Hypothalamic-hindbrain circuit for consumption-induced fear regulation.

To ensure survival, animals must sometimes suppress fear responses triggered by potential threats during feeding. However, the mechanisms underlying this process remain poorly understood. In the current study, we demonstrated that when fear-conditioned stimuli (CS) were presented during food consumption, a neural projection from lateral hypothalamic (LH) GAD2 neurons to nucleus incertus (NI) relaxin-3 (RLN3)-expressing neurons was activated, leading to a reduction in CS-induced freezing behavior in male mice. LH GAD2 neurons established excitatory connections with the NI. The activity of this neural circuit, including NI RLN3 neurons, attenuated CS-induced freezing responses during food consumption. Additionally, the lateral mammillary nucleus (LM), which received NI RLN3 projections, along with RLN3 signaling in the LM, mediated the decrease in freezing behavior. Collectively, this study identified an LH GAD2 -NI RLN3 -LM circuit involved in modulating fear responses during feeding, thereby enhancing our understanding of how animals coordinate nutrient intake with threat avoidance.