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Anhedonia requires MC4R-mediated synaptic adaptations in nucleus accumbens
Open accessAbstract
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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“Similarly, evoked AMPA receptor-mediated excitatory synaptic currents are reduced by chronic stress in D1, but not D2, MSNs [236], including in response to afferents from the hippocampus [193].”
From Plasticity of synapses and reward circuit function in the genesis and treatment of depression (2023) · cites this paper as [236]
In the citing paper
“Lim et al. [236] demonstrated that preventing stress-induced AMPA receptor loss in D1 MSNs was sufficient to prevent stress-induced loss of hedonic responses in sucrose preference and cocaine-induced place preference (although not the FST).”
From Plasticity of synapses and reward circuit function in the genesis and treatment of depression (2023) · cites this paper as [236]
In the citing paper
“Lim et al. found excitatory synaptic transmission following repeated restraint stress promoted long-term depression in D1-MSNs, but not D2-MSNs of the NAc core, suggesting a D1-MSN specific change in excitatory transmission mediates anhedonic outcomes (36).”
From Emerging Role for Nucleus Accumbens Medium Spiny Neuron Subtypes in Depression (2017) · cites this paper as [36]
In the citing paper
“Lim et al. found excitatory synaptic transmission following repeated restraint stress promoted long-term depression in D1-MSNs, but not D2-MSNs of the NAc core, suggesting a D1-MSN specific change in excitatory transmission mediates anhedonic outcomes (36).”
From Emerging Role for Nucleus Accumbens Medium Spiny Neuron Subtypes in Depression (2017) · cites this paper as [36]
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Metadata
- 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.
- Venue
- Nature
- Published
- 2012-07
- Volume
- 487
- Issue
- 7406
- Pages
- 183-189
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- 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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