Stimulus-specific hypothalamic encoding of a persistent defensive state.

Abstract

SummaryPersistent neural activity has been described in cortical, hippocampal, and motor networks as mediating working memory of transiently encountered stimuli1,2. Internal emotion states such as fear also exhibit persistence following exposure to an inciting stimulus3, but whether slow neural dynamics are involved is not well-studied. SF1+/Nr5a1+ neurons in the dorsomedial and central subdivisions of the ventromedial hypothalamus (VMHdm/c) are necessary for defensive responses to predators4–7. Optogenetic activation of VMHdmSF1 neurons elicits defensive behaviours that outlast stimulation5,8, suggesting the induction of a persistent internal state of fear or anxiety. Here we show that in response to naturalistic threatening stimuli, VMHdmSF1 neurons exhibit persistent activity lasting many tens of seconds. This persistent activity was correlated with, and required for, persistent defensive behavior in an open-field assay, and was dependent on neurotransmitter release from VMHdmSF1 neurons. Stimulation and calcium imaging experiments in acute slices revealed 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 stimuli. Computational modeling suggests that neither recurrent excitation nor slow-acting neuromodulators alone can account for persistent activity that maintains stimulus identity. Our results identify stimulus-specific slow neural dynamics in the hypothalamus, on a time scale orders of magnitude longer than that supporting working memory in the cortex9,10, as a contributing mechanism underlying a persistent emotion state. (238 words)