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Anhedonia requires MC4R-mediated synaptic adaptations in nucleus accumbens

Nature volume 487, pages 183–189 (2012)Cite this article

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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.

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Figure 1: α-MSH modifies excitatory synapses on NAc D1-MSNs.
Figure 2: Chronic-restraint stress modifies excitatory synapses on NAc D1-MSNs.
Figure 3: Knockdown of NAc MC4R prevents stress-induced weight loss and synaptic changes.
Figure 4: Chronic stress induces LTD in D1-MSNs.
Figure 5: MC4R activation and LTD in the NAc are required for stress-induced anhedonia.
Figure 6: MC4R activation and LTD in the NAc are required for stress-induced decreases in cocaine CPP.

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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.).

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  1. Department of Psychiatry and Behavioral Sciences, Nancy Pritzker Laboratory, Stanford University School of Medicine, 265 Campus Drive, Stanford, 94305, California, USA

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

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Contributions

The study was designed and results were interpreted by B.K.L. and R.C.M. with assistance from K.W.H., B.A.G. and P.E.R. Virus injections and rabies virus production were performed by B.K.L. and K.W.H. All experiments were performed and analysed by B.K.L. with assistance from B.A.G. for electrophysiology experiments and P.E.R. for CPP assays. The manuscript was written by B.K.L. and R.C.M. and edited by all authors.

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Correspondence to Robert C. Malenka.

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Lim, B., Huang, K., Grueter, B. et al. Anhedonia requires MC4R-mediated synaptic adaptations in nucleus accumbens. Nature 487, 183–189 (2012). https://doi.org/10.1038/nature11160

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