SUMMARY The highest cognitive functions such as reasoning, planning, and decision-making, are all, directly or indirectly, influenced by our past personal experiences, which are represented in hippocampal-cortical circuits as episodic memories. Dysfunction of these circuits has been linked to the most prevalent and challenging mental disorders of our time, ranging from dementia to anxiety, depression, and post-traumatic stress disorder. Understanding the neurobiological mechanisms of episodic memory formation and retrieval are therefore essential for the development of effective molecular and circuit-based therapies for such disorders. We posit a key role of activity-dependent inflammatory signaling in discrete dorsohippocampal (DH) projections to the retrosplenial cortex (RSC) DH-RSC circuit in the stabilization and persistence of stress-related memories. Aim 1 is designed to determine the contributions of discrete DH-RSC projections to early tagging of RSC and sustained inflammatory signaling in DH and RSC. Aim 2 will focus on the direct contribution of hippocampal Toll-like receptors (Tlr) to memory consolidation and induction of TGFb1 and Aim 3 will examine the contribution of TGFb to the cortical dependence of memories and deactivation of inflammatory signaling in the DH-RSC circuit. These aims will be tested in mouse models of episodic-like memories by applying projection-specific manipulations of the DH-RSC circuit, cell-specific genetic manipulations of Tlr9 and TGFb receptors, and quantitative molecular biologic and imaging approaches to monitor inflammatory signaling in memory circuits. We hope that circuit specific Tlr9/ TGFb signaling will emerge as candidate target for therapies for neuropsychiatric disorders rooted in episodic memory deficits. In this supplement, we propose to add Kendra Parker as a member in our project to study the role of Tlr9 in memory-related inflammatory signaling. Kendra Parker has defined her career goal explicitly as a future physician scientist. Our goal during her participation in this R01 project is to provide the training in research resulting in publications, and thus ensure that she receives a strong foundation toward that outcome. We welcome the opportunity to train an African American woman as a future leader in biological psychiatry, and in the field of neurobiology of memory in particular.