The interaction of disrupted Type II Neuregulin 1 and chronic adolescent stress on adult anxiety- and fear-related behaviors

The incidence of anxiety, mood, substance abuse disorders and schizophrenia increases during adolescence. Epidemiological evidence confirms that exposure to stress during sensitive periods of development can create vulnerabilities that put genetically predisposed individuals at increased risk for psychiatric disorders. Neuregulin 1 (NRG1) is a frequently identified schizophrenia susceptibility gene that has also been associated with the psychotic features of bipolar disorder. Previously, we established that Type II NRG1 is expressed in the hypothalamic–pituitary–adrenal (HPA) axis neurocircuitry. We also found, using a line of Nrg1 hypomorphic rats (Nrg1Tn), that genetic disruption of Type II NRG1 results in altered HPA axis function and environmental reactivity. The present studies used the Nrg1Tn rats to test whether Type II NRG1 gene disruption and chronic stress exposure during adolescence interact to alter adult anxiety- and fear-related behaviors. Male and female Nrg1Tn and wild-type rats were exposed to chronic variable stress (CVS) during mid-adolescence and then tested for anxiety-like behavior, cued fear conditioning and basal corticosterone secretion in adulthood. The disruption of Type II NRG1 alone significantly impacts rat anxiety-related behavior by reversing normal sex-related differences and impairs the ability to acquire cued fear conditioning. Sex-specific interactions between genotype and adolescent stress also were identified such that CVS-treated wild-type females exhibited a slight reduction in anxiety-like behavior and basal corticosterone, while CVS-treated Nrg1Tn females exhibited a significant increase in cued fear extinction. These studies confirm the importance of Type II NRG1 in anxiety and fear behaviors and point to adolescence as a time when stressful experiences can shape adult behavior and HPA axis function.

► Normal sex differences in anxiety behavior are reversed in Nrg1Tn rats.
► Adolescent stress exposure ameliorates sex differences in anxiety behavior.
► Disruption of Type II NRG1 disrupts fear learning and extinction.
► A gene by stress by sex interaction was revealed in extinction of fear memory.