Podcasts about astrocyte

TWiN explains a study showing that while groups of neurons, form the basis for memory, astrocytes are key components of the adaptive reponse to learning experiences, and regulate the flow of information during circuit plasticity and memory recall. Hosts: Vincent Racaniello, Jason Shepherd, and Tim Cheung Subscribe (free): Apple Podcasts, Google Podcasts, RSS Links for this episode MicrobeTV Discord Server Write your Senator, oppose RFK Jr nomination Astrocytes and memory (Nature) Timestamps by Jolene. Thanks! Music is by Ronald Jenkees Send your neuroscience questions and comments to twin@microbe.tv

Previously thought to be mere connective tissue and support for neurons, astrocytes are now understood to have many functions in the nervous system that are linked with seizures and epilepsy. Dr. Cecilie Nome spoke with Dr. Peter Bedner about astrocytes' involvement in epilepsy and how identifying and resolving astrocyte dysfunction is a new frontier in drug development.Relevant articles:de Ceglia R., et al. 2023. Specialized astrocytes mediate glutamatergic gliotransmission in the CNS. Nature 622, 120–129.Grote A., et al. 2023. ‘Hippocampal innate inflammatory gliosis only' in pharmacoresistant temporal lobe epilepsy. Brain 146(2), 549-560.Ravi V.M., et al. 2015. Astrocyte uncoupling as a cause of human temporal lobe epilepsy. 2015. Brain 138(5), 1208-1222. Support the Show.Sharp Waves episodes are meant for informational purposes only, and not as clinical or medical advice.Let us know how we're doing: podcast@ilae.org.The International League Against Epilepsy is the world's preeminent association of health professionals and scientists, working toward a world where no person's life is limited by epilepsy. Visit us on Facebook, X (Twitter), Instagram, and LinkedIn.

Embark on a journey through the neurons and synapses of brain science with William Korinek, the CEO of Astrocyte Pharmaceuticals. In a conversation that fuses the molecular intricacies of neuroprotection with the humanistic pursuit of medical advancement, Bill reveals his unique path from molecular biologist to biotech innovator. Together, we unravel the complexities of securing funding, the importance of strategic networking, and the scarcity of research dollars for conditions impacting millions globally. His insights into the world of neuroprotection therapies, especially the uncharted potential of astrocytes, promise to leave you enlightened and curious about the future of neurological care.First In Human is a biotech-focused podcast that interviews industry leaders and investors to learn about their journey to in-human clinical trials. Presented by Vial, a tech-enabled CRO, hosted by Simon Burns, CEO & Co-Founder. Episodes launch weekly on Tuesdays. To view the full transcript of this episode, click here.Interested in being featured as a guest on First In Human? Please reach out to owen@vial.com.

Clive Svendsen, Ph.D., leads groundbreaking experiments using stem cell transplants, uncovering unexpected findings. These trials aimed at improving ALS treatments, revealed higher success with upper motor neuron transplants compared to spinal cord methods. Svendsen's exploration of cortical transplants hints at a potential breakthrough. Moreover, his study of stem cell behavior in space opens doors to exciting medical advancements. Series: "Stem Cell Channel" [Health and Medicine] [Science] [Show ID: 39068]

Clive Svendsen, Ph.D., leads groundbreaking experiments using stem cell transplants, uncovering unexpected findings. These trials aimed at improving ALS treatments, revealed higher success with upper motor neuron transplants compared to spinal cord methods. Svendsen's exploration of cortical transplants hints at a potential breakthrough. Moreover, his study of stem cell behavior in space opens doors to exciting medical advancements. Series: "Stem Cell Channel" [Health and Medicine] [Science] [Show ID: 39068]

Clive Svendsen, Ph.D., leads groundbreaking experiments using stem cell transplants, uncovering unexpected findings. These trials aimed at improving ALS treatments, revealed higher success with upper motor neuron transplants compared to spinal cord methods. Svendsen's exploration of cortical transplants hints at a potential breakthrough. Moreover, his study of stem cell behavior in space opens doors to exciting medical advancements. Series: "Stem Cell Channel" [Health and Medicine] [Science] [Show ID: 39068]

Clive Svendsen, Ph.D., leads groundbreaking experiments using stem cell transplants, uncovering unexpected findings. These trials aimed at improving ALS treatments, revealed higher success with upper motor neuron transplants compared to spinal cord methods. Svendsen's exploration of cortical transplants hints at a potential breakthrough. Moreover, his study of stem cell behavior in space opens doors to exciting medical advancements. Series: "Stem Cell Channel" [Health and Medicine] [Science] [Show ID: 39068]

Clive Svendsen, Ph.D., leads groundbreaking experiments using stem cell transplants, uncovering unexpected findings. These trials aimed at improving ALS treatments, revealed higher success with upper motor neuron transplants compared to spinal cord methods. Svendsen's exploration of cortical transplants hints at a potential breakthrough. Moreover, his study of stem cell behavior in space opens doors to exciting medical advancements. Series: "Stem Cell Channel" [Health and Medicine] [Science] [Show ID: 39068]

Clive Svendsen, Ph.D., leads groundbreaking experiments using stem cell transplants, uncovering unexpected findings. These trials aimed at improving ALS treatments, revealed higher success with upper motor neuron transplants compared to spinal cord methods. Svendsen's exploration of cortical transplants hints at a potential breakthrough. Moreover, his study of stem cell behavior in space opens doors to exciting medical advancements. Series: "Stem Cell Channel" [Health and Medicine] [Science] [Show ID: 39068]

Clive Svendsen, Ph.D., leads groundbreaking experiments using stem cell transplants, uncovering unexpected findings. These trials aimed at improving ALS treatments, revealed higher success with upper motor neuron transplants compared to spinal cord methods. Svendsen's exploration of cortical transplants hints at a potential breakthrough. Moreover, his study of stem cell behavior in space opens doors to exciting medical advancements. Series: "Stem Cell Channel" [Health and Medicine] [Science] [Show ID: 39068]

