysis of the peptidergic network. 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/2022.10.27.514061v1?rss=1 Authors: Hidalgo, S., Anguiano, M., Tabuloc, C. A., Chiu, J. C. C. Abstract: Organisms adapt to seasonal changes in photoperiod and temperature to survive; however, the mechanisms by which these signals are integrated in the brain are poorly understood. We previously reported that EYES ABSENT (EYA) in Drosophila shows higher levels in cold temperature or short photoperiod, and genetic ablation of eya in the fly brain inhibits reproductive dormancy, suggesting that EYA promotes winter physiology. Nevertheless, the mechanisms by which EYA senses seasonal cues are unclear. Pigment-Dispersing Factor (PDF) is a neuropeptide important for photoentrainment and regulation of circadian output rhythms. Interestingly, PDF also regulates reproductive dormancy, suggesting that it may mediate the function of the circadian clock in modulating seasonal physiology. In this study, we investigated the role of PDF signaling in mediating the impact of EYA on seasonal biology. First, we subjected flies to different photoperiodic and temperature regimes and observed that PDF abundance is lower in cold and short days, compared to warm and long days. Interestingly, the response of PDF to seasonal cues is opposite of what was observed for EYA. We then determined the potential for PDF to convey seasonal cues and modulate EYA function in seasonality by assessing coexpression of EYA and PDF receptor. Our results indicated that PDF receptor (PDFR) is indeed coexpressed with EYA in the fly brain, including in the circadian clock neuronal network and neurons in the pars intercerebralis. We then manipulated PDF signaling in eya+ cells to show that PDF modulates seasonal adaptations in daily activity rhythm and ovary development via EYA-dependent and independent mechanisms. At the molecular level, manipulating PDF signaling impacted EYA protein abundance. Specifically, we showed that protein kinase A (PKA), an effector of PDF signaling, phosphorylates EYA and promotes its degradation. This explains the opposite responses of PDF and EYA abundance to changes in seasonal cues. In summary, our results support a model in which PDF signaling negatively modulates EYA levels to regulate seasonal physiology, linking the circadian clock to the modulation of seasonal adaptations. 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/2022.10.22.513332v1?rss=1 Authors: Psilopanagioti, A., Nikou, S., Logotheti, S., Arbi, M., Chartoumpekis, D. V., Papadaki, H. Abstract: Data on animals emphasize the importance of neuronal GLP-1 receptor (GLP-1R) for feeding suppression, although it is unclear whether astrocytes participate in the transduction of anorectic GLP-1R-dependent signals. In humans, the brain circuitry underlying these effects remains insufficiently investigated. The present study aimed to explore GLP-1R protein expression in human hypothalamus and its correlation with body mass index (BMI). Sections of hypothalamus from 28 autopsy cases, 11 with normal weight (BMI less than 25 Kg/m2) and 17 with non-normal weight (BMI greater than or equal to 25 Kg/m2), were examined using immunohistochemistry and double immunofluorescence labeling. Prominent GLP-1R immunoexpression was detected in neurons of several hypothalamic nuclei, including paraventricular, supraoptic, and infundibular nuclei, lateral hypothalamic area (LH), and basal forebrain nuclei. Interestingly, in LH, GLP-1R was significantly decreased in individuals with BMI greater than or equal to 25 Kg/m2, compared with normal weight counterparts (p=0.03). Furthermore, GLP-1R was negatively correlated ({tau}b=-0.347, p=0.024) with BMI levels only in the LH. GLP-1R extensively colocalized with the anorexigenic and anti-obesogenic neuropeptide nucleobindin-2/nesfatin-1, but not with the astrocytic marker glial fibrillary acidic protein. These data suggest a potential role for GLP-1R in the regulation of energy balance in human hypothalamus, possibly through interactions with nesfatin-1. In LH, an appetite- and reward-related brain region, reduced GLP-1R immunoexpression may contribute to dysregulation of homeostatic and/or hedonic feeding behavior. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

MEMOPROVE® is an innovative European Nootropic that, as its name implies, enhances memory and cognition. Whether you're a grad student, a hardworking professional, or just sick of forgetting where you left your keys - Neuropeptides can give you an edge. The active peptide in this Nootropic is N-PEP-12™.Read Full Reviewhttps://www.limitlessmindset.com/nootropics/1703-memoproveOrder MEMOPROVE®https://www.limitlessmindset.com/MEMOPROVEConfused?If you invest at least $100 in your Biohacking via LimitlessMindset.com, I will include a 30-minute free Biohacking consulting call with you. See my recommended Nootropics sources and Biohacking products here:https://www.limitlessmindset.com/membership/secret-societyForward a receipt of at least $100 to Consultations@LimitlessMindset.comJoin the Limitless Mindset email newsletterhttps://www.limitlessmindset.com/membership/community-membershipSupport My WorkMy Bookshttps://www.limitlessmindset.com/jr-booksDonateBitcoin: 3NPG27kVoBxyZNsCHXMGeZFLVWqVGGrjLPConnect with Jonathanon Facebookhttps://www.facebook.com/limitlessmindseton Twitterhttp://twitter.com/jroselandon Instagramhttps://www.instagram.com/roselandjonathan/on Gabhttps://gab.com/jroselandon Mindshttps://www.minds.com/jroselandon LBRYhttps://lbry.tv/@jroseland:fon Telegramhttps://t.me/limitlessjrI'm not a doctor, medical professional, or trained therapist. I'm a researcher and pragmatic biohacking practitioner exercising free speech to share evidence as I find it. I make no claims. Please practice skepticism and rational critical thinking. You should consult a professional about any serious decisions that you might make about your health.

