Unveiling the alcohol-dependent alterations in local dendritic translation of mRNAs in the prefrontal cortex during adolescence: ALCO-ADO

Programme(s): H2020-EU.1.3.2. - Nurturing excellence by means of cross-border and cross-sector mobility

Topic(s): MSCA-IF-2018 - Individual Fellowships

Call for proposal: H2020-MSCA-IF-2018

Funding Scheme: MSCA-IF-EF-RI - RI – Reintegration panel

Grant agreement ID: 839178

Project description

The adolescent brain on alcohol

Alcohol has a greater effect on teenagers than on adults because the brains of adolescents are still developing. Research has shown that developing brains are more prone to addiction. What is more, alcohol disrupts brain development. For instance, excessive alcohol consumption impairs the prefrontal cortex of the brain, which is implicated in planning complex cognitive behaviour, personality expression, decision-making, and moderating social behaviour. The EU-funded ALCO-ADO project aims to discover how alcohol modulates local translation of synaptic proteins in the prefrontal cortex during adolescence. It will also seek to identify the targeted synaptic mRNAs and analyse their involvement in altered synaptic plasticity underlying alcohol-dependent defective behaviours.

Objective

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 profoundly impairs PFC function, leading to long-lasting defective behaviors, psychological problems and neurocognitive defects. However, the precise mechanisms underlying alcohol-induced alterations in PFC maturation remain poorly understood. Alcohol addiction is considered being a maladaptive form of learning and memory, as alcohol usurps the molecular mechanisms underlying those processes, such as long-lasting synaptic plasticity. Long-lasting changes in the strength of synaptic connections mainly depend on the local translation of mRNAs at synaptic sites. It has been shown that alcohol modifies synaptic proteins composition by modulating the activity of key translation regulators, such as mTORC1 and eIF2α, in brain regions associated with the mesocorticolimbic pathway. Here, we propose to analyze the alcohol-dependent modifications of the synaptic translatome of specific neuronal populations (glutamatergic neurons and GABAergic interneurons) in the PFC of adolescent male and female mice, by using a multidisciplinary approach combining biochemistry, imaging, electrophysiology and behavioral tests. This project aims to uncover how alcohol modulates local translation of synaptic proteins in the PFC during adolescence, to identify the targeted synaptic mRNAs and analyze their involvement in altered synaptic plasticity underlying alcohol-dependent defective behaviors. In addition, this project aims at identifying the differential sensibility to alcohol’s effects between males and females as well as the differences in behavioral consequences.