Ventromedial hypothalamic output to the anterior hypothalamic area evokes complex escape behavior

The ventromedial hypothalamus (VMH) and anterior hypothalamic area (AHA) contribute to the orchestration of defensive responses to threat. We set out to test the effects of VMH to AHA (VMH→AHA) stimulation on behavior, organ-systems physiology, circulating pro-inflammatory cytokine levels, and brain activity patterns that support escape behavior. We used optogenetics in male and female SF1-Cre mice for behavioral assays, physiological measurements, and brain activity pattern mapping. For the first time, we demonstrate that VMH SF1 →AHA photostimulation increases complex escape behavior that requires three-dimensional navigation. Even in anesthetized mice, VMH→AHA photostimulation increases fractional shortening of the heart consistent with sympathetic arousal. In addition, we demonstrate that VMH→AHA photostimulation increases levels of the pro-inflammatory cytokine IL-6. In the brain, we find significant elevations of activity in the lateral habenula, anterior hypothalamic area, ventral premammillary nucleus, ventrolateral periaqueductal gray, and locus coeruleus. Significance statement We demonstrate that VMH→AHA photostimulation increases escape behavior that depends on a three dimensional route of navigation, increases levels of the cytokine IL-6, as well as increases activity in the lateral habenula, ventral premammillary nucleus, ventrolateral periaqueductal gray, and locus coeruleus. This work informs how hypothalamic circuitry drives behavioral and physiological responses that facilitate escape from threats in the environment.