A projection from the medial prefrontal cortex to the lateral septum modulates coping behavior on the shock-probe test.

Effective coping plays an important role in preventing stress-induced neuropsychiatric conditions. The ventromedial prefrontal cortex (vmPFC) has been associated with active, adaptive coping in humans and rodents. Chronic or severe stress has been shown to induce a maladaptive shift from active to passive coping behavior; however, the neural circuits for effective coping strategies remain unclear. In the current study, we demonstrated that neurons in the infralimbic (IL) subregion of rat vmPFC that project to the lateral septum (LS) were recruited by exposure to the shock probe in the shock-probe defensive burying (SPDB) test. Both chemogenetic inhibition of LS-projecting neurons in the IL and optogenetic inhibition of glutamatergic IL terminals in the LS selectively suppressed active burying responses in the SPDB test in non-stressed rats. In contrast, chemogenetic activation of the IL-LS pathway effectively reversed the shift from active coping to passive immobility in the SPDB test induced by chronic unpredictable stress (CUS). These results indicate that top-down regulation of the LS by a projection from the IL cortex is necessary for an active, adaptive behavioral coping response, and is sufficient to restore active coping that has been compromised by chronic stress. More broadly, these results point to the IL-to-LS circuit as a potential substrate underlying maladaptive shifts from active to passive coping behavior that are often associated with stress-related neuropsychiatric disorders.