Exposure to cocaine alters the structural and functional properties of medium spiny neurons (MSNs) in the Nucleus Accumbens (NAc). These changes suggest a rewiring of the NAc circuit, with an enhancement of excitatory synaptic connections onto MSNs. However, it is unknown how drug exposure alters the balance of long-range afferents onto different cell types in the NAc. Here we use whole-cell recordings, two-photon microscopy, optogenetics and pharmacogenetics to show how repeated cocaine alters connectivity in the mouse NAc medial shell. We first determine that cocaine selectively enhances amygdala innervation of D1-MSNs relative to D2-MSNs. We then show that amygdala activity is required for cocaine-induced changes to behavior and connectivity. Finally, we establish how heightened amygdala innervation can explain the structural and functional changes induced by cocaine. Our findings reveal how exposure to drugs of abuse fundamentally reorganizes cell-type and input-specific connectivity in the NAc.

We found that medium spiny neurons (MSNs) in both the direct and indirect pathways of the mouse nucleus accumbens (NAc) receive inputs from the cortex, thalamus and hippocampus. However, hippocampal inputs were much weaker onto indirect MSNs, where they contacted small spines located in the distal dendrites. This selective targeting means that these inputs must be gated by subthreshold depolarization to trigger action potentials and influence NAc output.