Clinical assessments of expectant mothers have revealed that ~30% of women consume alcohol during pregnancy. It is thus unsurprising that disorders which correspond to prenatal alcohol exposure (PAE) are among the most common of preventable illnesses in the United States. Anxiety disorders are among the most prevalent behavioral impairments arising from PAE and can be observed as early as childhood, however investigations of underlying biological contributions are largely absent from established research. This gap in knowledge limits our understanding of how alcohol alters developing anxiety circuits and subsequently prevents targeted treatment of PAE-induced anxiety symptoms. Utilizing rodent models, our lab has characterized a paradigm of moderate PAE which significantly alters GABAergic neurotransmission in the medial nucleus of the central amygdala (CeM), a brain region associated with the regulation of anxiety-like behavior. Furthermore, corticotrophin-releasing factor (CRF) receptor 1 (CRFR1) function is blunted within the CeM of adolescent, male offspring following PAE. Interestingly, preliminary data suggest that there is an increased sensitivity of CRFR1, as well as a directional switch in CRFR1-regulated GABA transmission in adolescents relative to what has been reported in adults. Together, these data contribute to our overarching hypothesis that the CRF system within the CeM contributes to an inappropriate stress response in ethanol-nave adolescents compared to adults, and increases anxiety-like behavior in PAE adolescents. To investigate these claims, we will first determine age differences in the CRF system within the CeM of adolescent and adult rats using whole cell electrophysiology, in situ hybridization and behavioral pharmacology. Secondly, we will assess moderate PAE-induced changes in CRF and CRFR1 within adolescent rats, that show increased anxiety-like behavior following PAE. Within this aim, comparisons of PAE and control (air-exposed) offspring will include investigations of CeM neurophysiology, mRNA levels for CRF and CRFR1, and behavioral response following CRFR1 activation. Successful completion of the proposed research will provide a comprehensive investigation of specific physiological impairments underlying PAE-induced anxiety, and will inform existing literature on variables, such as age and prenatal exposure, which may influence the sensitivity and function of the CRF system. Through the incorporation of multiple novel techniques for investigation, and under the guidance of experts in the alcohol and behavioral neuroscience field, this project will additionally provide the framework for a superior training experience in research.
The risk for developing generalized anxiety disorder is increased in adolescents who have been exposed to alcohol in utero. In this proposal, we will investigate how prenatal alcohol exposure alters the expression and function of stress-peptide CRF and receptor CRFR1, providing novel insights into mechanisms of alcohol- induced neurodevelopmental changes. We will also expand upon current understanding of CRF system?s function across age, and relate these findings to the development of CRFR1-targeted treatment for anxiety disorders.
