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Published October 29, 2020 | Submitted + Supplemental Material + Accepted Version
Journal Article Open

Stimulus-specific hypothalamic encoding of a persistent defensive state


Persistent neural activity in cortical, hippocampal, and motor networks has been described as mediating working memory for transiently encountered stimuli. Internal emotional states, such as fear, also persist following exposure to an inciting stimulus, 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. Optogenetic activation of these neurons, referred to here as VMHdm^(SF1) neurons, elicits defensive behaviours that outlast stimulation, 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, contribute to a persistent emotional state.

Additional Information

© 2020 Nature Publishing Group. Received 02 October 2019; Accepted 22 June 2020; Published 16 September 2020. 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. Data availability: The data that support the findings of this study are available from the corresponding author upon reasonable request. Code availability: Code for data analysis and modelling portions of this paper has been made publicly available at https://github.com/DJALab/VMHdm_persistence. These authors contributed equally: Ann Kennedy, Prabhat S. Kunwar, Ling-yun Li. Author Contributions: A.K., P.S.K., and D.J.A. conceptualized and designed the fibre photometry and microendoscopic imaging experiments. A.K., L.L., P.S.K., and D.J.A. conceptualized and designed the optogenetic loss-of-function experiments. D.A.W. and P.S.K. designed and built the imaging acquisition setup. P.S.K. performed imaging experiments. L.L. performed loss-of-function, rat exposure assay and imaging, tetanus toxin, and extracellular recording experiments. S.S. performed brain slice electrophysiology and Ca2+ imaging experiments and analysis. A.K. performed imaging data analysis and modeling. A.K., P.S.K., L.L., and D.J.A. wrote the manuscript. The authors declare no competing interests. Peer review information: Nature thanks Jaideep Bains, Larry Zweifel and the other, anonymous, reviewer(s) for their contribution to the peer review of this work.

Attached Files

Accepted Version - nihms-1606924.pdf

Submitted - 805317.full.pdf

Supplemental Material - 41586_2020_2728_Fig10_ESM.webp

Supplemental Material - 41586_2020_2728_Fig11_ESM.webp

Supplemental Material - 41586_2020_2728_Fig12_ESM.webp

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Supplemental Material - 41586_2020_2728_Fig9_ESM.webp

Supplemental Material - 41586_2020_2728_MOESM1_ESM.pdf

Supplemental Material - 41586_2020_2728_MOESM2_ESM.pdf


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August 22, 2023
October 23, 2023