A Gradient of Hippocampal Inputs to the Medial Mesocortex

Abstract

Summary: Memory-guided decisions depend on complex interactions between the hippocampus (HIPP) and medial mesocortical (MMC) regions, including the anterior cingulate (CG) and retrosplenial (RSC). The functional circuitry underlying these interactions is unclear. Using anatomy, electrophysiology, and optogenetics, we show that such circuitry is characterized by a functional-anatomical gradient. While the CG receives hippocampal excitatory projections originated in CA1 stratum pyramidale, the RSC additionally receives long-range inhibitory inputs from radiatum and lacunosum-moleculare. Such hippocampal projections establish bona fide synapses, with the RSC densely targeted on its superficial layers L1–L3 by a combination of inhibitory and excitatory synapses. We show that the MMC is targeted by dorsal-intermediate CA1 (diCA1) axons following a caudorostral gradient in which a dense, dual (excitatory/inhibitory), layer-specific projection is progressively converted in a sparse, excitatory, and diffuse projection. This gradient is reflected in higher oscillatory synchronicity between the HIPP and RSC in the awake-behaving animal, compatible with their known functional proximity and contrasting with that found in the CG. : Fernandes et al. used anatomy and in vitro and in vivo electrophysiology to show that hippocampal inputs to cingulate and retrosplenial regions, supporting memory-guided behaviors, follow a caudorostral gradient. The CG receives sparse excitatory projections, while the RSC receives dense excitatory/inhibitory synapses and exhibits increased oscillatory synchronicity in the awake-behaving animal.