ROLE OF PERIPHERAL IMMUNE-DERIVED MMP8 IN STRESS SUSCEPTIBILITY

ROLE OF PERIPHERAL IMMUNE-DERIVED MMP8 IN STRESS SUSCEPTIBILITY In this application we will examine how peripheral monocytes interface with the brain to mediate stress susceptibility (SUS) vs. resilience (RES). We and others have shown that stress mobilizes monocytes in the periphery by enhancing their proliferation and egress from bone marrow stores into the circulation and the trafficking them to target tissues, such as the brain. While we know that such effects have been linked to alterations in complex stress-related behaviors, the mechanisms by which these immune cells communicate with the brain has been largely unknown. Using single-cell RNA-sequencing along with advanced bioinformatics, we first defined the cellular and molecular pathways that interface monocytes and the brain during chronic social defeat stress (CSDS) exposure in mice. We find that CSDS increases matrix metalloproteinase 8 (MMP8)—a monocyte-enriched matrix metalloproteinase that can remodel the tissue extracellular matrix (ECMs) and promote blood brain barrier (BBB) permeability —in SUS, but not RES, mice. We further demonstrate that peripheral MMP8 directly infiltrates the NAc parenchyma to control ECM reorganization. Depleting MMP8 specifically in peripheral immune cells prevented stress-induced social avoidance behavior and alterations in NAc neurophysiology and extracellular matrix reorganization. Collectively, these data establish a novel mechanism by which peripheral immune factors can affect central nervous system function and behavior in the context of stress. Our team is now poised to exploit the many state-of-the-art tools in this application to gain a fundamentally more complete understanding of how the peripheral immune system can interface with the brain to control complex stress behaviors. First, we will define exactly how monocyte-derived MMP8 regulates the BBB and ECM reorganization and cell-type specific neurophysiological changes in NAc. We will also define the role of peripheral infiltration of MMP8 in NAc on social and non-social reward/reinforcement behaviors. Together these studies will provide novel insight into the brain-body mechanisms that drive stress susceptibility, with the ultimate goal of developing novel therapeutics targeting MMP8 to treat stress disorders.