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.07.25.550567v1?rss=1 Authors: Chen, J. A., Tsai, Y.-H., Linden, A. K., Kessler, J. A., Peng, C.-Y. Abstract: WW domain-containing transcription regulator 1 (TAZ) and Yes-associated protein (YAP) are transcriptional co-activators traditionally studied together as a part of the Hippo pathway and best known for their roles in stem cell proliferation and differentiation. Despite their similarities, TAZ and YAP can exert divergent cellular effects by differentially interacting with other signaling pathways that regulate stem cell maintenance or differentiation. In the developing central nervous system, In this study, we show that TAZ regulates astrocytic differentiation and maturation of postnatal neural stem and progenitor cells (NPCs), and that TAZ mediates some but not all of the effects of bone morphogenetic protein (BMP) signaling on astrocytic development. By contrast, TAZ and YAP both mediate effects on NPC fate of {beta}1-integrin and integrin-linked kinase (ILK) signaling, and these effects are dependent on extracellular matrix (ECM) cues. These findings demonstrate that TAZ and YAP perform divergent functions in the regulation of astrocyte differentiation, where YAP regulates cell cycle states of astrocytic progenitors and TAZ regulates differentiation and maturation from astrocytic progenitors into astrocytes. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.07.18.549563v1?rss=1 Authors: Lines, J., Baraibar, A. M., Nanclares, C., Martin, E., Aguilar, J. d. l. R., Kofuji, P., Navarrete, M., Araque, A. Abstract: Astrocytes are active cells involved in brain function through the bidirectional communication with neurons, in which the astrocyte calcium signal plays a crucial role. Synaptically-evoked calcium increases can be localized to independent subcellular domains or expand to the entire cell, i.e., calcium surge. In turn, astrocytes may regulate individual synapses by calcium-dependent release of gliotransmitters. Because a single astrocyte may contact ~100,000 synapses, the control of the intracellular calcium signal propagation may have relevant consequences on brain function by regulating the spatial range of astrocyte neuromodulation of synapses. Yet, the properties governing the spatial dynamics of the astrocyte calcium signal remains poorly defined. Imaging subcellular responses of cortical astrocytes to sensory stimulation in mice, we show that sensory-evoked astrocyte calcium responses originated and remained localized in domains of the astrocytic arborization, but eventually propagated to the entire cell if a spatial threshold of greater than 23% of the arborization being activated was surpassed. Using transgenic IP3R2-/- mice, we found that type-2 IP3 receptors were necessary for the generation of the astrocyte calcium surge. We finally show using in situ electrophysiological recordings that the spatial threshold of the astrocyte calcium signal consequently determined the gliotransmitter release. Present results reveal a fundamental property of astrocyte calcium physiology, i.e., a spatial threshold for the astrocyte intracellular calcium signal propagation, which depends on astrocyte intrinsic properties and governs the astrocyte integration of local synaptic activity and the subsequent neuromodulation. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.07.15.548687v1?rss=1 Authors: Rowland, H. A., Miller, G., Liu, Q., Sharp, N. R., Ng, B., Wei, T., Arunasalam, K., Koychev, I., Hedegaard, A., Ribe, E. M., Chan, D., Chessell, T., Kocagoncu, E., Lawson, J., Malhotra, P. A., Ridha, B. H., Rowe, J. B., Thomas, A. J., Zamboni, G., Zetterberg, H., Cader, Z., Wade-Martins, R., Lovestone, S., Nevado Holgado, A., Kormilitzin, A., Buckley, N. J. Abstract: Human iPSCs provide powerful cellular models of Alzheimers disease (AD) and offer many advantages over non-human models, including the potential to reflect variation in individual-specific pathophysiology and clinical symptoms Previous studies have demonstrated that iPSC-neurons from individuals with AD reflect clinical markers, including {beta}-amyloid (A{beta}) levels and synaptic vulnerability. However, despite neuronal loss being a key hallmark of AD pathology, many risk genes are predominantly expressed in glia, highlighting them as potential therapeutic targets. In this work iPSC-derived astrocytes were generated from a cohort of individuals with high versus low levels of the inflammatory marker YKL-40, in their cerebrospinal fluid (CSF). iPSC-derived astrocytes were treated with exogenous A{beta} oligomers and high content imaging demonstrated a correlation between astrocytes that underwent the greatest morphology change from patients with low levels of CSF-YKL-40 and more protective APOE genotypes. This finding was subsequently verified using similarity learning as an unbiased approach. This study shows that iPSC-derived astrocytes from AD patients reflect key aspects of the pathophysiological phenotype of those same patients, thereby offering a novel means of modelling AD, stratifying AD patients and conducting therapeutic screens. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.07.11.548505v1?rss=1 Authors: Preat, T., Rabah, Y., Pasquer, L., Sagar, N., Placais, P.-Y. Abstract: Astrocytes interact with neurons during cognitive processes. In particular, astrocytes help neurons to fight oxidative stress, a needed function since active neurons are prone to reactive oxygen species (ROS) damage due to their high mitochondrial activity and relatively poor antioxidant defenses. ROS also play major physiological functions, but it remains unknown how neuronal ROS signaling is activated during memory formation and if astrocytes play a role in that process. We discovered in Drosophila an astrocyte-to-neuron H2O2 signaling cascade essential for long-term memory formation. Stimulation of astrocytes by acetylcholine induces an intracellular calcium increase that triggers the formation of extracellular O2- by astrocytic NADPH oxidase. Superoxide dismutase 3 secreted by astrocytes converts O2- into H2O2, which is imported into neurons of the olfactory memory center (the mushroom body), as revealed by in vivo H2O2 imaging using an ultrasensitive sensor. Importantly, SOD3 activity requires Cu2+, which we show is delivered by the neuronal Amyloid Precursor Protein. Furthermore, we found that human amyloid-beta peptide, involved in Alzheimer s disease, inhibits the astrocytic cholinergic receptor and hampers memory formation by preventing H2O2 import into neurons. These findings could have major implications for the understanding of Alzheimer s disease etiology, as soluble synaptic Abeta42 correlates better with the pattern of cognitive decline in AD than amyloid plaques, and since early pathology in cholinergic neurons of the basal forebrain predicts memory defects. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.07.10.548401v1?rss=1 Authors: Chen, X., Sokirniy, I., Wang, X., Jiang, M., Mseis-Jackson, N., Williams, C., Mayes, K., Jiang, N., Puls, B., Du, Q., Shi, Y., Li, H. Abstract: While astrocyte-to-neuron (AtN) reprogramming holds great promise in regenerative medicine, the molecular mechanisms that govern this unique biological process remain elusive. MicroRNAs (miRNAs), as post-transcriptional regulators of gene expression, play crucial roles during development and under various pathological conditions. To understand the function of miRNAs during AtN reprogramming process, we performed RNA-seq of both mRNAs and miRNAs on human astrocyte (HA) cultures upon NeuroD1 overexpression. Bioinformatics analyses showed that NeuroD1 not only activates essential neuronal genes to initiate reprogramming process but also induces miRNA changes in HA. Among the upregulated miRNAs, we identified miR-375 and its targets, neuronal ELAVL genes (nELAVLs), which encode a family of RNA-binding proteins and are also upregulated by NeuroD1. We further showed that manipulating miR-375 level regulates nELAVLs expression during NeuroD1-mediated reprogramming. Interestingly, miR-375/nELAVLs are also induced by reprogramming factors Neurog2 and ASCL1 in HA suggesting a conserved function to neuronal reprogramming, and by NeuroD1 in the mouse astrocyte culture and spinal cord. Functionally, we showed that miR-375 overexpression improves NeuroD1-mediated reprogramming efficiency by promoting cell survival at early stages in HA even in cultures treated with the chemotherapy drug Cisplatin. Moreover, miR-375 overexpression does not appear to compromise maturation of the reprogrammed neurons in long term HA cultures. Lastly, overexpression of miR-375-refractory ELAVL4 induces apoptosis and reverses the cell survival-promoting effect of miR-375 during AtN reprogramming. Together, we demonstrate a neuro-protective role of miR-375 during NeuroD1-mediated AtN reprogramming and suggest a strategy of combinatory overexpression of NeuroD1 and miR-375 for improving neuronal reprogramming efficiency. