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This groundbreaking study has shed light on the potential of lycopene, a powerful antioxidant found in tomatoes, to combat depression-like behavior in mice subjected to chronic social defeat stress, a model for chronic stress. Researchers found that lycopene treatment significantly alleviated these behaviors. The study's key discovery centers around synaptic plasticity, the brain's ability to modify and strengthen connections between neurons, which is often impaired by stress. The research suggests that lycopene may exert its beneficial effects by enhancing synaptic plasticity, specifically through the BDNF-TrkB signaling pathway. This pathway is essential for neuronal growth, survival, and function, and plays a critical role in mood regulation. This breakthrough discovery linking lycopene, synaptic plasticity, and stress opens new avenues for depression research and potential treatment strategies. While these pre-clinical findings in mice are promising, further human studies are necessary to validate these results and explore the therapeutic potential of lycopene for depression.Disclaimers:"This information is for educational purposes only and should not be interpreted as medical advice.""The study discussed was conducted on mice. Further research, including human clinical trials, is needed to confirm these findings.""Always consult with a qualified healthcare professional before making any changes to your diet, supplement regimen, or treatment plan, especially if you have a medical condition or are taking medications.""This channel does not provide medical advice."#Lycopene #Depression #MentalHealth #BDNF #SynapticPlasticity #Neurobiology #PreclinicalResearch #MouseModel #ChronicSocialDefeatStress #Antioxidant #Breakthrough #StressResearchLycopene, depression, mental health, BDNF, synaptic plasticity, chronic social defeat stress, mouse model, antidepressant, natural remedies, carotenoid, brain health, neurobiology, TrkB pathway, mood regulation, behavioral study, preclinical research, lycopene benefits, dietary interventions, nutritional psychiatry, tomato benefits, antioxidant, brain function, neuroplasticity, synaptic strengthening, neuronal connections, animal model of depression, synaptic modulation, neurotrophic factors, stress, chronic stress, breakthrough researchZeng, Q., Gao, J., Liu, Y., Li, X., & Luo, J. (2023). Lycopene alleviates depression-like behavior in chronic social defeat stress-induced mice by promoting synaptic plasticity via the BDNF–TrkB pathway. Food Science and Nutrition, 11(1), 585–595. https://doi.org/10.1002/fsn3.70003
NOTHING DISCUSSED IN THIS PODCAST IS MEDCAL ADVICE In this weeks episode of Bioactive Riley (@cannabichem) talks with Chris Witowski the CEO and cofounder of the biotech company Psilera investigating new psychedelic substances for the treatment of conditions like anxiety, depression, and PTSD. Chris discusses the general pipeline for how Psilera goes about investigating new drug candidates as well as the advantages to non-hallucinogenic psychedelic drugs. Thanks for listening and subscribing to this channel- mad love Reach Chris and the rest of the Psilera team at: info@psilera.com twitter: @Psilera IG: @Psilera Papers discussed in this episode: "Psychedelics promote plasticity by directly binding to BDNF receptor TrkB" https://www.nature.com/articles/s4159... Thank you to our podcast sponsor Boveda, and check out humidity packs for your cannabis at https://bovedainc.com/
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.07.30.551185v1?rss=1 Authors: Javed, S., Chang, Y.-T., Cho, Y., Lee, Y.-J., Chang, H.-C., Haque, M., Lin, Y. C., Huang, W.-H. Abstract: Retinoic acid-induced 1 (RAI1) haploinsufficiency causes Smith-Magenis syndrome (SMS), a genetic disorder with symptoms including hyperphagia, hyperlipidemia, severe obesity, and autism phenotypes. Rai1 is a transcriptional regulator with a pan-neural expression pattern and hundreds of downstream targets. The mechanisms linking neural Rai1 to body weight regulation remain unclear. Here we find that hypothalamic brain-derived neurotrophic factor (Bdnf)-TrkB signalling is disrupted in SMS (Rai1+/-) mice. Selective Rai1 loss from all Bdnf-producing cells or from Bdnf-producing neurons in the paraventricular nucleus of the hypothalamus (PVH) induced obesity in mice. Electrophysiological recordings revealed that Rai1 ablation increased inhibitory synaptic transmission to PVHBdnf neurons and decreased intrinsic neuronal excitability. Chronic treatment of SMS mice with a partial agonist of tropomyosin receptor kinase B (TrkB), the cognate Bdnf receptor, delayed obesity onset. This treatment also partially rescued disrupted lipid profiles, insulin intolerance, and stereotypical repetitive behaviour in SMS mice. These data argue that Rai1 regulates body weight and metabolic function through hypothalamic Bdnf-producing neurons and that targeting TrkB signalling might improve associated SMS phenotypes. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
https://pdsp.unc.edu/rothlab/https://www.med.unc.edu/pharm/directory/bryan-roth-md-phd/Bryan Roth, MD, PhDMICHAEL HOOKER DISTINGUISHED PROFESSOR, PHARMACOLOGY DIRECTOR, NIMH PSYCHOACTIVE DRUG SCREENING PROGRAM, ESHELMAN SCHOOL OF PHARMACY FELLOW OF THE AMERICAN ACADEMY OF ARTS AND SCIENCES MEMBER OF THE NATIONAL ACADEMY OF MEDICINE OF THE NATIONAL ACADEMY OF SCIENCES MEMBER, LINEBERGER COMPREHENSIVE CANCER CENTERBryan Roth, MD, PhD, a Professor of Pharmacology at the University of North Carolina.Dr. Roth has been studying the molecular mechanisms of psychedelics since the 1980s. They discuss: serotonin 2A receptors in the mammalian brain; psychedelics & neuroplasticity; classic psychedelics (e.g. LSD, psilocybin, DMT) compared to drugs like ketamine & MDMA; TrkB receptors & BDNF; engineering novel drugs & psychiatric treatment methods; latest findings in psychedelic science.
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.07.14.549007v1?rss=1 Authors: Niu, C., Yue, X., An, J. J., Xu, H., Xu, B. Abstract: The brain-derived neurotrophic factor (BDNF) and its high-affinity receptor tropomyosin-related kinase receptor B (TrkB) are widely expressed in the central nervous system. It is well documented that neurons express BDNF and full-length TrkB (TrkB.FL), and a lower level of truncated TrkB (TrkB.T). With conflicting results, glial cells also have been reported to express BDNF and TrkB. In the current study, we employed a more sensitive and reliable genetic method to characterize the expression of BDNF and TrkB in glial cells in the mouse brain. We utilized three Cre mouse strains in which Cre recombinase is expressed in the same cells as BDNF, TrkB.FL, or all TrkB isoforms, and crossed them to Cre-dependent EGFP reporter mice to label BDNF- or TrkB- expressing cells. We performed immunohistochemistry with glial cell markers to examine the expression of BDNF and TrkB in microglia, astrocytes, and oligodendrocytes. Surprisingly, we found no BDNF- or TrkB- expressing microglia in the brain and spinal cord. Consistent with previous studies, most astrocytes only express TrkB.T in the adult brain. Moreover, there are a small number of astrocytes and oligodendrocytes that express BDNF, the function of which is to be determined. We also found that oligodendrocyte precursor cells, but not mature oligodendrocytes, express both TrkB.FL and TrkB.T in the adult brain. These results not only clarify the expression of BDNF and TrkB in glial cells, but also open opportunities to investigate previously unidentified roles of BDNF and TrkB in glial cells. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
Nick talks to Bryan Roth, MD, PhD, a Professor of Pharmacology at the University of North Carolina. Dr. Roth has been studying the molecular mechanisms of psychedelics since the 1980s. They discuss: serotonin 2A receptors in the mammalian brain; psychedelics & neuroplasticity; classic psychedelics (e.g. LSD, psilocybin, DMT) compared to drugs like ketamine & MDMA; TrkB receptors & BDNF; engineering novel drugs & psychiatric treatment methods; latest findings in psychedelic science.Support the showSign up for the free weekly Mind & Matter newsletter:[https://mindandmatter.substack.com/?sort=top]Learn how you can further support the podcast: [https://mindandmatter.substack.com/p/how-to-support-mind-and-matter]Become a Premium Subscriber to access full content library, including full premium episodes:[https://mindandmatter.substack.com/subscribe?utm_source=menu&simple=true&next=https%3A%2F%2Fmindandmatter.substack.com%2F]Try the Lumen device to optimize your metabolism for weight loss or athletic performance. Use code MIND for $50 off:[https://www.lumen.me/shop?fid=8731&utm_source=influencer&utm_medium=influencer&discount=MIND]
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.06.29.547069v1?rss=1 Authors: Rodriguez, L. A., Tran, M. N., Garcia-Flores, R., Pattie, E. A., Kim, S.-H., Shin, J. H., Lee, Y. K., Divecha, H. R., Montoya, C., Jaffe, A. E., Torres, L. C., Page, S. C., Martinowich, K. C. Abstract: The lateral septum (LS), a GABAergic structure located in the basal forebrain, is implicated in social behavior, learning and memory. We previously demonstrated that expression of tropomyosin kinase receptor B (TrkB) in LS neurons is required for social novelty recognition. To better understand molecular mechanisms by which TrkB signaling controls behavior, we locally knocked down TrkB in LS and used bulk RNA-sequencing to identify changes in gene expression downstream of TrkB. TrkB knockdown induces upregulation of genes associated with inflammation and immune responses, and downregulation of genes associated with synaptic signaling and plasticity. Next, we generated one of the first atlases of molecular profiles for LS cell types using single nucleus RNA-sequencing (snRNA-seq). We identified markers for the septum broadly, and the LS specifically, as well as for all neuronal cell types. We then investigated whether the differentially expressed genes (DEGs) induced by TrkB knockdown map to specific LS cell types. Enrichment testing identified that downregulated DEGs are broadly expressed across neuronal clusters. Enrichment analyses of these DEGs demonstrated that downregulated genes are uniquely expressed in the LS, and associated with either synaptic plasticity or neurodevelopmental disorders. Upregulated genes are enriched in LS microglia, associated with immune response and inflammation, and linked to both neurodegenerative disease and neuropsychiatric disorders. In addition, many of these genes are implicated in regulating social behaviors. In summary, the findings implicate TrkB signaling in the LS as a critical regulator of gene networks associated with psychiatric disorders that display social deficits, including schizophrenia and autism, and with neurodegenerative diseases, including Alzheimer's. 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/2023.06.26.546542v1?rss=1 Authors: Cook, A. A., Leung, T. C. S., Rice, M., Nachman, M., Zadigue-Dube, E., Watt, A. J. Abstract: Spinocerebellar ataxia type 6 (SCA6) is a rare disease that is characterized by cerebellar dysfunction. Patients have progressive motor coordination impairment, and postmortem brain tissue reveals degeneration of cerebellar Purkinje cells and a reduced level of cerebellar brain-derived neurotrophic factor (BDNF). However, the pathophysiological changes underlying SCA6 are not fully understood. We carried out RNA sequencing of cerebellar vermis tissue in a mouse model of SCA6, which revealed widespread dysregulation of genes associated with the endo-lysosomal system. Since disruption to endosomes or lysosomes could contribute to cellular deficits, we examined the endo-lysosomal system in SCA6. We identified alterations in multiple endosomal compartments in the Purkinje cells of SCA6 mice. Early endosomes were enlarged, while the size of the late endosome compartment was reduced. We also found evidence for impaired trafficking of cargo to the lysosomes. As the proper functioning of the endo-lysosomal system is crucial for the sorting and trafficking of signaling molecules, we wondered whether these changes could contribute to previously identified deficits in signaling by BDNF and its receptor tropomyosin kinase B (TrkB) in SCA6. Indeed, we found that the enlarged early endosomes in SCA6 mice accumulated both BDNF and TrkB. Furthermore, TrkB recycling to the cell membrane in recycling endosomes was reduced, and the late endosome transport of BDNF for degradation was impaired. Therefore, mis-trafficking due to aberrant endo-lysosomal transport and function could contribute to SCA6 pathophysiology through alterations to BDNF-TrkB signaling, as well as mishandling of other signaling molecules. Deficits in early endosomes and BDNF localization were rescued by chronic administration of a TrkB agonist, 7,8-DHF, that we have previously shown restores motor coordination and cerebellar TrkB expression. The endo-lysosomal system is thus both a novel locus of pathophysiology in SCA6, and a promising therapeutic target. 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/2023.04.09.536152v1?rss=1 Authors: Rhymes, E. R., Simkin, R. L., Surana, S. N., Tong, Y., Villarroel-Campos, D., Yang, X.