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 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 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 neurons. Stimulation and calcium imaging in acute slices showed that there is local excitatory connectivity between VMHdm neurons. Microendoscopic calcium imaging of VMHdm neurons revealed that persistent activity at the population level reflects heterogeneous dynamics among individual cells. Unexpectedly, distinct but overlapping VMHdm 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.