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.07.01.547315v1?rss=1 Authors: Deckers, C., Karbalaei, R., Miles, N. A., Harder, E. V., Witt, E., Harris, E. P., Reissner, K., Wimmer, M., Bangasser, D. A. Abstract: Astrocyte morphology affects function, including the regulation of glutamatergic signaling. This morphology changes dynamically in response to the environment. However, how early life manipulations alter adult cortical astrocyte morphology is underexplored. Our lab uses brief postnatal resource scarcity, the limited bedding and nesting (LBN) manipulation, in rats. We previously found that LBN promotes later resilience to adult addiction-related behaviors, reducing impulsivity, risky decision-making, and morphine self-administration. These behaviors rely on glutamatergic transmission in the medial orbitofrontal (mOFC) and medial prefrontal (mPFC) cortex. Here we tested whether LBN changed astrocyte morphology in the mOFC and mPFC of adult rats using a novel viral approach that, unlike traditional markers, fully labels astrocytes. Prior exposure to LBN causes an increase in the surface area and volume of astrocytes in the mOFC and mPFC of adult males and females relative to control-raised rats. We next used bulk RNA sequencing of OFC tissue to assess transcriptional changes that could increase astrocyte size in LBN rats. LBN caused mainly sex-specific changes in differentially expressed genes. However, Park7, which encodes for the protein DJ-1 that alters astrocyte morphology, was increased by LBN across sex. Pathway analysis revealed that OFC glutamatergic signaling is altered by LBN in males and females, but the gene changes in that pathway differed across sex. This may represent a convergent sex difference where glutamatergic signaling, which affects astrocyte morphology, is altered by LBN via sex-specific mechanisms. Collectively, these studies highlight that astrocytes may be an important cell type that mediates the effect of early resource scarcity on adult brain function. 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/2023.06.22.546157v1?rss=1 Authors: Karnam, S., Maurya, S., Ng, E., Choudhary, A., Thobani, A., Flanagan, J. G., Gronert, K. Abstract: Purpose: Glaucoma leads to vision loss due to retinal ganglion cell death. Astrocyte reactivity contributes to its neurodegeneration. Our recent study found that lipoxin B4 (LXB4), produced by retinal astrocytes, has direct neuroprotective actions on retinal ganglion cells. However, regulation of lipoxin formation and cellular targets for their neuroprotective activity in glaucoma remain to be defined. We investigated if ocular hypertension and inflammatory cytokines regulate astrocyte lipoxin pathway and if LXB4 can regulate astrocyte reactivity. Design: Experimental study. Subjects/Participants/Controls: C57BL/6J mice were administered silicon oil into the anterior chamber to induce ocular hypertension (n=40). Age and gender-matched mice served as control subjects (n=40). Methods: RNAscope in-situ hybridization, RNA-seq, and qPCR to analyze gene expression. LC/MS/MS lipidomics to assess functional expression of the lipoxin pathway. Retinal flat mounts and immunohistochemistry (IHC) to assess macroglia reactivity. OCT quantified the retinal layer thickness in vivo, and ERG assessed retinal function. Primary human brain astrocytes were used for in vitro reactivity experiments. Non-human primate optic nerves were used to assess gene and functional expression of the lipoxin pathway. Main Outcome Measures: Intraocular pressure, RGC function, OCT measurements, gene expression, in situ hybridization, lipidomic analysis, and IHC. Results: Gene expression and lipidomic analysis established functional expression of the lipoxin pathway in the mouse retina, optic nerve of mice and primates, as well as human brain astrocytes. Ocular hypertension caused significant dysregulation of this pathway, with an increase in 5-lipoxygenase (5-LOX) activity and a decrease in 15-lipoxygenase activity. This dysregulation was coincident with a marked upregulation of astrocyte reactivity in the mouse retina. Reactive human brain astrocytes also showed a marked increase in 5-LOX. Administration of LXB4 regulated the lipoxin pathway, restored and amplified LXA4 generation, and mitigated astrocyte reactivity in mouse retinas and human brain astrocytes. Conclusions: The lipoxin pathway is functionally expressed in retina and brain astrocytes, optic nerves of rodents and primates, a resident neuroprotective pathway that is downregulated in reactive astrocytes. Novel cellular targets for LXB4 neuroprotective action is inhibition of astrocyte reactivity and restoration of lipoxin generation. Amplifying the lipoxin pathway is a potential target to disrupt or prevent astrocyte reactivity in neurodegenerative diseases. 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/2023.05.04.539425v1?rss=1 Authors: Fulton, S. L., Bendl, J., Gameiro-Ros, I., Fullard, J. F., Al-Kachak, A., Lepack, A. E., Stewart, A. F., Singh, S., Poller, W. C., Bastle, R. M., Hauberg, M. E., Fakira, A. K., Chen, M., Durand-de Cuttoli, R., Cathomas, F., Ramakrishnan, A., Gleason, K., Shen, L., Tamminga, C. A., Milosevic, A., Russo, S. J., Swirski, F., Blitzer, R. D., Slesinger, P. A., Roussos, P., Maze, I. Abstract: Hyperexcitability in the orbitofrontal cortex (OFC) is a key clinical feature of anhedonic domains of Major Depressive Disorder (MDD). However, the cellular and molecular substrates underlying this dysfunction remain unknown. Here, cell-population-specific chromatin accessibility profiling in human OFC unexpectedly mapped genetic risk for MDD exclusively to non-neuronal cells, and transcriptomic analyses revealed significant glial dysregulation in this region. Characterization of MDD-specific cis-regulatory elements identified ZBTB7A, a transcriptional regulator of astrocyte reactivity, as an important mediator of MDD-specific chromatin accessibility and gene expression. Genetic manipulations in mouse OFC demonstrated that astrocytic Zbtb7a is both necessary and sufficient to promote behavioral deficits, cell-type-specific transcriptional and chromatin profiles, and OFC neuronal hyperexcitability induced by chronic stress, a major risk factor for MDD. These data thus highlight a critical role for OFC astrocytes in stress vulnerability and pinpoint ZBTB7A as a key dysregulated factor in MDD that mediates maladaptive astrocytic functions driving OFC hyperexcitability. 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/2023.05.03.539260v1?rss=1 Authors: Irwin, A. B., Martina, V., Sint Jago, S. C., Bahabry, R., Schreiber, A. M., Lubin, F. D. Abstract: Dysregulation of long non-coding RNAs (lncRNAs) have been associated with Alzheimer's disease (AD). However, the functional role of lncRNAs in AD remains unclear. Here, we report a crucial role for the lncRNA Neat1 in astrocyte dysfunction and memory deficits associated with AD. Transcriptomics analysis show abnormally high expression levels of NEAT1 in the brains of AD patients relative to aged-matched healthy controls, with the most significantly elevated levels in glial cells. In a human transgenic APP-J20 (J20) mouse model of AD, RNA-fluorescent in situ hybridization characterization of Neat1 expression in hippocampal astrocyte versus non-astrocyte cell populations revealed a significant increase in Neat1 expression in astrocytes of male, but not female, mice. This corresponded with increased seizure susceptibility in J20 male mice. Interestingly, Neat1 deficiency in the dCA1 in J20 male mice did not alter seizure threshold. Mechanistically, Neat1 deficiency in the dorsal area CA1 of the hippocampus (dCA1) J20 male mice significantly improved hippocampus-dependent memory. Neat1 deficiency also remarkably reduced astrocyte reactivity markers suggesting that Neat1 overexpression is associated with astrocyte dysfunction induced by hAPP/A{beta} in the J20 mice. Together, these findings indicate that abnormal Neat1 overexpression may contribute to memory deficits in the J20 AD model not through altered neuronal activity, but through astrocyte dysfunction. 