This is an application for a Mentored Research Scientist Development Award (K01) to support the career development of Dr. Heather Trantham-Davidson as an independent academic investigator in alcohol research. The candidate is an early-stage investigator with previous training in the area of prefrontal cortical function and is relatively new to the alcohol field. A comprehensive mentoring and research plan is presented that will provide training in the neurobiology of adolescent alcohol abuse and its long-term effects on brain and behavior. The career and research training the applicant will receive will be overseen by a strong mentoring team and supported by strong institutional commitment to the candidate's career development. The research proposed is an extension of the applicant's recent studies in the mentor's laboratory examining the effects of adolescent alcohol exposure on the prefrontal cortex (PFC) of adult rats. The proposed research plan will take full advantage of the mentoring team and environment to allow the candidate to develop a research program that is at the forefront of the adolescent alcohol field. The PFC is a brain region that is critically involved in cognitive function and inhibitory control, and adolescence represents a critical period of continued PFC development that parallels the maturation of these functions. Alcohol drinking typically begins during adolescence when consumption of large quantities, in binge-like episodic patterns, is common. Alterations in PFC function are associated with increased likelihood to engage in risky behaviors and poor decision-making. Epidemiological evidence suggests that adolescent alcohol exposure may result in life-long deficits in cognitive control of behavior that may stem from disruption of the normal developmental trajectory of the PFC. However, the specific cellular targets in the adult PFC that are disrupted by adolescent alcohol abuse remain unclear and will be elucidated by the experiments outlined in this proposal. The overarching hypothesis is that adolescent alcohol exposure produces a neuropathology of the PFC that manifests in the adult as deficits in dopamine modulation of deep-layer pyramidal neurons of the prelimbic subregion and its projections to subcortical nuclei. This hypothesis will be tested using a multidisciplinary approach that includes patch-clamp slice electrophysiology and behavioral studies involving operant tasks to assess risky decision-making. These studies will determine the cellular mechanisms of persistent cognitive dysfunction following adolescent alcohol exposure, yield novel and exciting new findings, and significantly advance our understanding of the cellular mechanisms mediating the effect of adolescent alcohol exposure on cognitive function in the adult. Together, this training and research plan will provide a solid foundation upon which the applicant can build an independent research program.
Adolescent alcohol use and abuse is a serious public health problem that may cause long-lasting changes in cognitive control of behavior. These cognitive alterations, in turn, may explain impairments in decision- making that persist into adulthood in individuals who consumed alcohol as adolescents. The experiments outlined in this mentored K01 application will investigate whether the effects of repeated insults of binge alcohol exposure on the normal developmental trajectory of the PFC impairs adolescent development and leads to increased risk-taking behavior that persists into adulthood.
