Abstract :
[en] Alcohol use disorder (AUD) is a devastating relapsing disease which represents the fourth leading cause of preventable death worldwide. The neural mechanisms of AUD have remained uncertain, and multiple genetic, psychological and environmental factors are thought to be involved. AUD has mainly been considered as a pathological condition in adults, but recent evidence suggests that the roots of alcohol addiction begin to grow during adolescence. Adolescence is a critical developmental period characterized by significant changes in brain architecture and behaviors. Brain maturation begins in posterior regions and progresses towards anterior higher-order regions, including the prefrontal cortex (PFC). The PFC is implicated in executive functions and its immaturity in adolescents is associated with lack of inhibitory control over behavior, increased impulsivity and desire of risk-taking. It is widely believed that the enhanced ability of the adolescent PFC to undergo experience-dependent changes is associated with heightened vulnerability to exogenous agents, including alcohol. According to the National Institute on Alcohol Abuse and Alcoholism (NIAAA), alcohol is the most consumed drug among adolescents, with 40% reporting regularly experiencing binge-drinking episodes. This pattern of alcohol consumption is particularly harmful as it may interfere with the ongoing maturation of frontal brain circuits, leading to profound long-lasting consequences on PFC structure and function. In particular, the adolescent PFC shows structural and molecular alterations with alcohol exposure such as reduced thickness and activity, neuroimmune genes induction, loss of cholinergic neurons, aberrant dendritic spine density, and alteration of dopamine neurotransmission. In addition, adolescent alcohol exposure (AAE) is related to serious psychological problems, comorbid psychopathology and detrimental neurocognitive consequences, and clinical studies have shown that AAE significantly increases the risk of developing psychiatric and behavioral disorders later in life, including addiction. Accordingly, animal studies have reported that AAE leads to impaired PFC function associated with defective behaviors. However, the precise cellular mechanisms underlying the alcohol-induced cognitive and behavioral impairments, the molecular mechanisms underlying defects in PFC maturation, and possible sex differences are still poorly understood.
Alcohol addiction is considered as a maladaptive form of learning and memory. Indeed, alcohol is thought to “usurp” the molecular mechanisms underlying those processes, including synaptic plasticity, which depends on the local translation of mRNAs at synaptic sites. It has recently been shown in adult mice that excessive alcohol consumption modifies synaptic protein composition in brain regions associated with the mesocorticolimbic pathway, promoting the development and maintenance of addiction. The mammalian target of rapamycin complex 1 (mTORC1) and the eukaryotic initiation factor 2α (eIF2α) are master regulators of local translation. We previously reported that alcohol binge-drinking in adult mice activates mTORC1 signaling in key striatal and cortical areas, enhancing synaptic protein translation and inducing neuroadaptations that in turn promote alcohol seeking and taking. Moreover, mTORC1 in the PFC is required for the retrieval of alcohol-associated memories, and has been associated with PFC development, connectivity and related behaviors. In parallel, eIF2α has been shown to regulate synaptic plasticity underlying memory and addiction, and has also been implicated in PFC function. However, the alcohol-dependent modulation of mTORC1 and eIF2α activity in the maturating PFC and the alcohol-induced defects in local translation have remained unknown. The specific aims of this project are (1) to determine whether AAE perturbs the maturation of the PFC and induces structural, physiological and/or behavioral defects; (2) to reveal whether alcohol modulates local dendritic translation via mTORC1 and/or eIF2α and leads to defective synaptic plasticity in the adolescent PFC; (3) to study the AAE-induced local translation alterations in specific neuronal subtypes and identify mRNA candidates. This work aims to provide new insight on the molecular mechanisms underlying alcohol’s actions in the maturating PFC by focusing on local translation.
By using a mouse model of voluntary adolescent binge drinking, we showed that excessive alcohol consumption during adolescence leads to long-lasting behavioral impairments in adulthood, such as increased anxiety and alcohol intake, as well as reduced cognitive performances. We also report that AAE increases mTORC1 signaling in the PFC of adolescent mice. By using transgenic mouse lines and Ribotag profiling, we are comparing the synaptic translatome of specific neuronal populations in the PFC (i.e. glutamatergic neurons and interneurons) in order to identify candidate synaptic mRNAs whose translation levels are modified by AAE.