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/2023.05.02.538934v1?rss=1 Authors: Wahis, J., Akkaya, C., Kirunda, A. M., Mak, A., Zeise, K., Verhaert, J., Gasparyan, H., Hovhannisyan, S., Holt, M. G. Abstract: Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.04.28.538740v1?rss=1 Authors: Windham, I. A., Ragusa, J. V., Wallace, E. D., Wagner, C. H., White, K. K., Cohen, S. Abstract: Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.04.19.537428v1?rss=1 Authors: Pryce Roberts, A., Dec, K., Tyrrell, V., O'Donnell, V. B., Harwood, A. J., Williams, J. Abstract: Sporadic Alzheimer's disease is the leading cause of dementia worldwide and the Apolipoprotein-E4 allele (APOE) is the strongest genetic risk factor but despite its importance, its role in disease pathogenesis is incompletely understood. The APOE gene encodes Apolipoprotein E (ApoE). Astrocytes are the main source of ApoE in the central nervous system (CNS) and are essential for homeostasis in health and disease. In response to CNS insult, a coordinated multicellular inflammatory response is triggered causing reactive astrogliosis with changes in astrocytic gene expression, cellular structure and function. Using a human embryonic stem-cell line with the neutral APOE33 genotype, we used CRISPR Cas-9 gene-editing technology to create isogenic APOE lines with an APOE44 genotype. We developed a modified protocol designed to produce quiescent astrocytes and then stimulated them to induce an astrogliotic A1 phenotype. Several potentially pathological APOE44-related phenotypes were identified in both quiescent cells and reactive A1 astrocytes including significantly decreased phagocytosis and impaired glutamate uptake in APOE44 astrocytes. There were also key differences in the inflammatory profiles of APOE33 and APOE44 astrocytes characterised by significantly decreased secretion of IL6, IL8 and several oxylipins in APOE44 quiescent astrocytes. In A1 astrocytes there was a pro-inflammatory phenotype in APOE44 astrocytes with increases in GRO, ENA78, IL6 and IL8, a decrease in IL10 as well as significant differences in oxylipin expression suggestive of a defect in their immunomodulatory function. As TNF- induced signaling in astrocytes is driven by Nuclear factor kappa B (NF-{kappa}B) we investigated the proteins of this pathway and found significantly higher levels of the p65 and I{kappa}B sub-units in both quiescent and A1 APOE44 astrocytes. This suggests that perturbation of NF-{kappa}B signaling may contribute to the damaging cell phenotypes that we observe and provides a new direction for targeted disease therapeutics. Given the large numbers of existing drugs that act on the NF-{kappa}B pathway, this could be realised in a relatively short timeframe. 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/2023.04.20.537627v1?rss=1 Authors: Frankle, L., Riley, A., Tomor, R., Lee, H., Jarzembak, K., Benedict, O., Sternbach, S., Shelestak, J., McDonough, J., Clements, R. Abstract: Glial cells, including astrocytes, microglia, and oligodendrocytes, are brain cells that support and dynamically interact with neurons and each other. These intercellular dynamics undergo changes during stress and disease states. In response to most forms of stress, astrocytes will undergo some variation of activation, meaning upregulation in certain proteins expressed and secreted and either upregulations or downregulations to various constitutive and normal functions. While types of activation are many and contingent on the particular disturbance that triggers these changes, there are two main overarching categories that have been delineated thus far: A1 and A2. Named in the convention of microglial activation subtypes, and with the acknowledgement that the types are not completely distinct or completely comprehensive, the A1 subtype is generically associated with toxic and pro-inflammatory factors, and the A2 phenotype is broadly associated with anti-inflammatory and neurogenic factors. The present study served to measure and document dynamic changes in these subtypes at multiple timepoints using an established experimental model of cuprizone toxic demyelination. The authors found increases in proteins associated with both cell types at different timepoints, with protein increases in the A1 marker C3d and the A2 marker Emp1 in the cortex at one week and protein increases in Emp1 in the corpus callosum at three days and four weeks. There were also increases in Emp1 staining specifically colocalized with astrocyte staining in the corpus callosum at the same timepoints as the protein increases, and in the cortex weeks later at four weeks. C3d colocalization with astrocytes also increased most at four weeks. This indicates simultaneous increases of both types of activation as well as the likely existence of astrocytes expressing both markers. The authors also found the increase in two A1 associated proteins (TNF alpha and C3d) did not show a linear relationship in line with findings from other research and indicating a more complex relationship between cuprizone toxicity and astrocyte activation. The increases in TNF alpha and IFN gamma did not occur at timepoints preceding increases in C3d and Emp1, showing that other factors also precipitate the subtypes associated (A1 for C3d and A2 for Emp1). These findings add to the body of research showing the specific early timepoints at which A1 and A2 markers are most increased during the course of cuprizone treatment, including the fact that these increases can be non-linear in the case of Emp1. This provides additional information on optimal times for targeted interventions during the cuprizone model. 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/2023.04.10.536254v1?rss=1 Authors: Golf, S. R., Trotter, J., Nakahara, G., Südhof, T. Abstract: Astrocytes exert multifarious roles in the formation, regulation, and function of synapses in brain, but the mechanisms involved remain unclear. Interestingly, astrocytes abundantly express neuroligins, postsynaptic adhesion molecules that bind to presynaptic neurexins. A pioneering recent study reported that loss-of-function of neuroligins in astrocytes impairs excitatory synapse formation and astrocyte morphogenesis. This study suggested a crucial function for astrocytic neuroligins but was puzzling given that constitutive neuroligin deletions do not decrease excitatory synapse numbers. Thus, we here examined the function of astrocytic neuroligins using a rigorous conditional genetic deletion of the major neuroligins (Nlgn1-3) in astrocytes. Our results show that early postnatal deletion of neuroligins from astrocytes has no effect on cortical or hippocampal synapses and does not alter the cytoarchitecture of astrocytes. Thus, astrocytic neuroligins are unlikely to shape synapse formation or astrocyte development but may have other important functions in astrocytes. 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/2023.04.03.535448v1?rss=1 Authors: Irala, D., Wang, S., Sakers, K., Nagendren, L., Ulloa-Severino, F. P., Bindu, D. S., Eroglu, C. Abstract: Astrocytes strongly promote the formation and maturation of synapses by secreted proteins. To date, several astrocyte-secreted synaptogenic proteins controlling different stages of excitatory synapse development have been identified. However, the identities of astrocytic signals that induce inhibitory synapse formation remain elusive. Here, through a combination of in vitro and in vivo experiments, we identified Neurocan as an astrocyte-secreted inhibitory synaptogenic protein. Neurocan is a chondroitin sulfate proteoglycan that is best known as a protein localized to the perineuronal nets. However, Neurocan is cleaved into two after secretion from astrocytes. We found that the resulting N- and C- terminal fragments have distinct localizations in the extracellular matrix. While the N-terminal fragment remains associated with perineuronal nets, the Neurocan C-terminal fragment localizes to synapses and specifically controls cortical inhibitory synapse formation and function. Neurocan knockout mice lacking the whole protein or only its C-terminal synaptogenic region have reduced inhibitory synapse numbers and function. Through super-resolution microscopy and in vivo proximity labeling by secreted TurboID, we discovered that the synaptogenic domain of Neurocan localizes to somatostatin-positive inhibitory synapses and strongly regulates their formation. Together, our results unveil a mechanism through which astrocytes control circuit-specific inhibitory synapse development in the mammalian brain. 