Hippocampal-Evoked Feedforward Inhibition in the Nucleus Accumbens

The nucleus accumbens (NAc) is critical for motivated behavior and is rewired following exposure to drugs of abuse. Medium spiny neurons (MSNs) in the NAc express either D1 or D2 receptors and project to distinct downstream targets. Differential activation of these MSNs depends on both excitation from long-range inputs and inhibition via the local circuit. Assessing how long-range excitatory inputs engage inhibitory circuitry is therefore important for understanding NAc function. Here, we use slice electrophysiology and optogenetics to study ventral hippocampal (vHPC)-evoked feedforward inhibition in the NAc of male and female mice. We find that vHPC-evoked excitation is stronger at D1+ than D1- MSNs, whereas inhibition is unbiased at the two cell types. vHPC inputs contact both parvalbumin-positive (PV+) and somatostatin-positive (SOM+) interneurons, but PV+ cells are preferentially activated. Moreover, suppressing PV+ interneurons indicates they are primarily responsible for vHPC-evoked inhibition. Finally, repeated cocaine exposure alters the excitation of D1+ and D1- MSNs, without concomitant changes to inhibition, shifting the excitation/inhibition balance. Together, our results highlight the contributions of multiple interneuron populations to feedforward inhibition in the NAc. Moreover, they demonstrate that inhibition provides a stable backdrop on which drug-evoked changes to excitation occur within this circuit.SIGNIFICANCE STATEMENT Given the importance of the nucleus accumbens (NAc) in reward learning and drug-seeking behaviors, it is critical to understand what controls the activity of cells in this region. While excitatory inputs to projection neurons in the NAc have been identified, it is unclear how the local inhibitory network becomes engaged. Here, we identify a sparse population of interneurons responsible for feedforward inhibition evoked by ventral hippocampal input and characterize their connections within the NAc. We also demonstrate that the balance of excitation and inhibition that projection neurons experience is altered by exposure to cocaine. Together, this work provides insight into the fundamental circuitry of this region as well as the effects of drugs of abuse.