Cited by 368Neurotransmitter Receptor Influence on BehaviorStress Responses and CortisolTreatment of Major Depression

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Anhedonia requires MC4R-mediated synaptic adaptations in nucleus accumbens

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Lim, Byung Kook, Huang, Kee Wui, Grueter, Brad A., Rothwell, Patrick E., Malenka, Robert C.·2012·Nature

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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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Authors: Lim, B. K., Huang, K. W., Grueter, B. A., Rothwell, P. E., & Malenka, R. C.
Affiliations: Stanford Medicine (US)
Corresponding author: Malenka, Robert C.
ORCID: Lim, Byung Kook
Huang, Kee Wui
Grueter, Brad A.
Rothwell, Patrick E.
Malenka, Robert C.
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2012-07
Volume: 487
Issue: 7406
Pages: 183-189
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/nature11160
PMC: PMC3397405
OpenAlex: W2022082745
Cited by: 368
References: 48
Citations by year: 2026: 11 · 2025: 22 · 2024: 24 · 2023: 26 · 2022: 24 · 2021: 37 · 2020: 25 · 2019: 30 · 2018: 29 · 2017: 30 · 2016: 20 · 2015: 40 · 2014: 22 · 2013: 24 · 2012: 4
FWCI: 11.86
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
Europe PMC (PubMed Central) (acceptedVersion)
PubMed Central (acceptedVersion)
RePEc: Research Papers in Economics (submittedVersion)
Funders: National Institute of Mental Health (F32MH096491)
National Institute on Drug Abuse (P01DA008227)
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
Health Sciences › Medicine › Pharmacology (medical) › Treatment of Major Depression
Keywords: anhedonia, chronic stress, depression, melanocortin-4 receptor, nucleus accumbens, medium spiny neurons, dopamine D1 receptor, excitatory synapses, synaptic plasticity, behavioural despair, feeding behaviour, cocaine reward, neuropeptides
MeSH terms: alpha-MSH, Animals, Behavior, Animal, Cocaine, Depression, Feeding Behavior, Nucleus Accumbens, Stress, Psychological, Signal Transduction, Weight Loss, Dopamine Uptake Inhibitors, Receptor, Melanocortin, Type 4, Mice, Electrical Synapses, Gene Knockdown Techniques, Anhedonia

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Anhedonia requires MC4R-mediated synaptic adaptations in nucleus accumbens

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