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/2023.04.02.535245v1?rss=1 Authors: Hayes, C., Morgan, N. I., Thomas, K., Pushie, M. J., Vijayasankar, A., Ashmore, B., Wontor, K., De Leon, M., Ashpole, N. Abstract: Ischemic stroke is a leading cause of death and disability, as therapeutic options for mitigating the long-term deficits precipitated by the event remain limited. Acute administration of the neuroendocrine modulator insulin-like growth factor-1 (IGF-1) attenuates ischemic stroke damage in preclinical models, and clinical studies suggest IGF-1 can reduce the risk of stroke and improve overall outcomes. The cellular mechanism by which IGF-1 exerts this protection is poorly defined, as all cells within the neurovascular unit express the IGF-1 receptor. We hypothesize that the functional regulation of both neurons and astrocytes by IGF-1 is critical in minimizing damage in ischemic stroke. To test this, we utilized inducible astrocyte-specific or neuron-specific transgenic mouse models to selectively reduce IGF-1R in the adult mouse brain prior to photothrombotic stroke. Acute changes in blood brain barrier permeability, microglial activation, systemic inflammation, and biochemical composition of the brain were assessed 3 hours following photothrombosis, and significant protection was observed in mice deficient in neuronal and astrocytic IGF-1R. When the extent of tissue damage and sensorimotor dysfunction was assessed for 3 days following stroke, only the neurological deficit score continued to show improvements, and the extent of improvement was enhanced with additional IGF-1 supplementation. Overall, results indicate that neuronal and astrocytic IGF-1 signaling influences stroke damage but IGF-1 signaling within these individual cell types is not required for minimizing tissue damage or behavioral outcome. 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/2023.03.23.534020v1?rss=1 Authors: Bell, S. M., Wareing, H., Hamshaw, A., De, S., New, E., Shaw, P. J., De Marco, M., Venneri, A., Blackburn, D. J., Ferraiuolo, L., Mortiboys, H. J. Abstract: Background: Astrocytes have multiple roles including providing neurons with metabolic substrates and maintaining neurotransmitter synaptic homeostasis. Astrocyte glucose metabolism plays a key role in learning and memory with astrocytic glycogen a key substrate supporting memory encoding. The neuronal support provided by astrocytes has a high metabolic demand. Deficits in astrocytic mitochondrial metabolic functioning and glycolysis could impair neuronal function. Changes to cellular metabolism are seen early in Alzheimers disease (AD). Understanding cellular metabolism changes in AD astrocytes could be exploited as a new biomarker or synergistic therapeutic agent when combined with anti-amyloid treatments in AD. Methods: In this project, we characterised mitochondrial and glycolytic function in astrocytes derived from patients with sporadic (n=6) and familial (PSEN1, n=3) forms of AD. Astrocytes were derived using direct reprogramming methods. Astrocyte metabolic outputs: ATP, and extracellular lactate levels were measured using luminescent and fluorescent protocols. Mitochondrial respiration and glycolytic function were measured using a Seahorse XF Analyzer. Hexokinase deficits identified where corrected by transfecting astrocytes with an adenovirus viral vector containing the hexokinase 1 gene. Results: There was a reduction of total cellular ATP of 20% (p=0.05 in sAD astrocytes) and of 48% (p less than 0.01) in fAD. A 44% reduction (p less than 0.05), and 80% reduction in mitochondrial spare capacity was seen in sAD and fAD astrocytes respectively. Reactive oxygen species (ROS) were increased in both AD astrocyte types (p=0.05). Mitochondrial complex I and II was significantly increased in sAD (p less than 0.05) but not in fAD. Astrocyte glycolytic reserve and extracellular lactate was significantly reduced when compared to controls in both sAD and fAD (p less than 0.05). We identified a deficit in the glycolytic pathway enzyme hexokinase, and correcting this deficit restored most of the metabolic phenotype in sAD but not fAD astrocytes. Conclusion: AD astrocytes have abnormalities in functional capacity of mitochondria and the process of glycolysis. These functional deficits can be improved by correcting hexokinase expression deficits with adenoviral vectors. This suggests that hexokinase 1 deficiency could potentially be exploited as a new therapeutic target for AD. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.03.20.533566v1?rss=1 Authors: Sun, W., Liu, Z., Jiang, X., Chen, M. B., Dong, H., Liu, J., Sudhof, T. C., Quake, S. R. Abstract: Memory encodes past experiences, thereby enabling future plans. The basolateral amygdala (BLA) is a center of salience networks that underlie emotional experience and thus plays a key role in long-term fear memory formation. Here we used spatial and single-cell transcriptomics to illuminate the cellular and molecular architecture of the role of the basolateral amygdala in long-term memory. We identified transcriptional signatures in subpopulations of neurons and astrocytes that were memory-specific and persisted for weeks. These transcriptional signatures implicate neuropeptide signaling, mitogen-activated protein kinase (MAPK), brain-derived neurotrophic factor (BDNF), cAMP response element-binding protein (CREB), ubiquitination pathways, and synaptic connectivity in long-term memory. We also discovered that a neuronal sub-population, defined by increased Penk expression and decreased Tac expression, constitutes the most prominent component of the BLA's memory engram. These transcriptional changes were observed both with single-cell RNAseq and with single-molecule spatial transcriptomics in intact slices, thereby providing a rich spatial map of a memory engram. The spatial data enabled us to show that this neuronal subpopulation further interacts with spatially related astrocytes that are essential for memory consolidation, indicating that neurons require interactions with astrocytes to encode long term memory. 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/2023.03.19.533284v1?rss=1 Authors: Mongredien, R., Anesio, A., Fernandes, G. J. D., Eagle, A. L., Maldera, S., Pham, C., Vilette, A., Bianchi, P. C., Franco, C., Louis, F., Gruszczynski, C., Betancur, C., Erdozain, A. M., Robison, A. J., Boucard, A. A., Li, D. J., Cruz, F. C., Gautron, S., Heck, N., Vialou, V. Abstract: Drug addiction involves profound modifications of neuronal plasticity in the nucleus accumbens, which may engage various cell types. Here, we report prominent effects of cocaine on calcium signals in astrocytes characterized by in vivo fiber photometry. Astrocyte calcium signals in the nucleus accumbens are sufficient and necessary for the acquisition of cocaine seeking behavior. We identify the astrocyte-secreted matricellular protein hevin as an effector of the action of cocaine and calcium signals on reward and neuronal plasticity. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.03.14.532493v1?rss=1 Authors: Cheng, Y.-T., Luna-Figueroa, E., Woo, J., Chen, H.-C., Lee, Z.