-L., Schiavo, G., Sleigh, J. N. Abstract: Charcot-Marie-Tooth disease (CMT) is a form of genetic peripheral neuropathy caused by mutations in many functionally diverse genes. The aminoacyl-tRNA synthetase (ARS) enzymes, which charge amino acids to partner tRNAs for protein synthesis, represent the largest protein family linked to CMT aetiology, suggestive of pathomechanistic commonalities. Dominant intermediate CMT type C (DI-CMTC) is caused by YARS1 mutations driving a toxic gain-of-function in the encoded tyrosyl-tRNA synthetase (TyrRS), which is mediated by exposure of consensus neomorphic surfaces through conformational changes of the mutant protein. In this study, we first showed that DI-CMTC-causing TyrRSE196K mis-interacts with the extracellular domain of the BDNF receptor TrkB, an aberrant association we have previously characterised for CMT type 2D (CMT2D)-causing mutant glycyl-tRNA synthetase. We then performed temporal neuromuscular assessments of recently generated YarsE196K mice modelling DI-CMT. Through in vivo imaging of exposed sciatic nerves, we determined that YarsE196K homozygotes display a selective, age-dependent impairment in axonal transport of neurotrophin-containing signalling endosomes, phenocopying CMT2D mice. Increasing BDNF in DI-CMTC mouse muscle, through injection of recombinant protein or muscle-specific gene therapy, resulted in complete axonal transport correction. Therefore, this work identifies a pathomechanism common to neuropathies caused by mutations in YARS1 and GARS1, and highlights the potential of boosting BDNF in muscles as a therapeutic strategy to treat ARS-related CMTs. 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/2023.03.01.530671v1?rss=1 Authors: Kasanga, E., Han, Y., Navarrete, W., McManus, R., Shifflet, M., Parry, C., Barahona, A., Manfredsson, F., Nejtek, V., Richardson, J. R., Salvatore, M. F. Abstract: Although glial cell line-derived neurotrophic factor (GDNF) showed efficacy in preclinical and early clinical studies to alleviate parkinsonian signs in Parkinsons disease (PD), later trials did not meet primary endpoints, giving pause to consider further investigation. While GDNF dose and delivery methods may have contributed to diminished efficacy, one crucial aspect of these clinical studies is that GDNF treatment across all studies began ~8 years after PD diagnosis; a time point representing several years after near 100% depletion of nigrostriatal dopamine markers in striatum and at least 50% in substantia nigra (SN), and is later than the timing of GDNF treatment in preclinical studies. With nigrostriatal terminal loss exceeding 70% at PD diagnosis, we utilized hemi-parkinsonian rats to determine if expression of GDNF family receptor, GFR-alpha1, and receptor tyrosine kinase, RET, differed between striatum and SN at 1 and 4 weeks following a 6-hydroxydopamine (6-OHDA) lesion. Whereas GDNF expression changed minimally, GFR-alpha1 expression decreased progressively in striatum and in tyrosine hydroxylase positive (TH+) cells in SN, correlating with reduced TH cell number. However, in nigral astrocytes, GFR-alpha1 expression increased. RET expression decreased maximally in striatum by 1 week, whereas in the SN, a transient bilateral increase occurred that returned to control levels by 4 weeks. Expression of brain-derived neurotrophic factor (BDNF) or its receptor, TrkB, were unchanged throughout lesion progression. Together, these results reveal that differential GFR-alpha1 and RET expression between the striatum and SN, and cell-specific differences in GFR-alpha1 expression in SN, occur during nigrostriatal neuron loss. Targeting loss of GDNF receptors appears critical to enhance GDNF therapeutic efficacy against nigrostriatal neuron loss. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
Akeem Gardner is the Founder and CEO of Canurta. In 2018 Akeem acquired an Industrial Hemp License from Health Canada and began to farm hemp as he embarked on his entrepreneurial venture, which allowed him to meet with the University of Guelph professors in the summer of 2019 to begin the cannflavin project. At CannMed 23, he will present “Targeting Glioblastoma Invasion and Survival with Cannabis-Derived Flavonoids”. During our conversation, Akeem provides a preview of that presentation, and insights into the following topics: What are flavonoids and how are they different from cannabinoids and terpenes The flavonoids that are unique to cannabis, also known as cannflavins Why cannflavins are not as well-studies as other cannabis compoundsHow Akeem became interested in cannflavinsCantura's method for isolating, capturing, and concentrating these moleculesPotential medical applications for cannflavins and how they may work in combination with cannabinoids Thanks to This Episode's Sponsor: Canurta Canurta is a preclinical biotechnology company pioneering the discovery and production of novel, polyphenol-rich ingredients to improve chronic disease prevention and recovery. Their research and technology unlocks the significant anti-inflammatory, anti-viral, anti-cancer and neuroprotective potential of plant polyphenols. Canurta aspires to improve health outcomes, promote longevity and pull humans and animals out of the cycle of chronic disease. To learn more visit canurta.com Additional Resources Interference of neuronal TrkB signaling by the cannabis-derived flavonoids cannflavins A and BAkeem Gardner on LinkedInRequest an Invitation to CannMed 23Review the Podcast!CannMed ArchiveCannMed Community Board [Facebook Group]Healthcare Provider Medical Cannabis Research Study
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.02.10.528062v1?rss=1 Authors: Akopian, A., Ruparel, S., Hovhannisyan, A. H., Lindquist, K., Tram, M., Perez, D., Mecklenburg, J., Salmon, A., Merlo, J., Corey, T. Abstract: Myogenous temporomandibular disorders (TMD-M) are the most prevalent group of painful orofacial conditions, and the second most frequent among musculoskeletal pain conditions. TMD-M is associated with an increased responsiveness of nerves innervating the masseter (MM), temporal (TM), medial pterygoid closing (MPM) and lateral pterygoid gliding muscles (LPM). Treatment of this disorder remains difficult and is further complicated by each muscle having diverse and functionally distinct nerve innervation. This study examined expression of sensory markers in MM, TM and LPM of adult male common marmosets, a type of non-human primate. Using immunohistochemistry, we found that masticatory muscles were predominantly innervated with A-fibers (NFH+). All C-fibers (pgp9.5+/NFH-) observed in masticatory muscles were peptidergic (CGRP+) and lacked antibody labeling for mrgprD, trpV1 and the silent nociceptive marker, CHRNA3. The proportion of C- to A-fibers was highest in LPM, while MM had a minimal percentage (6-8%) of C-fibers. Interestingly, C-fibers in masticatory muscle may have myelin sheath, since many NFH- nerves were labeled with GFAP+. A-fiber types were also dissimilar among these muscles. Thus, there are substantially more peptidergic A-fibers (CGRP+/NFH+) in TM and LPM compared to MM. Almost all A-fibers in MM expressed trkC, with some of them having trkB and parvalbumin (PV). In contrast, a lesser number of TM and LPM nerves expressed trkC, lacked trkB and had fewer PV+ fibers in LPM. Along with sensory fibers, the masticatory muscles contain sympathetic fibers (tyrosine hydroxylase; TH+), which are located around blood vessels. This TH expression was absent in trigeminal neurons. Overall, the masticatory muscles of male marmosets have distinct expression patterns when compared to each muscle of the jaw and cutaneous fibers innervated by DRG neurons. 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/2023.02.03.526966v1?rss=1 Authors: Surana, S., Villarroel-Campos, D., Panzi, C., Novoselov, S. S., Richter, S., Zanotti, G., Schiavo, G. Abstract: Tetanus toxin is one of the most potent neurotoxins and is the causative agent of tetanus. This neurotoxin binds to the neuromuscular junction and, after internalisation into motor neurons, undergoes long-distance axonal transport and transcytosis into spinal cord inhibitory interneurons. Inside the cytoplasm of interneurons, the catalytic chain of the toxin blocks neurotransmitter release, leading to spastic paralysis. Whilst the effects of tetanus toxin intoxication have been extensively studied, the molecular composition of its receptor complex is still poorly understood. We have previously shown that the extracellular matrix proteins nidogens are essential for binding of the toxin to the neuromuscular junction. In this study, we show that the tyrosine phosphatase LAR interacts with the nidogen-tetanus toxin complex and enables its uptake into motor neurons. Binding of LAR to the toxin complex is mediated by its fibronectin III domains, which we have harnessed to inhibit tetanus toxin entry into motor neurons. Surprisingly, this function of LAR is independent of its role in regulating the neurotrophic activity of the TrkB receptor, which has previously been shown to augment the axonal transport of signalling endosomes containing tetanus neurotoxin. These findings identify a multi-subunit complex acting as a protein receptor for tetanus neurotoxin, and demonstrate a novel endocytic trafficking route for extracellular matrix proteins in neurons. Our study paves the way for dissecting the molecular mechanisms that control the recognition and uptake of physiological ligands and pathological proteins at the neuronal plasma membrane, as well as their targeting to the axonal retrograde pathway for long-distance transport within the nervous system. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC
Dr. Ya-Jen Chiu from the Department of Life Science at National Taiwan Normal University in Taipei, discusses a research paper she co-authored that was published by Aging (Aging-US) in Volume 14, Issue 18, entitled, “Novel TRKB agonists activate TRKB and downstream ERK and AKT signaling to protect Aβ-GFP SH-SY5Y cells against Aβ toxicity.” DOI - https://doi.org/10.18632/aging.204306 Corresponding authors - Chiung-Mei Chen - cmchen@cgmh.org.tw, Ying-Chieh Sun - sun@ntnu.edu.tw, Guey-Jen Lee-Chen - t43019@ntnu.edu.tw Video - https://www.youtube.com/watch?v=1rT96K9VeZw Transcript - https://aging-us.net/2022/11/01/behind-the-study-novel-trkb-agonists-activate-trkb-and-downstream-erk-and-akt-signaling/ Abstract Decreased BDNF and impaired TRKB signaling contribute to neurodegeneration in Alzheimer's disease (AD). We have shown previously that coumarin derivative LM-031 enhanced CREB/BDNF/BCL2 pathway. In this study we explored if LM-031 analogs LMDS-1 to -4 may act as TRKB agonists to protect SH-SY5Y cells against Aβ toxicity. By docking computation for binding with TRKB using 7,8-DHF as a control, all four LMDS compounds displayed potential of binding to domain d5 of TRKB. In addition, all four LMDS compounds exhibited anti-aggregation and neuroprotective efficacy on SH-SY5Y cells with induced Aβ-GFP expression. Knock-down of TRKB significantly attenuated TRKB downstream signaling and the neurite outgrowth-promoting effects of these LMDS compounds. Among them, LMDS-1 and -2 were further examined for TRKB signaling. Treatment of ERK inhibitor U0126 or PI3K inhibitor wortmannin decreased p-CREB, BDNF and BCL2 in Aβ-GFP cells, implicating the neuroprotective effects are via activating TRKB downstream ERK, PI3K-AKT and CREB signaling. LMDS-1 and -2 are blood-brain barrier permeable as shown by parallel artificial membrane permeability assay. Our results demonstrate how LMDS-1 and -2 are likely to work as TRKB agonists to exert neuroprotection in Aβ cells, which may shed light on the potential application in therapeutics of AD. Sign up for free Altmetric alerts about this article - https://aging.altmetric.com/details/email_updates?id=10.18632%2Faging.204306 Keywords - aging, Alzheimer's disease, TRKB agonists, Aβ, neuroprotection, therapeutics About Aging-US Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways. Please visit our website at https://www.Aging-US.com and connect with us: SoundCloud - https://soundcloud.com/Aging-Us Facebook - https://www.facebook.com/AgingUS/ Twitter - https://twitter.com/AgingJrnl Instagram - https://www.instagram.com/agingjrnl/ YouTube - https://www.youtube.com/agingus LinkedIn - https://www.linkedin.com/company/aging/ Pinterest - https://www.pinterest.com/AgingUS/ Media Contact 18009220957 MEDIA@IMPACTJOURNALS.COM
