Unveiling the consequences of adolescent alcohol exposure on prefrontal cortex maturation

During adolescence, the brain undergoes intense maturation, particularly in the frontal areas. The prefrontal cortex (PFC) is implicated in executive functions, and its immaturity in adolescents is associated with increased impulsivity and heightened vulnerability to deleterious effects of drugs. Alcohol is the most consumed drug among adolescents, and its excessive consumption may interfere with the ongoing maturation of frontal brain circuits, leading to profound long-lasting consequences in PFC structure and function. Clinical studies have shown that excessive adolescent alcohol exposure (AAE) significantly increases the risk of developing psychiatric and behavioral disorders later in life, including addiction. However, the precise cellular mechanisms underlying the AAE-induced behavioral impairments, the molecular mechanisms underlying defects in PFC maturation, and possible sex differences are still poorly understood. It has been shown in adult mice that alcohol modifies long-lasting synaptic plasticity in brain regions associated with the mesocorticolimbic pathway, by modulating local translation of mRNAs at synaptic sites. Here we use a mouse model of voluntary adolescent binge drinking to study the consequences of AAE on PFC structure, function, and related behaviors. We report that while AAE does not impair behaviors during adolescence, it leads to severe long-lasting behavioral impairments in both males and females adult mice, such as reduced cognitive performances, increased alcohol intake and anxiety. In addition, preliminary results show that AAE modulates the activity of local translation regulators in the PFC, suggesting that AAE may interfere with synaptic plasticity during PFC maturation. By using transgenic mouse lines and Ribotag profiling, we will next compare the synaptic translatome of specific neuronal populations in the PFC (i.e. glutamatergic neurons and interneurons) in order to identify synaptic mRNAs whose translation is modulated by AAE during PFC maturation, and study their implication in AAE-induced structural, physiological and behavioral impairments.

This research is supported by the FRS-FNRS, the Leon Fredericq Foundation, the Francqui Foundation, the Brain and Behavior Research Foundation and the Queen Elizabeth Medical Foundation.