Proceedings of The Nutrition Society.2012 71(4):521-33 Autophagy. 2009 May; 5(4): 558–560 Molecular and Cellular Endocrinology Volume 472, 5 September 2018, Pages 40-49 Int J Mol Sci. 2020 Nov; 21(21): 8220. --- Send in a voice message: https://anchor.fm/dr-daniel-j-guerra/message Support this podcast: https://anchor.fm/dr-daniel-j-guerra/support

Fear-conditioning learning is a low-threshold enduring psychiatric process that prepares a defense against dangerous phenomena and reduces the need to iteratively relearn the signal. It is a pattern recognition response that can be modulated by experience and the severity of the stress signal and it is a response that deteriorates in the elderly and in certain neuropsycoses and anxiety disorders throughout life. Fear conditioning must be fluid to readjust according to reverse learning. Persistent fear and avoidance of the potential for fear-associated events are common presentations of social anxiety disorder (SAD) and avoidant behavior maintains SAD, thus it prevents the reversal of fear in social situations. The best treatment outcomes are CBT including exposure therapy, which leads to fear extinction. Pharmacotherapy including antidepressants, benzodiazepines, beta-blockers, anticonvulsants, or neuroleptics, are commonly administered with low efficacy. Neuropeptide Y (NPY), a 36-amino acid peptide, is the most abundant and widely distributed neuropeptide in the mammalian brain and it may be involved in social behavior and the fear circuitry, including activities in the amygdala, hippocampus, septum, periaqueductal gray, locus coeruleus, cerebral cortex, basal ganglia, hypothalamus, and thalamus. NPY is also a feeding simulant, regulator of blood pressure, bioenergetics , neuroendocrine hormone responses, neuronal excitability, and neuroplasticity including epigenetic mechanisms. Not surprisingly, exogenous NPY causes a variety of behavioral effects when administered into the brain of rodents including stimulation of food intake when administered into the hypothalamic paraventricular nucleus, and it promotes social interaction when administered into the dorsolateral septum and basolateral amygdala and has anxiolytic and antidepressant-like effects when administered intracerebroventricularly (i.c.v.).NPY also affects different aspects of fear-related behaviors, as shown in fear conditioning studies in rodents. Next time we will link Acid Sphingomyelinase to NPY and the anxiety disorders of the elderly.. Int J Mol Sci. 2020 Nov; 21(21): 8220. --- Send in a voice message: https://anchor.fm/dr-daniel-j-guerra/message Support this podcast: https://anchor.fm/dr-daniel-j-guerra/support

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.09.22.307033v1?rss=1 Authors: Imambocus, B. N., Wittich, A., Tenedini, F. M., Zhou, F., Hu, C., Sauter, K., Varela, E., Heredia, F., Casimiro, A. P., Macedo, A., Yang, C.-H., Schlegel, P., Pankratz, M. J., Miguel-Aliaga, I., Gontijo, A. M., Cardona, A., Soba, P. Abstract: Animals display a plethora of escape behaviors when faced with environmental threats. Selection of the appropriate response by the underlying neuronal network is key to maximize chances of survival. We uncovered a somatosensory network in Drosophila larvae that encodes two escape behaviors through input-specific neuropeptide action. Sensory neurons required for avoidance of noxious light and escape in response to harsh touch, each converge on discrete domains of the same neuromodulatory hub neurons. These gate harsh touch responses via short Neuropeptide F, but noxious light avoidance via compartmentalized, acute Insulin-like peptide 7 action and cognate Relaxin-family receptor signaling in connected downstream neurons. Peptidergic hub neurons can thus act as central circuit elements for first order processing of converging sensory inputs to gate specific escape responses. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.08.25.266080v1?rss=1 Authors: Liu, X., Yeo, S.-H., McQuillan, H. J., Herde, M. K., Hessler, S., Cheong, I., Porteous, R., Herbison, A. E. Abstract: The necessity and functional significance of neurotransmitter co-transmission remains unclear. The glutamatergic KNDy neurons co-express kisspeptin, neurokinin B (NKB) and dynorphin and exhibit a highly stereotyped synchronized behavior that reads out to the gonadotropin-releasing hormone (GnRH) neuron dendrons to drive episodic hormone secretion. Using expansion microscopy, we show that KNDy neurons make abundant close but non-synaptic appositions with the GnRH neuron dendron. Confocal GCaMP6 calcium imaging demonstrated that, of the neurotransmitters co-expressed by KNDy neurons, only kisspeptin was able to activate the GnRH neuron dendron. The selective deletion of kisspeptin from KNDy neurons resulted in mice in which the synchronized behavior of the KNDy neurons was maintained but their ability to drive episodic hormone secretion was abolished. This indicates that KNDy neurons drive episodic hormone secretion through converse modes of highly redundant neuropeptide co-transmission orchestrated by differential postsynaptic neuropeptide receptor expression at their two target sites. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.08.07.240440v1?rss=1 Authors: Atkinson, L. E., Liu, Y., McKay, F., Vandewyer, E., Viau, C., Irvine, A., Rosa, B. A., Li, Z., Marks, N. J., Maule, A. G., Mitreva, M., Beets, I., Li, L. E., Mousley, A. Abstract: Neural circuit synaptic connectivities (the connectome) provide the anatomical foundation for our understanding of nematode nervous system function. However, other non-synaptic routes of communication are known in invertebrates including extrasynaptic volume transmission (EVT), which enables short- and/or long-range communication in the absence of synaptic connections. Although EVT has been highlighted as a facet of Caenorhabditis elegans neurosignaling, no experimental evidence identifies body cavity fluid (pseudocoelomic fluid; PCF) as a vehicle for either neuropeptide or biogenic amine transmission. In the parasitic nematode Ascaris suum FMRFamide-like peptides encoded on flp-18 potently stimulate female reproductive organs but are only expressed in cells that are anatomically distant from the reproductive organ, with