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5-HT modulation of a medial septal circuit tunes social memory stability
Open accessAbstract
Social memory-the ability to recognize and remember familiar conspecifics-is critical for the survival of an animal in its social group 1,2. The dorsal CA2 (dCA2)3-5 and ventral CA1 (vCA1)6 subregions of the hippocampus, and their projection targets 6,7, have important roles in social memory. However, the relevant extrahippocampal input regions remain poorly defined. Here we identify the medial septum (MS) as a dCA2 input region that is critical for social memory and reveal that modulation of the MS by serotonin (5-HT) bidirectionally controls social memory formation, thereby affecting memory stability. Novel social interactions increase activity in dCA2-projecting MS neurons and induce plasticity at glutamatergic synapses from MS neurons onto dCA2 pyramidal neurons. The activity of dCA2-projecting MS cells is enhanced by the neuromodulator 5-HT acting on 5-HT 1B receptors. Moreover, optogenetic manipulation of median raphe 5-HT terminals in the MS bidirectionally regulates social memory stability. This work expands our understanding of the neural mechanisms by which social interactions lead to social memory and provides evidence that 5-HT has a critical role in promoting not only prosocial behaviours 8,9, but also social memory, by influencing distinct target structures.
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“Recent work has expanded our understanding of the circuit basis of social memory by demonstrating a critical role of inputs to CA2 pyramidal neurons from the medial septum (MS) [85].”
From Neural circuits regulating prosocial behaviors (2023) · cites this paper as [85]
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In the citing paper
“MS slice electrophysiology revealed that 5-HT increases the activity of MS neurons projecting to CA2 at least in part via disinhibition.”
From Neural circuits regulating prosocial behaviors (2023) · cites this paper as [85]
In the citing paper
“Ex vivo slice recordings revealed that a novel social interaction, but not interaction with a novel object, increased the strength of excitatory synapses between MS glutamatergic neurons and dorsal CA2 pyramidal neurons.”
From Neural circuits regulating prosocial behaviors (2023) · cites this paper as [85]
In the citing paper
“First, fiber photometry recordings of GCaMP6f fluorescence revealed a 5-HT1b receptor-dependent increase in the activity of MS cells projecting to CA2 during a novel social interaction but not during interactions with a familiar mouse or a novel object.”
From Neural circuits regulating prosocial behaviors (2023) · cites this paper as [85]
In the citing paper
“Importantly, reversing this synaptic strength increase following a social interaction by in vivo optogenetic application of LTD inducing stimuli prevented the expression of social memory.”
From Neural circuits regulating prosocial behaviors (2023) · cites this paper as [85]
In the citing paper
“However, local infusion of specific receptor antagonists into the MS revealed that OXT receptors were not required for social memory, which was prevented by a selective 5-HT1b receptor antagonist.”
From Neural circuits regulating prosocial behaviors (2023) · cites this paper as [85]
In the citing paper
“Chemogenetic inhibition of MS neurons projecting to CA2 impaired social memory while having no effects on basal sociability or inanimate object memory.”
From Neural circuits regulating prosocial behaviors (2023) · cites this paper as [85]
In the citing paper
“Third, local MS infusion of a 5-HT1b receptor agonist prolonged the duration of social memory.”
From Neural circuits regulating prosocial behaviors (2023) · cites this paper as [85]
In the citing paper
“Second, optogenetic manipulation of 5-HT inputs in the MS from the median raphe bidirectionally influenced social memory.”
From Neural circuits regulating prosocial behaviors (2023) · cites this paper as [85]
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Metadata
- Authors
- Wu, X., Morishita, W., Beier, K. T., Heifets, B. D., & Malenka, R. C.
- Affiliations
- Stanford University (US)
- University of California, Irvine (US)
- Stanford Medicine (US)
- Corresponding author
- Malenka, Robert C.
- Venue
- Nature
- Published
- 2021-10-06
- Volume
- 599
- Issue
- 7883
- Pages
- 96-101
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC9348902
- OpenAlex
- W3202576321
- Cited by
- 116
- References
- 50
- Citations by year
- 2026: 16 · 2025: 25 · 2024: 26 · 2023: 29 · 2022: 17 · 2021: 3
- FWCI
- 9.86
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institute on Aging (DP2AG067666)
- National Institute of Mental Health (K99MH122697, R00MH122697, K08MH110610)
- National Institute on Drug Abuse (R00DA041445)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Neuroendocrine regulation and behavior
- Keywords
- social memory, serotonin, 5-HT1B receptor, medial septum, ventral CA1, hippocampus, memory stability, synaptic plasticity, median raphe, social interaction, neuromodulation
- MeSH terms
- Animals, Female, Male, Memory, Neural Pathways, Neuronal Plasticity, Septal Nuclei, Serotonin, Social Behavior, Synapses, Pyramidal Cells, Glutamic Acid, Receptor, Serotonin, 5-HT1B, Mice, CA2 Region, Hippocampal, Optogenetics
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