Thesis, FRANZEN Rachelle

Abstract

Alcohol use disorder (AUD) is a chronic and multifactorial psychiatric condition characterized by compulsive alcohol consumption, loss of control over intake, and negative emotional states during abstinence. Although AUD is typically diagnosed in adulthood, increasing evidence indicates that its vulnerability has strong developmental origins, suggesting that early-life alcohol exposure contributes to the emergence of later compulsive drinking behaviors. In this context, adolescent alcohol exposure (AAE) may disrupt ongoing brain maturation processes and thereby increase the risk of developing AUD in adulthood. The central hypothesis of this work is that AAE alters the normal developmental trajectory of the PFC, leading to persistent molecular, cellular, and structural changes that contribute to long-term behavioral dysfunction. This hypothesis is supported by the prolonged maturation of the PFC during adolescence, a brain region essential for executive functions, decision-making, and emotional regulation. During this period, the PFC undergoes extensive synaptic remodeling and circuit refinement, making it particularly sensitive to environmental insults such as binge-drinking. Clinical and preclinical studies consistently show that AAE does not necessarily induce immediate behavioral deficits but leads to long-term consequences in adulthood, including increased anxiety- and depressive-like behaviors, impaired cognitive flexibility, and enhanced alcohol consumption. Based on this framework, this master’s thesis investigates how AAE affects PFC development at multiple levels. At the cellular level, we focused on layer II/III projection neurons and interneurons, which are essential for cortical connectivity and the regulation of excitatory-inhibitory balance. At the molecular levels, we examined activity-dependent translational control mechanisms, with a particular focus on the eukaryotic elongation factor 2 (eEF2) pathway, a key regulator of synaptic protein synthesis. Although only a limited number of studies have implicated eEF2 signaling in addiction-related processes, dysregulation of the eEF2/eEF2K pathway has been associated with altered synaptic plasticity and prefrontal cortex dysfunction. Finally, we sought to link these molecular alterations to structural changes in neuronal architecture, including dendritic complexity and spine morphology in layer II/III projection neurons, as well as a potential changes in interneuron populations. Together, this work seeks to provide an integrated understanding of how AAE disrupts PFC maturation and contributes to long-term vulnerability to behavioral alterations.