PROJECT SUMMARY In our decades-long pursuit of understanding the central nervous system (CNS) and the pathophysiology of devastating neurological and psychiatric conditions, research has nearly exclusively focused on one particular kind of “brain cell,” the neuron. However, 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. As the most abundant glial cells, astrocytes form extensive and intimate associations with neurons throughout the entire CNS. The prevailing assumption has been that astrocytes perform a passive supportive role for CNS neurons. However, accumulating evidence including our own studies have supported a functional versatility of astrocytic regulation in different neural circuits as well as diverse aspects of complex behaviors. Despite progress in this direction, the mechanisms underlying the diversity and specificity of interaction between astrocytes and distinct neuron populations remains elusive. In this proposal, we aim to establish a multidimensional model of astrocyte- neuron interaction in the prefrontal circuit by addressing a series of fundamental questions: How do astrocytes regulate discrete neuronal subpopulations linked to various behavioral systems within a single brain region? Can astrocytes discriminate between synapses from distinct neuronal ensembles based on local signals? If so, what are the molecular pathways and structural basis encoding the specificity of astrocyte-neuron interaction? Our proposed research will integrate state-of-the-art techniques for genetic/chemogenetic manipulation of astrocytic signaling and in vivo Ca2+ imaging of neuronal activities in freely behaving mice to reveal the functional interaction between astrocytes and neurons. We will also generate new tools and analysis platforms that will unveil the structural dynamics and cell-type specific proteomes at the interface between astrocytic processes and synapses of discrete neuronal ensembles. The completion of this study will yield novel, critical insights into the complexity and heterogeneity of astrocyte-neuron interaction on the functional, structural, and proteomic levels with an unprecedented depth. Importantly, physiological and molecular abnormalities of both astrocytes and neurons are implicated in numerous neurological and psychiatric disorders, such as Alzheimer’s disease, Parkinson’s disease, autism spectrum disorders and epilepsy. Thus, the proposed research will have a great potential to inspire the development of novel therapeutics targeted at astrocyte-neuron interaction to treat a wide range of brain disorders.

PROJECT NARRATIVE As the most numerous non-neuronal cell types in the mammalian brain, astrocytes form close associations with neurons and regulate various aspects of neuronal function. The goal of this project is to elucidate the structural, functional and molecular basis mediating the communication between astrocytes and distinct projection neurons in the prefrontal circuit. Abnormalities of astrocyte-neuron interaction have been implicated in numerous neurological and psychiatric disorders, and thus the proposed research is highly relevant to a broad range of mental disorders and may guide the development of innovative treatment.