no known synaptic connections to this tissue. Here we report a new non-synaptic mode of signaling in nematodes mediated by neuropeptides within the PCF. Our data show that: (i) A. suum PCF (As-PCF) contains a catalogue of neuropeptides including FMRFamide-like peptides and neuropeptide-like proteins; (ii) the A. suum FMRFamide-like peptide As-FLP-18A dominates the As-PCF peptidome; (iii) As-PCF potently modulates nematode reproductive muscle function ex vivo, mirroring the effects of synthetic FLP-18 peptides; (iv) As-PCF activates the C. elegans FLP-18 receptors NPR-4 and -5; (v) As-PCF alters C. elegans behavior and, (vi) FLP-18 and FLP-18 receptors display pan-phylum distribution in nematodes. Here we provide the first direct experimental evidence that supports an extrasynaptic volume route for neuropeptide transmission in nematodes. These data demonstrate non-synaptic signaling within the nematode functional connectome and are pertinent to receptor deorphanisation approaches underpinning drug discovery programs for nematode pathogens. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.07.29.227090v1?rss=1 Authors: Moss, A., Robbins, S., Achanta, S., Kuttippurathu, L., Turick, S., Nieves, S., Hanna, P., Smith, E. H., Hoover, D. B., Chen, J., Cheng, Z., Ardell, J. L., Shivkumar, K., Schwaber, J. S., Vadigepalli, R. Abstract: We developed a spatially-tracked single neuron transcriptomics map of an intrinsic cardiac ganglion - the right atrial ganglionic plexus (RAGP) that is a critical mediator of vagal control of the sinoatrial node (SAN) activity. We developed a 3D representation of RAGP with extensive mapping of neurons and used neuronal tracing to identify the spatial distribution of the subset of neurons that project to the SAN. RNAseq of laser capture microdissected neurons revealed a distinct composition of RAGP neurons compared to CNS neuronal subtypes. High-throughput qPCR of hundreds of laser capture microdissected single neurons led to a surprising finding that cholinergic and catecholaminergic neuronal markers Th and Chat were correlated, suggesting multipotential phenotypes that can drive neuroplasticity within RAGP. Interestingly, no single gene or module was an exclusive marker of RAGP neuronal connectivity to SAN. Neuropeptide-receptor coexpression analysis revealed a combinatorial paracrine neuromodulatory network within RAGP, informing follow-on studies on the vagal control of RAGP to regulate cardiac function in health and disease. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.07.24.219725v1?rss=1 Authors: Klose, M. K., Bruchez, M. P., Deitcher, D. L., Levitan, E. S. Abstract: Neuropeptides control many behaviors, including circadian rhythms. However, because monitoring neuropeptide release in the brain is challenging, analysis of peptidergic circuits often has relied on monitoring surrogates in the soma based on the paradigm that synaptic transmission is mediated exclusively by Ca2+ influx induced by propagating action potentials. Here live imaging demonstrates that neuropeptide release by Drosophila small ventrolateral (s-LNv) clock neurons does not conform to this paradigm. First, neuropeptide release from terminals peaks hours after sunrise, which was not evident from electrical and Ca2+ data. Second, inconsistent with global release by propagating action potentials, release from terminals is preceded by hours by release from the soma, a compartment not usually considered in peptidergic transmission. The timing of release from the two neuronal compartments reflects different mechanisms: terminals require Ca2+ influx, as expected with coupling to electrical activity, while somatic release is based on intracellular IP3 signaling. Upon cell specific disruption of the somatic mechanism, daily neuropeptide release from terminals remains rhythmic and the period of daily locomotor activity is unaffected, but behavioral rhythmicity is reduced. Thus, rhythmic bouts of anatomically, mechanistically and temporally distinct release from a single neuron control neuropeptide dependent features of circadian behavior. Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.04.27.064550v1?rss=1 Authors: Ramachandran, S., Banerjee, N., Bhattacharya, R., Touroutine, D., Lambert, C. M., Schoofs, L., Beets, I., Francis, M. M. Abstract: Neuromodulators promote adaptive behaviors in response to either environmental or internal physiological changes. These responses are often complex and may involve concerted activity changes across circuits that are not physically connected. It is not well understood how neuromodulatory systems act across circuits to elicit complex behavioral responses. Here we show that the C. elegans NLP-12 neuropeptide system, related to the mammalian cholecystokinin system, shapes responses to food availability by selectively modulating the activity of head and body wall motor neurons. NLP-12 modulation of the head and body wall motor circuits is generated through conditional involvement of alternate GPCR targets. The CKR-1 GPCR is highly expressed in the head motor circuit, and functions to enhance head bending and increase trajectory reorientations during local food searching, primarily through stimulatory actions on SMD head motor neurons. In contrast, NLP-12 activation of CKR-1 and CKR-2 GPCRs regulates body bending under basal conditions, primarily through actions on body wall motor neurons. Thus, locomotor responses to changing environmental conditions emerge from conditional NLP-12 stimulation of head or body wall motor neuron targets. Copy rights belong to original authors. Visit the link for more info

In light of Valentine's Day this past Friday, I felt it was fitting to do an episode dedicated to the "love neuropeptide". Oxytocin has been sensationalized a bit; however, there is evidence to support its role in promoting social behavior, bonding, trust, cooperation, and enhancing feelings of attractiveness toward one's partner. However, oxytocin may also enhance negative feelings such as envy, gloating, and prejudice. For more details, make sure to tune in!IG: Dr.SCaligiuriFB: ThePeoplesScientistTwitter: DrSCaligiuriLinked In: Dr. Stephanie CaligiuriTIkTok: Dr.SCaligiuri See acast.com/privacy for privacy and opt-out information.

