Biology subjects

Virmani, G.

Publications and source records attributed to Virmani, G..

6 recordsLinked to original sources

bioRxiv2026

Noradrenergic Depletion by DSP-4 Reduces Morphological Complexity of Hippocampal Astrocytes

BackgroundNorepinephrine (NE) released from locus coeruleus (LC) projections regulates astrocyte structure and function through adrenergic receptor signaling. We previously showed that increasing noradrenergic tone with the NE reuptake inhibitor desipramine increases astrocyte ramification in the molecular layer of the dentate gyrus. However, whether tonic LC-derived noradrenergic tone is required to maintain astrocyte morphological complexity in vivo, and whether {beta}-adrenergic receptor activation is the effector pathway, remained unclear. MethodsAdult male C57BL/6J mice received DSP-4 (50 mg/kg x 3 days i.p.), a selective LC neurotoxin, with or without concurrent isoproterenol that continued for 21 additional days post cessation of DSP-4 treatment (ISO; 2 mg/kg/day x 24 days), or saline (n = 4 mice per group). Animals were sacrificed 22 days after the final DSP-4 injection. Noradrenergic denervation was confirmed by dopamine {beta}-hydroxylase (DBH) immunostaining. GFAP-immunostained astrocytes in the molecular layer of the dentate gyrus were morphologically characterized using Sholl analysis. Astrocyte density was quantified by SOX9 immunostaining. ResultsDSP-4 produced >83% reduction in DBH fiber coverage in the molecular layer. Sholl analysis revealed significant reductions in astrocyte branching complexity in both treatment groups, with the reductions concentrated at distances of 5-15 {micro}m from the soma. The maximum number of intersections was also significantly reduced in both groups. Unexpectedly, ISO did not rescue morphological complexity. While DSP-4 alone did not alter astrocyte density, as measured by the number of SOX9-expressing astrocytes, DSP-4+ISO increased SOX9-positive cell density, dissociating the effects of adrenergic signaling on morphology from those on cell numbers. ConclusionsLC-derived noradrenergic tone is required for the maintenance of astrocyte arbour complexity in the dentate gyrus molecular layer. {beta}-adrenergic receptor activation alone is insufficient to restore structural integrity following noradrenergic denervation, yet promotes astrocyte density independently of structural remodeling. These findings have implications for understanding how LC neurodegeneration in Alzheimers disease and depression may compromise hippocampal astrocyte structure and function.

neuroscience↗

bioRxiv2026

Primate Astrocyte Evolution Controls the Tempo of Neuronal Development

Prolonged neuronal maturation, also referred to as neoteny, constitutes a hallmark of human brain evolution. Yet, the mechanisms controlling neotenic brain development remain poorly understood, and have been defined as neuron-intrinsic. Astrocytes shape synapse formation, activity, and elimination, and have changed substantially between humans and other species. Yet, whether the evolutionary divergence in astrocytes shapes the timing of neuronal maturation is unknown. Here, we show that astrocytes from humans and their closest living relatives, chimpanzees, exert contrasting effects on neuronal maturation: chimpanzee astrocytes accelerate it, whereas human astrocytes delay it, without affecting neuronal survival. Through comparative transcriptomics and epigenomics, we find that evolutionarily reduced APOE expression in human astrocytes underlies the observed delay in neuronal maturation: restoring APOE levels in human astrocytes accelerates neuronal development. We further establish that the Hippo-TEAD signaling represses APOE expression in human astrocytes, revealing a link between the enhanced morphological complexity of human astrocytes and the observed reduced tempo of neuronal development in their presence. Strikingly, neuronal genes differentially impacted by human and chimpanzee astrocytes are associated with schizophrenia, Alzheimers disease, and epilepsy, linking astrocyte evolution to disease vulnerability. Altogether, these findings establish that brain neoteny is partly a glial phenomenon, revealing that understanding the pace of human brain development requires understanding how astrocytes, not only neurons, have evolved.

neuroscience↗

bioRxiv2025

Tunneling Nanotube-like Connections in the Developing Cerebellum: Distinct from Cytokinetic and Intercellular Bridges

Intercellular communication is essential for brain development. While classical modes--paracrine, juxtacrine, and synaptic signaling--are well characterized, emerging evidence suggests that membranous bridges, such as tunneling nanotubes (TNTs), forming de novo between cells and mainly described in vitro, may also contribute. Yet their presence and function in vivo remain unclear, partly due to the difficulty of distinguishing them from other intercellular connections (ICs). Building on connectomic observations in fixed tissue reporting ICs in the external granule layer (EGL) of the developing cerebellum, we examined their nature in postnatal day 7 (P7) mice. Using immunofluorescence, sparse genetic labelling, and live imaging, we distinguished division-independent ICs from cytokinetic bridges (CBs) and intercellular bridges (IBs). CBs were detected in the EGL, whereas IBs were not observed in this region. In addition to CBs, we identified membranous protrusions which appeared to link clonally and non-clonally related cells. The presence of these ICs reinforces previous connectomic evidence in fixed tissue and raises the possibility that they may participate in intercellular communication during cerebellar development. These findings warrant further investigation into a potentially underexplored mode of communication in the developing brain.

