Alcohol is the most consumed drug among adolescents, with 40% of them reporting regularly experiencing binge-drinking episodes, consuming more than 5 drinks in two hours and reaching blood alcohol concentrations above 0.08g/dl. This pattern of alcohol consumption is particularly harmful as it may interfere with the ongoing maturation of frontal brain circuits, and clinical studies have shown that AAE significantly increases the risk of developing psychiatric and behavioral disorders later in life, including ddiction. However, the precise cellular mechanisms underlying behavioral deficits, the molecular mechanisms underlying alcohol-induced defects in PFC maturation, and possible gender differences are still poorly understood.
We developed a mouse model of voluntary alcohol binge-drinking during adolescence, and reported that AAE induces the progressive development of behavioral impairments related to PFC malfunction. Although differences were noted between males and females, AAE similarly impacted male and female behaviors. Importantly, no major behavioral impairments was observed short-term after AAE, suggesting that AAE induces a progressive development of behavioral defects, which only emerge in adulthood. Our findings are of great importance regarding the major public health issue that is adolescent binge-drinking, and could help refining the prevention strategies against harmful alcohol use in youth. All data are available in a Mendeley dataset DOI: 10.17632/gtnmrbtmt4.1.
It has 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 alcohol addiction. The mammalian target of rapamycin complex 1 (mTORC1) and the eukaryotic initiation factor 2α (eIF2α) are master regulators of local translation. However, the alcohol- dependent modulation of mTORC1 and eIF2α activity in the maturating PFC and the consequences of alcohol-induced defects in local translation have remained unknown.
Our preliminary results suggest that AAE activates mTORC1 but not eIF2a activity specifically in the prelimbic and infralimbic regions of the PFC. Furthermore, we observed that the AAE-dependent increased mTORC1 activity is mostly present in the Ctip2+ layer V neurons. We are investigating whether modulation of mTORC1 activity in the PFC projection neurons rescues the AAE-induced behavioral defects.
We performed a Ribotag-RNA-seq experiment to specifically analyze the “translatome” of PFC projection neurons in AAE and water-exposed P43 animals. We are currently performing the bioinformatics analysis in order to identify synaptic RNA candidates whose translation is modulated by AAE in the PFC.