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2022.10.31.514622v1?rss=1 Authors: Tombesi, G., Chen, C., Favetta, G., Plotegher, N., Sevegnani, M., Marte, A., Battisti, I., Civiero, L., Onofri, F., Piccoli, G., Arrigoni, G., Manzoni, C., Parisiadou, L., Greggio, E. Abstract: Dendritic spines, small protrusions of the dendrites, constitute the postsynaptic compartment of excitatory synapses. Filamentous actin is the major cytoskeletal constituent of dendritic spines, whose dynamic nature allows them to plastically remodel their shape and volume in response to stimuli. Notably, dendritic spine abnormalities are linked to a number of neurological and neurodegenerative disorders. Here, we show that the Parkinson disease (PD)-associated kinase LRRK2 participates in spine remodeling processing by binding a panel of actin-related proteins enriched in postsynaptic compartments. Phosphorylation of LRRK2 Ser935, which controls LRRK2 subcellular localization, rapidly increases upon brain-derived neurotrophic factor (BDNF) stimulation of differentiated SH-SY5Y cells and primary mouse neurons. Affinity-purification coupled with mass spectrometry (AP-MS/MS) analysis revealed that LRRK2 interactome is significantly reshaped upon BDNF stimulation, with an interconnected network of actin cytoskeleton-associated proteins increasing their binding to LRRK2. Accordingly, Lrrk2 knockout primary neurons exhibit impaired response to BDNF-induced spinogenesis and TrkB signaling. In vivo, one-month old Lrrk2 knockout mice exhibit defects in spine maturation, a phenotype that disappears with age. Finally, by comparing the phosphoproteomes of Lrrk2 wild-type versus Lrrk2 G2019S PD mutant synaptosomes, we found that the differentially phosphorylated proteins are enriched in categories related to postsynaptic structural organization. Taken together, our study discloses a critical function of LRRK2 in shaping dendritic spine morphology during development and defines a mechanistic role of the kinase in postsynaptic actin-cytoskeletal dynamics. 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/2022.10.17.512538v1?rss=1 Authors: Shiu, F. H., Skelton, H., Berglund, K., Fernandez, A. M., Gutekunst, C.-A. N., Robinson, E. R., Wang, Z., Gross, R. E. Abstract: Previous studies in human patients and rodent models of Parkinsons disease (PD) have established neuroprotection of dopaminergic (DA) neurons in substantia nigra pars compacta (SNC) by physical exercise, but the precise origin of this neuroprotective effect has yet to be elucidated. In this study, we tested a hypothesis that enhanced activity of DA neurons in SNC results in neuroprotection using the unilateral 6-hydroxydopamine (6-OHDA) injection model in mice. To increase activity of DA neurons chronically and specifically, we injected an adeno-associated viral vector carrying a step-function luminopsin (SFL) - a fusion protein of light-emitting Gaussia luciferase and light-sensing step-function channelrhodopsin 2 - into SNC ipsilateral to 6-OHDA using the pan-neuronal human synapsin I promoter or the Cre-lox system in transgenic mice expressing the recombinase under control of the tyrosine hydroxylase (TH) promoter. Upon application of SFL substrate, coelenterazine (CTZ), the luciferase moiety of luminopsin emits bioluminescence which in turn activate the opsin moiety. Daily injection of CTZ for 4 weeks ameliorated a stereotypical behavior, namely ipsiversive rotations, induced by unilateral 6-OHDA. In addition, postmortem immunohistochemistry against TH revealed less severe neurodegeneration of DA neurons compared to vehicle-injected control animals. Furthermore, when mice were pretreated with ANA-12, a selective antagonist for tropomyosin receptor kinase B (TrkB), the behavioral improvement and neuroprotective effect were diminished. These results suggest that increased neuronal activity of DA neurons provides neuroprotection against 6-OHDA injury and alleviates its symptoms through the brain-derived neurotrophic factor-TrkB pathway. 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/2022.09.07.506934v1?rss=1 Authors: Jetsonen, E., Didio, G., Winkel, F., Llach Pou, M., Boj, C., Kuczynski-Noyau, L., Voikar, V., Guirado, R., Taira, T., Lauri, S. E., Castren, E., Umemori, J. Abstract: Critical period-like plasticity (iPlasticity) can be reinstated in the adult brain by several interventions, including drugs and optogenetic modifications. We have demonstrated that a combination of iPlasticity with optimal training improves behaviors related to neuropsychiatric disorders. In this context, the activation of TrkB, a receptor for BDNF, in Parvalbumin positive (PV+) interneurons has a pivotal role in cortical network changes. However, it is unknown if the activation of TrkB in PV+ interneurons is important for other plasticity-related behaviors, especially for learning and memory. Here, using mice with heterozygous conditional TrkB deletion in PV+ interneurons (PV-TrkB hCKO) in Intellicage and fear erasure paradigms, we show that chronic treatment with fluoxetine, a widely prescribed antidepressant drug that is known to promote the activation of TrkB, enhances behavioral flexibility in spatial and fear memory, largely depending on the expression of the TrkB receptor in PV+ interneurons. In addition, hippocampal long-term potentiation (LTP) was enhanced by chronic treatment with fluoxetine in wild-type mice, but not in PV-TrkB hCKO mice. Transcriptomic analysis of PV+ interneurons after fluoxetine treatment indicated intrinsic changes in synaptic formation and downregulation of enzymes involved in perineuronal net (PNN) formation. Consistently, immunohistochemistry has shown that the fluoxetine treatment alters PV expression and reduces PNNs in PV+ interneurons, and here we show that TrkB expression in PV+ interneurons is required for these effects. Together, our results provide molecular and network mechanisms for the induction of critical period-like plasticity in adulthood. 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/2022.08.26.505413v1?rss=1 Authors: Biojone, C., Cannarozzo, C., Seiffert, N., Diniz, C., Brunello, C., Castren, E., Casarotto, P. Abstract: Brain-derived neurotrophic factor (BDNF) acting upon its receptor Neurotrophic tyrosine kinase receptor 2 (NTRK2, TRKB) plays a central role in the development and maintenance of synaptic function and activity- or drug-induced plasticity. TRKB possesses an inverted cholesterol-recognition and alignment consensus sequence (CARC), suggesting this receptor can act as a cholesterol sensor. We have recently shown that antidepressants drugs directly bind to the CARC domain of TRKB dimers, and that this binding as well as biochemical and behavioral responses to antidepressants are lost with a mutation in the TRKB CARC motif (Y433F). However, it is not clear if this mutation can also compromise the receptor function and lead to behavioral alterations. Here, we observed that Y433F mutation does not alter BDNF binding to TRKB, or BDNF-induced dimerization of TRKB. In this line, primary cultures from embryos of heterozygous Y433F mutant mice (hTRKB.Y433F) are responsive to BDNF-induced activation of TRKB, and samples from adult mice do not show any difference on TRKB activation compared to wild-type littermates (TRKB.wt). The behavioral phenotype of hTRKB.Y433F mice is indistinguishable from the wild-type mice in cued fear conditioning, contextual discrimination task or the elevated plus maze, whereas mice heterozygous to BDNF null allele show a phenotype in context discrimination task. Taken together, our results indicate that Y433F mutation in the TRKB CARC motif does not show signs of loss-of-function of BDNF responses, while antidepressant binding to TRKB and responses to antidepressants are lost in Y433F mutants, making them an interesting mouse model for antidepressant research. Copy rights belong to original authors. Visit the link for more info Podcast created by PaperPlayer
Welcome to The Nonlinear Library, where we use Text-to-Speech software to convert the best writing from the Rationalist and EA communities into audio. This is: A Brief Excursion Into Molecular Neuroscience, published by Jan on April 10, 2022 on LessWrong. TL;DR: Poking fun at complicated nomenclature (p̴͓̂͘á̴̻͌s̶̻̗͋͑ṯ̸̹̈́̌à̶̳), identifying a pretty important signaling factor in the brain, and arbitrating (part of) the Guzey/Mendonça debate. Previously in this series: How to build a mind - neuroscience edition. The Emperor's New Ǫ̵͎͊G̶̦̉̇l̶͉͇̝̽͆̚i̷͔̓̏͌c̷̱̙̍̂͜k̷̠͍͌l̷̢̍͗̃n̷̖͇̏̆å̴̤c̵̲̼̫͑̎̆ (Ǫ̵͎͊G̶̦̉̇l̶͉͇̝̽͆̚i̷͔̓̏͌c̷̱̙̍̂͜k̷̠͍͌l̷̢̍͗̃n̷̖͇̏̆å̴̤c̵̲̼̫͑̎̆ is an intentionally garbled version of the word O-GlcNAc. The reasons for garbling it will hopefully become clear while reading this essay!) Flashback: It's June 7th, 2017. The transformer architecture will drop on the arxiv in 5 days, Hugh Hefner will die in less than 3 months, and the computational neuroscience community is having a field day on Twitter. It started with this tweet from Michael Nitabach from Yale School of Medicine complaining about opaque jargon in theoretical papers: There was a bit of goofy back and forth about the (un)importance of mathematical vocabulary in neuroscience, some attempts at explaining the term, and eventually the call for a workshop on "Manifold-splaining", which happened half a year later. There are some things to be said here about how we use terminology or what manifolds actually are, but I'm bringing this up because I distinctly remember an offhand comment that someone made at that workshop. The comment was that it's unfair that experimentalists get to write things like "O-GlcNAc signaling entrains the circadian clock by inhibiting BMAL1/CLOCK ubiquitination," and nobody gives them hell for writing their papers in Klingon. Or at least they are not getting enough hell for it. When I was first confronted with the alphabet soup that calls itself molecular neuroscience, I was awed by my colleagues, who appeared to be fluent in speaking p̴͓̂͘á̴̻͌s̶̻̗͋͑ṯ̸̹̈́̌à̶̳. It took me a year or two to figure out that they also do not know what most of the terms mean - and for most abbreviations, there are only a handful of people in the world who can decode them. But nobody likes to acknowledge that they don't know what things mean publicly. Therefore everybody nods along when they read Ǫ̵͎͊G̶̦̉̇l̶͉͇̝̽͆̚i̷͔̓̏͌c̷̱̙̍̂͜k̷̠͍͌l̷̢̍͗̃n̷̖͇̏̆å̴̤c̵̲̼̫͑̎̆. So it's fine if you don't know what it means. Almost nobody does. Let's talk about BDNF. Perhaps you are the kind of person that takes the preceding paragraphs as a challenge, and you'd like to learn to speak p̴͓̂͘á̴̻͌s̶̻̗͋͑ṯ̸̹̈́̌à̶̳ yourself. Or perhaps you like to read about different levels of abstraction, what we gain by using them, and how we can transition between them. Or perhaps you're having a slow day and want to learn something funky. In all those cases, this essay is certainly for you. But perhaps you are a very busy person, and you tend to be very selective about how you spend your time. Perhaps you want to be sure that if you're going to dive into this mess of molecules, you'll be able to get a Pareto-sized chunk of insight in return. Perhaps you've been hurt before and have difficulties trusting any molecule. In all those cases, this section is here to assuage you. Let me motivate why you might care about the protagonist of this essay, the "brain-derived neurotrophic factor" (BDNF). Argument from interestingness. BDNF has shown up repeatedly in the rationality-sphere over the last years: Alexey Guzey's thesis about why you shouldn't sleep circles around BDNF. Natália Mendonça's counter-thesis that you should sleep all the time attacks Guzey's claims about BDNF. Scott Alexander explained a few years ago how an increase in BDNF plays a central role in the function of antidepressants. Then there was a big Cell paper that argued for the importance of the canonical BDNF receptor (TrkB) rather than BDNF....
Link to original articleWelcome to The Nonlinear Library, where we use Text-to-Speech software to convert the best writing from the Rationalist and EA communities into audio. This is: A Brief Excursion Into Molecular Neuroscience, published by Jan on April 10, 2022 on LessWrong. TL;DR: Poking fun at complicated nomenclature (p̴͓̂͘á̴̻͌s̶̻̗͋͑ṯ̸̹̈́̌à̶̳), identifying a pretty important signaling factor in the brain, and arbitrating (part of) the Guzey/Mendonça debate. Previously in this series: How to build a mind - neuroscience edition. The Emperor's New Ǫ̵͎͊G̶̦̉̇l̶͉͇̝̽͆̚i̷͔̓̏͌c̷̱̙̍̂͜k̷̠͍͌l̷̢̍͗̃n̷̖͇̏̆å̴̤c̵̲̼̫͑̎̆ (Ǫ̵͎͊G̶̦̉̇l̶͉͇̝̽͆̚i̷͔̓̏͌c̷̱̙̍̂͜k̷̠͍͌l̷̢̍͗̃n̷̖͇̏̆å̴̤c̵̲̼̫͑̎̆ is an intentionally garbled version of the word O-GlcNAc. The reasons for garbling it will hopefully become clear while reading this essay!) Flashback: It's June 7th, 2017. The transformer architecture will drop on the arxiv in 5 days, Hugh Hefner will die in less than 3 months, and the computational neuroscience community is having a field day on Twitter. It started with this tweet from Michael Nitabach from Yale School of Medicine complaining about opaque jargon in theoretical papers: There was a bit of goofy back and forth about the (un)importance of mathematical vocabulary in neuroscience, some attempts at explaining the term, and eventually the call for a workshop on "Manifold-splaining", which happened half a year later. There are some things to be said here about how we use terminology or what manifolds actually are, but I'm bringing this up because I distinctly remember an offhand comment that someone made at that workshop. The comment was that it's unfair that experimentalists get to write things like "O-GlcNAc signaling entrains the circadian clock by inhibiting BMAL1/CLOCK ubiquitination," and nobody gives them hell for writing their papers in Klingon. Or at least they are not getting enough hell for it. When I was first confronted with the alphabet soup that calls itself molecular neuroscience, I was awed by my colleagues, who appeared to be fluent in speaking p̴͓̂͘á̴̻͌s̶̻̗͋͑ṯ̸̹̈́̌à̶̳. It took me a year or two to figure out that they also do not know what most of the terms mean - and for most abbreviations, there are only a handful of people in the world who can decode them. But nobody likes to acknowledge that they don't know what things mean publicly. Therefore everybody nods along when they read Ǫ̵͎͊G̶̦̉̇l̶͉͇̝̽͆̚i̷͔̓̏͌c̷̱̙̍̂͜k̷̠͍͌l̷̢̍͗̃n̷̖͇̏̆å̴̤c̵̲̼̫͑̎̆. So it's fine if you don't know what it means. Almost nobody does. Let's talk about BDNF. Perhaps you are the kind of person that takes the preceding paragraphs as a challenge, and you'd like to learn to speak p̴͓̂͘á̴̻͌s̶̻̗͋͑ṯ̸̹̈́̌à̶̳ yourself. Or perhaps you like to read about different levels of abstraction, what we gain by using them, and how we can transition between them. Or perhaps you're having a slow day and want to learn something funky. In all those cases, this essay is certainly for you. But perhaps you are a very busy person, and you tend to be very selective about how you spend your time. Perhaps you want to be sure that if you're going to dive into this mess of molecules, you'll be able to get a Pareto-sized chunk of insight in return. Perhaps you've been hurt before and have difficulties trusting any molecule. In all those cases, this section is here to assuage you. Let me motivate why you might care about the protagonist of this essay, the "brain-derived neurotrophic factor" (BDNF). Argument from interestingness. BDNF has shown up repeatedly in the rationality-sphere over the last years: Alexey Guzey's thesis about why you shouldn't sleep circles around BDNF. Natália Mendonça's counter-thesis that you should sleep all the time attacks Guzey's claims about BDNF. Scott Alexander explained a few years ago how an increase in BDNF plays a central role in the function of antidepressants. Then there was a big Cell paper that argued for the importance of the canonical BDNF receptor (TrkB) rather than BDNF....
