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Stimulus-specific neural encoding of a persistent, internal defensive state in the hypothalamus

View ORCID ProfileAnn Kennedy, Prabhat S. Kunwar, Lingyun Li, Daniel Wagenaar, David J. Anderson
doi: https://doi.org/10.1101/805317
Ann Kennedy
1Division of Biology and Biological Engineering 156-29, Tianqiao and Chrissy Chen Institute for Neuroscience, California Institute of Technology, Pasadena, California 91125, USA
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  • ORCID record for Ann Kennedy
Prabhat S. Kunwar
1Division of Biology and Biological Engineering 156-29, Tianqiao and Chrissy Chen Institute for Neuroscience, California Institute of Technology, Pasadena, California 91125, USA
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Lingyun Li
1Division of Biology and Biological Engineering 156-29, Tianqiao and Chrissy Chen Institute for Neuroscience, California Institute of Technology, Pasadena, California 91125, USA
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Daniel Wagenaar
1Division of Biology and Biological Engineering 156-29, Tianqiao and Chrissy Chen Institute for Neuroscience, California Institute of Technology, Pasadena, California 91125, USA
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David J. Anderson
1Division of Biology and Biological Engineering 156-29, Tianqiao and Chrissy Chen Institute for Neuroscience, California Institute of Technology, Pasadena, California 91125, USA
2Howard Hughes Medical Institute, California Institute of Technology, 1200 East California Blvd, Pasadena, California 91125 USA
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  • For correspondence: wuwei@caltech.edu
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Summary

Persistent neural activity has been described in cortical, hippocampal, and motor networks as mediating short-term working memory of transiently encountered stimuli1–4. Internal emotion states such as fear also exhibit persistence following exposure to an inciting stimulus5,6, but such persistence is typically attributed to circulating stress hormones7–9; whether persistent neural activity also plays a role has not been established. SF1+/Nr5a1+ neurons in the dorsomedial and central subdivision of the ventromedial hypothalamus (VMHdm/c) are necessary for innate and learned defensive responses to predators10–13. Optogenetic activation of VMHdmSF1 neurons elicits defensive behaviors that can outlast stimulation11,14, suggesting it induces a persistent internal state of fear or anxiety. Here we show that VMHdmSF1 neurons exhibit persistent activity lasting tens of seconds, in response to naturalistic threatening stimuli. This persistent activity was correlated with, and required for, persistent thigmotaxic (anxiety-like) behavior in an open-field assay. Microendoscopic imaging of VMHdmSF1 neurons revealed that persistence reflects dynamic temporal changes in population activity, rather than simply synchronous, slow decay of simultaneously activated neurons. Unexpectedly, distinct but overlapping VMHdmSF1 subpopulations were persistently activated by different classes of threatening stimuli. Computational modeling suggested that recurrent neural networks (RNNs) incorporating slow excitation and a modest degree of neurochemical or spatial bias can account for persistent activity that maintains stimulus identity, without invoking genetically determined “labeled lines”15. Our results provide causal evidence that persistent neural activity, in addition to well-established neuroendocrine mechanisms, can contribute to the ability of emotion states to outlast their inciting stimuli, and suggest a mechanism that could prevent over-generalization of defensive responses without the need to evolve hardwired circuits specific for each type of threat.

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Posted October 16, 2019.
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Stimulus-specific neural encoding of a persistent, internal defensive state in the hypothalamus
Ann Kennedy, Prabhat S. Kunwar, Lingyun Li, Daniel Wagenaar, David J. Anderson
bioRxiv 805317; doi: https://doi.org/10.1101/805317
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Stimulus-specific neural encoding of a persistent, internal defensive state in the hypothalamus
Ann Kennedy, Prabhat S. Kunwar, Lingyun Li, Daniel Wagenaar, David J. Anderson
bioRxiv 805317; doi: https://doi.org/10.1101/805317

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