ADOLESCENT SLEEP RESTRICTION AND ALCOHOL DRINKING HAVE DIVERGENT LONG-LASTING EFFECTS ON BRAIN AND BEHAVIOR

Chronic sleep restriction (CSR) and alcohol drinking (AD) are prevalent during adolescence and both have been independently linked to greater vulnerability to neuropsychiatric disorders. However, the biological mechanisms linking these adolescent experiences to long-term outcomes remain poorly understood, and it is unclear whether CSR and AD interact synergistically to affect brain maturation and behaviour. Here, we used Marchigian Sardinian alcohol preferring rats to map the long-lasting effects of adolescent CSR, AD, and their combination on adult behaviour. Moreover, we used bulk RNA-seq and immunofluorescence microscopy to investigate the molecular mechanisms triggered by adolescent CSR and AD in prefrontal cortex (PFC), a brain region undergoing protracted maturation. We found that CSR escalates adolescent alcohol preference and consumption (REML model, sleep loss F(1,56)=11.70 p=0.0012, sleep loss x time F(3.7, 190.4)=2.62 p=0.040), and results in higher alcohol intake in adulthood relative to sleep controls (unpaired t-test p=0.026). Moreover, CSR biases adult behaviour toward risk-taking, whereas AD reduces active coping responses. RNA-seq analysis revealed that CSR upregulates synaptic gene expression across both drinking conditions, whereas alcohol exerts opposite transcriptional effects depending on sleep status. CSR and AD modulate a common set of synapse-related genes but drive their expression in opposite directions, resulting in divergent effects on adult PFC synaptic density. In conclusion, adolescent CSR and AD induce lasting, and partly opposing, molecular and structural remodelling of PFC circuitry, leading to persistent alterations in adult behavioural regulation.