Age-related effects on the association between alcohol use, severity and resting-state fMRI: A rat study comparing adolescent-onset and adult-onset drinking

Abstract

Adolescence is marked by neurodevelopmental changes that increase reward sensitivity, risk-taking, and behavioural control challenges, heightening the risk of alcohol use and dependence. Alcohol's impact on resting-state functional connectivity (RSFC) may explain this risk, though comparisons to adulthood remain limited. This study examined age-related differences in the association between RSFC and alcohol use severity in rats that initiated low or high voluntary alcohol consumption during adolescence or adulthood. Forty-two male rats were selected based on their alcohol consumption levels after two months of exposure: adolescent (PND42) onset low (N = 12) and high drinking (N = 7) rats, and adult (PND77) onset low (N = 11) and high drinking (N = 12) rats. RSFC was measured 4-10 days after exposure ceased, and group-ICA identified networks. Permutation tests assessed associations between onset age and use severity on RSFC. Low drinking was associated with increased RSFC within the salience network compared to high drinking. High adolescent onset alcohol consumption was associated with increased Default Mode Network (DMN) connectivity relative to low use. Connectivity in this area was generally stronger in adult compared to adolescent onset groups. An age group effect was observed, with overall higher DMN-thalamic connectivity in adult versus adolescent onset rats. In conclusion, high adolescent alcohol use was associated with increased DMN connectivity compared to low use, potentially reflecting altered self-referential processing or withdrawal susceptibility in adulthood. In adult-onset rats, the observed increases in DMN and DMN-thalamic connectivity may reflect developmental differences rather than alcohol exposure. These findings highlight the need for further research on DMN connectivity and its role in AUD risk and resilience, particularly regarding adolescent alcohol use, and the inclusion of a control group without alcohol access to better isolate the effects of alcohol consumption.

Keywords: Adolescent; Alcohol drinking; Animal models; Brain development; Resting-state functional connectivity; Substance-related disorders.