A translational perspective on the anti-anhedonic effect of ketamine and its neural underpinnings

Anhedonia, a pronounced reduction in interest or pleasure in any of life’s daily activities, is a cardinal symptom of major depression. In this Perspective article, we synthesise the recent evidence from rodent, monkey and human neuroimaging literature to highlight how the habenula, a small evolutionarily conserved subcortical structure located in the midbrain, may orchestrate the behavioural expression of anhedonia across fronto-mesolimbic networks. We then review how this circuitry can be modulated by ketamine, an NMDA receptor antagonist with rapid antidepressant properties. We propose that experimental paradigms founded in reinforcement learning and value-based decision-making can usefully probe this network and thereby help elucidate the mechanisms underlying ketamine’s rapid antidepressant action.