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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Inputs to CA2 pyramidal neurons from the medial septum play a critical role in social memory.
“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]
A novel social interaction, but not interaction with a novel object, increased the strength of excitatory synapses between medial septum glutamatergic neurons and dorsal CA2 pyramidal neurons.
“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]
Fiber photometry recordings of GCaMP6f fluorescence revealed a 5-HT1b receptor-dependent increase in the activity of medial septum cells projecting to CA2 during a novel social interaction but not during interactions with a familiar mouse or a novel object.
“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]
Reversing the synaptic strength increase following a social interaction by in vivo optogenetic application of long-term depression inducing stimuli prevented the expression of social memory.
“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]
Serotonin increases the activity of medial septum neurons projecting to CA2 at least in part via disinhibition.
“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]
Local infusion of specific receptor antagonists into the medial septum revealed that oxytocin receptors were not required for social memory, which was prevented by a selective 5-HT1b receptor antagonist.
“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]
Chemogenetic inhibition of medial septum neurons projecting to CA2 impaired social memory while having no effects on basal sociability or inanimate object memory.
“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]
Local medial septum infusion of a 5-HT1b receptor agonist prolonged the duration of social memory.
“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]
Optogenetic manipulation of serotonin inputs in the medial septum from the median raphe bidirectionally influenced social memory.
“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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Modulation of aggression by social novelty recognition memory in the hippocampal CA2 region
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Optogenetics: Pinpoint Light on Precise Neuromodulation
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From eye to AI: Studying rodent social behavior in the era of machine learning
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- 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
- Social Sciences › Psychology › Social Psychology › 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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