Dynamic encoding of social threat and spatial context in the hypothalamus

Abstract

14Territorial animals must be able to express social aggression or avoidance in a manner 15 appropriate to spatial context and dominance status. Recent studies indicate that the 16 ventromedial hypothalamus controls both innate aggression and avoidance, suggesting that it 17 may encode an internal state of threat common to both behaviors. Here we used single unit in 18 vivo calcium microendoscopy to identify neurons in the mouse ventromedial hypothalamus 19 encoding social threat. Threat neurons were activated during social defeat as well as when the 20 animal performed risk assessment. Unexpectedly, threat neurons were also activate in the 21 chamber where the animal had been previously defeated and a distinct set of neurons emerged 22 that were active in its home chamber, demonstrating the dynamic encoding of spatial context 23 in the hypothalamus. Ensemble analysis of neural activity showed that social defeat induced a 24 change in the encoding of social information and optogenetic activation of ventromedial 25 hypothalamus neurons was able to elicit avoidance after, but not before social defeat, 26 demonstrating a functional reorganization of the pathway by social experience. These findings 27 reveal how instinctive behavior circuits in the hypothalamus dynamically encode spatial and 28 sensory cues to drive adaptive social behaviors.

Mapping the neural circuitry of predator fear in the nonhuman primate

“…Our findings have two important implications for our understanding of fear in humans. First, our discovery makes it likely that the medial hypothalamus plays a similar role in encoding an internal state of threat in primates as it does in rodents (Kunwar 2015;Silva et al 2016a;Esteban Masferrer et al 2018;Krzywkowski et al 2019;Masferrer et al 2018;Kennedy et al 2019). Notably, VMHdm in rodents is required for the induction and expression of both innate and conditioned predator fear (Silva et al 2013(Silva et al , 2016Kunwar 2015) and stimulation of VMHdm in monkeys and humans is sufficient to elicit an intense defensive emotional state (Wilent 2010;Lipp and Hunsperger 1978).…”

Mapping the neural circuitry of predator fear in the nonhuman primate

“…This finding has two important implications for our understanding of fear in humans. First, our discovery makes it likely that the medial hypothalamus plays a similar role in encoding an internal state of threat in primates as it does in rodents (10,21,30–32). Notably, VMHdm in rodents is required for the induction and expression of both innate and conditioned predator fear (8,10,21) and stimulation of VMHdm in monkeys and humans is sufficient to elicit an intense defensive emotional state (11,33).…”

Sensory-thresholded switch of neural firing states in a computational model of the ventromedial hypothalamus

“…[4][5][6] Extensive work has been carried out on a central node in this system, the ventromedial hypothalamus (VMH), and inhibition of this nucleus blocks defensive responses to predator and social threats, [7,8] while activation elicits flight behavior. [8][9][10][11][12][13] Consistent with its anatomical conservation between rodents and primates [5,12] electrical stimulation of VMH in humans elicits intense arousal, negative emotion, and panic, [14] supporting the hypothesis that VMH encodes an internal defensive state that is relevant to understanding instinctive fear in humans. [15] In vivo single unit electrophysiology and calcium endoscopy recordings in freely behaving mice have revealed that VMH encodes both sensory and motor features of defensive behavior.…”

“…[15] In vivo single unit electrophysiology and calcium endoscopy recordings in freely behaving mice have revealed that VMH encodes both sensory and motor features of defensive behavior. [10,16] Single unit electrophysiology recordings were carried out in VMH as mice approached and then fled a live rat, a natural predator. Twenty-eight percent of units showed significant changes in firing during the approach-to-flight behavior.…”

“…We explored whether a computational model of local VMH circuitry could give rise to the transition in firing state observed during approach-to-flight behavior [10,16] and be used to constrain future experimental circuit manipulation studies. We aimed to produce a parsimonious model in which three firing features would emerge: 1) distinct Assessment+ and Flight+-like cell populations, 2) a sensoryinput thresholded abrupt change in global firing state, and 3) a simultaneous and opposite change in firing activity of Assessment+ and Flight+-like cells at threshold.…”