An intra-amygdala circuit specifically regulates social fear learning
Open accessAbstract
Adaptive social behavior requires transmission and reception of salient social information. Impairment of this reciprocity is a cardinal symptom of autism. The amygdala is a critical mediator of social behavior and is implicated in social symptoms of autism. Here we found that a specific amygdala circuit, from the lateral nucleus to the medial nucleus (LA-MeA), is required for using social cues to learn about environmental cues that signal imminent threats. Disruption of the LA-MeA circuit impaired valuation of these environmental cues and subsequent ability to use a cue to guide behavior. Rats with impaired social guidance of behavior due to knockout of Nrxn1, an analog of autism-associated gene NRXN, exhibited marked LA-MeA deficits. Chemogenetic activation of this circuit reversed these impaired social behaviors. These findings identify an amygdala circuit required to guide emotional responses to socially significant cues and identify an exploratory target for disorders associated with social impairments.
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The majority of KO rats exhibited inappropriate sexual mounting behaviour towards same-sex and same-genotype social interaction partners.
“The majority of KO rats exhibited inappropriate sexual mounting behaviour towards same-sex and same-genotype social interaction partners (see also Twining et al. 2017)”
From Neurexin1α knockout in rats causes aberrant social behaviour: relevance for autism and schizophrenia (2025) · cites this paper as Twining et al. 2017
The Results section ('The LA-MeA circuit in a condition with impaired social behavior'; page not provided) reports mounting directed toward a male conspecific in 5 of 16 Nrxn knockout rats, and says mounting also occurred in knockout pairs housed together. It does not support 'the majority': 5 of 16 is a minority, and no proportion is given for the housed pairs. The Methods classify mounting as an aggressive episode, not sexual behaviour. (LLM, conf=0.90)
Experimental — accuracy not yet measuredPrevious studies with nrxn1-deficient rats have shown altered patterns of social interest.
“altered patterns of social interest (Twining et al. 2017)”
From Neurexin1α knockout in rats causes aberrant social behaviour: relevance for autism and schizophrenia (2025) · cites this paper as Twining et al. 2017
In rats, an additional intra-amygdala circuit from the lateral nucleus to the medial nucleus is necessary for the social transfer of fear.
“In rats, an additional intra-amygdala circuit from the lateral nucleus to the medial nucleus is also necessary for the social transfer of fear [109].”
From Neural circuits regulating prosocial behaviors (2023) · cites this paper as [109]
In mice, both congenital knockout and haploinsufficiency of Shank3 lead to diminished social interest in others and are associated with disruption of cortical and subcortical circuits thought to be involved in ASD and its ontogenesis.
“In mice, both congenital knockout and haploinsufficiency of Shank3 leads to diminished social interest in others and is associated with the disruption of cortical and subcortical circuits thought to be involved in ASD 22–26 and its ontogenesis 22,25,27,28.”
From Reduced sociability and social agency encoding in adult Shank3-mutant mice are restored through gene re-expression in real time (2021) · cites this paper as [28]
All enclosures were well-habituated and did not require conditioning, allowing consistent study of neuronal response across multiple interleaved trials.
“All enclosures were well-habituated and did not require conditioning (e.g. tone-shock pairing) 28, therefore, allowing us to consistently study neuronal response across multiple interleaved trials.”
From Reduced sociability and social agency encoding in adult Shank3-mutant mice are restored through gene re-expression in real time (2021) · cites this paper as [28]
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“The reported effects of deleting Nrxn1 on rodent social affiliation are varied, including decrease (24, 25), increase (26), and no change in the behavior (27, 28).”
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Structure and function of the medial amygdala
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A dyad shows mutual changes during social buffering of conditioned fear responses in male rats
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“Many of these areas are highly interconnected in a 54 bidirectional manner [13-17], and some were shown to be involved in various, at times opposing, 55”
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Genetic factors associated with empathy in humans and mice
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“observational fear paradigm, a previous study showed that Nrxn1 KO rats showed impaired vicarious freezing and 48hr social fear memory caused by reduced synaptic transmission in an intra-amygdala circuit (Twining et al., 2017).”