In this podcast Tabitha Farrar talks to Micheal Lutter about the recently published paper titled: Novel and ultra-rare damaging variants in neuropeptide signaling are associated with disordered eating behaviors   From the paper: Abstract Objective Eating disorders develop through a combination of genetic vulnerability and environmental stress, however the genetic basis of this risk is unknown. Methods To understand the genetic basis of this risk, we performed whole exome sequencing on 93 unrelated individuals with eating disorders (38 restricted-eating and 55 binge-eating) to identify novel damaging variants. Candidate genes with an excessive burden of predicted damaging variants were then prioritized based upon an unbiased, data-driven bioinformatic analysis. One top candidate pathway was empirically tested for therapeutic potential in a mouse model of binge-like eating. Results An excessive burden of novel damaging variants was identified in 186 genes in the restricted-eating group and 245 genes in the binge-eating group. This list is significantly enriched (OR = 4.6, p

Did you know that your body can heal itself of most known diseases? Sounds like a bold claim, but fortunately for us frail bodied humans, it's true. The key is simple and two-fold: Stop doing whatever it was that made you sick in the first place, and give your body whatever it needs to heal itself. In this episode, we present a highly enlightening and inspiring conversation with our guest Wendi Michelle of Next Health, Hollywood's premier wellness center. Wendi not only healed herself of chronic Lyme disease but has also helped many others learn how to become their own doctor and cure their own health issues. Wendi is a veteran biohacker, and has a profound understanding of not only the human body, but also many powerful, yet obscure alternative healing modalities and technologies. In this powerful episode you will learn the secrets of Wendi's own healing miracles, and discover the methods by which you can take control of your body, and live a long and healthy life, free of chronic disease and suffering. Do the world a favor and pass this episode on to one friend who could use some hope and encouragement on their road to recovery. To your health, Luke PS: Part Two drops this Friday! We'll be focusing on the solution-oriented stuff. Don't miss out. PPS: SPECIAL LIMITED DISCOUNT FOR THE AUDIENCE - $79 discount for a week of cryotherapy (if in LA area). Or $375 off towards the Genetic fit test program (locally or long-distance). Just mention your pal Luke. www.next-health.com   Episode breakdown:  My biohacking twin/ a conversation The failure of modern medicine What is Lyme disease, and where did it come from? Are deer to blame? How does the Lyme bacteria have the ability to shapeshift into a fungus when attacked by antibiotics How she cured herself of lyme disease using alternative therapies like intravenous ozone, high dose Vitamin C, Hydrogen Peroxide, and Colloidal Silver   Some of the costly treatments she is thankful to avoid How to boost your immune system by taking care of your gut biome The magic of Neuropeptide shots for pain relief  Giving your body what it needs to heal itself  Getting to know your bodies own wisdom, and creating a diet that works for you Why you should avoid cheese How eating fat makes you skinny How to eat a healthy diet without becoming a control freak The importance of avoiding corn and soy The dangers of vegetable oils Remember... PART TWO drops this Friday. Tune in for the solution-oriented stuff.  Visit this episode's guest page here.   THIS SHOW IS BROUGHT TO YOU BY: ORGANIFI. This product has changed the green juice game for me. A green powdered superfood that comes in portable packets perfect for travel, keeping in your car or bag. On-demand instant green juice that is alkalizing, energizing and gives you mental clarity. What else is so special about it? Zero glycemic index & comes with all 11 most important superfoods: turmeric, chlorella, wheat grass, spirulina, mint, moringa, ashwagandha, lemon, beets, coconut, matcha green tea. Awesome stuff! Save 20% using coupon code "LIFESTYLIST" FOUR SIGMATIC:Melt away stress, boost immunity, relax & sleep deeper, improve productivity, increase brain power, get stimulation without jitters. Sound like all the good stuff you want? Welcome to the medicinal fungi kingdom with Four Sigmatic's highest quality mushroom & herbs in little packets of magical power that you can add to your coffee or warm drink. Your discount hookup is 15% off when you use "THELIFESTYLIST" coupon code.  HELP SUPPORT THIS SHOW! Starting and growing a podcast requires a ton of time, energy, and money. Do you appreciate this information, and want to support my mission to deliver as much life enhancing information as possible to as many people as possible? The easiest, and most effective way you can help is to do this: 1. Go to Lukestorey.com/support and donate towards show production costs 2. Subscribe to the show by clicking “subscribe” in iTunes 3. Write us a review in iTunes 4. Share this show with 1 friend right now You’d be amazed how much these four simple steps do to help us grow! Here’s the magic link for reviews. Thank you from the bottom of my heart for listening, and joining me on this journey we call life.

(Bloomberg) -- Taking Stock with Kathleen Hays and Pimm Fox. Guest: Paul Wahlgren, Managing Director of Skyler Brand Ventures, on luxury skin care and their patended neuropeptide technology used in a new concentrate for the face: XEP-30.

