Circuit Level Mechanisms of Ketamine’s Antidepressant Action: From Stress Induced Nucleus Accumbens Atrophy to Plasticity Driven Rescue of Motivation
- Describe how chronic stress produces profound effort related deficits and structural atrophy in D1 medium spiny neurons of the nucleus accumbens, a hub of reward computation, and how these circuit changes map onto anhedonia in depression
- Explain how a single ketamine administration, assessed after the drug has fully cleared, induces lasting synaptic plasticity that restores activity in NAc D1 MSNs and rescues stress driven motivational impairments
- Highlight how ketamine re engages two stress sensitive excitatory pathways (medial prefrontal cortex NAc and hippocampus NAc), each contributing complementary but distinct roles in restoring reward seeking behavior
- Outline next steps to translating these circuit findings to humans using functional connectivity and morphometric data analyses as a biomarker of antidepressant treatment outcome