Ventromedial hypothalamic neurons control a defensive emotion state

Abstract

Defensive behaviors reflect underlying emotion states, such as fear. The hypothalamus plays a role in such behaviors, but prevailing textbook views depict it as an effector of upstream emotion centers, such as the amygdala, rather than as an emotion center itself. We used optogenetic manipulations to probe the function of a specific hypothalamic cell type that mediates innate defensive responses. These neurons are sufficient to drive multiple defensive actions, and required for defensive behaviors in diverse contexts. The behavioral consequences of activating these neurons, moreover, exhibit properties characteristic of emotion states in general, including scalability, (negative) valence, generalization and persistence. Importantly, these neurons can also condition learned defensive behavior, further refuting long-standing claims that the hypothalamus is unable to support emotional learning and therefore is not an emotion center. These data indicate that the hypothalamus plays an integral role to instantiate emotion states, and is not simply a passive effector of upstream emotion centers.

DOI: http://dx.doi.org/10.7554/eLife.06633.001

eLife digest

Animals have evolved a large number of ‘defensive behaviors’ to deal with the threat of predators. Examples include reptiles camouflaging themselves to avoid discovery, fish and birds swarming to confuse predators, insects releasing toxic chemicals, and humans readying themselves to fight or flee.

In mammals, defensive behaviors are thought to be mediated by a region of the brain called the amygdala. This structure, which is known as the brain's ‘emotion center’, receives and processes information from the senses about impending threats. It then sends instructions on how to deal with these threats to other regions of the brain including the hypothalamus, which pass them on to the brain regions that control the behavioral, endocrine and involuntary responses of the mammal.

For many years it has been thought that the role of the hypothalamus is to serve simply as a relay for emotion states encoded in the amygdala, rather than as an emotion center itself. However, Kunwar et al. have now challenged this assumption with the aid of a technique called optogenetics, in which light is used to activate specific populations of genetically labeled neurons. When light was used to directly activate neurons within the ventromedial hypothalamus in awake mice, the animals instantly froze and/or fled, just as they would when faced with a predator. Given that the optical stimulation had completely bypassed the amygdala, this suggested that the hypothalamus must be capable of generating this defensive response without any input from the amygdala.

The freezing and fleeing responses resembled the responses to a predator in a number of key ways. Mice chose to avoid areas of their cage in which they had received the stimulation, suggesting that—like a predator—these areas induced an unpleasant emotional state, perhaps akin to anxiety or fear. Freezing and fleeing persisted for several seconds after the stimulation had stopped, just as freezing and fleeing responses to predators do not immediately cease after the threat has gone. And finally, destroying the neurons targeted by the stimulation made mice less likely to avoid one of their main predators, the rat. It also made the animals less anxious.

Overall the results suggest that the hypothalamus may be more than simply a relay for the amygdala, and that ‘amygdala-centric’ views of emotion processing may need to be re-visited.

DOI: http://dx.doi.org/10.7554/eLife.06633.002