Animal models for studies of alcohol effects on the trajectory of age-related cognitive decline

There is growing interest in understanding how ethanol use interacts with advancing age to influence the brain and cognition. Animal models are employed to investigate the cellular and molecular mechanisms of brain aging and age-related neurodegenerative diseases that underlie cognitive decline. However, all too often research on problems and diseases of the elderly are conducted in healthy young animals, providing little clinical relevance. The validity of animal models is discussed, and confounds due to age-related differences in anxiety, sensory-motor function, and procedural learning are highlighted in order to enhance the successful translation of preclinical results into clinical settings. The mechanism of action of ethanol on brain aging will depend on the dose, acute or chronic treatment, or withdrawal from treatment and the age examined. Due to the fact that humans experience alcohol use throughout life, important questions concern the effects of the dose and duration of ethanol treatment on the trajectory of cognitive function. Central to this research will be questions of the specificity of alcohol effects on cognitive functions and related brain regions that decline with age, as well as the interaction of alcohol with mechanisms or biomarkers of brain aging. Alternatively, moderate alcohol use may provide a source of reserve and resilience against brain aging. Longitudinal studies have the advantage of being sensitive to detecting the effects of treatment on the emergence of cognitive impairment in middle age and can minimize effects of stress/anxiety associated with the novelty of alcohol exposure and behavioral testing, which disproportionately influence aged animals. Finally, the effect of alcohol on senescent neurophysiology and biomarkers of brain aging are discussed. In particular, the interaction of age and effects of alcohol on inflammation, oxidative stress, N-methyl-d-aspartate receptor function, and the balance of excitatory and inhibitory synaptic transmission are highlighted.