In this podcast episode, George D. Demetri, MD, and Alexander Drilon, MD, discuss emerging data on the efficacy, safety, and clinical role of second-generation TRK inhibitors that can overcome acquired resistance to first-generation agents in NTRK fusion–positive solid tumors. Topics include:Mechanisms of acquired resistance to TRK inhibitor therapyClinical trial data on the second-generation inhibitors selitrectinib and repotrectinibSafety profiles of first- vs second-generation TRK inhibitorsPresenters:George D. Demetri, MDProfessor of MedicineHarvard Medical SchoolHarvard UniversityCo-Director, Ludwig Center at HarvardSenior Vice President for Experimental TherapeuticsDirector, Sarcoma CenterDana-Farber Cancer InstituteBoston, MassachusettsAlexander Drilon, MDChief, Early Drug DevelopmentAttending, ThoracicMemorial Sloan Kettering Cancer CenterNew York, New YorkLink to full program, including downloadable slides:https://bit.ly/2YFIPfr
In this episode, George D. Demetri, MD, and Alexander Drilon, MD, discuss key clinical data leading to FDA approvals and current indications for first-generation TRK inhibitors in NTRK fusion–positive solid tumors and ROS1-positive NSCLC. Topics include:Basket trials leading to FDA approvals of larotrectinib and entrectinibCurrent pan-tumor indications for first-generation TRK inhibitors in NTRK fusion–positive solid tumors as well as ROS1-positive NSCLCSequencing treatment with TRK inhibition in patients with solid tumorsClinically relevant similarities and differences between larotrectinib and entrectinibPresenters:George D. Demetri, MDProfessor of MedicineHarvard Medical SchoolHarvard UniversityCo-Director, Ludwig Center at HarvardSenior Vice President for Experimental TherapeuticsDirector, Sarcoma CenterDana-Farber Cancer InstituteBoston, MassachusettsAlexander Drilon, MDChief, Early Drug DevelopmentAttending, ThoracicMemorial Sloan Kettering Cancer CenterNew York, New YorkLink to full program, including downloadable slidesets:https://bit.ly/2YFIPfr
In this episode, George D. Demetri, MD, and Alexander Drilon, MD, discuss the biologic rationale behind testing for NTRK fusions in patients with various solid tumors, along with clinical strategies for testing. Topics include:Differences between NTRK fusions vs gene mutationsFrequency of NTRK fusions by age and tumor typeWhen to test patients for NTRK fusions and interpreting reportsMethods of testing: multiplex gene testing, next-generation sequencing of DNA vs RNA, immunohistochemistry, and liquid biopsyPresenters:George D. Demetri, MDProfessor of MedicineHarvard Medical SchoolHarvard UniversityCo-Director, Ludwig Center at HarvardSenior Vice President for Experimental TherapeuticsDirector, Sarcoma CenterDana-Farber Cancer InstituteBoston, MassachusettsAlexander Drilon, MDChief, Early Drug DevelopmentAttending, ThoracicMemorial Sloan Kettering Cancer CenterNew York, New YorkLink to full program:https://bit.ly/2YFIPfrLink to slideset based on this podcast:https://bit.ly/3amgU6w
导读：TATA，Sasha飔,Litchi，小艺责编：Effie Liu主播：可盐胖胖背景音乐：夏影（麻枝淮）
导读：TATA，Sasha飔,Litchi，小艺责编：Effie Liu主播：可盐胖胖背景音乐：夏影（麻枝淮）
Diabetics who received 1 g of vitamin C daily showed improvements in blood pressure, oxidative stress Khon Kaen University (Thailand), May 21, 2021 Findings from a randomized, double-blind, cross-over trial reported on February 25, 2021 in the Chinese Journal of Physiology revealed an association between intake of vitamin C and a reduction in blood pressure before and after exercise among men and women with type 2 diabetes. “During exercise, mechanical stress on the arterial wall is increased, leading to an increased release of vasodilators by the endothelium (e.g., nitric oxide, bradykinin, etc.),” explained authors C. Boonthongkaew and colleagues at Khon Kaen University in Thailand. “This response can attenuate blood pressure (BP) after acute exercise at low, moderate, and high intensity in normotensive individuals. However, the magnitude of this effect seems to decline in type 2 diabetes patients because of endothelial dysfunction.” The trial included 24 type 2 diabetics with poorly controlled disease who received 1,000 milligrams vitamin C or a placebo daily for six weeks, followed by a six-week washout period, followed by six weeks of the alternate intervention. For inclusion in the study, participants were required to have a blood pressure of ≤140/90 mmHg or less, maintained if necessary with antihypertensive treatment. Twenty-minute low-intensity exercise sessions were conducted on the day before and the last day of each treatment period. Blood pressure was measured before, immediately after and 60 minutes after the exercise sessions. Blood samples collected before and after exercise were analyzed for plasma vitamin C levels, markers of lipid peroxidation and nitric oxide concentration. Compared to pre-intake, participants who received vitamin C experienced an average 12.8 mmHg reduction in systolic BP and an 8.9 mmHg reduction in diastolic BP when at rest before exercise. Immediately after exercise, systolic and diastolic BP were lower by 11.4 mmHg and 6.8 mmHg, and an hour after exercise, systolic and diastolic BP were lower by 12.5 mmHg and 8.9 mmHg in the vitamin C group compared to baseline values. No significant differences between pre- and post-treatment measurements occurred in the placebo group. When compared to the placebo, participants who received vitamin C also had lower systolic and diastolic BP before and after the post-supplementation exercise sessions. Post-intake, plasma vitamin C and nitric oxide levels were higher, and markers of lipid peroxidation were lower among vitamin C patients before and immediately after exercise compared to baseline, while the placebo group experienced no significant changes. And when compared to the placebo, vitamin C and nitric oxide were higher and lipid peroxidation markers were lower before and after the exercise session among participants who had received the vitamin. In their discussion of the findings, the authors remarked that vitamin C’s ability to decrease oxidative stress helps prevent nitric oxide from being degraded by free radicals, which results in higher nitric oxide levels that benefit endothelial function and BP. They announced that the study is the first to report the effect of vitamin C compared to a placebo on BP before and within an hour after exercise. “This study suggests that 6‑week vitamin C [intake] decreased pre-exercise and postexercise blood pressures, possibly due to improved oxidative stress and nitric oxide release,” they concluded. Making mindfulness meditation more helpful starts with understanding how it can be harmful Brown University, May 18, 2021 Mindfulness-based meditation programs have emerged as a promising treatment for conditions ranging from stress to sleeplessness to depression. In some cases, they're even offered to people—schoolkids or employees, for example—who aren't actively seeking help or who haven't been screened for suitability. Yet most research and discourse about these programs focuses only on their benefits, with little investigation of the risks or the potential for adverse effects. A recent review of nearly 7,000 studies of meditation practices found that less than 1% of them measured adverse effects. Willoughby Britton, an associate professor of psychiatry and human behavior at Brown University, said that this is largely because assessing adverse effects (a process known as "harms monitoring") in non-pharmacological treatments like mindfulness-based meditation programs is difficult to do well. To address that gap, Britton conducted a new study on adverse effects in mindfulness-based programs that identified common obstacles to harms monitoring and, importantly, showed how to address them. The study also found that the rates of adverse effects from mindfulness were similar to those found in other psychological treatments. The study was published on May 18 in Clinical Psychological Science. "Our ultimate goal is to maximize the efficacy of mindfulness-based meditation while minimizing harms," said Britton, who directs the Clinical and Affective Neuroscience Laboratory at Brown. "In order to address risks and modify treatment accordingly, you need thorough and detailed knowledge about potential harms. Our study, the most comprehensive of its kind, provides a blueprint for how to accurately assess the risks of mindfulness-based meditation programs." Why no one wants to talk about meditation's adverse effects The adverse effects of mindfulness-based meditation programs are often an unpleasant topic for providers and participants alike, Britton said. For the study, she and her colleagues reviewed the most current harms monitoring best practices from regulatory agencies like the World Health Organization, the National Institutes of Health and the U.S. Food and Drug Administration. In the paper, they outlined the key considerations around assessing adverse effects, including hesitancy of participants to report negative reactions to treatment because of feelings of shame or a desire to please the researcher or instructor. Researchers and mindfulness teachers (Britton is both) are understandably more focused on the help they can provide than any harm they could cause. As a result, a lack of negative feedback from participants is often interpreted as evidence of absence of harm. "It's very easy for our enthusiasm and desire to help to become a kind of blindness," Britton explained. Another complicating factor, she said, is the lack of knowledge of proper harms assessment. "Often the mindfulness teacher will ask the class, 'Did anyone have any challenges with your meditation practice this week?'" Britton said. "But participants, in general, tend to avoid answering open-ended questions asked by the teacher in a public setting. Research has shown that having someone other than the teacher ask specific questions in a private setting will increase the likelihood of honest reporting." Finally, she highlighted the fact that term "adverse" is a highly subjective judgment that can vary across people and even across the same person in different contexts. "The re-living of a previous trauma may be healing for some and destabilizing for others, in the same way that the drowsiness caused by cold medicine—or meditation—may be undesirable or 'adverse' in the morning but highly desirable before bed," she said. What's more, Britton added, the literature shows that mental health treatment providers (like therapists or doctors) may dismiss patient complaints or reframe them as a sign that the therapy is working. Designing a model assessment Britton's research team followed 24 current harms monitoring guidelines to assess the nature and frequency of meditation-related adverse effects in mindfulness-based programs. The study participants were representative of typical meditators in the U.S.: predominantly middle-age women seeking methods to self-manage mild to severe levels of anxiety, depression and stress. After completing one of three versions of an eight-week mindfulness meditation program, participants were interviewed by a researcher unaffiliated with the treatment about their experiences, with 44 questions based on previous research of meditation-related challenges. To more accurately and thoroughly capture patient perspectives, this study allowed each participant to evaluate the emotional tone or "valence" of each of 44 meditation-related experiences as well as the impact it had on their life and functioning. By asking participants specific questions about duration and impact, researchers were able to differentiate temporary distress, negative-impact side effects and "lasting bad effects." In this way, the researchers sought to clarify which effects were experienced as "adverse" on a case-by-case basis. To accommodate the varying definitions of harm, results were reported in tiers of severity ranging from "transient distress during meditation" (i.e., temporary) to "enduring impairment in functioning"—or "lasting bad effects." The "what" is as important as the "how" The significance of the study, Britton said, has as much to do with what it found as how it found it. "The fact that meditation can cause altered states, for example, isn't news: It's something that people have been talking about for centuries," Britton said. "What we haven't been very good about is measuring the impact and significance of these states on individual participants." Of the 96 participants, 58% reported at least one meditation-related adverse effect, which ranged from perpetual hypersensitivity to nightmares to traumatic re-experiencing. Meditation-related adverse effects with negative impacts on functioning occurred in 37% of the sample. Six percent of the sample had "lasting bad effects," or impairments in functioning lasting more than one month. Notably, the researchers say, this rate is similar to those of other psychological treatments. In the study, meditation-related effects with negative impacts tended to be associated with signs of what's called dysregulated arousal—for example, the participants reported feeling anxious, hyper-stimulated or emotionally flat or disconnected after meditating. This is important for instructors and participants to note, Britton said, because unlike the experiences of anxiety or insomnia, a feeling of being dissociated or emotionally checked-out is not always experienced as unpleasant and can provide some relief, especially for a person suffering from intense anxiety. Yet in the study, this feeling of dissociation tended to predict more significant and lasting impairment in functioning. "This is where the differentiation between valence and impact becomes important, because the valence, or emotional tone, of an experience might be not particularly distressing at the time," Britton said. "Meditators are often taught to reappraise their experience as not being problematic, and to accept it for what it is. Our results are basically saying that when it comes to dissociation, this approach isn't going to work." Britton and colleagues also found that the open-ended question "Have you had any unexpected, unpleasant, adverse or challenging experiences as a result of mindfulness meditation practice during or following the program?" underestimated the true rate by 70%, confirming the inadequacy of open-ended questions compared to specific ones. The study concludes that the active ingredient of these therapeutic programs, which is mindfulness meditation practice, can be associated with both transient distress and enduring negative impacts on life and functioning. Britton said that it is important to note that adverse effects and benefits are not mutually exclusive: many of the same participants who reported adverse effects also reported improvements in depression. Britton noted that the intent of the study, as well as of her broader research, is not to discourage mindfulness-based meditation programs—rather, it is to generate findings on both the positive and negative effects so that providers and meditators can make informed decisions. She compared mindfulness to aspirin, as an example. This medicine-cabinet staple can cause nausea, heartburn and stomach cramps—and taking a daily aspirin can cause gastrointestinal bleeding in some people. But these potential adverse effects do not take away from aspirin's many benefits. Instead, detailed knowledge about the benefits and risks allows practitioners to make educated, effective and safe recommendations to specific patients. "That's where we need to get with mindfulness, too," Britton said. "Our study is an attempt to bring harms monitoring up to the standards of other treatments so that providers can identify events that require monitoring and intervention in order to maximize the safety and efficacy of mindfulness-based meditation." Vitamin B6, vitamin D and green tea compound could improve uterine fibroids Sandro Pertini Hospital (Italy), May 19, 2021 In an article whose title asks the question, “Uterine fibroids treatment: do we have new valid alternative?” findings from researchers from Sandro Pertini Hospital in Rome suggest the answer may be “yes.” The article, published in the April 2021 issue of the European Review for Medical and Pharmacological Sciences reported a benefit for intake of vitamin B6, vitamin D and epigallocatechin gallate (EGCG, a flavonoid that occurs in green tea) in women with uterine fibroids (myomas), benign tumors of the uterus that affect a significant percentage of reproductive-aged women. Uterine fibroids adversely impact fertility, and unfortunately, there are few treatment options for women who desire to become pregnant. The study included 95 women who had between one and five fibroids. Forty-one participants received 5 milligrams (mg) vitamin B6, 25 micrograms (1,000 international units) vitamin D and 150 mg EGCG twice daily for four months, while a control group of 54 women were monitored without receiving the vitamin B6, vitamin D and EGCG. The number and volume of fibroids was measured using ultrasound before and after the treatment period. Fibroid vascularization was measured by color flow Doppler ultrasound, which color codes blood flow to indicate the direction of flow and/or the presence of high blood turbulence. Other factors assessed at these time points included the presence of heavy bleeding, pelvic pain and health/quality of life. Overall improvement was assessed by a questionnaire, the Patient Global Impression of Improvement (PGI-I), administered to participants who completed the four-month study. After four months, total fibroid volume significantly decreased by 37.9% among participants who received vitamins B6 and D, plus ECGC, while increasing by 5.5% among women who did not receive the nutrients. Similar results were observed in a subgroup of participants who were smokers – fibroid volume was significantly reduced with the supplement combination. Doppler visualization of blood flow to the myomas suggested reduced vascularization in the intervention group and increased vascularization in the control group. Pelvic pain and health, including the participants’ all-over impressions of improvement, significantly improved in comparison with pretreatment levels in the group that received the nutrients while no change occurred in the control group. Specifically, 85.4% of women taking the supplement reported improvements in their PGI-I score, with 73.2% reporting their symptoms were “very much better”. No side effects were reported. Authors Donatella Miriello and colleagues concluded that the study’s findings “showed the effectiveness and safety of a 4-month oral [intake of] a combination of vitamin D, EGCG and vitamin B6 in reducing uterine fibroids’ volume and improving the quality of life of childbearing women. Thus, this…may represent a valid alternative to the classic ‘wait and see’ approach and, at the same time, an adjuvant treatment that could be administered along with pharmacological therapies, even before surgery to reduce the occurrence of possible complications.” Nitrate-Rich Vegetables Increase Plasma Nitrate and Nitrite Concentrations and Lower Blood Pressure in Healthy Adults Maastricht University (Netherlands), May 21, 2021 Background: Dietary nitrate is receiving increased attention due to its reported ergogenic and cardioprotective properties. The extent to which ingestion of various nitrate-rich vegetables increases postprandial plasma nitrate and nitrite concentrations and lowers blood pressure is currently unknown. Objective: We aimed to assess the impact of ingesting different nitrate-rich vegetables on subsequent plasma nitrate and nitrite concentrations and resting blood pressure in healthy normotensive individuals. Methods: With the use of a semirandomized crossover design, 11 men and 7 women [mean ± SEM age: 28 ± 1 y; mean ± SEM body mass index (BMI, in kg/m2): 23 ± 1; exercise: 1–10 h/wk] ingested 4 different beverages, each containing 800 mg (∼12.9 mmol) nitrate: sodium nitrate (NaNO3), concentrated beetroot juice, a rocket salad beverage, and a spinach beverage. Plasma nitrate and nitrite concentrations and blood pressure were determined before and up to 300 min after beverage ingestion. Data were analyzed using repeated-measures ANOVA. Results: Plasma nitrate and nitrite concentrations increased after ingestion of all 4 beverages (P < 0.001). Peak plasma nitrate concentrations were similar for all treatments (all values presented as means ± SEMs: NaNO3: 583 ± 29 μmol/L; beetroot juice: 597 ± 23 μmol/L; rocket salad beverage: 584 ± 24 μmol/L; spinach beverage: 584 ± 23 μmol/L). Peak plasma nitrite concentrations were different between treatments (NaNO3: 580 ± 58 nmol/L; beetroot juice: 557 ± 57 nmol/L; rocket salad beverage: 643 ± 63 nmol/L; spinach beverage: 980 ± 160 nmol/L; P = 0.016). When compared with baseline, systolic blood pressure declined 150 min after ingestion of beetroot juice (from 118 ± 2 to 113 ± 2 mm Hg; P < 0.001) and rocket salad beverage (from 122 ± 3 to 116 ± 2 mm Hg; P = 0.007) and 300 min after ingestion of spinach beverage (from 118 ± 2 to 111 ± 3 mm Hg; P < 0.001), but did not change with NaNO3. Diastolic blood pressure declined 150 min after ingestion of all beverages (P < 0.05) and remained lower at 300 min after ingestion of rocket salad (P = 0.045) and