Anxiety disorders, such as posttraumatic stress disorder (PTSD), are characterized by a high prevalence and debilitating symptoms. However, the current first-line treatment for these conditions, which consists of selective serotonin reuptake inhibitors (SSRIs) and cognitive behavioral therapy, alongside symptomatic treatment with benzodiazepines, does not represent by far a functional solution for all affected patients. Therefore, identifying and characterizing novel candidates for alternative anxiolytic therapies are a crucial focus of psychiatric and neurobiological research. This study focuses on Neuropeptide S (NPS), a newly identified endogenous neuropeptide that has been shown to exert strong anxiolytic effects upon intracerebral injection in rodents. In an approach that combines basic research with incipient clinically relevant application, novel mechanisms and brain targets of NPS-mediated anxiolytic effects were identified, and a noninvasive application procedure also applicable in patients, namely the intranasal administration, was established for the first time for NPS in mouse models. In a first step, the feasibility of intranasal NPS delivery was established in mice using fluorophore-coupled NPS to allow intracerebral tracking. This method permitted for the first time tracking of intranasally applied substances within the brain at a single-cell resolution. These results not only proved the applicability of intranasal NPS administration in the mouse, but also allowed identification and characterization of hitherto undescribed cerebral NPS target cells, which were shown to be most likely exclusively neurons. Moreover, specific uptake of fluorescently labeled NPS in the hippocampus provided the first direct evidence linking this brain region, a well-known major player in the regulation of fear expression, to the NPS circuitry. Further investigation into the functional role of the hippocampus in NPS-elicited anxiolytic effects revealed that local microinjections of NPS into the ventral CA1 (vCA1) region are sufficient to elicit anxiolysis in C57BL6/N mice on the elevated plus maze (EPM). In a second step, behavioral and molecular effects of intranasal NPS treatment were characterized in C57BL/6N mice. Intranasal application of NPS was shown here to produce anxiolytic effects similar to those described by others after intracerebral injection. This finding represents the basis for the implementation of a future NPS-based therapy via nasal sprays in patients suffering from anxiety disorders. Furthermore, the molecular effects of NPS treatment on cerebral protein expression were examined here for the first time. This research led to identification of novel downstream targets of NPS-mediated regulation in the hippocampus and the prefrontal cortex. These new targets include proteins involved in the glutamatergic system and in synaptic plasticity, both of which are known to be dysregulated in anxiety disorders. Finally, the effects of intranasal NPS treatment, hitherto described only in non-pathological animal models, were examined for the first time in mouse models of anxiety disorders, namely the high anxiety behavior (HAB) mice and a mouse model of PTSD. In HAB mice, NPS treatment elicited anxiolytic effects similar to those observed in C57BL/6N mice. In the mouse model of PTSD, NPS counteracted disease-related changes in expression levels of hippocampal synaptic proteins. To sum up, this work expands the current state-of-knowledge concerning the molecular and mechanistic background of NPS-mediated anxiolysis by characterizing the role of the hippocampus in the NPS circuitry and by identifying novel downstream targets of NPS. The data on anxiolytic effects of intranasal NPS treatment especially in mouse models of anxiety disorders furthermore establishes the therapeutic potential of NPS as a novel anxiolytic treatment.

A neurobiologist studies social behaviors and neuromodulation

The final episode features hormones, an aromatic that contains the combination of neuropeptides that enhance the efficacy of human pheromones, herbals, using topicals including COQ10, DMAE and ALA to regenerate collagen and elastin to repair skin damage and the positive impact of intimate relationships and sex on healthy-aging. Anti-aging expert, Nicholas Perricone, MD, FACN, a board certified clinical dermatologist, and founder and CEO of N.V. Perricone M.D., Ltd. and author of three New York Times #1 Best Sellers, The Perricone Promise, The Perricone Prescription and The Wrinkle Cure and his most recent book, Dr. Perricone's 7 Secrets to Beauty, Health and Longevity discusses new techniques in the preservation of beauty and healthy-aging.