-F., Harmanci, A. S., Deneen, B. Abstract: Communication between neurons and glia plays an important role in establishing and maintaining higher order brain function. Astrocytes are endowed with complex morphologies which places their peripheral processes in close proximity to neuronal synapses and directly contributes to their regulation of brain circuits. Recent studies have shown that excitatory neuronal activity promotes oligodendrocyte differentiation; whether inhibitory neurotransmission regulates astrocyte morphogenesis during development is unknown. Here we show that inhibitory neuron activity is necessary and sufficient for astrocyte morphogenesis. We found that input from inhibitory neurons functions through astrocytic GABABR and that its deletion in astrocytes results in a loss of morphological complexity across a host of brain regions and disruption of circuit function. Expression of GABABR in developing astrocytes is regulated in a region-specific manner by SOX9 or NFIA and deletion of these transcription factors results in region-specific defects in astrocyte morphogenesis, which is conferred by interactions with transcription factors exhibiting region-restricted patterns of expression. Together our studies identify input from inhibitory neurons and astrocytic GABABR as universal regulators of morphogenesis, while further revealing a combinatorial code of region-specific transcriptional dependencies for astrocyte development that is intertwined with activity-dependent processes. 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/2023.03.06.531247v1?rss=1 Authors: Saetra, M. J., Ellingsrud, A. J., Rognes, M. E. Abstract: The complex interplay between chemical, electrical, and mechanical factors is fundamental to the function and homeostasis of the brain, but the effect of electrochemical gradients on brain interstitial fluid flow, solute transport, and clearance remains poorly quantified. Here, via in-silico experiments based on biophysical modeling, we estimate water movement across astrocyte cell membranes, within astrocyte networks, and within the extracellular space (ECS) induced by neuronal activity, and quantify the relative role of different forces (osmotic, hydrostatic, and electrical) on transport and fluid flow under such conditions. Our results demonstrate how neuronal activity in the form of extracellular ionic input fluxes may induce complex and strongly-coupled chemical-electrical-mechanical interactions in astrocytes and ECS. Furthermore, we observe that the fluid dynamics are crucially coupled to the spatial organization of the intracellular network, with convective and electrical drift dominating ionic diffusion in astrocyte syncytia. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.03.02.529949v1?rss=1 Authors: Bosworth, A. P., Contreras, M., Novak, S. W., Sancho, L., Salas, I. H., Manor, U., Allen, N. J. Abstract: The maturation and stabilization of appropriate synaptic connections is a vital step in the development of neuronal circuits, however the molecular signals underlying these processes are not fully understood. We show that astrocytes, through production of glypican 5 (GPC5), are required for maturation and refinement of synapses in the developing mouse cortex. In the absence of astrocyte GPC5 thalamocortical synapses in the visual cortex show structural immaturity during the critical period, including smaller presynaptic terminals, decreased postsynaptic density area, and presence of more postsynaptic partners at multisynaptic connections. This structural immaturity is accompanied by a delay in developmental incorporation of GLUA2-containing calcium impermeable AMPARs at intracortical synapses. The functional impact of this is that mice lacking astrocyte GPC5 exhibit increased levels of ocular dominance plasticity in adulthood. This shows astrocyte GPC5 is necessary for maturation and stabilization of synaptic connections in typical development, with implications for understanding disorders with altered synaptic function, including Alzheimer disease, where GPC5 levels are altered. 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/2023.02.21.529451v1?rss=1 Authors: Gleichman, A. J., Kawaguchi, R., Sofroniew, M. V., Carmichael, S. T. Abstract: Astrocytes, one of the most prevalent cell types in the central nervous system (CNS), are critically involved in neural function in both health and disease. Genetically manipulating astrocytes is an essential tool in understanding and affecting their roles. Adeno-associated viruses (AAVs) enable rapid genetic manipulation; however, astrocyte specificity of AAVs can be limited, with high off-target expression in neurons and sparsely in endothelial cells. Here, we report the development of a cassette of miRNA targeting sequences (4x6T) which triggers transgene degradation specifically in neurons and endothelial cells. 4x6T increases astrocytic expression of Cre with a viral reporter from less than 50% to greater than 99% in four tested serotypes in mice, and confers astrocyte specificity in two inducible forms of Cre; Dre; and reporters. We also present empty vectors to add 4x6T to other cargo, independently and in Cre/Dre-dependent forms. This toolbox of AAVs provides a way to rapidly manipulate astrocytes throughout the CNS. 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/2023.02.20.529180v1?rss=1 Authors: Janeckova, L., Knotek, T., Kriska, J., Hermanova, Z., Kirdajova, D., Kubovciak, J., Berkova, L., Tureckova, J., Camacho Garcia, S., Galuskova, K., Kolar, M., Anderova, M., Korinek, V. Abstract: Glia cells expressing neuron-glial antigen 2 (NG2) play a critical role as oligodendrocyte precursor cells (OPCs) in the healthy brain; however, their differentiation potential after ischemic injury remains an unresolved question. Here, we aimed to elucidate the heterogeneity and role of NG2 glia in the ischemic brain. We used transgenic mice to label NG2-expressing cells and their progeny with red fluorescent protein tdTomato in the healthy brains and those after focal cerebral ischemia (FCI). Based on single-cell RNA sequencing, the labeled glial cells were divided into five distinct subpopulations. The identity of these subpopulations was determined based on gene expression patterns. In addition, membrane properties were further analyzed using the patch-clamp technique. Three of the observed subpopulations represented OPCs, whereas the fourth group exhibited characteristics of cells destined for oligodendrocyte fate. The fifth subpopulation of NG2 glia carried astrocytic markers. Importantly, we detected features of neural progenitors in these cells. This subpopulation was present in both healthy and post-ischemic tissue; however, its gene expression changed after ischemia, with genes related to neurogenesis being more abundant. Neurogenic gene expression was monitored over time and complemented by immunohistochemical staining, which showed increased numbers of Purkinje cell protein 4-positive NG2 cells at the edge of the ischemic lesion 12 days after FCI, and NeuN-positive NG2 cells 28 days after injury, indicating the existence of neuron-like cells that develop from NG2 glia in the ischemic tissue. Our results provide further insight into the differentiation plasticity and neurogenic potential of NG2 glia after stroke. 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/2023.02.15.528709v1?rss=1 Authors: Lin, S.-S., Zhou, B., Chen, B.-J., Jiang, R., Li, B., Illes, P., Semyanov, A., Tang, Y., Verkhratsky, A. Abstract: Astrocyte atrophy is the main histopathological hallmark of the major depressive disorder (MDD) in humans and in animal models of depression. Here we show that electroacupuncture prevents astrocyte atrophy in the prefrontal cortex and alleviates depressive-like behaviour in mice subjected to the chronic unpredictable mild stress (CUMS). Treatment of mice with CUMS induced depressive-like phenotypes as confirmed by sucrose preference test, tail suspension test, and forced swim test. These behavioural changes were paralleled with morphological atrophy of astrocytes in the prefrontal cortex, revealed by analysis of 3D reconstructions of confocal Z-stack images of mCherry expressing astrocytes. This morphological atrophy was accompanied with a decrease in expression of cytoskeletal linker Ezrin, associated with formation of astrocytic leaflets, which form astroglial synaptic cradle. Electroacupuncture at the acupoint ST36 as well as treatment with anti-depressant fluoxetine prevented depressive-like behaviours, astrocytic atrophy and down-regulation of astrocytic ezrin. In conclusion, our data further strengthen the notion of a primary role of astrocytic atrophy in depression and reveal astrocytes as cellular target for electroacupuncture in treatment of depressive disorders. