Ucn3 and CRF-R2 in the medial amygdala regulate complex social dynamics

Nat Neurosci. 2016 Nov;19(11):1489-1496. doi: 10.1038/nn.4346. Epub 2016 Jul 18.


Social encounters are associated with varying degrees of emotional arousal and stress. The mechanisms underlying adequate socioemotional balance are unknown. The medial amygdala (MeA) is a brain region associated with social behavior in mice. Corticotropin-releasing factor receptor type-2 (CRF-R2) and its specific ligand urocortin-3 (Ucn3), known components of the behavioral stress response system, are highly expressed in the MeA. Here we show that mice deficient in CRF-R2 or Ucn3 exhibit abnormally low preference for novel conspecifics. MeA-specific knockdown of Crfr2 (Crhr2) in adulthood recapitulated this phenotype. In contrast, pharmacological activation of MeA CRF-R2 or optogenetic activation of MeA Ucn3 neurons increased preference for novel mice. Furthermore, chemogenetic inhibition of MeA Ucn3 neurons elicited pro-social behavior in freely behaving groups of mice without affecting their hierarchal structure. These findings collectively suggest that the MeA Ucn3-CRF-R2 system modulates the ability of mice to cope with social challenges.

MeSH terms

  • Amygdala / metabolism*
  • Animals
  • Behavior, Animal / physiology
  • Corticotropin-Releasing Hormone / metabolism
  • Inhibition, Psychological
  • Mice
  • Mice, Knockout
  • Neurons / metabolism
  • Receptors, Corticotropin-Releasing Hormone / genetics
  • Receptors, Corticotropin-Releasing Hormone / metabolism*
  • Social Behavior*
  • Urocortins / genetics
  • Urocortins / metabolism*


  • CRF receptor type 2
  • Receptors, Corticotropin-Releasing Hormone
  • Ucn3 protein, mouse
  • Urocortins
  • Corticotropin-Releasing Hormone