Bei der vorliegenden Literaturstudie handelt es sich um eine Zusammenfassung der funktionellen Morphologie der Nebenniere von Haussäugetieren. Vergleichend werden einzelne Strukturen und Funktionen der Nebenniere beim Menschen und einigen Nagern beschrieben. Die Nebennieren (Glandula suprarenalis s. adrenalis) von Menschen und Haussäugetieren bestehen aus zwei sowohl funktionell als auch embryologisch verschiedenen Anteilen: der Nebennierenrinde (Cortex glandulae suprarenalis) und dem Nebennierenmark (Medulla glandulae suprarenalis). Die Nebennierenrinde entsteht aus mesodermalen Anteilen, während die Zellen des Nebennierenmarks Abkömmlinge der sympathoadrenalen Zelllinie sind, die aus der Neuralleiste wandern. Die Nebenniere enthält im Vergleich zu anderen Organen vermehrt Blutgefäße und Nerven. Die zentripetal verlaufenden Blutgefäße, die hohe Konzentrationen von Rindenhormonen enthalten, beeinflussen direkt die adrenomedullären Zellen. Histologisch lässt sich die Nebennierenrinde zwischen der Kapselschicht und der Medulla, morphologisch und funktionell aufgrund ihrer Steroidkapazität, von außen nach innen, in drei verschiedene Zonen, Zona glomerulosa, Zona fasciculata und Zona reticularis unterteilen: Die Zona glomerulosa synthetisiert Mineralokortikoide, die Zona fasciculata Glukokortikoide und die Zona reticularis Androgen bei Primaten, sowie Glukokortikoide bei anderen Spezies. Ultrastrukturell geben das ER (endoplasmatisches Reticulum), die Mitochondrien und Lipidtröpfchen in den adrenokortikalen Zellen wesentliche Hinweise auf Veränderungen von funktionellen Zuständen. Das Nebennierenmark enthält hauptsächlich A- und NA-chromaffine Zellen und in geringer Menge small granule chromaffin cells (SGC) sowie die Ganglienzellen. Das Verhältnis von A-Zellen zu NA-Zellen sowie die Lokalisation der chromaffinen Zellen im Nebennierenmark variieren zwischen den Spezies. Die chromaffinen Zellen setzen Adrenalin, Noradrenalin und andere Substanzen ins Blut frei und üben dabei vielfältige Kontrolle auf verschiedene Gewebe sowie Organe aus. Katecholamine und regulatorische Peptide können direkt oder indirekt durch den Blutfluss die adrenokortikalen Zellen regulieren. Die Regulation der adrenalen Funktion ist äußerst komplex. Die Nebennieren produzieren zahlreiche Hormone, Neuropeptide, Neurotransmitter und Zytokine. Die Zellen innerhalb der Nebenniere beeinflussen sich gegenseitig und passen so die Funktion der Nebenniere an verschiedene Situationen an. Die chromaffinen Zellen wurden in der Nebennierenrinde, und umgekehrt, die adrenokortikalen Zellen innerhalb der Medulla bei manchen Spezies nachgewiesen. Diese Tatsache weist auf eine topographische und funktionelle Beziehung zwischen Nebennierenrinde und Nebennierenmark hin, welche neuronal und parakrin reguliert wird. Ferner spielen die Nebennieren eine wichtige Rolle bei Reaktionen in verschiedenen Stresssituationen sowie auch im Immunsystem.

Bisher wird in der Literatur keine standardisierte tierexperimentelle Methode beschrieben, mit der in der Frühphase der Knochenheilung ausreichend interfragmentäres Gewebevolumen für die histologische, biochemische oder immunocytochemische Analyse gewonnen werden kann. Es wird ein entsprechend variiertes Distanzosteosynthesemodell vorgestellt, das aus dem Frakturbereich der Kaninchentibia ausreichend Gewebe für differenzierte Analysen liefert. Mit guter Vaskularität, hoher Knochenappositionsrate sowie schneller Zellproliferation und –differenzierung scheint der Kaninchenknochen für relativ begrenzte Untersuchungszeiträume und für Fragestellungen zur Frühphase der Knochenheilung besonders geeignet. Untersuchungen an diesem Modell zum qualitativen und quantitativen Nachweis unterschiedlicher Zellen im interfragmentären Raum zu verschiedenen Zeitpunkten der Frakturheilung werden beschrieben, besondes berücksichtigt dabei neuropeptidpositive Nervenfasern, vor allem das Calcitonin gene-related peptide (CGRP). Daten und Fakten zu Vorkommen, Verteilung, Struktur, Sequenz und Biochemie des Peptids, wie sie die aktuelle internationale Literatur dokumentiert, ergänzen den experimentellen Teil der Arbeit. An der Tibia von insgesamt 30 Tieren wurde – in einem standardisierten operativen Verfahren – ein definierter interfragmentärer Raum geschaffen. Nach Ablauf des vorgesehenen Beobachtungszeitraumes erfolgte die Tötung der Tiere vor Entnahme des jeweiligen Präparates. Nach Freilegen der Osteosynthese wurde im interfragmentären Raum ein definiertes 3mm dickes zylinderförmiges Segment entnommen und fixiert; außerdem wurden jeweils osteotomienah und –fern zwei weitere Gewebeproben aus dem Markraum der Tibia isoliert. Die anschließenden Untersuchungen im gewonnenen Material umfaßten mikroskopische Analysen der Morphologie von Hämatom, Fibringerüst, Granulationsgewebe während unterschiedlicher Phasen der Frakturheilung, die immunocytochemische Darstellung neuropeptidpositiver Fasern und mikroskopische qualitative und quantitative Analysen neuropeptidpositiver Fasern zu den gewählten Zeitpunkten. Bei den nach 5 Tagen getöteten Tieren fanden sich in den untersuchten Präparaten vor allem ein konsolidiertes Frakturhämatom. Ein feines Fibrinnetz war in den Randgebieten des interfragmentären Raumes zu sehen. Gefäßlakunen, Kapillaren und Mineralisationsinseln waren nicht erkennbar. In der zweiten Tiergruppe konnte gezeigt werden, daß nach 10 Tagen der Abbau schollig zerfallener Erythrozyten durch Phagozyten weiter vorangeschritten war; Der Zellgehalt verringerte sich insgesamt zugunsten einer beginnenden Faserbildung. Das Fibrinnetz hatte weiter zugenommen und zeigte vereinzelt Septen; Am 15. Tag postop. war das Fibrinnetz