Ventral Subiculum Inputs to Nucleus Accumbens Medial Shell Preferentially Innervate D2R Medium Spiny Neurons and Contain Calcium Permeable AMPARs

Ventral subiculum (vSUB) is the major output region of ventral hippocampus (vHIPP) and sends major projections to nu-cleus accumbens medial shell (NAcMS). Hyperactivity of the vSUB-NAcMS circuit is associated with substance use disorders and the modulation of vSUB activity alters drug seeking and drug reinstatement behavior in rodents. However, to the best of our knowledge, the cell type-specific connectivity and synaptic transmission properties of the vSUB-NAcMS circuit have never been directly examined. Instead, previous functional studies have focused on total ventral hippocampal (vHIPP) output to NAcMS without distinguishing vSUB from other subregions of vHIPP, including ventral CA1 (vCA1). Using ex vivo electro-physiology, we systematically characterized the vSUB-NAcMS circuit with cell type-and synapse-specific resolution in male and female mice and found that vSUB output to dopamine receptor type-1 (D1R) and type-2 (D2R) expressing medium spiny neurons (MSNs) displays a functional connectivity bias for D2R MSNs. Furthermore, we found that vSUB-D1R and vSUB-D2R MSN synapses contain calcium-permeable AMPA receptors in drug-naive mice. Finally, we find that, distinct from other glutamatergic inputs, cocaine exposure selectively induces plasticity at vSUB-D2R synapses. Importantly, we directly compared vSUB and vCA1 output to NAcMS and found that vSUB synapses are functionally distinct and that vCA1 output recapitulated the synaptic properties previously ascribed to vHIPP. Our work highlights the need to consider the contributions of individ-ual subregions of vHIPP to substance use disorders and represents an important first step toward understanding how the vSUB-NAcMS circuit contributes to the etiologies that underlie substance use disorders.