Cortico-Hippocampal Mechanisms of Context Memory

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ABSTRACT Episodic memories, particularly those associated with stressful experiences, often persist throughout a lifetime. While extensive research has helped us to better understand the hippocampal mechanisms mediating the formation of episodic memories, the role of the cortex is less well understood. Our project seeks to establish the contribution of the retrosplenial cortex (RSC), and its interactions with the dorsal hippocampus (DH), to the encoding, consolidation, and retrieval of contextual fear-provoking memories. We propose that RSC, by integrating dorsohippocampal (DH) inputs, plays a principal role in the processing of contextual memories from the earliest stages of memory encoding to remote retrieval, but that RSC, rather than DH, is the gateway of information to other parts of the neocortex. We also posit that three distinct DH-RSC projections contribute to the formation, recent, and remote retrieval of context memories, whereas layer 5 RSC neurons contribute to long-term memory consolidation. Our approaches will consist of conditional genetic and chemogenetic manipulations of individual RSC neuronal populations as well as DH-RSC projections. This will be complemented by optogenetic-electrophysiological approaches of the functional neuroanatomy of DH-RSC projections and RSC layer-specific analyses of immediate early gene responses related to memory. Understanding the molecular and circuit mechanisms of RSC function as they relate to memory will inform the development of novel treatment approaches for cognitive deficits in patients suffering from neurological and psychiatric disorders. Ideally, our findings will identify cortical pathways whose stimulation can bypass the requirement for the hippocampus in memory formation and can thus serve as a novel treatment option.