nicht mehr erkennbar, stattdessen neu entstandenes Bindegewebe, Gefäßstrukturen und vereinzelte Mineralisations-inseln. Perivaskulär, an den Gefäßsinusoiden und begleitend zu Precursorzell-ansammlungen ließen sich frühestens am 10. und spätestens am 15. Tag nach der Osteotomie mit Hilfe immunocytochemischer Verfahren neuropeptidpositive Fasern nachweisen. In diesen Untersuchungen konnte CGRP im Gegensatz zu bisher durchgeführten Versuchen unterschiedlicher Autoren erstmals schon in der Frühphase der Frakturheilung nachweisen werden. Dies ist von besonderer Bedeutung, da die Innnervation des Knochens ein hochentwickeltes regulatorisches Element repräsentiert, das sowohl lokale Anforderungen registriert wie auch durch Freisetzung aktiver Neuropeptide den gesamten Knochenstoffwechsel unmittelbar beeinflußt. Wie aus früheren Studien hervorgeht, sind Neuropeptide dort zahlreich vorhanden, wo hohe Knochenstoffwechselraten zu verzeichnen sind. Außerdem sind sie häufig in unmittelbarer Nähe von Blutgefäßen konzentriert. Die Beobachtung, daß CGRP während der frühen Frakturheilung hauptsächlich in der Nähe von Blutgefäßen auftritt, legt den Schluß nahe, daß es durch seine bekannten vasodilatierenden Eigenschaften den Blutfluß in die verletzte Region verstärkt und so die Knochenheilung unterstützt. Experimentelle Untersuchungen zeigen, daß neurale Einflüsse auf den Knochen von Neuropeptiden vermittelt werden. Wie alle regulativen Proteine und Faktoren agieren Neuropeptide über Second-messenger-Systeme und können auch in niedrigen Konzentrationen das Remodeling beeinflussen. Durch ihre sensorische Funktion nehmen Nervenfasern mechanische Ansprüche wahr und setzen im weiteren Verlauf Neuropeptide frei. Sie sind in der Lage, die Lücke zwischen systemischen und primär lokalen regulativen Elementen zu füllen. Grundsätzlich ist die Selbstheilung des Knochens durch die Größe des Defekts limitiert. Meist sind chirugische Interventionen nötig und die unterschiedlichsten Hilfsmittel unumgänglich. In jüngster Zeit sind v.a. Knochenersatzmaterialien von zunehmender Bedeutung. Ihre Zukunft scheint in der Entwicklung osteoinduktiver Implantate zu liegen. Auch unter diesem Aspekt gewinnt unser Distanzosteosynthesemodell besondere Bedeutung. Der große interfragmentäre Raum bietet optimale Bedingungen für gezielte Untersuchungen, die zur Weiterentwicklung von Knochen-ersatzmaterialien führen können.

Diese Arbeit konnte eine inhibitorische Kontrolle der HPA-Achse unter basalen und Streß-induzierten Bedingungen durch intrazerebrales OXT zeigen, die zumindest anteilig über Neuronen des hypothalamischen PVN vermittelt wird. Die neurohypophysäre Freisetzung von OXT und das angstbezogene Verhalten scheinen hingegen von zentralem OXT unabhängig zu sein. Eine ähnliche Funktion bei der Regulation der HPA-Achse und des Angstverhaltens wurde bereits für AVP beschrieben. Also sind beide Neuropeptide, wenn sie zentral freigesetzt werden, an der Modulation der Streßreaktion beteiligt und diese Funktion ist dissoziiert von ihrer peripheren Freisetzung und Wirkung. Während der peripartalen Periode, die Trächtigkeit, Geburt und Laktation einschließt, sind morphologische und funktionelle Veränderungen von OXT-Neuronen bekannt. So erfolgt eine spezifische Aktivierung des Systems durch Reproduktions-bezogene Stimuli, während, wie auch hier bestätigt werden konnte, die Streßreaktivität der selben Neuronen inhibiert wird. Ähnlich ist die Streßreaktivität der HPA-Achse während Trächtigkeit und Laktation reduziert. So wurde in dieser Arbeit erstmalig eine Suppression der ACTH- und Corticosteron-Freisetzung auch während des Geburtsvorganges beschrieben. Die Untersuchung der Wechselwirkungen des zentralen OXT-Systems und der hypophysären Sekretion nach Streß-Exposition zeigte deutlich veränderte Effekte intrazerebral freigesetzten OXTs während der peripartalen Periode. Bezüglich der HPA-Achse konnte ein Nachlassen der tonischen Inhibition durch zentrales OXT beobachtet werden, während nun die Streßinduzierte neurohypophysäre Freisetzung von OXT sowie das angstbezogene Verhalten auf der plus-maze dadurch kontrolliert wurden. Die während der peripartalen Periode verminderte Streßreaktivität der HPA-Achse wird also, entgegen der primären Hypothese, offensichtlich nicht durch das aktivierte OXT-System vermittelt. Da sowohl die HPA-Achse als auch das OXT-System z. T. durch endogene Opiate beeinflußt werden, lag die Vermutung nahe, daß Opiat-Rezeptoren die Reproduktionsbezogenen Modifikationen der neuroendokrinen Streßreaktivität vermitteln. Diese Hypothese konnte in der Tat bestätigt werden. Die Stimulation der HPA-Achse virginer Weibchen durch endogene Opiate verschwand gegen Ende der Trächtigkeit und resultierte in einer effektiven Inhibition der HPA-Achse während der Geburt. Während die neurohypophysäre OXTFreisetzung bei virginen Tieren nicht durch Opiate beeinflußt wurde, entwickelte sich während der späten Trächtigkeit und während der Geburt einen effektive Kontrolle durch endogene Opiate. Die zentrale Freisetzung von OXT im PVN unterlag keinen merklichen Reproduktions-bedingten Modifikationen, wurde jedoch unabhängig von der peripheren Sekretion durch