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.02.09.527854v1?rss=1 Authors: Kaur, G., Pant, P., Bhagat, R., Seth, P. Abstract: Neurotropic viruses can cross the otherwise dynamically regulated blood-brain barrier (BBB) and affect the brain cells. Zika virus (ZIKV) is an enveloped neurotropic Flavivirus known to cause severe neurological complications, such as encephalitis and foetal microcephaly. In the present study, we used human brain microvascular endothelial cells (hBMECs) and human progenitor derived astrocytes to form a physiologically relevant BBB model. We used this model to investigate the effects of ZIKV envelope (E) protein on properties of cells comprising the BBB. E protein is the principal viral protein involved in interaction with host cell surface receptors, facilitating the viral entry. Our findings show that ZIKV E protein results in activation of both hBMECs and astrocytes. hBMECs showed reduced expression of endothelial junction proteins - ZO-1, Occludin and VE-Cadherin, which are crucial in establishing and maintaining the BBB. As a result, ZIKV E protein triggered alteration in BBB integrity and permeability. We also found upregulation of genes involved in leukocyte recruitment along with increased proinflammatory chemokines and cytokines upon exposure to E protein. Furthermore, E protein resulted in astrogliosis as seen by increased expression of GFAP and Vimentin. Both BBB cell types exhibited inflammatory response following exposure to E protein which may influence viral access into the central nervous system (CNS), resulting in infection of other CNS cells. Overall, our study provides valuable insights into the transient changes that occur at the site of BBB upon ZIKV infection. 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/2023.02.06.527058v1?rss=1 Authors: Sabetta, Z., Krishna, G., Curry, T., Adelson, P. D., Thomas, T. C. Abstract: Traumatic brain injury (TBI) manifests late-onset and persisting clinical symptoms with implications for sex differences and increased risk for the development of age-related neurodegenerative diseases. Few studies have evaluated chronic temporal profiles of neuronal and glial pathology that include sex as a biological variable. After experimental diffuse TBI, late-onset and persisting somatosensory hypersensitivity to whisker stimulation develops at one-month post-injury and persists to at least two months post-injury in male rats, providing an in vivo model to evaluate the temporal profile of pathology responsible for morbidity. Whisker somatosensation is dependent on signaling through the thalamocortical relays of the whisker barrel circuit made up of glutamatergic projections between the ventral posteromedial nucleus of the thalamus (VPM) and primary somatosensory barrel cortex (S1BF) with inhibitory (GABA) innervation from the thalamic reticular nucleus (TRN) to the VPM. To evaluate the temporal profiles of pathology, male and female Sprague Dawley rats (n = 5-6/group) were subjected to sham surgery or midline fluid percussion injury (FPI). At 7-, 56-, and 168-days post-injury (DPI), brains were processed for amino-cupric silver stain and glial fibrillary acidic protein (GFAP) immunoreactivity, where pixel density of staining was quantified to determine the temporal profile of neuropathology and astrocyte activation in the VPM, S1BF, and TRN. FPI induced significant neuropathology in all brain regions at 7 DPI. At 168 DPI, neuropathology remained significantly elevated in the VPM and TRN, but returned to sham levels in the S1BF. GFAP immunoreactivity was increased as a function of FPI and DPI, with an FPI x DPI interaction in all regions and an FPI x Sex interaction in the S1BF. The interactions were driven by increased GFAP immunoreactivity in shams over time in the VPM and TRN. In the S1BF, GFAP immunoreactivity increased at 7 DPI and declined to age-matched sham levels by 168 DPI, while GFAP immunoreactivity in shams significantly increased between 7 and 168 days. The FPI x Sex interaction was driven by an overall greater level of GFAP immunoreactivity in FPI males compared to FPI females. Increased GFAP immunoreactivity was associated with an increased number of GFAP-positive soma, predominantly at 7 DPI. Overall, these findings indicate that FPI, time post-injury, sex, region, and aging with injury differentially contribute to chronic changes in neuronal pathology and astrocyte activation after diffuse brain injury. Thus, our results highlight distinct patterns of pathological alterations associated with the development and persistence of morbidity that supports chronic neuropathology, especially within the thalamus. Further, data indicate a convergence between TBI-induced and age-related pathology where further investigation may reveal a role for divergent astrocytic phenotypes associated with increased risk for neurodegenerative diseases. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.01.06.522870v1?rss=1 Authors: Riggins, T. E., Whitsitt, Q. A., Saxena, A., Hunter, E., Hunt, B., Thompson, C. H., Moore, M. G., Purcell, E. K. Abstract: Implanted microelectrode arrays hold immense therapeutic potential for many neurodegenerative diseases. However, a foreign body response limits long-term device performance. Recent literature supports the role of astrocytes in the response to damage to the central nervous system (CNS) and suggests that reactive astrocytes exist on a spectrum of phenotypes, from beneficial to neurotoxic. The goal of our study was to gain insight into the subtypes of reactive astrocytes responding to electrodes implanted in the brain. In this study, we tested the transcriptomic profile of two reactive astrocyte culture models (cytokine cocktail or lipopolysaccharide, LPS) utilizing RNA sequencing, which we then compared to differential gene expression surrounding devices inserted into rat motor cortex via spatial transcriptomics. We interpreted changes in the genetic expression of the culture models to that of 24 hour, 1 week and 6 week rat tissue samples at multiple distances radiating from the injury site. We found overlapping expression of up to ~250 genes between in vitro models and in vivo effects, depending on duration of implantation. Cytokine-induced cells shared more genes in common with chronically implanted tissue ( greater than or equal to 1 week) in comparison to LPS-exposed cells. We revealed localized expression of a subset of these intersecting genes (e.g., Serping1, Chi3l1, and Cyp7b1) in regions of device-encapsulating, glial fibrillary acidic protein (GFAP)-expressing astrocytes identified with immunohistochemistry. We applied a factorization approach to assess the strength of the relationship between reactivity markers and the spatial distribution of GFAP-expressing astrocytes in vivo. We also provide lists of hundreds of differentially expressed genes between reactive culture models and untreated controls, and we observed 311 shared genes between the cytokine induced model and the LPS-reaction induced control model. Our results show that comparisons of reactive astrocyte culture models with spatial transcriptomics data can reveal new biomarkers of the foreign body response to implantable neurotechnology. These comparisons also provide a strategy to assess the development of in vitro models of the tissue response to implanted electrodes. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2023.01.08.523173v1?rss=1 Authors: Ahmadpour, N., Kantroo, M., Stobart, M. J., Salamovska, T., O'Hara, F., Erickson, D., Carrion-Falgarona, S., Stobart, J. L. Abstract: Cortical astrocytes encode sensory information through their calcium dynamics, but it remains unclear if modulation of astrocyte calcium transients can change somatosensory circuits and behaviour in vivo. Here, we used a novel knockdown approach to selectively reduce astrocyte N-methyl-D-aspartate receptors (NMDAR). We found that these ionotropic receptors contribute to astrocyte Ca2+ transients encoding sensory information. This was essential for the optimal processing of sensory information in nearby neurons, since a reduction in astrocyte NMDARs caused circuit dysfunction and impaired neuronal responses to stimulation. This led to sensory discrimination deficits in the animal. Overall, our findings show that astrocytes can rapidly respond to glutamatergic transmission via their NMDAR and these receptors are an important component for astrocyte-neuron interactions that regulate cortical sensory discrimination in vivo. Copy rights belong to original authors. Visit the link for more info Podcast created by Paper Player, LLC

