Abstract
Chronic alcohol use is associated with cognitive decline that impedes behavioral change during rehabilitation. Despite this, addiction therapy does not address cognitive deficits, and there is poor understanding regarding the mechanisms that underlie this decline. We established a rodent model of chronic voluntary alcohol use to measure ensuing cognitive effects and underlying pathology. Rats had intermittent access to alcohol or an isocaloric solution in their home cage under voluntary 2-bottle choice conditions. In Experiments 1 and 2 cognition was assessed using operant touchscreen chambers. We examined performance in a visual discrimination and reversal task (Experiment 1), and a 5-choice serial reaction time task (Experiment 2). For Experiment 3, rats were perfused immediately after cessation of alcohol access period, and volume, cell density and microglial populations were assessed in the prefrontal cortex and striatum. Volume was assessed using the Cavalieri probe, while cell and microglial counts were estimated using unbiased stereology with an optical fractionator. Alcohol-exposed and control rats showed comparable acquisition of pairwise discrimination; however, performance was impaired when contingencies were reversed indicating reduced behavioral flexibility. When tested in a 5-choice serial reaction time task alcohol-exposed rats showed increased compulsivity and increased attentional bias towards a reward associated cue. Consistent with these changes, we observed decreased cell density in the prefrontal cortex. These findings confirm a detrimental effect of chronic alcohol and establish a model of alcohol-induced cognitive decline following long-term voluntary intake that may be used for future intervention studies.
Highlights
Chronic alcohol use is associated with cognitive decline that impedes behavioral change during rehabilitation
Findings from human post-mortem tissue suggest that the mechanism(s) for cognitive decline and dementia in alcohol use disorder (AUD) are likely distinct from those found in the most common degenerative brain disorders[29], it is possible that alcohol consumption is a contributory factor to some of these disorders via actions on toll-like receptors[30]
Microglial activation in turn causes the release of proinflammatory cytokines, which may result in cell death and reduced neurogenesis[34,35,36]
Summary
Chronic alcohol use is associated with cognitive decline that impedes behavioral change during rehabilitation. When tested in a 5-choice serial reaction time task alcohol-exposed rats showed increased compulsivity and increased attentional bias towards a reward associated cue Consistent with these changes, we observed decreased cell density in the prefrontal cortex. These findings confirm a detrimental effect of chronic alcohol and establish a model of alcohol-induced cognitive decline following long-term voluntary intake that may be used for future intervention studies. To understand the cognitive changes that occur in chronic AUD, a model where voluntary alcohol intake occurs over a protracted period is required. Converging evidence from post-mortem studies and animal models suggests that neuroinflammation mediated by increased microglial activation might be a factor in neurodegeneration that occurs after chronic alcohol exposure[3,24]. Most animal studies use involuntary alcohol intake, which may confound the stated findings
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