Date of Award

2015

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Neuroscience

College

College of Graduate Studies

First Advisor

L. Judson Chandler

Second Advisor

Heather L. Trantham-Davidson

Third Advisor

John J. Woodward

Fourth Advisor

Howard C. Becker

Fifth Advisor

C. Fernando Valenzuela

Abstract

The prefrontal cortex (PFC) is thought to play an important role in 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 that coincides with improvements in cognitive control and decision-making. Environmental insults that occur during this period may be particularly damaging to the PFC, 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 high levels of intoxication followed by a short period of abstinence. This dissertation addresses the hypothesis that binge-like adolescent alcohol (AIE) exposure alters the development of neurotransmitter systems in the prelimbic PFC (PrL-C) and as a result, PFC-dependent cognitive functions are compromised in adulthood. First, the effect of adolescent alcohol abuse on dopaminergic neurotransmission in the adult PrL-C was examined. AIE compromised adult protein expression of the dopamine-related enzymes tyrosine hydroxylase and catechol-O-methyl transferase. Electrophysiology studies revealed a loss of D1 receptor modulation of pyramidal neuron evoked firing in adult layer V PrL-C. The next part of this dissertation focuses on the effect of AIE on development of the PrL-C GABA system. AIE produced marked reductions in GABAA receptor-mediated tonic currents in pyramidal neurons in layer V PrL-C. This effect appears to be largely mediated by developmental alterations specifically in GABAA receptors containing the δ-subunit. The dissertation concludes by assessing the effect of AIE on risky decision-making in adulthood. Furthermore, given the role of GABA in decision-making, exploratory studies sought to enhance tonic GABA currents using the novel δ-GABAA receptor positive allosteric modulator AA29504 and testing the effect of the drug on risk/reward decision-making. The results suggest that AIE did not alter risk/reward decision-making in adulthood. Moreover, AA29504 administration did not alter decision-making on the probabilistic discounting task. Taken together, this dissertation reveals that AIE exposure results in persistent deficits in both dopaminergic and GABAergic neurotransmission in the adult PrL-C that may contribute to deficits in PFC-dependent behavioral control in adulthood.

Rights

All rights reserved. Copyright is held by the author.

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