Background: Prenatal alcohol exposure (PAE) results in dysregulation of the offspring hypothalamic-pituitary-adrenal (HPA) axis, increasing sensitivity to stressors and vulnerability to stress-related disorders. We have previously shown that exposure to chronic mild stress (CMS) in adulthood significantly increases anxiety-like behaviors (elevated plus maze) in PAE males and females compared to controls. To explore neurobiological mechanisms linking HPA dysregulation and altered anxiety-like behavior, we investigated neuropeptide (corticotropin-releasing hormone [CRH] and arginine vasopressin [AVP]) expression in brain areas involved in the stress neurocircuitry of animals from this previous behavioral study. Methods: Adult PAE, pair-fed (PF), and ad libitum fed control (C) male and female offspring exposed to CMS or remaining undisturbed (non-CMS) were terminated 30 minutes following behavioral testing. Results: In the paraventricular nucleus, CMS increased CRH mRNA levels in PAE compared to PF and C males and increased AVP mRNA levels in PAE compared to C males, with no differential effects for CRH or AVP in females. In the central nucleus of the amygdala, there was an increase in CRH mRNA expression overall, regardless of CMS condition or sex, in PAE compared to C animals. Moreover, in PF males, CMS increased AVP mRNA levels in the paraventricular nucleus, resulting in a decreased CRH/AVP ratio compared to PAE males, and decreased amygdala CRH mRNA compared to that in the non-CMS condition. Conclusions: CMS differentially altered central HPA peptide expression in PAE and PF animals compared to their control counterparts, with a possible shift toward greater CRH mediation of HPA regulation in PAE males, and greater AVP mediation of HPA regulation in PF males. However, changes in CRH and AVP expression do not align fully with the anxiogenic profile observed in our previous behavior study, suggesting that other neuronal substrates and limbic forebrain regions also contribute to increased anxiety-like behavior following CMS. Prenatal alcohol exposure (PAE) results in HPA dysregulation. We investigated underlying mechanisms in adult PAE and control animals following chronic mild stress (CMS). CMS differentially altered the balance between CRH and AVP in PAE and PF males, but not in females, compared to their control counterparts, with a possible shift toward greater CRH mediation in PAE, and AVP mediation in PF. Thus, HPA dysregulation appears to occur through different mechanisms, and in a stress- and sex-dependent manner, in PAE and PF animals.

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Keywords Amygdala, Arginine vasopressin, Corticotropin-releasing hormone, Hypothalamic-pituitary-adrenal axis, Prenatal alcohol (ethanol) exposure
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Journal Alcoholism: Clinical and Experimental Research
Lan, N. (Ni), Hellemans, K, Ellis, L. (Linda), & Weinberg, J. (Joanne). (2015). Exposure to Chronic Mild Stress Differentially Alters Corticotropin-Releasing Hormone and Arginine Vasopressin mRNA Expression in the Stress-Responsive Neurocircuitry of Male and Female Rats Prenatally Exposed to Alcohol. Alcoholism: Clinical and Experimental Research, 39(12), 2414–2421. doi:10.1111/acer.12916