Anhedonia requires MC4R-mediated synaptic adaptations in nucleus accumbens

Byung Kook Lim, Kee Wui Huang, Brad A. Grueter, Patrick E. Rothwell and Robert C. Malenka ()
Additional contact information
Byung Kook Lim: Nancy Pritzker Laboratory, Stanford University School of Medicine, 265 Campus Drive
Kee Wui Huang: Nancy Pritzker Laboratory, Stanford University School of Medicine, 265 Campus Drive
Brad A. Grueter: Nancy Pritzker Laboratory, Stanford University School of Medicine, 265 Campus Drive
Patrick E. Rothwell: Nancy Pritzker Laboratory, Stanford University School of Medicine, 265 Campus Drive
Robert C. Malenka: Nancy Pritzker Laboratory, Stanford University School of Medicine, 265 Campus Drive

Nature, 2012, vol. 487, issue 7406, 183-189

Abstract: Abstract Chronic stress is a strong diathesis for depression in humans and is used to generate animal models of depression. It commonly leads to several major symptoms of depression, including dysregulated feeding behaviour, anhedonia and behavioural despair. Although hypotheses defining the neural pathophysiology of depression have been proposed, the critical synaptic adaptations in key brain circuits that mediate stress-induced depressive symptoms remain poorly understood. Here we show that chronic stress in mice decreases the strength of excitatory synapses on D1 dopamine receptor-expressing nucleus accumbens medium spiny neurons owing to activation of the melanocortin 4 receptor. Stress-elicited increases in behavioural measurements of anhedonia, but not increases in measurements of behavioural despair, are prevented by blocking these melanocortin 4 receptor-mediated synaptic changes in vivo. These results establish that stress-elicited anhedonia requires a neuropeptide-triggered, cell-type-specific synaptic adaptation in the nucleus accumbens and that distinct circuit adaptations mediate other major symptoms of stress-elicited depression.

Date: 2012
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DOI: 10.1038/nature11160

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