PROJECT SUMMARY/ABSTRACT Composed of a latticework of proteoglycans and associated molecules, the brain extracellular matrix (ECM) is a medium for synaptic plasticity. The expression of chondroitin sulfate proteoglycans (CSPGs), most notably aggrecan (gene: Acan), has been shown to mediate the closure of critical periods of plasticity through the formation of perineuronal nets, structures thought to stabilize synaptic connections. Furthermore, enzymatic digestion of hippocampal ECM results in contextual learning deficits, suggesting that ECM may stabilize learning-related synaptic changes. The dentate gyrus of the hippocampus, a critical learning structure, has abundant aggrecan in its molecular layer, and dentate gyrus granule cells (DG GCs) continuously produce Acan mRNA in adulthood. Thus, aggrecan production by dentate gyrus neurons may underlie the stability of memory processes. Preliminary data presented here show that genetic deletion of Acan in dentate gyrus neurons results in remote contextual discrimination deficits. This proposal will test the hypothesis that activity-dependent aggrecan expression by DG GCs following learning is essential for DG ensemble separation and memory precision at retrieval. First, the effect of contextual fear learning on DG GC Acan expression and deposition will be characterized (Aim 1). Next, DG-specific Acan deletion will be used to test if aggrecan production is necessary for recent or remote contextual memory precision (Aim 2). Lastly, using microendoscopic calcium imaging, I will describe how aggrecan deletion changes DG GC ensemble properties (Aim 3). Altogether, this proposal aims to elucidate the extracellular matrix's role in mammalian learning and memory and the underlying molecular and network mechanisms. Furthermore, given that alterations to brain ECM are found in neurodegenerative and psychiatric conditions, understanding the physiologic properties of ECM may yield insights into disease pathophysiology and potential therapeutic avenues. These research goals will be realized in conjunction with a comprehensive training plan aimed at developing the applicant’s career as a physician-scientist. This training will include consistent, rigorous mentorship in conceptual and technical skills from two highly-qualified mentors, one of whom is a physician-scientist. The research and training proposed here will be carried out at the University of California, San Francisco, which offers both a world- class neuroscience research environment and an exceptional medical school for clinical training.