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

Cell. 2018 May 17;173(5):1265-1279.e19. doi: 10.1016/j.cell.2018.03.037.


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.

Keywords: BNST; DMH; Nk3R; NkB; Tac2; aggression; amygdala; fear; neuropeptides; social isolation; stress.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antipsychotic Agents / pharmacology
  • Behavior, Animal / drug effects
  • Brain / metabolism*
  • Brain / pathology
  • Female
  • Genetic Vectors / administration & dosage
  • Genetic Vectors / genetics
  • Male
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Neurokinin B / genetics
  • Neurokinin B / metabolism*
  • Neurons / cytology
  • Neurons / metabolism
  • Protein Isoforms / genetics
  • Protein Isoforms / metabolism
  • Protein Precursors / antagonists & inhibitors
  • Protein Precursors / genetics
  • Protein Precursors / metabolism*
  • RNA Interference
  • RNA, Small Interfering / genetics
  • Receptors, Tachykinin / antagonists & inhibitors
  • Receptors, Tachykinin / metabolism
  • Social Isolation*
  • Stress, Psychological*
  • Tachykinins / antagonists & inhibitors
  • Tachykinins / genetics
  • Tachykinins / metabolism*
  • Up-Regulation / drug effects


  • Antipsychotic Agents
  • Protein Isoforms
  • Protein Precursors
  • RNA, Small Interfering
  • Receptors, Tachykinin
  • Tachykinins
  • preprotachykinin
  • Neurokinin B