Biology subjects

Chao, M. V.

Publications and source records attributed to Chao, M. V..

8 recordsLinked to original sources

bioRxiv2026

Astrocytes mediate a positive feedback loop for oxytocin

Social interactions are critical for well-being and survival. Oxytocin neurons in the paraventricular nucleus of the hypothalamus help regulate social behaviors in many species, and respond to social stimuli to promote pro-social interactions. Here, we show that chronic social isolation reduced production of oxytocin peptide, and led to a delay in the onset of huddling behavior upon resocialization in male mice. Exogenous oxytocin treatment prevented both the behavioral and molecular effects of social deprivation. Using conditional knockouts, we found that oxytocin-induced oxytocin expression was mediated by local hypothalamic astrocytes. Oxytocin signaling in astrocytes upregulated the expression of a retinoic acid-synthesizing enzyme Aldh1a1, and retinoic acid increased oxytocin expression. These findings reveal a mechanism in which astrocytes can sense and control neuropeptide levels to influence social behaviors.

neuroscience↗

bioRxiv2025

Microglia coordinate activity-dependent protein synthesis in neurons through metabolic coupling

De novo protein synthesis is required for long-lasting synaptic plasticity and memory, but it comes with a great metabolic cost. In the mammalian brain, it remains unclear which cell types and biological mechanisms are critical for sensing and responding to increased metabolic demand. Here we demonstrate that microglia, resident macrophages of the brain, coordinate metabolic coupling between endothelial cells, astrocytes, and neurons to fuel protein synthesis in active neurons. Increasing metabolic demand via a motor task stimulates microglia to secrete the hypoxia-responsive protein CYR61, increasing glucose transporter expression in brain vasculature. Depleting microglia reduces training-induced metabolic fluxes and neuronal protein synthesis, which can be reproduced by blocking CYR61 signaling. Thus, we define a neuroimmune metabolic circuit required for on-demand protein synthesis in mouse motor cortex.

neuroscience↗

bioRxiv2025

Astrocytes connect specific brain regions through plastic gap junctional networks

Traditionally, neuronal axons have been considered the primary mediators of functional connectivity among brain regions. However, the role of astrocyte-mediated communication has been largely underappreciated. While astrocytes communicate with one another through gap junctions, the extent and specificity of this communication remain poorly understood. Astrocyte gap junctions are necessary for memory formation1,2, synaptic plasticity3-5, coordination of neuronal signaling6, and closing the visual and motor critical periods7,8. These findings indicate that this form of communication is essential for proper central nervous system development and function. Despite their significance, studying astrocyte gap junctional networks has been challenging. Current methods like slice electrophysiology disrupt network connectivity and introduce artifacts due to tissue damage. To overcome these limitations, we developed a vector-based approach that labels molecules as they are fluxed by astrocyte gap junctions in awake, behaving animals. We then used whole-brain tissue clearing9,10 to image these intact, three-dimensional astrocyte networks. We show that multiple astrocyte networks traverse the mouse brain. These networks selectively connect specific regions, rather than diffusing indiscriminately, and vary in size and organization. We observe local networks are confined to single brain regions and long-range networks robustly interconnecting multiple regions across hemispheres, often exhibiting patterns distinct from known neuronal networks. Further, we demonstrate that astrocyte networks undergo structural reorganization in adult brain following sensory deprivation. These discoveries reveal a previously unrecognized mode of communication between distant brain regions, mediated by plastic networks of gap junction-coupled astrocytes.

neuroscience↗

bioRxiv2025

Mapping the spatiotemporal dynamics of de novo protein synthesis during long-term memory formation

The formation of new associative long-term memory (LTM) following Pavlovian conditioning is dependent upon multiple, temporally distinct windows of mRNA translation. Current methods lack the temporal specificity to robustly characterize the dynamics of protein synthesis throughout the rodent brain following conditioning. Here we resolve these technological limitations and demonstrate that in awake mice, the retro-orbital (RO) injection of azidohomoalanine (AHA) enables the labelling and subsequent visualization of the brain de novo proteome, with labelling periods as short as 30 minutes. Combining this advancement in de novo proteomic labelling with tissue clearing, we identified brain region, cell-type, and neuronal sub-population specific changes in de novo protein synthesis in mice following an auditory threat conditioning paradigm. This approach also allowed us to track the changes in de novo protein synthesis over time, revealing that conditioning-induced changes in mRNA translation exhibit remarkable temporal specificity in brain regions such as the somatosensory cortex. Taken together, our findings highlight how this novel labelling technique can be used to map the highly intricate temporal and spatial dynamics of mRNA translation after behavioral conditioning.

