Corticotropin-releasing factor neurotransmission in the insular cortex regulates anxiogenic-like behavior to acute restraint stress: A site-specific study in rats.

The insular cortex (IC) plays a key role in anxiety responses to stress, with functional differences along its rostrocaudal axis, but the underlying neurochemical mechanisms remain unclear. Although corticotropin-releasing factor (CRF) is present in the IC, its contribution to stress-induced anxiety has not been established. Thus, we investigated the role of CRF neurotransmission in the anterior (aIC), rostral-posterior (rpIC) and caudal-posterior (cpIC) subregions of the IC in anxiogenic-like responses to acute restraint stress. We also assessed the role of CRF neurotransmission in restraint-evoked changes on neuronal activation across IC subregions. For this, male Wistar rats underwent restraint stress following local microinjections of the selective CRF1 antagonist CP376395 or CRF into IC subregions. Anxiety-like behavior was evaluated using the elevated plus maze (EPM), and neuronal activation was assessed by Fos immunoreactivity. We found that acute restraint stress evoked anxiogenic-like behavior in the EPM. CRF1 receptor antagonism in the aIC and cpIC inhibited the restraint-evoked anxiogenic effect. Treatment of the rpIC with CRF also abolished the behavioral change in the EPM evoked by restraint stress. Neuronal activation analysis showed that restraint increased Fos-positive cells in the aIC and rpIC, while decreased them in the cpIC. Microinjection of CP376395 in the aIC caused further increase in local neuronal activation, while administration of CRF into the cpIC completely blocked the restraint-evoked change. These results indicate that CRF neurotransmission within the IC contributes to restraint-induced anxiety-like behavior in a site-specific manner along the rostrocaudal axis, which is mediated by complex modulation of local neuronal activation.