The Neuropeptide Tac2 Controls a Distributed Brain State Induced by Chronic Social Isolation Stress

Chronic social isolation causes severe psychological effects in humans, but their neural bases remain poorly understood. 2 weeks (but not 24 hr) of social isolation stress (SIS) caused multiple behavioral changes in mice and induced brain-wide upregulation 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. [Display omitted] •Chronic social isolation stress (SIS) causes a pervasive change in brain state•SIS broadly upregulates expression of Tac2/NkB in multiple brain regions•Tac2 upregulation is necessary and sufficient for behavioral influences of SIS•NkB acts locally in different brain areas to orchestrate behavioral effects of SIS The Tac2 neuropeptide system orchestrates the complex behavioral effects of chronic social isolation stress by acting locally in multiple brain regions, suggesting the therapeutic potential of Nk3R antagonists for managing behavioral changes upon prolonged social isolation.