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The ventromedial hypothalamus is a central node of the mammalian predator defense network. Stimulation of this structure in rodents and primates elicits abrupt defensive responses, including flight, freezing, sympathetic activation, and panic, while inhibition reduces defensive responses to predators. The major efferent target of the ventromedial hypothalamus is the dorsal periaqueductal gray (dPAG), and stimulation of this structure also elicits flight, freezing, and sympathetic activation. However, reversible inhibition experiments suggest that the ventromedial hypothalamus and periaqueductal gray play distinct roles in the control of defensive behavior, with the former proposed to encode an internal state necessary for the motivation of defensive responses, while the latter serves as a motor pattern initiator. Here, we used electrophysiological recordings of single units in behaving male mice exposed to a rat to investigate the encoding of predator fear in the dorsomedial division of the ventromedial hypothalamus (VMHdm) and the dPAG. Distinct correlates of threat intensity and motor responses were found in both structures, suggesting a distributed encoding of sensory and motor features in the medial hypothalamic-brainstem instinctive network. SIGNIFICANCE STATEMENT Although behavioral responses to predatory threat are essential for survival, the underlying neuronal circuits remain undefined. Using single unit in vivo electrophysiological recordings in mice, we have identified neuronal populations in the medial hypothalamus and brainstem that encode defensive responses to a rat predator. We found that both structures encode both sensory as well as motor aspects of the behavior although with different kinetics. Our findings provide a framework for understanding how innate sensory cues are processed to elicit adaptive behavioral responses to threat and will help to identify targets for the pharmacological modulation of related pathologic behaviors., (Copyright © 2020 the authors.)

Arousal from sleep in response to CO 2 is a critical protective phenomenon. Dysregulation of CO 2 -induced arousal contributes to morbidity and mortality from prevalent diseases, such as obstructive sleep apnea and sudden infant death syndrome. Despite the critical nature of this protective reflex, the precise mechanism for CO 2 -induced arousal is unknown. Because CO 2 is a major regulator of breathing, prevailing theories suggest that activation of respiratory chemo- and mechano-sensors is required for CO 2 -induced arousal. However, populations of neurons that are not involved in the regulation of breathing are also chemosensitive. Among these are serotonin (5-HT) neurons in the dorsal raphe nucleus (DRN) that comprise a component of the ascending arousal system. We hypothesized that direct stimulation of these neurons with CO 2 could cause arousal from sleep independently of enhancing breathing. Dialysis of CO 2 -rich acidified solution into DRN, but not medullary raphe responsible for modulating breathing, caused arousal from sleep. Arousal was lost in mice with a genetic absence of 5-HT neurons, and with acute pharmacological or optogenetic inactivation of DRN 5-HT neurons. Here we demonstrate that CO 2 can cause arousal from sleep directly, without requiring enhancement of breathing, and that chemosensitive 5-HT neurons in the DRN critically mediate this arousal. Better understanding mechanisms underlying this protective reflex may lead to interventions to reduce disease-associated morbidity and mortality. SIGNIFICANCE STATEMENT Although CO 2 -induced arousal is critical to a number of diseases, the specific mechanism is not well understood. We previously demonstrated that serotonin (5-HT) neurons are important for CO 2 -induced arousal, as mice without 5-HT neurons do not arouse to CO 2 Many have interpreted this to mean that medullary 5-HT neurons that regulate breathing are important in this arousal mechanism. Here we found that direct application of CO 2 -rich aCSF to the dorsal raphe nucleus, but not the medullary raphe, causes arousal from sleep, and that this arousal was lost with genetic ablation or acute inhibition of 5-HT neurons. We propose that 5-HT neurons in the dorsal raphe nucleus can be activated directly by CO 2 to cause arousal independently of respiratory activation., (Copyright © 2018 the authors 0270-6474/18/381915-11$15.00/0.)