spinach (P = 0.001) beverages. Conclusions: Ingestion of nitrate-rich beetroot juice, rocket salad beverage, and spinach beverage effectively increases plasma nitrate and nitrite concentrations and lowers blood pressure to a greater extent than sodium nitrate. These findings show that nitrate-rich vegetables can be used as dietary nitrate supplements. High-intensity interval training improves spatial memory in rats University of Tsukuba (Japan), May 17, 2021 Researchers at the University of Tsukuba have found that, despite only covering about one-third of the distance in HIIT compared with that covered in endurance training, similar improvements in exercise capacity and brain function were observed for both forms of exercise. "We investigated how rats' muscles and brains—specifically, the region of the brain involved in spatial learning called the hippocampus—adapted to these types of exercise, and how the rats consequently learned and remembered navigating mazes," explains Professor Hideaki Soya, the principal investigator. In the experiment, rats were assigned to one of three groups—resting, endurance running, or alternating intervals (short sprints and rest)—during training sessions on treadmills five days/week for four weeks. Both endurance running and HIIT resulted in weight loss, greater muscle mass, and the ability to exercise longer compared with controls; however, increased cellular aerobic capacity was found in the soleus (a muscle with predominantly slow-twitch fibers that makes it functionally well suited to endurance) and in the plantaris (a muscle with predominantly fast-twitch fibers for meeting high-energy functional demands) in the endurance-running and HIIT groups, respectively. Rats in both groups demonstrated better memory of spatial learning trials in searching for an escape platform in a water maze. In the hippocampus, increased cell development—neurogenesis—was also observed for both forms of exercise; however, levels of a signaling protein that promotes neurogenesis (BDNF) were increased by HIIT but not by endurance running, whereas the levels of its receptor (TrkB) were increased by both. Given that BDNF expression is known to be affected by exercise, why didn't endurance running increase BDNF expression? The answer may lie in the mediating role of stress on BDNF expression; exercise is a type of stress. While stress indicators in both exercise groups were found to be similar, this line of enquiry may lead to future studies: "In this study, we showed that an HIIT exercise regimen with a low exercise volume nevertheless improves spatial memory, and we demonstrated that these improvements are supported by changes in neuronal plasticity in the hippocampus. In a previous study, we found that continuous light-intensity training had a similar beneficial effect, whereas continuous high-intensity training did not," Professor Soya summarizes. "Thus, it seems that the benefits yielded by exercise may actually depend on optimization, that is, a trade-off between exercise time and intensity." A future where exercise regimens can be tailored to improve both physical and cognitive features may be on the horizon. Hygiene rules are also effective against new coronavirus variants Ruhr-University Bochum (Germany), May 21, 2021 The researchers found that the variants have a similar surface stability as the wild type virus under laboratory conditions, but can be effectively eliminated by disinfection and thorough hand washing, heat or alcohol treatment. They report their results in the Journal of Infectious Diseases from 16 May 2021. For this study, the team from the Department for Molecular and Medical Virology and the Chair of Materials Discovery and Interfaces at Ruhr-Universität Bochum (RUB) cooperated with the European Virus Bioinformatics Center Jena, the University Hospital Duisburg-Essen and Paracelsus Medical University Nuremberg. The fact that viruses change genetically over time is well known. Variants of concern are those that give the virus an advantage, for example by allowing it to replicate faster, become more infectious or enable it to evade the immune response. The British and South African variants have accumulated several mutations which result in an increased transmission and, in some cases, lead to more severe courses of disease. "Therefore, the question arose whether they also differ from the original variant in terms of their sensitivity to hygiene measures," explains Toni Meister from Ruhr-Universität Bochum. Heat, soap, alcohol For this reason, the team analysed how long the variants remain infectious on surfaces made of steel, silver, copper and on face masks and how they can be rendered harmless by means of soap, heat or alcohol. It turned out that both variants, as well as the wild type virus, could be inactivated when treated with at least 30 percent alcohol for at least 30 seconds. "Common disinfectants are therefore effective against all these variants," says Stephanie Pfänder from RUB. Thorough hand washing with soap could also lower the risk of infection. Heat also works against the virus: after 30 minutes at 56 degrees Celsius, all variants were rendered harmless. To find out whether the stability of the different mutant variants on surfaces differs from each other, they analyzed the amount of infectious virus particles on surfaces made of steel, copper, silver and on surgical and FFP2 masks over 48 hours. "The surface stability did not differ between the virus variants," points out Eike Steinmann from the Department for Molecular and Medical Virology at RUB. "As described several times before, copper in particular has a very strong antiviral effect". In conclusion, the team did not detect any differences between the different mutants in terms of their sensitivity to different hygiene measures. Pink drinks can help you run faster and further, study finds University of Westminster, May 12, 2021 A new study led by the Centre for Nutraceuticals in the University of Westminster shows that pink drinks can help to make you run faster and further compared to clear drinks. The researchers found that a pink drink can increase exercise performance by 4.4 per cent and can also increase a 'feel good' effect which can make exercise seem easier. The study, published in the journal Frontiers in Nutrition, is the first investigation to assess the effect of drink colour on exercise performance and provides the potential to open a new avenue of future research in the field of sports drinks and exercise. During the study participants were asked to run on a treadmill for 30 minutes at a self-selected speed ensuring their rate of exertion remained consistent. Throughout the exercise they rinsed their mouths with either a pink artificially sweetened drink that was low in calories or a clear drink which was also artificially sweetened and low in calories. Both drinks were exactly the same and only differed in appearance - the researchers added food dye to the pink drink to change the colour. The researchers chose pink as it is associated with perceived sweetness and therefore increases expectations of sugar and carbohydrate intake. Previous studies have also shown that rinsing the mouth with carbohydrates can improve exercise performance by reducing the perceived intensity of the exercise, so the researchers wanted to assess whether rinsing with a pink drink that had no carbohydrate stimulus could elicit similar benefits through a potential placebo effect. The results show that the participants ran an average 212 metres further with the pink drink while their mean speed during the exercise test also increased by 4.4 per cent. Feelings of pleasure were also enhanced meaning participants found running more enjoyable. Future exploratory research is necessary to find out whether the proposed placebo effect causes a similar activation to the reward areas of the brain that are commonly reported when rinsing the mouth with carbohydrates. Talking about the study, Dr Sanjoy Deb, corresponding author on the paper from the University of Westminster, said: "The influence of colour on athletic performance has received interest previously, from its effect on a sportsperson's kit to its impact on testosterone and muscular power. Similarly, the role of colour in gastronomy has received widespread interest, with research published on how visual cues or colour can affect subsequent flavour perception when eating and drinking. "The findings from our study combine the art of gastronomy with performance nutrition, as adding a pink colourant to an artificially sweetened solution not only enhanced the perception of sweetness, but also enhanced feelings of pleasure, self-selected running speed and distance covered during a run."
https://astralcodexten.substack.com/p/a-look-down-track-b I. Depression probably has something to do with decreased synaptogenesis in the brain, maybe the hippocampus in particular. Neurons are less likely to respond to stimuli by connecting to other neurons. The whole network becomes sparser than usual, and dysfunctional thought-loops that thrive in sparse network conditions start taking over. We understand parts of the pathways that regulate synaptic growth. When the body wants more synapses, it releases neurotrophic hormones like BDNF (brain-derived neurotrophic factor). These activate various receptors including tropomyosin receptor kinase B (TrkB, affectionately pronounced "track B" because it's one of two related pathways for these signals). TrkB then something Ras mTORC something something synaptogenesis now you're not depressed anymore hooray. Pictured: BDNF binds to TrkB. The IRS confiscates 1/2 of it as taxes, which radicalizes the receptor and makes it join Gab (see footnote 1), where it tweets out an SOS message to the Ras of Ethiopia. But the left wing of the receptor joins the Palestine Liberation Council and moves to California (see footnotes 2+). California has sunshine and good beaches, so you stop feeling depressed. This part sort of makes sense. But it coexists uneasily with other puzzle pieces in our knowledge of depression. For example, we give people SSRIs, their serotonin levels go up, and this makes them feel better. Why? Because of BDNF something TrkB something mTORC something? Probably; mice with dysregulated BDNF/TrkB systems don't benefit from antidepressants. But why does more serotonin cause BDNF something TrkB something? I've looked for years for a paper that says something like "by the way, serotonin makes cells release more BDNF". But despite a few suggestive links I don't see anyone strongly asserting that they understand this.
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.10.15.340851v1?rss=1 Authors: Perez-Sisques, L., Martin-Flores, N., Masana, M., Solana, J., Llobet, A., Romani-Aumedes, J., Canal, M., Campoy, G., Garcia, E., Sanchez, N., Fernandez, S., Gilbert, J. P., Rodriguez, M. J., Man, H., Feinstein, E., Williamson, D., Soto, D., Gasull, X., Alberch, J., Malagelada, C. Abstract: RTP801/REDD1 is a stress-regulated protein whose upregulation is necessary and sufficient to trigger neuronal death in in vitro and in vivo models of Parkinson's and Huntington's diseases and is up regulated in compromised neurons in human postmortem brains of both neurodegenerative disorders. Indeed, in both Parkinson's and Huntington's disease mouse models, RTP801 knockdown alleviates motor-learning deficits. Here, we investigated the physiological role of RTP801 in neuronal plasticity. RTP801 is found in rat, mouse and human synapses. The absence of RTP801 enhanced excitatory synaptic transmission in both neuronal cultures and brain slices from RTP801 knock-out (KO) mice. Indeed, RTP801 KO mice showed improved motor learning, which correlated with lower spine density but increased basal filopodia and mushroom spines in the motor cortex layer V. This paralleled with higher levels of synaptosomal GluA1 and TrkB receptors in homogenates derived from KO mice motor cortex, proteins that are associated with synaptic strengthening. Altogether, these results indicate that RTP801 has an important role modulating neuronal plasticity in motor learning. Copy rights belong to original authors. Visit the link for more info
This month on Episode 17 of the Discover CircRes podcast, host Cindy St. Hilaire highlights four featured articles from the September 25 and October 9 issues of Circulation Research. This episode features an in-depth conversation with Drs David Dichek, Sina Gharib and Tomáš Vaisar regarding their study titled Parallel Murine and Human Plaque Proteomics Reveals Pathways of Plaque Rupture. Article highlights: Cai, et al. Single Cell RNA-Seq in Arteriosclerosis Schuhmann, et al. CD84 in Ischemic Stroke VanOudenhove, et al. Gene Regulatory Dynamics of Developing Human Heart Nie, et al. Periostin is a Target to Treat PH Dr Cindy St. Hilaire: Hi, welcome to Discover CircRes, the podcast of the American Heart Association's journal Circulation Research. I'm your host, Dr Cindy St. Hilaire, from the Vascular Medicine Institute at the University of Pittsburgh, and today I'll be highlighting four articles selected from the late September and early October issues of CircRes. I'll also be interviewing Drs David Dichek, Sina Gharib, and Tomáš Vaisar regarding their study titled Parallel Murine and Human Plaque Proteomics Reveals Pathways of Plaque Rupture. The first article I want to share is titled Single Cell RNA Sequencing of Allograft Cells in Transplant Arteriosclerosis. The first author is Jingjing Cai and the corresponding author is Qingbo Xu from Zhejiang university in Hangzhou, China. Arteriosclerosis is a major contributor to organ transplant failure. The thickening and stiffening of arteries within the grafts results in diminished blood flow supplies and diminished organ function. While it is well understood that atherosclerosis is an inflammatory disease, the details of the cellular and molecular players on this transplant-specific pathology are lacking. Now, Cai and colleagues used single cell RNA sequencing to identify a consensus of cells and cytokines in sclerotic transplanted aortas in mice. Two weeks after transplant, the grafted vessels exhibited signs of arteriosclerosis and by four weeks, this remodeling had worsened significantly. Analyzing the RNA transcripts of over 12,000 individual cells isolated at both two and four weeks, the team discovered that the number of T-cells was greatly increased throughout the process. An early abundance of macrophages gave way to a later wave of B cells and there was also evidence of the development of tertiary lymphoid tissue. They further found that chemokine CCL121 was up regulated after transplant, both the mRNA in the tissues, as well as the protein levels in the animal's blood. The authors then went on to show that blocking CCL121 or its attracting partner, CXC3, significantly delayed arteriosclerosis in the grafted vessel. Hence, this work not only defines the cellular and molecular drivers of arteriosclerosis in grafted vessels, but highlights potential molecular targets for future therapeutic interventions. The second article I want to share is titled CD84 Links T-cell and Platelet Activity in Cerebral Thrombo-inflammation in Acute Stroke. The first author is Michael Schuhmann and the corresponding author is David Stegner, and the work was completed at University of Würzburg in Germany. Ischemic stroke is caused by the occlusion of cerebral blood vessels and it is a leading cause of death and disability worldwide. Despite treatments to degrade or remove clots such as mechanical thrombectomy, infarct size itself can continue to grow even when blood perfusion is re-established. Thrombo-inflammatory processes are thought to mediate this worsening injury, with both T-cells and activated platelets playing a role. Because both T-cells and activated platelets express CD84, which is a self-binding adhesion molecule involved in lymphocyte activation, this team tested the hypothesis that CD84 might mediate stroke inflammatory processes. They went on to show that mice lacking CD84 have smaller infarct sizes with reduced T-cell inflammation after stroke than wild-type animals. Furthermore, mice that specifically lack CD84 in either T-cells or platelets also experienced smaller infarcts. The team went on to show that CD84 promotes T cell migration in vitro. And then in patients with stroke, high expression of CD84 in platelets was associated with poor outcomes. Together, these results suggest that activated CD84-secreting platelets encourage inflammatory T cell migration to the infarct site. And that blocking CD84 activity could be a novel therapeutic strategy for minimizing inflammatory injury after stroke. The third article I want to share is titled Epigenomic and Transcriptomic Dynamics During Human Heart Organogenesis. The first author is Jennifer VanOudenhove and the corresponding author is Justin Cotney. And they're from the University of Connecticut. Congenital heart defects, or CHDs, are common birth abnormalities and while some genes have been linked to congenital heart defects, the majority, close to 60%, have unknown etiologies. It's thought that multiple genetic and environmental factors contribute to congenital heart defects. One of which could be variations in both cis and trans regulatory regions of the genome. To find such heart specific regulatory regions, this team examined heart tissue from human embryos obtained four to eight weeks after conception. They performed chromatin immunoprecipitation experiments to scour the heart genomes for histone modifications associated with increased or decreased gene transcription. They also performed transcriptome analysis to see whether the genomic regions identified by chip corresponded with the activity status of nearby genes. In total, the team found more than 12,000 previously unknown enhancers that were enriched for binding sites for heart specific transcription factors, some of which included GATA, MEF2 and Nkx. These binding sites tended to be close to genes activated in the heart. Many of the regions also contain sequence variations that have been associated with atrial fibrillation. These newly identified sites are potential congenital heart defect candidate loci and the authors have now made their data readily available so that other investigators may study it. The last article I want to share with you before we switch to our interview is titled Periostin: a Potential Therapeutic Target for Pulmonary Hypertension? The first author is Xiaowei Nie from the Shenzhen Third People's Hospital and the corresponding authors are Jingyu Chen and Jin-Song Bian from the Wuxi People's Hospital and the National University of Singapore, respectively. Pulmonary hypertension, or PH for short, is a life-threatening disease where an excess in the proliferation of vascular smooth muscle cells and the deposition of extracellular matrix thickens the walls of the lung vasculature, which leads to an increase in pulmonary blood pressure and ultimately contributes to right heart failure. Vasodilatory medications can be used to treat the symptoms of the disease. However, these medications do not prevent or reverse the underlying pathogenic remodeling. This study now suggests that drugs targeting the secreted extracellular matrix protein, periostin, might be a potential therapeutic strategy for the treatment of pulmonary hypertension. Periostin is an abundant protein in the lung arteries of pulmonary hypertension patients. And it is thought to be involved in cell adhesion and wound healing mechanisms, such as the proliferation and the migration of smooth muscle cells. The team confirmed increased production of periostin in patient lungs, and also found the same to be true for mice with an induced model of pulmonary hypertension. They also showed that genetic deletion of periostin attenuated pulmonary hypertension in mice, while suppression of periostin via RNA inhibition could even reverse pathological vessel thickening and the subsequent right ventricle hypertrophy. The team went on to identify factors HIF-1a and TrkB as factors that mediate periostin's effects in cultured arterial cells. And they suggest that blocking either of these factors or by blocking periostin itself could be a novel strategy for the treatment of pulmonary hypertension patients. Drs Tomáš Vaisar, Sina Gharib, and David Dichek from the University of Washington in Seattle, Washington are here with me today and we're going to discuss their recent study titled Parallel Murine and Human Plaque Proteomics Reveals Pathways of Plaque Rupture. Thank you all so much for joining me today and congratulations on this beautiful and interesting study. So this is an atherosclerotic study, but unlike many in the field, it's really looking at the end stage event called plaque rupture. So for those listeners who are unfamiliar with the term, plaque rupture is when an atherosclerotic plaque degrades and its contents are exposed to the circulation, which can then induce a clotting event and lead to all sorts of adverse pathologies, myocardial infarction, transient ischemic events, stroke. So I'm wondering if we if maybe you can give us a little bit of background about what's known and what really is unknown at least before your study regarding plaque rupture. Dr David Dichek: So