Distinct Dorsal and Ventral Hippocampal CA3 Outputs Govern Contextual Fear Discrimination

Considerable work emphasizes a role for hippocampal circuits in governing contextual fear discrimination. However· the intra- and extrahippocampal pathways that route contextual information to cortical and subcortical circuits to guide adaptive behavioral responses are poorly understood. Using terminal-specific optogenetic silencing in a contextual fear discrimination learning paradigm· we identify opposing roles for dorsal CA3-CA1 (dCA3-dCA1) projections and dorsal CA3-dorsolateral septum (dCA3-DLS) projections in calibrating fear responses to certain and ambiguous contextual threats· respectively. Ventral CA3-DLS (vCA3-DLS) projections suppress fear responses in both certain and ambiguous contexts· whereas ventral CA3-CA1 (vCA3-vCA1) projections promote fear responses in both these contexts. Lastly· using retrograde monosynaptic tracing· ex vivo electrophysiological recordings· and optogenetics,· we identify a sparse population of DLS parvalbumin (PV) neurons as putative relays of dCA3-DLS projections to diverse subcortical circuits. Taken together· these studies illuminate how distinct dCA3 and vCA3 outputs calibrate contextual fear discrimination.