Neurons get a lot of attention—but researchers think this star-shaped brain cell type could hold the key to treating some disorders.

Neurons get a lot of attention—but researchers think this star-shaped brain cell type could hold the key to treating some disorders.

Dilek Colak, PhD, shares the results of recent work identifying aberrant Ca2+ signaling in ASD astrocytes as a mechanism that contributes to specific behavioral and neuronal deficits. Series: "Stem Cell Channel" [Health and Medicine] [Science] [Show ID: 37673]

Dilek Colak, PhD, shares the results of recent work identifying aberrant Ca2+ signaling in ASD astrocytes as a mechanism that contributes to specific behavioral and neuronal deficits. Series: "Stem Cell Channel" [Health and Medicine] [Science] [Show ID: 37673]

Dilek Colak, PhD, shares the results of recent work identifying aberrant Ca2+ signaling in ASD astrocytes as a mechanism that contributes to specific behavioral and neuronal deficits. Series: "Stem Cell Channel" [Health and Medicine] [Science] [Show ID: 37673]

Dilek Colak, PhD, shares the results of recent work identifying aberrant Ca2+ signaling in ASD astrocytes as a mechanism that contributes to specific behavioral and neuronal deficits. Series: "Stem Cell Channel" [Health and Medicine] [Science] [Show ID: 37673]

Dilek Colak, PhD, shares the results of recent work identifying aberrant Ca2+ signaling in ASD astrocytes as a mechanism that contributes to specific behavioral and neuronal deficits. Series: "Stem Cell Channel" [Health and Medicine] [Science] [Show ID: 37673]

Dilek Colak, PhD, shares the results of recent work identifying aberrant Ca2+ signaling in ASD astrocytes as a mechanism that contributes to specific behavioral and neuronal deficits. Series: "Stem Cell Channel" [Health and Medicine] [Science] [Show ID: 37673]

Dilek Colak, PhD, shares the results of recent work identifying aberrant Ca2+ signaling in ASD astrocytes as a mechanism that contributes to specific behavioral and neuronal deficits. Series: "Stem Cell Channel" [Health and Medicine] [Science] [Show ID: 37673]

Support the show to get full episodes and join the Discord community. Brains are often conceived as consisting of neurons and "everything else." As Elena discusses, the "everything else," including glial cells and in particular astrocytes, have largely been ignored in neuroscience. That's partly because the fast action potentials of neurons have been assumed to underlie computations in the brain, and because technology only recently afforded closer scrutiny of astrocyte activity. Now that we can record calcium signaling in astrocytes, it's possible to relate how astrocyte signaling with each other and with neurons may complement the cognitive roles once thought the sole domain of neurons. Although the computational role of astrocytes remains unclear, it is clear that astrocytes interact with neurons and neural circuits in dynamic and interesting ways. We talk about the historical story of astrocytes, the emerging modern story, and Elena shares her views on the path forward to understand astrocyte function in cognition, disease, homeostasis, and - Elena's favorite current hypothesis - their integrative role in negative feedback control. Elena's website.Twitter: @elenagalea1Related papersA roadmap to integrate astrocytes into Systems Neuroscience.Elena recommended this paper: Biological feedback control—Respect the loops. 0:00 - Intro 5:23 - The changing story of astrocytes 14:58 - Astrocyte research lags neuroscience 19:45 - Types of astrocytes 23:06 - Astrocytes vs neurons 26:08 - Computational roles of astrocytes 35:45 - Feedback control 43:37 - Energy efficiency 46:25 - Current technology 52:58 - Computational astroscience 1:10:57 - Do names for things matter

TWiN explains the finding that in the mouse visual cortex, astrocytes are key elements in the experience-dependent wiring of brain circuits. Hosts: Vincent Racaniello, Jason Shepherd, Timothy Cheung, and Vivianne Morrison Subscribe (free): Apple Podcasts, Google Podcasts, RSS, email Become a patron of TWiN! Links for this episode Astrocytes close the critical period (Science) Timestamps by Jolene. Thanks! Music is by Ronald Jenkees Send your neuroscience questions and comments to twin@microbe.tv