Stimulus-specific hypothalamic encoding of a persistent defensive state

Persistent neural activity has been described in cortical, hippocampal, and motor networks as mediating working memory of transiently encountered stimuli(1,2). Internal emotion states such as fear also exhibit persistence following exposure to an inciting stimulus(3), 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 predators(4–7). Optogenetic activation of VMHdm(SF1) neurons elicits defensive behaviours that outlast stimulation(5,8), suggesting the induction of a persistent internal state of fear or anxiety. Here we show that in response to naturalistic threatening stimuli, VMHdm(SF1) 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 VMHdm(SF1) neurons. Stimulation and calcium imaging experiments in acute slices revealed 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 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 cortex(9,10), as a contributing mechanism underlying a persistent emotion state. (238 words)