neuroscience↗

bioRxiv2023

Defining the molecular identity and morphology of glia limitans superficialis astrocytes in mouse and human

Astrocytes are a highly abundant glial cell type that perform critical homeostatic functions in the central nervous system. Like neurons, astrocytes have many discrete heterogenous subtypes. The subtype identity and functions are, at least in part, associated with their anatomical location and can be highly restricted to strategically important anatomical domains. Here, we report that astrocytes forming the glia limitans superficialis, the outermost border of brain and spinal cord, are a highly specialized astrocyte subtype and can be identified by a single marker: Myocilin (Myoc). We show that Myoc+ astrocytes cover the entire brain and spinal cord surface, exhibit an atypical morphology, and are evolutionarily conserved from rodents to humans. Identification of this highly specialized astrocyte subtype will advance our understanding of CNS homeostasis and potentially be targeted for therapeutic intervention to combat peripheral inflammatory effects on the CNS.

neuroscience↗

bioRxiv2023

SorCS2 binds progranulin and regulates motor axon outgrowth

Motor neuron development requires an orchestrated action of trophic factors and guidance cues for axons to reach their targets. Here, we identify SorCS2 as a novel receptor for progranulin (PGRN) that is required for motor axon outgrowth in zebrafish and mice. In both species motor neurons express SorCS2, and PGRN is produced in cells juxta-positioned the projecting axon, but in mice the neurons also co-express PGRN. In zebrafish, sorcs2 knockdown produces stunted and aberrantly branched motor axons, and in Sorcs2-/- mice, forelimb innervation and motor neuron regeneration are substantially perturbed; phenotypes also observed in fish and mice lacking PGRN. SorCS2 binds PGRN and while motor neuron cultures from wildtype mice respond to exogenous PGRN by axon outgrowth, knockout neurons are unresponsive. Remarkably, when co-expressed in the same cells, SorCS2 controls secretion of PGRN. We conclude that SorCS2 navigates motor neuron development and enables axon regeneration through binding of PGRN.

developmental biology↗

bioRxiv2022

Oxytocin attenuates microglial activation and restores social and non-social memory in the APP/PS1 mouse model of Alzheimer's disease

Alzheimers disease (AD) is the main cause of dementia in the elderly and is characterized by memory loss, social withdrawal and neurodegeneration, eventually leading to death. Brain inflammation has emerged as a key pathogenic mechanism in AD. We hypothesized that oxytocin, a pro-social hypothalamic neuropeptide with anti-inflammatory properties, could have therapeutic actions in AD. We investigated oxytocin production in mouse models of AD, and evaluated the therapeutic potential of intranasal oxytocin. We observed lower levels of hypothalamic oxytocin in wild-type mice following brain infusion of amyloid-{beta} oligomers (A{beta}Os), as well as in APP/PS1 AD model mice. Treatment of APP/PS1 mice with intranasal oxytocin reduced microglial activation and favored deposition of A{beta} in dense core plaques, a potentially neuroprotective mechanism. Oxytocin further alleviated social and non-social memory impairments in APP/PS1 mice. Our findings point to oxytocin as a potential therapeutic target to reduce brain inflammation and correct memory deficits in AD.

neuroscience↗

bioRxiv2019

Topoisomerase 2-dependent nuclear DNA damage shapes extracellular growth factor responses through AKT phosphorylation dynamics to control virus latency

The mTOR pathway integrates both extracellular and intracellular signals and serves as a central regulator of cell metabolism, growth, survival and stress responses. Neurotropic viruses, such as herpes simplex virus-1 (HSV-1), also rely on cellular AKT-mTORC1 signaling to achieve viral latency. Here, we define a novel genotoxic response whereby spatially separated signals initiated by extracellular neurotrophic factors and nuclear DNA damage are integrated by the AKT-mTORC1 pathway. We demonstrate that endogenous DNA double-strand breaks (DSBs) mediated by Topoisomerase 2{beta}-DNA cleavage complex (TOP2{beta}cc) intermediates are required to achieve AKT-mTORC1 signaling and maintain HSV-1 latency in neurons. Suppression of host DNA repair pathways that remove TOP2{beta}cc trigger HSV-1 reactivation. Moreover, perturbation of AKT phosphorylation dynamics by downregulating the PHLPP1 phosphatase led to AKT mis-localization and disruption of DSB-induced HSV-1 reactivation. Thus, the cellular genome integrity and environmental inputs are consolidated and co-opted by a latent virus to balance lifelong infection with transmission.

molecular biology↗