The prefrontal cortex (PFC) is thought to play an important role in the cognitive processes that are negatively impacted by alcohol exposure. Compared to other brain regions, the neuronal connections of the PFC undergo a critical period of reorganization and refinement during adolescence and this coincides with improvement in cognitive control and decision making. Environmental insults that occur during this period may be particularly damaging to prefrontal cortex, resulting in aberrant neurodevelopment along with long-lasting effects on cognitive functioning that negatively impacts decision-making and behavioral control. Experimentation with alcohol typically begins during adolescence when it is often consumed in excessive binge-like episodes resulting in a cycle of very high levels of intoxication followed by a short period of abstinence. This proposal will examine the effects of binge-like adolescent alcohol exposure on development of GABAA receptor-mediated neurotransmission in the PFC. Strong supportive preliminary data is presented that suggests that a specific tonic current regulated by extrasynaptic delta-GABAA-type receptors is reduced in adult rats exposed to alcohol during adolescence, and we hypothesize that this will impair cognitive function of the PFC. This is supported by additional preliminary data showing that adult rats exposed to alcohol during adolescence exhibited decreases in behavioral flexibility on an operant set-shifting task. This proposal will use biochemical, electrophysiological and behavioral approaches to examine the effect of adolescent alcohol abuse on the development of GABAergic neurotransmission and cognitive function and in particular, behavioral flexibility of the adult PFC. The overarching hypothesis of this proposal is that binge-like alcohol exposure during adolescence results in disruption of development of GABAergic neurotransmission in the adult PFC and cognitive function. The proposed studies and related training plan will not only further the career development of the applicant, but the results obtained from these studies will significantly advance our understanding of the long- term consequences of adolescent alcohol abuse on prefrontal function and cognitive control of behavior in the adult.
The effect of adolescent alcohol exposure on neurodevelopment is highly relevant to public health since it may cause long-lasting changes in cognitive control of behavior. The proposed studies will contribute to a better understanding of the how adolescent alcohol abuse impacts the development of the inhibitory system in the prefrontal cortex and will provide novel insight into the neurobiology of adolescent alcohol abuse.