A neural circuit for regulating a behavioral switch in response to prolonged uncontrollability in mice

Persistence in the face of failure helps to overcome challenges. But the ability to adjust behavior or even give up when the task is uncontrollable has advantages. How the mammalian brain switches behavior when facing uncontrollability remains an open question. We generated two mouse models of behavioral transition from action to no-action during exposure to a prolonged experience with an uncontrollable outcome. The transition was not caused by pain desensitization or muscle fatigue and was not a depression-/learned-helplessness-like behavior. Noradrenergic neurons projecting to GABAergic neurons within the orbitofrontal cortex (OFC) are key regulators of this behavior. Fiber photometry, microdialysis, mini-two-photon microscopy, and tetrode/optrode in vivo recording in freely behaving mice revealed that the reduction of norepinephrine and downregulation of alpha 1 receptor in the OFC reduced the number and activity of GABAergic neurons necessary for driving action behavior resulting in behavioral transition. These findings define a circuit governing behavioral switch in response to prolonged uncontrollability. [Display omitted] •Prolonged uncontrollability results in behavioral switch from action to no-action•Noradrenergic neurons projecting to OFC GABAergic neurons regulate the behavior•Reduction in norepinephrine and/or alpha 1 receptor reduces OFC GABAergic activity•Reduction in GABAergic activity promotes the behavioral transition to no-action Li et al. establish two animal models relevant to giving up, quitting, and/or stopping an unsuccessful behavior in mice. They show that noradrenergic neurons and inhibitory neurons are major regulators of the behavior. Transition from action to no-action occurs because of reductions in norepinephrine and inhibitory neuronal activity in the orbitofrontal cortex.