Cortico-Hippocampal Mechanisms of Context Memory

Traumatic experiences frequently give rise to persistent and distressing memories, which can easily be retrieved by cues or contexts associated with those experiences. While extensive research has helped us to better understand the hippocampal mechanisms mediating the formation of negatively valenced episodic memories, the cortical mechanisms of memory and their dependence on the hippocampus are not well understood. Our project seeks to establish the contribution of the retrosplenial cortex (RSC) to the encoding, consolidation, and retrieval of context-specific, 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 the hippocampus, is the gateway of information to other parts of the neocortex. We also posit that three distinct DH-RSC projections contribute to the formation, retrieval, and recognition of context memories, whereas layer 5 RSC neurons contribute to the consolidation of long-term memory. 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 layer-specific analyses of the functional neuroanatomy of DH-RSC projections and their effects on immediate early gene responses associated with memory-related neuronal activity. We expect that the results of this work will advance our understanding of the cortical processing of episodic memories. In individuals suffering from affective disorders, such memories can give rise to sustained fear, anxiety, and depression symptoms, for which effective therapies are still lacking. In patients with cognitive disorders, activation of the identified circuits may help to retrieve their episodic memories. Our findings may therefore contribute to the identification of novel neurobiological targets for treatment of these disorders.