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Stimulus-specific hypothalamic encoding of a persistent defensive state
Open accessPublished version of a preprint
Abstract
Persistent neural activity in cortical, hippocampal, and motor networks has been described as mediating working memory for transiently encountered stimuli 1,2. Internal emotional states, such as fear, also persist following exposure to an inciting stimulus 3, but it is unclear whether slow neural dynamics are involved in this process. Neurons in the dorsomedial and central subdivisions of the ventromedial hypothalamus (VMHdm/c) that express the nuclear receptor protein NR5A1 (also known as SF1) are necessary for defensive responses to predators in mice 4-7. Optogenetic activation of these neurons, referred to here as VMHdm SF1 neurons, elicits defensive behaviours that outlast stimulation 5,8, which suggests the induction of a persistent internal state of fear or anxiety. Here we show that in response to naturalistic threatening stimuli, VMHdm SF1 neurons in mice exhibit activity that lasts for many tens of seconds. This persistent activity was correlated with, and required for, persistent defensive behaviour in an open-field assay, and depended on neurotransmitter release from VMHdm SF1 neurons. Stimulation and calcium imaging in acute slices showed that there is local excitatory connectivity between VMHdm SF1 neurons. Microendoscopic calcium imaging of VMHdm SF1 neurons revealed that persistent activity at the population level reflects heterogeneous dynamics among individual cells. Unexpectedly, distinct but overlapping VMHdm SF1 subpopulations were persistently activated by different modalities of threatening stimulus. Computational modelling suggests that neither recurrent excitation nor slow-acting neuromodulators alone can account for persistent activity that maintains stimulus identity. Our results show that stimulus-specific slow neural dynamics in the hypothalamus, on a time scale orders of magnitude longer than that of working memory in the cortex 9,10, contribute to a persistent emotional state.
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“Persistent activity seems to be a hallmark of hypothalamic neurons, which can be highly interconnected and have long integration periods42–45.”
From Neural circuitry for maternal oxytocin release induced by infant cries (2023) · cites this paper as [44]
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Metadata
- Authors
- Kennedy, A., Kunwar, P. S., Li, L.-Y., Stagkourakis, S., Wagenaar, D. A., & Anderson, D. J.
- Affiliations
- California Institute of Technology (US)
- Corresponding author
- Anderson, David J.
- Venue
- Nature
- Published
- 2020-09-16
- Volume
- 586
- Issue
- 7831
- Pages
- 730-734
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC7606611
- OpenAlex
- W2980638619
- Cited by
- 144
- References
- 63
- Citations by year
- 2026: 18 · 2025: 25 · 2024: 26 · 2023: 35 · 2022: 21 · 2021: 12 · 2020: 5
- FWCI
- 9.74
- Type
- journal article
- Language
- en
- Open access
- green
- doi.org
- Locations
- Nature (publishedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- CaltechAUTHORS (California Institute of Technology) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health
- National Institute of Mental Health (R01MH112593, R01MH123612, K99MH117264, U19MH114830, R00MH117264, R01MH070053)
- Topics
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Life Sciences › Neuroscience › Cognitive Neuroscience › Neural dynamics and brain function
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- persistent activity, ventromedial hypothalamus, steroidogenic factor 1, fear, defensive behavior, threatening stimuli, neurotransmitter release
- MeSH terms
- Acoustic Stimulation, Animals, Anxiety, Calcium, Computer Simulation, Cues, Fear, Hypothalamus, Male, Neurons, Predatory Behavior, Time Factors, Neurotransmitter Agents, Mice, Optogenetics
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