The impact of adolescent drinking on traumatic brain injury-induced cognitive deficits and alcohol preference in adult C57BL/6J mice.

Abstract

Background: Industrial workers and active military personnel within combat roles face heightened risk for blast pressure wave traumatic brain injury (bTBI). Previous studies have shown that experiencing TBI is associated with increased alcohol (EtOH) consumption and illicit substance use. Notably, alcohol use typically begins during late adolescence or early adulthood, a period that precedes many TBI incidents; moreover, early-onset drinking is further associated with heightened risk of developing an alcohol use disorder (AUD) even in the absence of TBI. Adolescent binge drinking can induce lasting cognitive and astrocyte changes, impacting brain recovery and repair. However, the impact of adolescent drinking history on behavioral recovery after bTBI and its role in the subsequent escalation of alcohol consumption remain unexplored. Here, we used a mouse model to investigate how adolescent (PND28-42) and young adult (PND60-90) EtOH consumption affects behavioral outcomes following bTBI. We aim to determine whether the history of adolescent binge drinking contributes to bTBI-induced escalation in EtOH intake, preference, or worsened fear memory and anxiety.

Methods: Adolescent mice were subjected to drinking in the dark (DID) EtOH paradigm for 4 weeks, then randomly assigned to sham, mild-bTBI, or severe-bTBI. Behavioral testing was conducted, followed by a second DID.

Results: Both EtOH and bTBI independently induced hyperlocomotor activity in a sex-dependent manner. These findings reflect an increase in risk-taking rather than generalized anxiety. Importantly, a history of adolescent EtOH consumption synergistically worsened bTBI-induced impaired fear extinction in both sexes. Changes in EtOH preference post-bTBI are context-dependent, with male mice showing a significant decrease in preference following mild-bTBI and prior EtOH exposure, while females exhibited a trend toward increased preference post-bTBI, with significant increases in preference observed only when comparing pre- to post-bTBI drinking behavior.

Conclusions: Both males and females exhibited vulnerability to the combined effects of adolescent EtOH consumption and bTBI on fear extinction, while female mice showed a unique vulnerability to the escalation in EtOH preference.