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5-HT release in nucleus accumbens rescues social deficits in mouse autism model
Open accessAbstract
Dysfunction in prosocial interactions is a core symptom of autism spectrum disorder. However, the neural mechanisms that underlie sociability are poorly understood, limiting the rational development of therapies to treat social deficits. Here we show in mice that bidirectional modulation of the release of serotonin (5-HT) from dorsal raphe neurons in the nucleus accumbens bidirectionally modifies sociability. In a mouse model of a common genetic cause of autism spectrum disorder-a copy number variation on chromosome 16p11.2-genetic deletion of the syntenic region from 5-HT neurons induces deficits in social behaviour and decreases dorsal raphe 5-HT neuronal activity. These sociability deficits can be rescued by optogenetic activation of dorsal raphe 5-HT neurons, an effect requiring and mimicked by activation of 5-HT1b receptors in the nucleus accumbens. These results demonstrate an unexpected role for 5-HT action in the nucleus accumbens in social behaviours, and suggest that targeting this mechanism may prove therapeutically beneficial.
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“Work utilizing a circuit-based approach to examine the role of 5-HT release from DR inputs in the NAc revealed that optogenetic activation of DR 5-HT inputs increased sociability while optogenetic inhibition of these inputs decreased sociability, as measured by the juvenile interaction and three-chamber sociability assays [47].”
From Neural circuits regulating prosocial behaviors (2023) · cites this paper as [47]
In the citing paper
“Furthermore, pharmacological blockade of 5-HT1b receptors in the NAc via local infusion of a selective antagonist prevented the enhanced sociability due to activation of DR 5-HT neurons [47].”
From Neural circuits regulating prosocial behaviors (2023) · cites this paper as [47]
In the citing paper
“Importantly, unlike the release of DA in the NAc caused by optogenetic stimulation or administration of drugs of abuse [11,21,53,54], 5-HT release in the NAc is not acutely reinforcing [11,21,47] but see ref. [55].”
From Neural circuits regulating prosocial behaviors (2023) · cites this paper as [47]
In the citing paper
“and reduction in their intrinsic excitability [47].”
From Neural circuits regulating prosocial behaviors (2023) · cites this paper as [47]
In the citing paper
“Optogenetic activation of DR 5-HT inputs in the NAc rescued the social deficits present in these mice”
From Neural circuits regulating prosocial behaviors (2023) · cites this paper as [47]
In the citing paper
“which was associated with decreases in DR 5-HT neuron activity during social encounters”
From Neural circuits regulating prosocial behaviors (2023) · cites this paper as [47]
In the citing paper
“this rescue was dependent upon activation of presynaptic 5-HT1b receptors [47].”
From Neural circuits regulating prosocial behaviors (2023) · cites this paper as [47]
In the citing paper
“In a 16p11.2deletion mouse model, selective deletion of the syntenic chromosomal region specifically in DR 5-HT neurons induced deficits in sociability”
From Neural circuits regulating prosocial behaviors (2023) · cites this paper as [47]
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Metadata
- Authors
- Walsh, J. J., Christoffel, D. J., Heifets, B. D., Ben-Dor, G. A., Selimbeyoglu, A., Hung, L. W., Deisseroth, K., & Malenka, R. C.
- Affiliations
- Stanford University (US)
- Stanford Medicine (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Malenka, Robert C.
- ORCID
- Venue
- Nature
- Published
- 2018-08
- Volume
- 560
- Issue
- 7720
- Pages
- 589-594
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC8164568
- OpenAlex
- W2887399686
- Cited by
- 256
- References
- 50
- Citations by year
- 2026: 26 · 2025: 40 · 2024: 34 · 2023: 35 · 2022: 29 · 2021: 32 · 2020: 30 · 2019: 25 · 2018: 4
- FWCI
- 13.53
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Simons Foundation
- National Institute of Mental Health (K08MH110610, F32MH103949)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Autism Spectrum Disorder Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Keywords
- serotonin release, nucleus accumbens, dorsal raphe neurons, sociability, social dysfunction, autism spectrum disorder, 5-HT1B receptor, optogenetic stimulation, serotonergic neurons, mouse model
- MeSH terms
- Autism Spectrum Disorder, Animals, Chromosome Deletion, Chromosomes, Human, Pair 16, Disease Models, Animal, Humans, Male, Neural Pathways, Nucleus Accumbens, Serotonin, Social Behavior, Synteny, Chromosomes, Mammalian, Mice, Optogenetics, Dorsal Raphe Nucleus
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