Anhedonia requires MC4R-mediated synaptic adaptations in nucleus accumbens

Byung Kook Lim, Kee Wui Huang, Brad A. Grueter, Patrick E. Rothwell, Robert C. Malenka

Research output: Contribution to journalArticlepeer-review

210 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)183-189
Number of pages7
JournalNature
Volume487
Issue number7406
DOIs
StatePublished - Jul 12 2012

Bibliographical note

Funding Information:
Acknowledgements We thank J. Kauer, D. Lyons and members of the Malenka laboratory for comments. The rabies virus complementary DNA plasmid and viral component-expressing plasmids were gifts from K. Conzelmann and I. Wickersham. BAC transgenic mice were provided by N. Calakos. BHK-B19G cells were a gift from E. Callaway. The AAVs used in this study were produced by the Stanford Neuroscience Gene Vector and Virus Core. The AAV-DJ helper plasmid was a gift from M. Kay. B.K.L. is supported by a Davis Foundation Postdoctoral Fellowship in Eating Disorders Research. We acknowledge funding from the National Institutes of Health (R.C.M.).

Copyright:
Copyright 2013 Elsevier B.V., All rights reserved.

Fingerprint Dive into the research topics of 'Anhedonia requires MC4R-mediated synaptic adaptations in nucleus accumbens'. Together they form a unique fingerprint.

Cite this