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Self-citationSocially Transferred Stress Experience Modulates Social Affective Behaviors in Rats
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“The amygdala is sensitive to and regulates social behavior (Twining et al., 2017; Hu et al., 2021; Opendak et al., 2021; Terranova et al., 2022).”
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“Each CS–US pairing was separated by inter-tone interval (ITI) of 1 min (modified from [69].”
MethodEffects of a social stimulus on gene expression in a mouse model of fragile X syndrome
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“The positive correlation between lateral and medial amygdala c-Fos levels in response to a social stimulus align with recent work demonstrating the importance of the intra-amygdalar pathway in processing social behavior and formulating an appropriate response in the context of social fear learning [81].”
BackgroundNeurexin1α knockout in rats causes aberrant social behaviour: relevance for autism and schizophrenia
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“The majority of KO rats exhibited inappropriate sexual mounting behaviour towards same-sex and same-genotype social interaction partners (see also Twining et al. 2017), which was virtually absent in WT animals.”
Prior stress experience modulates social preference for stressed conspecifics in male rats
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“…(Widagdo et al. 2016; Siddiqui et al. 2017; Marshall and Bredy 2019), inter and transgenerational inheritance (Arai et al. 2009; Debiec and Sullivan 2014), social fear transmission (Twining et al. 2017) and sex differences (Bangasser and Wicks 2017; Maeng et al. 2017; Velasco et al. 2019).”
BackgroundA modified mouse model for observational fear learning and the influence of social hierarchy
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“OFL is the most used behavior paradigm in studying rodents’ fear contagion, in which an unconditioned stimulus (US) is vicariously provided by observing conspecifics receiving foot shocks (Jeon et al., 2010; Kim et al., 2012; Twining et al., 2017).”
BackgroundA novel paradigm for observational learning in rats
Rautio, I. V., Holmberg, E. H., Kurup, D., Dunn, B. A., & Whitlock, J. R. (2023) · Cognitive Neurodynamics · doi:10.1007/s11571-023-10022-8 · Cited by 6 · see citing works
“Observational learning, on the other hand, per - mits individuals to gain knowledge by interacting with or (Bruchey et al. 2010 ; Jeon et al. 2010 ; Twining et al. 2017; Allsop et al. 2018 ).”
BackgroundContemporary strategies for dissecting the neuronal basis of neurodevelopmental disorders
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- Authors
- Twining, R. C., Vantrease, J. E., Love, S., Padival, M., & Rosenkranz, J. A.
- Affiliations
- Rosalind Franklin University of Medicine and Science (US)
- Venue
- Nature Neuroscience
- Published
- 2017-01-23
- Volume
- 20
- Issue
- 3
- Pages
- 459-469
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC5323274
- OpenAlex
- W2580165755
- Cited by
- 93
- References
- 52
- Citations by year
- 2026: 3 · 2025: 8 · 2024: 9 · 2023: 8 · 2022: 16 · 2021: 11 · 2020: 11 · 2019: 13 · 2018: 8 · 2017: 6
- FWCI
- 5.96
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Simons Foundation
- Rosalind Franklin University of Medicine and Science
- Simons Foundation Autism Research Initiative
- National Institute of Mental Health (R01MH109484, R01MH084970)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Social Sciences › Psychology › Social Psychology › Neuroendocrine regulation and behavior
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- amygdala, lateral amygdala, medial amygdala, autism spectrum disorder, social behavior, NRXN1, chemogenetic activation, threat cues
- MeSH terms
- Animals, Conditioning, Classical, Cues, Fear, Learning, Male, Neural Pathways, Receptors, Cell Surface, Social Behavior, Excitatory Postsynaptic Potentials, Rats, Gene Knockout Techniques, Basolateral Nuclear Complex, Corticomedial Nuclear Complex
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