endogene Opiate beeinflußt. Auch hier kehrte sich die bei virginen Tieren deutliche Stimulation der OXT-Freisetzung im PVN in eine effektive Inhibition während der Trächtigkeit um. Diese Modifikationen in der Wirkung von Opiat-Rezeptoren scheinen sowohl lokal als auch funktionell eng begrenzt zu sein, da auch bei trächtigen Tieren veränderte Opiat-Wirkungen weder hinsichtlich der OXT-Freisetzung im SON noch der verhaltensbiologischen Streßbewältigung beobachtet werden konnten. Die primäre Intention der Arbeit, die funktionelle Relevanz zentralen OXTs bei der Expression von Angstverhalten und der Streßreaktivität der HPA-Achse zu klären, konnte mittels des Tiermodells der peripartalen Periode nicht weiter verfolgt werden. Erstens verschwand die bei männlichen und virginen Tieren beschriebene Kontrolle der HPA-Achse durch endogenes OXT während Trächtigkeit und Laktation. Zweitens deutet die nur bei trächtigen und laktierenden Tieren beobachtete anxiolytische Wirkung zentralen OXTs eine während der peripartalen Periode von neuroendokrinen Parametern dissoziierte Regulation verhaltensbiologischer Streßreaktionen an. Drittens erlauben die vielfältigen systemischen Modifikationen während der Reproduktion, einschließlich schwankender Konzentrationen von Sexualhormonen und der Veränderungen des endogenen Opiat-Systems, keine unbeeinflußte Untersuchung einzelner Streßhormon-Systeme. Deshalb war es sinnvoller, sich dem Tiermodell der HAB/LAB-Ratten zuzuwenden, das pathophysiologische Veränderungen der Emotionalität vorweist. Hier konnte die Assoziation von verhaltensbiologischen und neuroendokrinen Streßreaktionen selektiv untersucht werden. Zunächst wurden die HAB/LAB-Tiere einer verhaltensbiologischen Charakterisierung unterzogen, die stabile Linien-spezifische Verhaltens-Unterschiede unter allen untersuchten Bedingungen bestätigen konnte. Die neuroendokrine Charakterisierung der Zuchttiere zeigte bei HAB-Männchen eine Assoziation der extremen Ängstlichkeit mit einer erhöhten Reaktivität der HPA-Achse auf einen emotionalen Stressor (open-arm). Jedoch konnte weder im Blut noch im PVN unter basalen oder stimulierten Konditionen eine differentielle Freisetzung von OXT gezeigt werden. Mit diesem Ergebnis konnte kein kausaler Zusammenhang des Linien-spezifisch unterschiedlichen Angstverhaltens und der unterschiedlichen Reaktivität der HPA-Achse auf Streß mit der zentralen oder peripheren OXT-Freisetzung festgestellt werden. Da jedoch eine erhöhte basale und Schwimmstreßinduzierte Freisetzung von AVP im PVN männlicher HABs ermittelt werden konnte, wurden weitere Untersuchungen bezüglich dieses Neuropetides unternommen. So konnte bei männlichen HAB-Ratten mittels in situ Hybridisierung eine signifikant höhere basale Expression von AVP-mRNA in magnozellulären Neuronen des PVN nachgewiesen werden. Die periphere AVP-Sekretion unter basalen und open-arm-stimulierten Konditionen zeigte weder Unterschiede zwischen HABs und LABs noch eine effektive Stimulation durch Streß- Exposition, so daß die erhöhte AVP-mRNA-Expression bei HABs die Grundlage für die gesteigerte zentrale Freisetzung bilden dürfte. Diese Ergebnisse signalisieren eine Interaktion von extremem Angstverhalten, erhöhter Streßreaktivität der HPA-Achse und gesteigerter Freisetzung von AVP im PVN bei HAB-Ratten. Unterstützt wurde diese Theorie auch durch die Normalisierung des pathologischen Dex/CRH-Tests bei HABs durch Applikation eines AVP-Antagonisten. Trotz dieser überzeugenden Hinweise sollten noch weitere Untersuchungen folgen, die durch Ausschalten der hypothalamischen AVP-Freisetzung mittels Antagonisten oder antisense targeting die Kausalität dieser Zusammenhänge klären könnten. Neben der gesteigerten Reaktivität der HPA-Achse zeigten HAB-Ratten eine höhere periphere Freisetzung von Prolaktin unter basalen und Streß-stimulierten Bedingungen. Da dieses Ergebnis u. a. eine differentielle Aktivierung des zentralen Dopaminund /oder Serotonin-Systems andeutet, sollten auch in dieser Hinsicht weitere Untersuchungen erfolgen, da auch diese Neurotransmitter mittelbaren oder unmittelbaren Einfluß auf die HPA-Achse ausüben können und zudem bei der Entstehung von Angst- /Depressions-Erkrankungen beteiligt zu sein scheinen. Wie durch die cross-mating-Studie bestätigt, liegt bei HAB/LAB-Ratten eine eindeutige genetische Determination des zwischen den Linien differierenden angstbezogenen Verhaltens vor. Die Untersuchung perinataler Faktoren ergab zwar eine mögliche hormonelle Beeinflussung von HAB-Föten durch eine chronisch erhöhte Plasmakonzentration mütterlichen Corticosterons, jedoch dürfte diese allenfalls einen modulierenden Einfluß auf die fötale Entwicklung haben. So bietet dieses Tiermodell einzigartige Möglichkeiten nicht nur zum Studium der neuroendokrinen Grundlagen psychopathologischer Emotionalität sondern auch der genetischen Korrelate. Solche genetischen Studien, z. B. die Suche nach "quantitative trait loci" oder genetische Assoziationsstudien bei den HAB/LAB-Ratten werden möglicherweise einen großen Beitrag zum Verständnis der Entstehung psychiatrischer Erkrankungen beim Menschen leisten und zu einer spezifischeren pharmakologischen Therapie führen können.