Friday, May 9, 2025
5/9/2025
Astrocytic regulation of prefrontal neural circuits and avoidance behavior - PROJECT SUMMARY The major goals of neuroscience are to understand how the central nervous system (CNS) processes information, generates emotions, stores memories, and drives behavior. Considerable effort has been devoted to the study of neurons, yet neurons do not act alone in the brain. Thus, much is to be gained from understanding the interplay between neurons and other non-neuronal cells, particularly glial cells. Astrocytes are the most numerous glial cells and are present throughout the entire CNS. Their existence and close proximity to neurons were recognized more than a century ago. However, our understanding of astrocytes is still in its infancy. Unlike neurons, astrocytes do not transmit electrical action potentials, but instead utilize complex intracellular Ca2+ signaling to communicate with each other and mediate their effects on neurons and other cells. These astrocytic Ca2+ signals occur throughout the entire cell, both spontaneously and in response to neuronal activity. Mounting evidence has implicated astrocytic Ca2+ signaling as essential to modulating neuronal function and animal behaviors. Importantly, abnormalities of astrocyte Ca2+ signaling are implicated in numerous neurological and psychiatric disorders. However, despite progress, the physiological significance of astrocyte Ca2+-dependent signaling for the function(s) of neural microcircuits in vivo, for animal behavior, and for brain diseases remains incompletely understood. In this proposal, we aim to determine the roles of astrocyte Ca2+ signaling in regulating the prefrontal neural circuit activity as well as avoidance behavior by addressing a series of fundamental questions: What is the physiological relevance of astrocyte Ca2+ signaling from the medial prefrontal cortex (mPFC) in avoidance behavior and does astrocyte Ca2+ signaling display subregional heterogeneity (Aim 1)? Whether and how attenuated astrocyte Ca2+ signaling in the mPFC affect the prefrontal neuronal activity and avoidance behavior (Aim 2)? Whether and how enhanced astrocyte Ca2+ signaling in the mPFC affect the prefrontal neuronal activity and avoidance behavior (Aim 3)? Our proposed research will integrate state-of-the- art techniques for genetic/chemogenetic manipulation of mPFC astrocytes and in vivo Ca2+ imaging of activity dynamics of astrocytes and defined neuronal populations in freely-behaving mice to reveal the fundamental mechanisms of astrocytes in mediating behavior. This investigation will yield novel, critical insights into the intercellular communications between astrocytes and neurons. These insights will have a great potential to inspire the development of new therapies to treat a wide range of brain disorders.
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