the pathogenesis of acute myocardial infarction and stroke was really unknown for many years. And the idea that it was due to acute thrombosis was really confirmed by a study probably 30 years ago, that did angioscopy in the coronary arteries, proximal to a myocardial infarction, and visualized actual clot so that the clot was confirmed to be associated with the acute event. At that point, the question became why would a coronary artery form a clot? And that led to identification of, or histologic studies that identified ruptured caps of atherosclerotic plaques, exposure of the blood to the thrombogenic contents of the lesion, and a thrombus. However, it was not known what the initiating event was in rupture of the plaque cap. And there were a lot of hypotheses and a lot of nice work, but it does still remain an unknown. A significant amount of focus has been devoted to the possibility that proteolysis is the initiating event. And that was sort of the takeoff point from our study because we had developed a mouse model where proteolysis clearly was associated with rupture of plaque caps. And we decided we wanted to get more into the biochemistry of what was going on and go beyond the histology. So that was really what led up to our study. Dr Cindy St. Hilaire: It's really interesting. So, mice are really good and obviously really useful, very well-known model systems to study atherosclerosis and particularly the initial drivers and maybe the mechanisms of the disease pathogenesis, but like many models systems, they're not perfect. So I'm wondering if you could discuss the limitations of murine model systems and specifically for this study, how you were able to overcome some of those limitations. Dr David Dichek: So the limitations of mouse models of plaque rupture are that essentially none of them duplicate the histology of human plaque rupture, particularly the thrombus that occurs on top of the plaque rupture. So there are various mouse models where caps are disrupted, but there's not acute thrombosis. It has been argued in the vascular community as to whether these models are authentic models of plaque rupture, because they don't have the superimposed thrombosis. And the counter argument is well, mice aren't people, they have different hemostatic and coagulation factors that may be differentially regulated. The hemodynamics of small mouse arteries is different from human mouse arteries. And the fact that you don't get a thrombus doesn't necessarily mean that you're not modeling the process that would cause it. So we really accepted that argument as being valid and felt that the occurrence of frank plaque rupture, and that was in our Circulation paper in 2010, in these lesions in the mice, really validated it as an authentic model of cap disruption. And so I agree it's arguable, whether this is an authentic model. But we actually took that issue head on by saying, well, is the biochemistry of the ruptured plaque similar to the biochemistry of a ruptured human plaque? And that if there were similarities that we would gain more confidence in our model being an authentic model of plaque rupture and that it matched not only the histology, but also the biochemistry. Dr Cindy St. Hilaire: One of the main tools you used, you used shotgun proteomics, which I think is just a great name for it. And also a algorithmic learning tool or analysis tool called proteomaps. I was wondering if you could give us a little bit of background about the proteomic aanalysis involved, what does that entail? Especially, when you're comparing a teeny tiny mouse plaque to a larger human plaque and then how that analysis was done? Dr Tomáš Vaisar: So the shotgun proteomics term was coined by John Yates, but way back in the early 1990s. And it's essentially the way how you enumerate the proteins and in more recent forms, you even quantify the abundance of the proteins in a very complex mixture. So shotgun proteomics essentially takes a protein sample. And in this case it was an extract of the tissue and uses protease, trypsin typically, to cut the proteins down to peptides, which are relatively small and relatively well behaved compared to intact proteins. And then using tandem mass spectrometry combined with liquid chromatography separation, basically aims to sequence every single of those peptides or majority of the peptides. And then based from the identification of the sequence of individual peptides piece back together like a jigsaw puzzle, what was the protein present in the original mixture? Dr Cindy St. Hilaire: That's so interesting. I know it's been around for a while. I'm always impressed by it. Dr Tomáš Vaisar: And then the other approach we use it's called Proteomap developed by Ben Cravatt, collaborator on this paper at La Jolla. And that approach uses basically the shotgun approach but as a first step uses gel electrophoresis, SDS PAGE electrophoresis to fractionate the very complex mixture to size segments. Dr Tomáš Vaisar: So you run your complex mixture on a gel, you slice it by size and then run shotgun proteomics experiment on each of those slices after gel digestion. And then Ben developed a set of tools where you identify the proteins and their abundance in each of the bands based on the size and the way it's applied to formation or mapping of proteolytic events is based on the idea of that intact protein will show up at the molecular weight of the intact protein but if it was cleaved by a protease, it will also show up at the molecular weight, which is smaller corresponding to the fragments formed by proteolysis. Then you use set of bioinformatics tools to piece this all together and generate the Proteomaps. Dr Cindy St. Hilaire: You pick it apart, throw it in the machine and then put it back together. That's so cool. It's so amazing. So what were the main findings that you were able to pull out of your comparisons? And I think you had three main groups, if I understood it right? There's the transgenic mouse that has the plaques that don't rupture, and then there's the atherosclerotic mouse that had the transgenic bone marrow, and then you had the human. Can you tell us a little bit about the different groups you compared and then what ultimately you found? Dr David Dichek: Sure. Yes. You are absolutely right. We had what we refer to as the straight transgenic mice that are either transgenic for macrophage overexpressed uPA or not. We also had older mice who had advanced atherosclerosis and receive bone marrow transplants from mice that either had uPA overexpression in bone marrow or not and then we had the human plaque. So those were the three groups. So what we found was that looking at the proteome of those three groups, we were able to find some common biological processes, and this was really Sina's work, but taking the proteomics data and analyzing it with sophisticated bioinformatics tools. We looked not only at the overlap in specific proteins among the models, but the overlap in biological processes, because it may be in different species that there are different proteins, different actors carrying out the same roles. And that's been described in other systems as well. So we were able to identify not only common biological processes, but surprisingly, we were able to identify decreases in specific category of proteins, basement membrane proteins that were common to two of the models, the straight transgenic and the human model and loss of these proteins certainly has a plausible role in precipitating plaque rupture. So I think one aspect of the analysis that's worthy of note is that we initially thought we would observe more profound changes in the bone marrow transplant mice because they had more advanced atherosclerosis. And in fact, we found fewer changes than in the straight transgenic mice, but thinking about it after letting the data talk to us, rather than trying to impose our own on the data- Dr Cindy St. Hilaire: Always a good idea. Dr David Dichek: ... was that the straight transgenic mice were telling us we've been overexpressing urokinase for 20 weeks since we were conceived, and the bone marrow transplant mice had it for only eight weeks. And indeed they had far less loss of basement membrane proteins and far fewer changes in their plaques than the mice that had expressed it for a longer time. And so when one placed the three groups in a chronology of exposure to protease activity with the bone marrow transplant mice, being the shortest exposure than the straight transgenic mice, and then the humans who've had decades of exposure, it really tells you a nice chronological story about the biological processes leading to plaque rupture. And I think that's a generally applicable lesson and can be applied to other problems in cardiovascular biology. And that is when you have a biological process for which you can't get human tissue until after it's occurred because you can't go in and biopsy. Dr Cindy St. Hilaire: I have that problem with valve calcifications that you can't take your valve out early. Dr David Dichek: If you can get a mouse model that duplicates the pathology, then you have access to the steps leading up to the event. And that's what we tried to construct in this study. And really it was really Sina’s analyses that allowed us to make those connections. Dr Sina Gharib: Yeah. Of course, David was kind of the mastermind behind the design of the experiments on the developing of genetic models and Tomáš is a renowned expert in proteomics analysis. And I kind of joined more on the bioinformatics component of this study, tried to put some of the large data that was being generated together. And as David and Tomáš mentioned, of course atherosclerosis is a very complex disease with many, many components. And then of course the mouse model doesn't quite capture all the different pathophysiological events that happen. So one of the aims of this study was to try to integrate and merge the findings from these model without coming a priori with a bias or a pathway or a candidate gene, we decided to do a relatively unbiased shotgun proteomics approach, we actually do for everything. So the challenge then was how to put it all together. And as Tomáš mentioned, there are statistical tools to try to identify a relative abundance of proteins. But, a few things that pure biologists often don't have to encounter is, you're not one or two different proteins, you're looking at thousands of proteins. So there are issues, statistical issues, such as multiple comparisons. If you looked for changes, you're going to find changes just by random chance. So a lot of statistical adjustments had to be made to ensure that those were adjusted for. This are also pathways and processes that were coming out of these results. There's many different pathways that were interrogated. And again, statistically, you want to adjust for the fact that many of those could have been there by random chance. So there's a fair amount of statistical methods that need to be applied for this data. We also did somewhat more sophisticated pathway analysis where we develop networks based on the differential expressed proteins between the ruptured and unruptured plaques to identify connection among these proteins and identify hubs which are highly connected nodes that could potentially drive the biology of a network. So other types of kind of deeper statistical analysis was done, which are maybe more hypothesis-generating because we actually did not follow up on some of these candidates, but I think they really do provide a map or framework to then pursue more mechanistic experiments to see what happens if we knocked out this highly connected node at the plaque rupture site to see if we can either stabilize or manipulate the biology as plaque rupture. Dr Cindy St. Hilaire: Yeah. I mean, that's really the strength of these unbiased approaches is you can come up with so many more novel targets and pathways that might be contributing. So they're just really great. So one thing I found really interesting, you mentioned that you saw a clear distinction in the proteome and I think it was specifically talking about the human samples because they were large enough to see ruptured area versus non ruptured area, but you really saw a distinct difference in the proteomes of the ruptured area of the plaque versus the non ruptured area of the plaque. And obviously the models you were using are overexpressing a protease. So of course there's a role for proteolysis in this process, which you've now firmly established, but I'm wondering if there are other processes that might also erode the basement membrane. And did you pull up anything that might suggest of other things that are happening or even are there other hypothesis out there that we could test with an approach like yours? Dr David Dichek: I think the pathways that came up have probably all been implicated previously. We have processes like inflammation and complement activation, immune response, thrombosis. That's a post-hoc event. I think what was most unexpected was the decrease in the abundance to basement membrane proteins rather than collagens. So collagen has become the sort of signature protein of stable and unstable plaques and used as a surrogate, people do Picrosirius red staining. It's easy to detect with a histochemical stain, you don't even need an antibody. And surprisingly, we found very few differences in collagens and actually no differences in the type 1 or type 3 collagen, which are thought to be the primary stabilizers of the plaque cap. They weren't significantly different in between ruptured and stable areas of the same plaque. So that was certainly a big surprise. Dr Cindy St. Hilaire: Yeah. Because that would indicate that it's not necessary... We always say thinning of the cap, which obviously we know that there's remodeling, it can get thinner. But you kind of found that the contents were the same, but it's the basement really that was eroded. Dr David Dichek: Yeah. The basement membrane proteins were lost. It used to be said in physiology that if you discovered something new, you should just go to the German literature and go back 30 years and it had already been described. And so, looking back in the literature, there are actually the work of Jean-Baptiste Michelle in France and a scientist in Finland, Petri Kovanen, have actually focused on the potential role of basement membrane in unstable atherosclerosis many years ago, but it was kind of buried in the collagen hypothesis. And I think it needs resurrection. Dr Cindy St. Hilaire: Well, I think this paper has done that so well done there. That's great. Dr Tomáš Vaisar: Would be worthwhile to know that of course, the way you prepare the samples may affect what exactly you're seeing. But we've done very careful characterization of the sample preparation of the extraction procedure to focus, to enrich the exosomal matrix proteins because of this collagen hypothesis. And even with that, we basically saw no difference. Dr David Dichek: Yeah. I think that's an excellent point. If we hadn't found collagen in our extracts, we would not be able to conclude a lot about it. And how you do the extraction, how you process the samples here can really influence what you find. We call it unbiased, but there are technical biases that enter, especially in sample preparation, but our extraction process really was able to extract collagens as well as elastin, which is really infamous for being a- Dr Cindy St. Hilaire: Difficult. Dr David Dichek: ... I really think we were getting a good sampling of the matrix here. Dr Cindy St. Hilaire: I don’t know iif there is an answer for this question, but it's something I'm always thinking about. We always talk about athero being so prevalent because there's no kind of evolutionarily the way to tamp it down, it happens later in life. But can you think of any advantage that the vasculature would have in eroding the basement membrane or altering proteases in a response? I was just trying to think, is this just harnessing a wound healing process that's gone awry or could this ever be protective at all in any way? Dr David Dichek: Well, I think you hit the nail on the head, at least according to my bias. It's a healing response gone awry and that you can really draw out the pathways, basement membrane digestion release of chemotactic peptides as part of the inflammatory response, attraction of more inflammatory cells and then a potential healing response that unfortunately results in digestion of the matrix, which has a morbid or fatal consequence rather than physiologic remodeling. And you're right, that's not selected against. It's selected for, in settings in earlier life infections, for example, perhaps neoplasia, but it's not selected against in late life because people are post reproductive. Dr Cindy St. Hilaire: So what's next for these studies? What questions are you going to attack next with either these models or with some of your proteomic findings? Dr David Dichek: Well, we were just talking about that recently, Tomáš and I, and I think we'd like to look at... For one study, we're interested in doing, plaques that are high risk based on MRI imaging, which is really very well developed here at the University of Washington. And many of those patients have endarterectomies and they don't have ruptured plaques. So they are in a high risk group. So they undergo a endarterectomy for that. Not because they've had a plaque rupture and those plaques might be particularly instructive because they're pre event and won't have the healing response to thrombotic response. And it would be really interesting to see if our studies were confirmed. So that's one direction we're going in. Dr Cindy St. Hilaire: That would be amazing. Luckily, you have access to a whole bunch of human tissue for those kinds of really high impact studies. Dr Sina Gharib: I just wanted to point out that one of the advantages of doing proteomics and being part of the scientific community is that we made all this data available in the manuscript for other researchers to access and confirm. So, really probably the best way to procced with this is to have other investigators replicate our findings and expand on it. So I just want to bring that up because all of that data that was generated has been included within the supplements of this manuscripts and it's accessible to any scientist who wants to pursue further. Dr David Dichek: Yeah, I would add one other direction we'd like to go is we still like to know what the substrates are. We think their disappearance based on their abundance is due to proteolysis. But boy, would it be exciting if we could detect fragments. We were unable to do that in the study, probably because they were lost either in vivo or in processing. Technical advancements in that area, and maybe Tomáš can speak to that, might enable us to actually find more direct evidence of proteolysis. Dr Tomáš Vaisar: Yeah, I mean, to start with, it's really hard to determine physiological substrates of proteases. There's a huge amount of literature identifying proteolytic substrates in vitro, but the physiological substrates are really extremely hard to determine, and especially physiologic in vivo confirming that because in vitro, in a tube, you can mix whatever you want and you modify the ratio of proteins to protease substrate, and you can cleave almost everything with anything. It's a little exaggeration, but it's close. While the physiology substrates in the really complex milia of tissues is extremely hard. And so there has been several approaches developed and one of them is the Proteomaps. The other one is an approach called TAILS developed by Chris Overall at UBC that uses the idea of formation of the neo termini and then tagging the neo termini. So that in the actual sample, you can specifically detect these neo termini formed. But even with that approach, it's really hard to determine what are actual physiological substrates. And on top of that, what are the cleavage sites of the proteases? Dr Cindy St. Hilaire: And I guess the third being, if those substrates are cleaved, are they circulating and can we detect them in a blood sample? That would be, I guess, the gold standard. Well, thank you all so much for joining me today. Congratulations on this really very cool study. Being into human and translational work, I always love mouse studies that bring in lots of human samples. So congratulations on that. And I look forward to your future publications on this. Dr Tomáš Vaisar: Thanks a lot. Dr David Dichek: Thanks. Dr Cindy St. Hilaire: That's it for the highlights from the late September and early October issues of Circulation Research. Thank you so much for listening. Please check out the CircRes Facebook page and follow us on Twitter and Instagram with the handle @CircRes and #DiscoverCircRes. Thank you to our guests, Drs David Dichek, Sina Gharib, and Tomáš Vaisar. This podcast is produced by Rebecca McTavish and Ishara Ratnayake, edited by Melissa Stoner and supported by the editorial team of Circulation Research. Some of the copy texts for the highlighted articles is provided by Ruth Williams. I'm your host, Dr Cindy St. Hilaire. And this is Discover CircRes, your on-the-go source for the most up-to-date and exciting discoveries in basic cardiovascular research.
