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^1,2. 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 mice^4–7. Optogenetic activation of these neurons, referred to here as VMHdm^SF1 neurons, elicits defensive behaviours that outlast stimulation^5,8, 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^9,10, contribute to a persistent emotional state.