Impact of chronic alcohol and stress on mid-life cognition and locus coeruleus integrity

Revka, O.; Belculfine, S. J.; Fitts, L.; Nippert, K. E.; Teves, C. A.; Reis, P. M.; Tenney, S.; Packer, B. E.; Alvarez, I. G.; Milstein, O.; da Silva, M. C.; Moorman, D. E.; Vazey, E.

doi:10.1101/2025.11.20.689500

bioRxiv · 10.1101/2025.11.20.689500

Impact of chronic alcohol and stress on mid-life cognition and locus coeruleus integrity

Revka, O.·Belculfine, S. J.·Fitts, L.·Nippert, K. E.·Teves, C. A.·Reis, P. M.·Tenney, S.·Packer, B. E.·Alvarez, I. G.·Milstein, O.·da Silva, M. C.·Moorman, D. E.·Vazey, E.

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Abstract

BackgroundExcessive alcohol consumption and stress are associated with structural and functional alterations in the brain and impaired cognition. However, the persistence of long-term neural impacts after alcohol and stress are less understood. This study investigated midlife cognition and neuropathological changes following a history of alcohol and stress exposure. MethodsC57BL/6J mice acclimated to ethanol drinking (15% v/v) before exposure to four cycles of alternating chronic intermittent ethanol (CIE) vapor exposure and repeated forced swim stress (FSS), with control groups exposed to air and no stress (AIR/NS). After three months of abstinence, mice were evaluated at midlife (11 months old) on volitional drinking and a final CIE/FSS challenge for stress induced drinking. Spatial learning and cognitive flexibility were assessed using the Barnes maze before brains were collected to evaluate locus coeruleus integrity at 12 months old. ResultsCIE/FSS increased volitional alcohol intake, and this drinking phenotype persisted through to midlife despite extended abstinence. CIE/FSS mice showed intact spatial learning but impaired flexibility in the Barnes maze reversal phase. Flexibility impairments were driven by decreased time in the target quadrant and increased errors during the reversal test compared to AIR/NS. Furthermore, CIE/FSS mice showed pathological measures of reduced locus coeruleus integrity common to dementia related disorders, including elevated markers of oxidative stress, apoptosis and reduced autoinhibitory function. ConclusionsOur findings highlight the long-lasting impact of alcohol and stress exposure on cognition, with flexibility impairments persisting into midlife. In addition to cognitive changes, alcohol and stress history produced pathological changes in the locus coeruleus, an area known to mediate cognitive flexibility via its forebrain projections. Together, these results give an insight into the long-lasting impacts of chronic alcohol and stress and how they may accelerate age-related cognitive decline.

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Revka, O., Belculfine, S. J., Fitts, L., Nippert, K. E., Teves, C. A., Reis, P. M., Tenney, S., Packer, B. E., Alvarez, I. G., Milstein, O., da Silva, M. C., Moorman, D. E., Vazey, E.. 2025-11-21. Impact of chronic alcohol and stress on mid-life cognition and locus coeruleus integrity. https://doi.org/10.1101/2025.11.20.689500

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