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.10.01.321570v1?rss=1 Authors: Fletcher, J. L., Dill, L. K., Wood, R. J., Wang, S., Robertson, K., Murray, S. S., Zamani, A., Semple, B. D. Abstract: Young children have a high risk of sustaining a traumatic brain injury (TBI), which can have debilitating life-long consequences. Importantly, the young brain shows particular vulnerability to injury, likely attributed to ongoing maturation of the myelinating nervous system at the time of insult. Here, we examined the effect of acute treatment with partial tropomyosin receptor kinase B (TrkB) agonist, LM22A-4, on the pathological and neurobehavioral outcomes after pediatric TBI, with the hypothesis that targeting TrkB would minimize tissue damage and support functional recovery. We focused on myelinated tracts-- the corpus callosum and external capsules-- based on recent evidence that TrkB activation potentiates oligodendrocyte remyelination. Male mice at postnatal day 21 received an experimental TBI or sham surgery. Acutely post-injury, extensive cell death, a robust glial response and disruption of compact myelin were evident in the injured brain. TBI or sham mice then received intranasal saline vehicle or LM22A-4 for 14 days. Behavior testing was performed from 4 weeks post-injury, and brains were collected at 5 weeks for histology. TBI mice showed hyperactivity, reduced anxiety-like behavior, and social memory impairments. LM22A-4 ameliorated the abnormal anxiolytic phenotype but had no effect on social memory deficits. Use of spectral confocal reflectance microscopy detected persistent myelin fragmentation in the external capsule of TBI mice at 5 weeks post-injury, which was accompanied by regionally distinct deficits in oligodendrocyte progenitor cells and post-mitotic oligodendrocytes, as well as chronic reactive gliosis and atrophy of the corpus callosum and injured external capsule. LM22A-4 treatment ameliorated myelin deficits in the perilesional external capsule, as well as tissue volume loss and the extent of reactive gliosis. However, there was no effect of this TrkB agonist on oligodendroglial populations detected at 5 weeks post-injury. Collectively, our results demonstrate that targeting TrkB immediately after TBI during early life confers neuroprotection and preserves myelin integrity, and this was associated with some improved neurobehavioral outcomes as the pediatric injured brain matures. Copy rights belong to original authors. Visit the link for more info
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.09.11.292565v1?rss=1 Authors: Gupta, R., Dittmeier, M., Wohlleben, G., Luzak, V., Wegat, V., Segebarth, D., Bady, E., Langlhofer, G., Wachter, B., Havlicek, S., Lüningschrör, P., Villmann, C., Polat, B., Monoranu, C. M., Kuper, J., Blum, R. Abstract: Trk receptors and gene fusions of NTRK are targets in precision oncology. Classical Trk signalling concepts fail to explain ligand-independent signalling of intracellular TrkB or NTRK fusion proteins. Here, we show that abundance of the intracellular domain of TrkB is sufficient for ligand-independent autophosphorylation. This constitutive TrkB signalling reduced actin filopodia dynamics, could phosphorylate FAK, and changed cell morphology. Mutating Y705 in the kinase domain of TrkB alone specifically blocked these pathways. Engineered intracellular kinase domain proteins and a cancer-related intracellular NTRK2-fusion protein (SQSTM1-NTRK2) also underwent constitutive activation. In migrating glioblastoma-like U87MG cells, self-active TrkB kinase reduced cell migration. Moreover, we found evidences for constitutively active, intracellular TrkB in tissue of human grade IV glioblastoma. Structural modelling of the kinase domain let us postulate that 'release from cis-autoinhibition by abundance' is sufficient for TrkB/FAK/Actin signalling via Y705. These constitutive signalling pathways could be fully blocked within minutes by clinically approved, anti-tumorigenic Trk inhibitors. In conclusion, our data provide an explanation and biological function for TrkB kinase domain signalling in the absence of a ligand. Copy rights belong to original authors. Visit the link for more info
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.09.02.279745v1?rss=1 Authors: Houtz, J., Liao, G.-Y., Xu, B. Abstract: Mutations in the TrkB neurotrophin receptor lead to profound obesity in humans, and expression of TrkB in the dorsomedial hypothalamus (DMH) is critical for maintaining energy homeostasis. However, the functional implications of TrkB-expressing neurons in the DMH (DMHTrkB) on energy expenditure are unclear. Additionally, the neurocircuitry underlying the effect of DMHTrkB neurons on energy homeostasis has not been explored. In this study, we show that activation of DMHTrkB neurons leads to a robust increase in adaptive thermogenesis and energy expenditure without altering heart rate or blood pressure, while silencing DMHTrkB neurons impairs thermogenesis. Furthermore, we reveal neuroanatomically and functionally distinct populations of DMHTrkB neurons that regulate food intake or thermogenesis. Activation of DMHTrkB neurons projecting to the raphe pallidus stimulates thermogenesis and increased energy expenditure, whereas DMHTrkB neurons that send collaterals to the paraventricular hypothalamus and preoptic area inhibit feeding. Together, our findings provide evidence that DMHTrkB neuronal activity plays an important role in regulating energy expenditure and delineate distinct neurocircuits that underly the separate effects of DMHTrkB neuronal activity on food intake and thermogenesis. Copy rights belong to original authors. Visit the link for more info
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.08.28.271676v1?rss=1 Authors: Martinez-Marmol, R., Chai, Y., Khan, Z., Kim, S. B., Hong, S. M., Gormal, R., Lee, D., Lee, J. K., Lee, M. K., Kim, S. Y., Meunier, F. A. Abstract: The traditional medicinal mushroom Hericium erinaceus has long been known for enhancing the peripheral nerve regeneration through targeting nerve growth factor (NGF) neurotrophic activity. It was also reported to protect against ageing-dependent cognitive decline in wildtype and in Alzheimer's disease mouse models suggesting a yet to be defined action on neurons of the central nervous system. Here, we purified and identified biologically active compounds from H. erinaceus, based on their ability to promote neurite outgrowth in hippocampal neurons. N-de phenylethyl isohericerin (NDPIH), an isoindoline compound from this mushroom together with its hydrophobic derivative hericene A, were highly potent in inducing extensive axon outgrowth and neurite branching in the absence of serum demonstrating high neurotropic activity. NDPIH also induced enlarged growth cones suggestive of a brain-derived neurotrophic factor (BDNF)-like activity. Pharmacological inhibition of tropomyosin receptor kinase B (TrkB) by ANA12 prevented NDPIH-induced neurotrophic activity providing evidence that NDPIH acts via TrkB receptors to mediate its neurotrophic effect in central neurons. Finally, in vivo treatment with H. erinaceus crude extract and hericene A significantly increased BDNF and downstream pathway and enhanced learning and memory in the novel object recognition memory test. Our results suggest that hericene A can promote BDNF-like activity in neurons in vitro and in vivo thereby enhancing recognition memory. Copy rights belong to original authors. Visit the link for more info
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.08.22.262923v1?rss=1 Authors: Bronfman, F. C., Moya-Alvarado, G. Abstract: Brain-Derived Neurotrophic Factor (BDNF) is broadly expressed in many circuits of the central nervous system (CNS). It binds TrkB and p75 to trigger different signaling pathways, including ERK1/2 and PI3K-mTOR, to induce dendritic growth and synaptic plasticity. When binding to BDNF, TrkB and p75 are endocytosed to signaling endosomes to continue signaling inside the cell. Whether BDNF/TrkB-p75 signaling endosomes in axons are regulating long-distance signaling in cell bodies to modify neuronal morphology is unknown. Here, we studied the functional role of BDNF signaling endosomes in long-distance regulation of dendritic growth using compartmentalized cultures of rat and mouse cortical neurons derived from p75exonIII knock-out or TrkBF616A knock-in mice. By applying BDNF to distal axons, we showed the capacity of axonal BDNF to increase dendritic arborization in cell bodies. This process depended on TrkB activity, but not p75 expression. In axons, BDNF/TrkB co-localized with Rab5 endosomes and increased active Rab5. Also, dynein was required for BDNF long-distance signaling, consistent with sorting and transport of signaling endosomes. Using neurons derived from TrkBF616A knock-in mice and the 1NM-PP1 inhibitor, we were able to demonstrate that TrkB receptors activated in the axons by BDNF, were required in the neuronal cell body to increase TrkB activity and phosphorylation of CREB. Also, we were able to visualize endosomes containing activated TrkB. PI3K activity was not required in the axons for dynein dependent BDNF responses. However, dendritic arborization induced by axonal BDNF signaling required both nuclear CREB and PI3K activation in cell bodies. Consistently, axonal BDNF increased protein translation in cell bodies and CREB and PI3K and mTOR activity were required for this process. Altogether, these results show that BDNF/TrkB signaling endosomes generated in axons allows long-distance control of dendritic growth coordinating both transcription and protein translation. Our results suggest a role of BDNF-TrkB signaling endosomes wiring circuits in the CNS. Copy rights belong to original authors. Visit the link for more info
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.08.14.251389v1?rss=1 Authors: Mirisis, A. A., Kopec, A. M., Carew, T. J. Abstract: Signaling through distinct growth factor pathways is required for long-term memory (LTM) in Aplysia. In a two-trial paradigm, Trial 1 TrkB signaling is required for expression of the immediate early gene apc/ebp, which is transient and necessary, but insufficient, for LTM formation. A prolonged increase in apc/ebp gene expression, which is both necessary and sufficient for LTM is achieved through TGF{beta} signaling during Trial 2. Here we demonstrate: (1) the prolonged increase in apc/ebp expression is not dependent on de novo transcription but is dependent on p38 MAPK activity induced by TGF{beta} ; (2) Trial 2 increases the interaction between apc/ebp mRNA and the stabilizing RNA-binding protein ApELAV; and (3) inhibition of the apc/ebp mRNA-ApELAV interaction blocks induction of LTM. These results reveal a novel role for post-transcriptional gene regulation: the stabilization of a specific transcript, apc/ebp, by ELAV-like proteins, as a critical molecular step in LTM formation. Copy rights belong to original authors. Visit the link for more info
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.08.13.249615v1?rss=1 Authors: Lesnikova, A., Casarotto, P. C., Fred, M. S., Voipio, M., Winkel, F., Steinzeig, A., Antila, H., Umemori, J., Biojone, C., Castren, E. Abstract: Perineuronal nets (PNNs) are an extracellular matrix structure rich in chondroitin sulphate proteoglycans (CSPGs) which preferentially encase parvalbumin-containing (PV+) interneurons. PNNs restrict cortical network plasticity but the molecular mechanisms involved are unclear. We found that reactivation of ocular dominance plasticity in the adult visual cortex induced by chondroitinase (chABC)-mediated PNN removal requires intact TRKB signaling in PV+ neurons. Additionally, we demonstrate that chABC increases TRKB phosphorylation (pTRKB), while PNN component aggrecan attenuates BDNF-induced pTRKB in cortical neurons in culture. We further found that protein tyrosine phosphatase sigma (PTP{sigma}, PTPRS), receptor for CSPGs, interacts with TRKB and restricts TRKB phosphorylation. PTP{sigma} deletion increases phosphorylation of TRKB in vivo and in vitro, and juvenile-like plasticity is retained in the visual cortex of adult PTP{sigma} deficient mice (PTP{sigma}+/-). The antidepressant drug fluoxetine, which is known to promote TRKB phosphorylation and reopen critical period-like plasticity in the adult brain, disrupts the interaction between TRKB and PTP{sigma} by binding to the transmembrane domain of TRKB. We propose that both chABC and fluoxetine reopen critical period-like plasticity in the adult visual cortex by promoting TRKB signaling in PV+ neurons through inhibition of TRKB dephosphorylation by the PTP{sigma}-CSPG complex. Copy rights belong to original authors. Visit the link for more info
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.07.24.220129v1?rss=1 Authors: Wang, S., Leem, J., Podvin, S., Hook, V., Kleschevnikov, N., Savchenko, P., Dhanani, M., Zhou, K., Kelly, I., Zhang, T., Miyanohara, A., Kleschevnikov, A., Wagner, S., Trojanowski, J., Roth, D., Patel, H., Patel, P., Head, B. P. Abstract: AD presents with severe neurodegeneration which leads to cognitive deficits and dementia. Identifying the molecular signals that attenuate neurodegeneration in AD may be exploited as therapeutic targets. This study revealed that transgenic AD mice (PSAPP) exhibit decreased caveolin-1 (Cav-1), a membrane/lipid raft (MLR) scaffolding protein that organizes synaptic signaling components. Subcellularly, Cav-1 and full length (fl)-TrkB were significantly decreased in MLRs. We thus developed an in vivo gene therapy that re-expresses neuronal-targeted Cav-1 using the synapsin promoter (SynCav1). While AD mice showed significant learning and memory deficits at 9 and 11 months, AD mice that received hippocampal SynCav1 (AD-SynCav1) maintained normal learning and memory at 9 and 11 months respectively. Furthermore, AD-SynCav1 mice showed preserved hippocampal MLR-localized fl-TrkB, synaptic ultrastructure, dendritic arborization and axonal myelin content, all of which occurred independent of reducing amyloid deposit and astrogliosis. Thus, SynCav1 demonstrates translational potential to treat AD by delaying neurodegeneration. Copy rights belong to original authors. Visit the link for more info