neuroscience↗

bioRxiv2021

Hippocampal astroglial hypertrophy in mice subjected to early life maternal deprivation

Early-life stress (ELS), including chronic deprivation of maternal care, exerts persistent life-long effects on animal physiology and behavior, and is associated with several neurodevelopmental disorders. Long-lasting changes in neuronal plasticity and electrophysiology are documented extensively in the animal models of ELS. However, the role of astroglia in the lasting effects of ELS remains elusive. Astrocytes are intricately involved in the regulation of synaptic physiology and behavior. Moreover, astrocytes play a major role in the innate and adaptive immune responses in the central nervous system (CNS). The role of immune responses and neuroinflammation in the altered brain development and persistent adverse effects of ELS are beginning to be explored. Innate immune response in the CNS is characterized by a phenomenon called astrogliosis, a process in which astrocytes undergo hypertrophy, along with changes in gene expression and function. While the immune activation and neuroinflammatory changes concomitant with ELS, or in juveniles and young adults have been reported, it is unclear whether mice subjected to ELS exhibit astrogliosis-like alterations well into late-adulthood. Here, we subjected mice to maternal separation from postnatal day 2 to day 22 and performed comprehensive morphometric analysis of hippocampal astrocytes during late-adulthood. We found that the astrocytes in the stratum radiatum region of the CA1 hippocampal subfield from maternally separated mice exhibit significant hypertrophy as late as 8 months of age, revealing the crucial changes in astrocytes that manifest long after the cessation of ELS. This study highlights the persistence of neuroinflammatory changes in mice exposed to ELS.

neuroscience↗

bioRxiv2020

Automated Morphometric Analysis Reveals Plasticity Induced by Chronic Antidepressant Treatment in Hippocampal Astrocytes

Nervous system development and plasticity involves changes in cellular morphology, making morphological analysis a valuable exercise in the study of nervous system development, function and disease. Morphological analysis is a time-consuming exercise requiring meticulous manual tracing of cellular contours and extensions. We have developed a software tool, called SMorph, to rapidly analyse the morphology of cells of the nervous system. SMorph performs completely automated Sholl analysis. It extracts 23 morphometric features based on cell images and Sholl analysis parameters, followed by Principal Component Analysis. SMorph is tested on neurons, astrocytes and microglia and reveals subtle changes in cell morphology. Using SMorph, we found that chronic 21-day treatment with antidepressant desipramine results in a significant structural remodeling in hippocampal astrocytes. Given the proposed involvement of astroglial structural changes and atrophy in major depression in humans, our results reveal a novel kind of structural plasticity induced by chronic antidepressant administration.

neuroscience↗

bioRxiv2020

Subfield-specific Effects of Chronic Mild Unpredictable Stress on Hippocampal Astrocytes

Major Depressive Disorder (MDD) is a debilitating neuropsychiatric illness affecting over 20% of the population worldwide. Despite its prevalence, our understanding of its pathophysiology is severely limited, thus hampering the development of novel therapeutic strategies. Recent advances have clearly established astrocytes as major players in the pathophysiology, and plausibly pathogenesis, of major depression. In particular, astrocyte density in the hippocampus is severely diminished in MDD patients and correlates strongly with the disease outcome. Moreover, astrocyte densities from different subfields of the hippocampus show varying trends in terms of their correlation to the disease outcome. Given the central role that hippocampus plays in the pathophysiology of depression and in the action of antidepressant drugs, changes in hippocampal astrocyte density and physiology may have a significant effect on behavioral symptoms of MDD. In this study, we used Chronic Mild Unpredictable Stress (CMUS) in mice, which induces a depressive-like state, and examined its effects on astrocytes from different subfields of the hippocampus. We used S100{beta} immunostaining to estimate the number of astrocytes per mm2 from various hippocampal subfields. Furthermore, using confocal images of fluorescently labeled GFAP-immunopositive hippocampal astrocytes, we quantified various morphology-related parameters and performed Sholl analysis. We found that CMUS exerts differential effects on astrocyte cell density, ramification, cell radius, surface area, and process width of hippocampal astrocytes from different hippocampal subfields. Taken together, our study reveals that chronic stress doesnt uniformly affect all hippocampal astrocytes; but exerts its effects differentially on different astrocytic subpopulations within the hippocampus.

neuroscience↗