Central Oxytocin, Vasopressin, and Corticotropin-Releasing Factor Receptor Densities in the Basal Forebrain Predict Isolation Potentiated Startle in Rats

Abstract

Individual differences in resiliency to particular stressors may be mediated by specific neuropeptide receptor patterns in the brain. Here, we explored this issue by using a multivariate approach to identify brain sites in which oxytocin (OTR), vasopressin (V1aR), and corticotropin-releasing factor type 1 (CRF1) or type 2 receptor binding covaried with a measure of isolation-induced anxiety: isolation potentiated startle (IPS). Partial least squares (PLS) analysis identified three binding sites, the shell of the nucleus accumbens (AccSh), lateral bed nucleus of the stria terminalis, and intermediate zone of the lateral septum, in which CRF1, V1aR, and OTR receptors, respectively, covaried with IPS. Multiple regression analysis demonstrated that the three binding sites accounted for more of the variation in IPS as a linear combination than when considered individually. Using the same multiple regression model, the linear combination of the same three binding sites/peptide receptors measured in a new group of animals successfully predicted their IPS values. There were no differences in binding between grouped and isolated animals, suggesting that the patterns are trait effects rather than a consequence of isolation. Based on the finding that CRF1 receptors in the AccSh were positively correlated with IPS, we infused CRF directly into the AccSh and found that it significantly potentiated startle after a short isolation period but not under grouped conditions. This result directly supported the predictions made by the combined PLS/regression approach. These results suggest that the integrated activity of neuropeptide systems mediating both social behavior and anxiety underlie IPS.