Ketamine rescues anhedonia by cell-type- and input-specific adaptations in the nucleus accumbens

Ketamine is recognized as a rapid and sustained antidepressant, particularly for major depression unresponsive to conventional treatments. Anhedonia is a common symptom of depression for which ketamine is highly efficacious, but the underlying circuits and synaptic changes are not well understood. Here, we show that the nucleus accumbens (NAc) is essential for ketamine's effect in rescuing anhedonia in mice subjected to chronic stress. Specifically, a single exposure to ketamine rescues stress-induced decreased strength of excitatory synapses on NAc-D1 dopamine receptor-expressing medium spiny neurons (D1-MSNs). Using a cell-specific pharmacology method, we establish the necessity of this synaptic restoration for the sustained therapeutic effects of ketamine on anhedonia. Examining causal sufficiency, artificially increasing excitatory synaptic strength onto D1-MSNs recapitulates the behavioral amelioration induced by ketamine. Finally, we used opto- and chemogenetic approaches to determine the presynaptic origin of the relevant synapses, implicating monosynaptic inputs from the medial prefrontal cortex and ventral hippocampus.