The Involvement of Type II NRG1 in Neuroendocrine and Behavioral Stress Reactivity

Abstract

Exposure to stress can result in an increased risk for psychiatric disorders, especially among genetically predisposed individuals. The specific susceptibility genes that mediate the interaction with stress in psychiatric populations have not been clearly identified. One candidate may be the Neuregulin 1 (NRG1) gene, which has been repeatedly identified by association studies as a susceptibility gene for schizophrenia and bipolar disorder. In the rat, the neurons of the hypothalamic paraventricular nucleus (PVN), which control the neuroendocrine response to stress, show strong expression of Nrg1 mRNA. However, there is virtually no information on the role of NRG1 in hypothalamic-pituitary-adrenal (HPA) axis function, and whether the protein is expressed in the PVN is unknown. The present studies utilize a unique line of Nrg1 hypomorphic rats (Nrg1<superscript>Tn</superscript>), which exhibit reduced expression of both the mRNA and protein corresponding to the Type II NRG1 isoform. After confirming that Type II NRG1 is expressed in the neurocircuitry involved in regulating HPA axis responses to environmental stimuli, the Nrg1<superscript>Tn</superscript> rats were then used to test the hypothesis that genetically compromised Type II NRG1 in the brain creates a vulnerability to stress, which is present during adolescence, and disrupts normal adult behaviors associated with neuropsychiatric illnesses in a sex-specific manner. In support of this hypothesis, the studies described herein established a sex-specific effect of disrupting Type II NRG1 on HPA axis regulation, such that male Nrg1<super>Tn</super> rats demonstrated increased basal HPA axis drive and female Nrg1<super>Tn</super> rats demonstrated enhanced recovery from an acute stressor. In addition, males with disrupted Type II NRG1 were more behaviorally reactive while females were less reactive in measures of open field habituation, prepulse inhibition and anxiety on the elevated plus maze. Finally, disruption of Type II NRG1 conferred a resistance against the enduring effects of adolescent chronic stress on anxiety in adulthood, which was dependent on sex and the type of stressor. Together these findings provide evidence that Type II NRG1 may be involved in the regulation of both neuroendocrine and behavioral stress reactivity.