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.07.01.182931v1?rss=1 Authors: Fernandez, K., Watabe, T., Tong, M., Meng, X., Tani, K., Kujawa, S., Edge, A. Abstract: TrkB agonist drugs are shown here to have a significant effect on the regeneration of afferent cochlear synapses after noise-induced synaptopathy. The effects were consistent with regeneration of cochlear synapses that we observed in vitro after synaptic loss due to kainic acid-induced glutamate toxicity and were elicited by administration of TrkB agonists, amitriptyline and 7,8- dihydroxyflavone, directly into the cochlea via the posterior semicircular canal 48 h after exposure to noise. Synaptic counts at the inner hair cell and wave 1 amplitudes in the ABR were partially restored 2 weeks after drug treatment. Effects of amitriptyline on wave 1 amplitude and afferent auditory synapse numbers in noise-exposed ears after systemic (as opposed to local) delivery were profound and long-lasting; synapses in the treated animals remained intact one year after the treatment. However, the effect of systemically delivered amitriptyline on synaptic rescue was dependent on dose and the time window of administration: it was only effective when given before noise exposure at the highest injected dose. The long-lasting effect and the efficacy of post-exposure treatment indicate a potential broad application for the treatment of synaptopathy, which often goes undetected until well after the original damaging exposure(s). Copy rights belong to original authors. Visit the link for more info
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.06.28.175927v1?rss=1 Authors: Guyon, N., Rakauskas Zacharias, L., van Lunteren, J. A., Immenschuh, J., Fuzik, J., Märtin, A., Xuan, Y., Zilberter, M., Kim, H., Meletis, K., Lopes-Aguiar, C., Carlen, M. Abstract: Inhibitory interneurons expressing parvalbumin (PV) in the prefrontal cortex (PFC) are central to excitatory/inhibitory (E/I) balance, generation of gamma oscillations, and cognition. Dysfunction of PV interneurons disrupts information processing and cognitive behavior. Tyrosine receptor kinase B (trkB) signaling is known to regulate the differentiation and maturation of cortical PV interneurons during development, but is also suggested to be involved in the activity and network functions of PV interneurons in the adult brain. Using a novel viral strategy for cell-type and region-specific expression of a dominant negative trkB in adult mice, we show that reduced trkB signaling in PV interneurons in the PFC leads to pronounced morphological, physiological, and behavioral changes. Our results provide evidence for a critical role of trkB signaling in the function of PV interneurons in the adult brain, local network activities central to prefrontal circuit dynamics, and cognitive behavior. Copy rights belong to original authors. Visit the link for more info
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.05.12.090811v1?rss=1 Authors: van Berkel, A. A., Santos, T. C., Shaweis, H., van Weering, J. R. T., Toonen, R. F. G., Verhage, M. Abstract: Loss of the exocytic Sec1/MUNC18 protein MUNC18-1 or its t-SNARE partners SNAP25 and syntaxin-1 results in rapid, cell-autonomous and unexplained neurodegeneration, which is independent of their known role in synaptic vesicle exocytosis. cis-Golgi abnormalities are the earliest cellular phenotypes before degeneration occurs. Here, we investigated whether these Golgi abnormalities cause defects in the constitutive and regulated secretory pathway that may explain neurodegeneration. Electron microscopy confirmed that loss of MUNC18-1 expression results in a smaller cis-Golgi. In addition, we now show that medial-Golgi and the trans-Golgi Network are also affected. However, stacking and cisternae ultrastructure of the Golgi were normal. Overall ultrastructure of null mutant neurons was remarkably normal just hours before cell death occurred. Anterograde ER-to-Golgi and Golgi exit of endogenous and exogenous proteins were normal. In contrast, loss of MUNC18-1 caused reduced retrograde Cholera Toxin transport from the plasma membrane to the Golgi. In addition, MUNC18-1-deficiency resulted in abnormalities in retrograde TrkB trafficking. We conclude that MUNC18-1 deficient neurons have normal anterograde yet reduced retrograde transport to the Golgi. This imbalance in transport routes provides a plausible explanation for the observed Golgi abnormalities and cell death in MUNC18-1 deficient neurons. Copy rights belong to original authors. Visit the link for more info
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.04.27.063503v1?rss=1 Authors: Winkel, F., Voigt, M. B., Didio, G., Mateo, S., Jetsonen, E., Llach Pou, M., Steinzeig, A., Ryazantseva, M., Harkki, J., Englund, J., Khirug, S., Rivera, C., Palva, S., Taira, T., Lauri, S., Umemori, J., Castren, E. Abstract: Critical period plasticity during early postnatal life is followed by a consolidated state through the maturation of interneuron networks and development of perineuronal nets (PNN) surrounding parvalbumin (PV) interneurons. However, critical period-like plasticity can be induced in the adult brain (iPlasticity). Over a shorter time scale, PV interneurons can alternate between high and low plasticity states (PV-plasticity) to regulate memory encoding and consolidation. We now show that iPlasticity and PV-plasticity in the adult visual cortex are induced by the activation of TrkB neurotrophin receptors in PV interneurons. Optical activation of TrkB specifically in PV interneurons switches adult cortical networks into a state of elevated plasticity within minutes. The activation changes PV properties characterized by ocular dominance plasticity and reduced PV and PNN expression. Our results show that TrkB activity within PV interneurons is essential for iPlasticity and orchestrates plasticity states within adult cortical networks. Copy rights belong to original authors. Visit the link for more info
The neurotrophic factor BDNF has opposite effects on cocaine- and morphine-induced neuroplasticity.
Background: Hearing loss is a frequent long-term complication of pneumococcal meningitis (PM). Its main pathological correlate is damage to the organ of Corti and loss of spiral ganglion neurons. The only current treatment option is cochlear implants which require surviving neurons. Here, we investigated the impact of systemically applied neurotrophin-3 (NT-3) on long-term hearing loss and the survival of neurons. Methods: Eighteen hours after infection with S. pneumoniae, C57BL/6 mice were treated with a combination of ceftriaxone with NT-3 or dexamethasone or placebo. Hearing, cochlear damage, and brain damage were assessed by audiometry and histology. Results: The main findings from immunohistochemical visualization of neurotrophins (NT-3, BDNF) and their receptors (TrkB, TrkC, and p75) in the cochlea were (i) enhanced staining for the cell survival-promoting receptor TrkB and (ii) increased NT-3 staining in NT-3 treated mice, showing that systemically applied NT-3 reaches the cochlea. The major effects of adjunctive NT-3 treatment were (i) a reduction of meningitis-induced hearing impairment and (ii) a reduction of spiral ganglion neuronal loss. The efficacy of NT-3 therapy was comparable to that of dexamethasone. Conclusion: Systemically applied NT-3 might be an interesting candidate to improve hearing outcome after pneumococcal meningitis.
Fakultät für Biologie - Digitale Hochschulschriften der LMU - Teil 03/06
Pathological changes in the dopaminergic system account for a number of devastating illnesses including schizophrenia, psychosis, depression, addiction, obsessive compulsive disorder or the most well known Parkinson’s disease (PD). The nigrostriatal pathway is an important component of the dopaminergic (DA) system mediating voluntary movement and originates in the ventral midbrain from where substantia nigra pars compacta (SN) neurons send their axons to the dorsal striatum. Massive loss of SN neurons as seen in PD leads to postural imbalance, rigidity, tremor and bradykinesia, however, the precise mechanisms involved in the maintenance and the demise of SN neurons are poorly understood. Endogenous neurotrophic factors such as the Glial cell line-derived neurotrophic factor (GDNF; signaling via the Ret receptor tyrosine kinase) and Brain-derived neurotrophic factor (BDNF; signaling via the TrkB receptor tyrosine kinase) were reported to have protective and rescuing properties on DA neurons; however, their physiological roles in SN neurons remained unknown. Inactivation of the oxidative stress suppressor DJ-1 causes PD; remarkably, mice lacking DJ-1 function do not display overt SN degeneration, suggesting that additional DJ-1 interactors compensate for loss of DJ-1 function. To begin characterizing the cellular and molecular networks mediating SN neuron survival, I used mouse genetics to investigate the roles and the interaction between GDNF/BDNF-mediated trophic signaling and the DJ-1-mediated stress response in SN neurons. While mice lacking TrkB function specifically in SN neurons display a normal complement of SN neurons up to 24-months, loss of Ret function in DA neurons causes adult-onset and progressive SN degeneration, suggesting that GDNF/Ret signaling is required for long-term maintenance of SN neurons. I then generated and aged mice lacking Ret and DJ-1 and found remarkably that they display an enhanced SN degeneration relative to mice lacking Ret. Thus, DJ-1 promotes survival of Ret-deprived SN neurons. Interestingly, the survival requirement for Ret and DJ-1 is restricted to those SN neurons which express the ion channel GIRK2, project exclusively to the striatum and specifically degenerate in PD. This is the first in vivo evidence for a pro-survival role of DJ-1. To understand how DJ-1 interacts molecularly with Ret signaling, I performed epistasis analysis in Drosophila melanogaster. Although DJ-1 orthologs DJ-1A and DJ-1B are dispensable for fly development, the developmental defects induced by targeting constitutively active Ret to the retina were suppressed in a background of reduced DJ-1A/B function. Moreover, DJ-1A/B interacted genetically with Ras/ERK, but not PI3K/Akt signaling to regulate photoreceptor neuron development. Flies with reduced ERK activity and lacking DJ-1B function had more severe defects in photoreceptor neuron and wing development than flies with reduced ERK function. These observations establish, for the first time, a physiological role for DJ-1B in the intact Drosophila. Our findings suggest that the triple interaction between aging, trophic insufficiency and cellular stress may cause Parkinsonism. Because Ret and DJ-1 show convergence of their pro-survival activities, we predict that striatal delivery of GDNF might be most effective in PD patients carrying DJ-1 mutations. A better understanding of the molecular connections between trophic signaling, cellular stress and aging will accelerate the process of drug development in PD.
Support of ageing neurons by endogenous neurotrophic factors such as glial cell line-derived neurotrophic factor (GDNF) and brain-derived neurotrophic factor (BDNF) may determine whether the neurons resist or succumb to neurodegeneration. GDNF has been tested in clinical trials for the treatment of Parkinson disease (PD), a common neurodegenerative disorder characterized by the loss of midbrain dopaminergic (DA) neurons. BDNF modulates nigrostriatal functions and rescues DA neurons in PD animal models. The physiological roles of GDNF and BDNF signaling in the adult nigrostriatal DA system are unknown. We generated mice with regionally selective ablations of the genes encoding the receptors for GDNF (Ret) and BDNF (TrkB). We find that Ret, but not TrkB, ablation causes progressive and adult-onset loss of DA neurons specifically in the substantia nigra pars compacta, degeneration of DA nerve terminals in striatum, and pronounced glial activation. These findings establish Ret as a critical regulator of long-term maintenance of the nigrostriatal DA system and suggest conditional Ret mutants as useful tools for gaining insights into the molecular mechanisms involved in the development of PD.
Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.04.22.055087v1?rss=1 Authors: Cramer, T., Gill, R., Thirouin, Z. S., Vaas, M., Sampath, S., Noya, S. B., Chang, P. K. Y., Wu, P., Barker, P., Paolicelli, R. C., Klohs, J., McKinney, A. R., Tyagarajan, S. K. Abstract: Microglia interact with neurons to facilitate synapse plasticity; however, signal transducers between microglia and neuron remain unknown. Here, using in vitro organotypic hippocampal slice cultures and transient MCAO in genetically-engineered mice in vivo, we report that at 24 h post-ischemia microglia release BDNF to downregulate glutamatergic and GABAergic synaptic transmission within the penumbra area. Analysis of the CA1 hippocampal formation in vitro shows that proBDNF and mBDNF downregulate dendritic spine and gephyrin scaffold stability through p75NTR and TrkB receptors respectively. Post-MCAO, we report that in the penumbra and in the corresponding contralateral hemisphere similar neuroplasticity occur through microglia activation and gephyrin phosphorylation at Ser268, Ser270. Targeted deletion of the Bdnf gene in microglia or GphnS268A/S270A (phospho-null) point-mutations protect against ischemic brain damage, neuroinflamation and synapse downregulation post-MCAO. Collectively, we report a new unanticipated role for gephyrin phosphorylation in inflammation and microglia activation for neuroprotective plasticity after transient ischemia. Copy rights belong to original authors. Visit the link for more info
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