Department of Psychiatry, Washington University in St. Louis School of Medicine, St. Louis, MO, USA; Taylor Family Institute for Innovative Psychiatric Research, Washington University in St. Louis School of Medicine, St. Louis, MO, USA.
2 papers in the library · 26 citations · publishing 2023-2025
Ketamine rapidly and sustainably alleviates anhedonia, a core symptom of depression, by restoring weakened excitatory synapses onto D1-medium spiny neurons in the nucleus accumbens of chronically stressed mice. Artificially strengthening these synapses reproduces ketamine's behavioral benefits, while blocking the synaptic restoration prevents the therapeutic effect. The relevant synaptic inputs originate from the medial prefrontal cortex and ventral hippocampus.
Ketamine rapidly alleviates anhedonia, a core symptom of depression involving loss of pleasure, but the underlying brain mechanisms were unclear. In mice subjected to chronic stress, a single dose of ketamine restored stress-induced weakening of excitatory synapses on specific neurons in the nucleus accumbens (NAc), a reward center. These neurons, called D1 dopamine receptor-expressing medium spiny neurons (D1-MSNs), showed increased synaptic strength after ketamine. Artificially mimicking this change produced the same behavioral improvement, confirming its causal role. Ketamine acted on inputs from the medial prefrontal cortex and ventral hippocampus to NAc D1-MSNs, and blocking plasticity at these inputs prevented the behavioral effect. The findings demonstrate that ketamine rescues anhedonia through cell-type-specific and input-specific synaptic adaptations in the reward circuitry.