INDEPENDENT HYPOTHALAMIC CIRCUITS FOR SOCIAL AND PREDATOR FEAR

Fear is a distressing negative sensation induced by a perceived threat. This emotion is necessary for the survival of the individual, since it guarantees appropriate responses to life challenging threats. In the last decades research on the neural mechanisms underling such emotion both in humans and in animal models have been mostly focused on the amygdala. In particular fear models in rodents typically rely on foot shock based paradigms. However, innate and learned fear elicited by other stimuli such as predators or aggressive members of the same species has been shown to be regulated by other circuits where the triggering, coordination and the expression of fear seem to be centered in the hypothalamus and periaqueductal grey. Nevertheless very little is known about the function and physiology of these structures in fear processing. To study the function of the medial hypothalamic fear circuit, we developed a novel behavioral paradigm to measure innate and conditioned fear responses to social and predator threats in mice. We subsequently created tools to selectively inhibit specific hypothalamic nuclei during the fear and we observed the inhibition of the ventromedial hypothalamus, a nucleus previously studied for its function in feeding, sex and aggression, specifically impaired social and predator fear but not foot shock fear. Moreover we demonstrated that different portions of this nucleus account for fear to different threats with the dorsomedial portion, previously implicated in feeding function, processing predator fear, and the ventrolateral portion, previously implicated in sex and aggression, processing social fear. Our results demonstrate that the hypothalamus plays a crucial role in fear processing even if it is not recruited during foot shock exposure, suggesting that it might be a good target for the treatment of fear related disorders like panic or phobias and we are now trying to identify possible drugs specifically acting in this area. On the other hand, we showed that specific hypothalamic subnuclei are recruited selectively during social or predator fear, corroborating the hypothesis that different types of fear are processed by separate brain circuits. Such evidence opens the possibility of targeted therapy of pathological fear in humans. Interestingly these same hypothalamic structures are fundamental regulators of non-fear motivated behaviors that are essential for survival such as feeding behavior, aggression and sex and we are now investigating how the same nuclei can orchestrate multiple functions.