Stimulus-specific hypothalamic encoding of a persistent defensive state

Ann Kennedy, Prabhat S. Kunwar, Ling yun Li, Stefanos Stagkourakis, Daniel A. Wagenaar, David J. Anderson*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

87 Scopus citations

Abstract

Persistent neural activity in cortical, hippocampal, and motor networks has been described as mediating working memory for transiently encountered stimuli1,2. Internal emotional states, such as fear, also persist following exposure to an inciting stimulus3, 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 mice4–7. Optogenetic activation of these neurons, referred to here as VMHdmSF1 neurons, elicits defensive behaviours that outlast stimulation5,8, which suggests the induction of a persistent internal state of fear or anxiety. Here we show that in response to naturalistic threatening stimuli, VMHdmSF1 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 VMHdmSF1 neurons. Stimulation and calcium imaging in acute slices showed that there is local excitatory connectivity between VMHdmSF1 neurons. Microendoscopic calcium imaging of VMHdmSF1 neurons revealed that persistent activity at the population level reflects heterogeneous dynamics among individual cells. Unexpectedly, distinct but overlapping VMHdmSF1 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 cortex9,10, contribute to a persistent emotional state.

Original languageEnglish (US)
Pages (from-to)730-734
Number of pages5
JournalNature
Volume586
Issue number7831
DOIs
StatePublished - Oct 29 2020

Funding

Acknowledgements We thank R. Palmiter for providing TetTox–GFP in advance of publication; H. Inagaki, M. Meister, L. F. Abbott, U. Rutishauser, and members of the Anderson lab for helpful comments on the manuscript; R. Remedios for help with miniscope imaging; L. Liu for teaching silicon probe recording; A. Vinograd for preliminary imaging experiments; T. Davidson and K. Deisseroth for teaching fibre photometry; B. Yang for helping with the TetTox fibre photometry experiment; X. Da, J. S. Chang and C. Kim for technical assistance, X. Da and C. Chiu for laboratory management and G. Mancuso for administrative support. This work was supported by NIH Grant R01 MH112593. K99 MH117264 to A.K., a Helen Hay Whitney Foundation Postdoctoral Fellowship to L.L., and the EMBO ALTF 736-2018 to S.S. D.J.A. is an Investigator of the Howard Hughes Medical Institute.

ASJC Scopus subject areas

  • General

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