Disruption of the neuregulin 1 gene in the rat alters HPA axis activity and behavioral responses to environmental stimuli

Exposure to stress can result in an increased risk for psychiatric disorders, especially among genetically predisposed individuals. Neuregulin 1 (NRG1) is a susceptibility gene for schizophrenia and is also associated with psychotic bipolar disorder. In the rat, the neurons of the hypothalamic paraventricular nucleus show strong expression of Nrg1 mRNA. In patients with schizophrenia, a single nucleotide polymorphism in the 5′ region of NRG1 interacts with psychosocial stress to affect reactivity to expressed emotion. However, there is virtually no information on the role of NRG1 in hypothalamic–pituitary–adrenal axis function, and whether the protein is expressed in the paraventricular nucleus is unknown. The present studies utilize a unique line of Nrg1 hypomorphic rats (Nrg1Tn) generated by gene trapping with the Sleeping Beauty transposon. We first established that the Nrg1Tn rats displayed reduced expression of both the mRNA and protein corresponding to the Type II NRG1 isoform. After confirming, using wild type animals, that Type II NRG1 is expressed in the neurocircuitry involved in regulating hypothalamic–pituitary–adrenal axis responses to environmental stimuli, the Nrg1Tn rats were then used to test the hypothesis that altered expression of Type II NRG1 disrupts stress regulation and reactivity. In support of this hypothesis, Nrg1Tn rats have disrupted basal and acute stress recovery corticosterone secretion, differential changes in expression of glucocorticoid receptors in the pituitary, paraventricular nucleus and hippocampus, and a failure to habituate to an open field. Together, these findings point to NRG1 as a potential novel regulator of neuroendocrine responses to stress as well as behavioral reactivity.

Research Highlights
► Nrg1Tn rats exhibit reduced expression of Type II NRG1 mRNA and protein.
► Type II NRG1 is expressed in the neurocircuitry that regulates HPA axis responses.
► Nrg1Tn rats exhibit altered neuroendocrine stress reactivity.
► Nrg1Tn rats exhibit altered GR expression and disrupted corticosterone secretion.
► Type II NRG1 plays a role in behavioral habituation to environmental stimuli.