No abstract

Chronic social isolation causes severe psychological effects in humans, but their neural bases remains poorly understood. Two weeks (but not 24 hrs) of social isolation stress (SIS) caused multiple behavioral changes in mice, and induced brain-wide up-regulation of the neuropeptide tachykinin 2 (Tac2)/neurokinin B (NkB). Systemic administration of an Nk3R antagonist prevented virtually all of the behavioral effects of chronic SIS. Conversely, enhancing NkB expression and release phenocopied SIS in group-housed mice, promoting aggression and converting stimulus-locked defensive behaviors to persistent responses. Multiplexed analysis of Tac2/NkB function in multiple brain areas revealed dissociable, region-specific requirements for both the peptide and its receptor in different SIS-induced behavioral changes. Thus, Tac2 coordinates a pleiotropic brain state caused by SIS, via a distributed mode of action. These data reveal the profound effects of prolonged social isolation on brain chemistry and function, and suggest potential new therapeutic applications for Nk3R antagonists.

A lack of automated, quantitative, and accurate assessment of social behaviors in mammalian animal models has limited progress toward understanding mechanisms underlying social interactions and their disorders such as autism. Here we present a new integrated hardware and software system that combines video tracking, depth sensing, and machine learning for automatic detection and quantification of social behaviors involving close and dynamic interactions between two mice of different coat colors in their home cage. We designed a hardware setup that integrates traditional video cameras with a depth camera, developed computer vision tools to extract the body "pose" of individual animals in a social context, and used a supervised learning algorithm to classify several well-described social behaviors. We validated the robustness of the automated classifiers in various experimental settings and used them to examine how genetic background, such as that of Black and Tan Brachyury (BTBR) mice (a previously reported autism model), influences social behavior. Our integrated approach allows for rapid, automated measurement of social behaviors across diverse experimental designs and also affords the ability to develop new, objective behavioral metrics.

SummaryAll animals possess a repertoire of innate (or instinctive1,2) behaviors, which can be performed without training. Whether such behaviors are mediated by anatomically distinct and/or genetically specified neural pathways remains a matter of debate3-5. Here we report that hypothalamic neural ensemble representations underlying innate social behaviors are shaped by social experience. Estrogen receptor 1-expressing (Esr1+) neurons in the ventrolateral subdivision of the ventromedial hypothalamus (VMHvl) control mating and fighting in rodents6-8. We used microendoscopy9 to image VMHvl Esr1+ neuronal activity in male mice engaged in these social behaviours. In sexually and socially experienced adult males, divergent and characteristic neural ensembles represented male vs. female conspecifics. But surprisingly, in inexperienced adult males, male and female intruders activated overlapping neuronal populations. Sex-specific ensembles gradually separated as the mice acquired social and sexual experience. In mice permitted to investigate but not mount or attack conspecifics, ensemble divergence did not occur. However, 30 min of sexual experience with a female was sufficient to promote both male vs. female ensemble separation and attack, measured 24 hr later. These observations uncover an unexpected social experience-dependent component to the formation of hypothalamic neural assemblies controlling innate social behaviors. More generally, they reveal plasticity and dynamic coding in an evolutionarily ancient deep subcortical structure that is traditionally viewed as a “hard-wired” system.