The neural circuits mediating fear to naturalistic threats are poorly understood. Here we demonstrate that functionally independent populations of neurons in the ventromedial hypothalamus (VMH), a region implicated in feeding, sex, and aggression, are essential for predator and social fear in mice. Our study establishes a critical role for VMH in fear and carries implications for the selective intervention in pathological fear in humans.

The amygdala has been shown to be essential for the processing of acute and learned fear across animal species. However, the downstream neural circuits that mediate these fear responses differ depending on the nature of the threat, with separate pathways identified for predator, conspecific, and physically harmful threats. In particular, the dorsomedial part of the ventromedial hypothalamus (VHMdm) is critical for the expression of defensive responses to predator. Here, we tested the hypothesis that this circuit also participates in predator fear memory by transient pharmacogenetic inhibition of VMHdm and its downstream effector, the dorsal periaqueductal grey, during predator fear learning in the mouse. Our data demonstrate that neural activity in VMHdm is required for both the acquisition and recall of predator fear memory, while that of its downstream effector, the dorsal periaqueductal grey, is required only for the acute expression of fear. These findings are consistent with a role for the medial hypothalamus in encoding an internal emotional state of fear.

Plant S1-like nucleases, often referred to as nuclease I enzymes, are the main class of enzymes involved in nucleic acid degradation during plant programmed cell death. The catalytically active site of these enzymes shows a significant similarity to the well-described P1 nuclease from Penicillium citrinum. Previously published studies reported that plant S1-like nucleases possess catalytic activities similar to their fungal orthologs, i.e. they hydrolyze single-stranded DNA and RNA, and less efficiently double-stranded DNA, in the presence of zinc ions. Here we describe a comprehensive study of the nucleolytic activities of all Arabidopsis S1-like paralogs. Our results revealed that different members of this family are characterized by a surprisingly large variety of catalytic properties. We found that, in addition to Zn(2+)-dependent enzymes, this family also comprises nucleases activated by Ca(2+) and Mn(2+), which implies that the apparently well-known S1 nuclease active site in plant nucleases is able to cooperate with different activatory ions. Moreover, particular members of this class differ in their optimum pH value and substrate specificity. These results shed new light on the widely accepted classification of plant nucleases which is based on the assumption that the catalytic requirements of plant nucleases reflect their phylogenetic origin. Our results imply the need to redefine the understanding of the term 'nuclease I'. Analysis of the phylogenetic relationships between S1-like enzymes shows that plant representatives of this family evolve toward an increase in catalytic diversity. The importance of this process for the biological functions of plant S1-type enzymes is discussed.

Social aggression and avoidance are defensive behaviors expressed by territorial animals in a manner appropriate to spatial context and experience. The ventromedial hypothalamus controls both social aggression and avoidance, suggesting that it may encode a general internal state of threat modulated by space and experience. Here, we show that neurons in the mouse ventromedial hypothalamus are activated both by the presence of a social threat as well as by a chamber where social defeat previously occurred. Moreover, under conditions where the animal could move freely between a home and defeat chamber, firing activity emerged that predicted the animal’s position, demonstrating the dynamic encoding of spatial context in the hypothalamus. Finally, we found that social defeat induced a functional reorganization of neural activity as optogenetic activation could elicit avoidance after, but not before social defeat. These findings reveal how the hypothalamus dynamically encodes spatial and sensory cues to drive social behaviors.

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.

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