Ketamine rescues anhedonia by cell-type and input specific adaptations in the Nucleus Accumbens

Ketamine's role in providing a rapid and sustained antidepressant response, particularly for patients unresponsive to conventional treatments, is increasingly recognized. A core symptom of depression, anhedonia, or the loss of enjoyment or interest in previously pleasurable activities, is known to be significantly alleviated by ketamine. While several hypotheses have been proposed regarding the mechanisms by which ketamine alleviates anhedonia, the specific circuits and synaptic changes responsible for its sustained therapeutic effects are not yet understood. Here, we show that the nucleus accumbens (NAc), a major hub of the reward circuitry, is essential for ketamine's effect in rescuing anhedonia in mice subjected to chronic stress, a critical risk factor in the genesis of depression in humans. 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). By using a novel cell-specific pharmacology method, we demonstrate that this cell-type specific neuroadaptation is necessary for the sustained therapeutic effects of ketamine. To test for causal sufficiency, we artificially mimicked ketamine-induced increase in excitatory strength on D1-MSNs and found that this recapitulates the behavioral amelioration induced by ketamine. Finally, to determine the presynaptic origin of the relevant glutamatergic inputs for ketamine-elicited synaptic and behavioral effects, we used a combination of opto- and chemogenetics. We found that ketamine rescues stress-induced reduction in excitatory strength at medial prefrontal cortex and ventral hippocampus inputs to NAc D1-MSNs. Chemogenetically preventing ketamine-evoked plasticity at those unique inputs to the NAc reveals a ketamine-operated input-specific control of hedonic behavior. These results establish that ketamine rescues stress-induced anhedonia via cell-type-specific adaptations as well as information integration in the NAc via discrete excitatory synapses.