Stress Facilitates the Development of Cognitive Dysfunction After Chronic Ethanol Exposure

Abstract

BACKGROUND Chronic exposure to stress or alcohol can drive neuroadaptations that alter cognition. Alterations in cognition may contribute to alcohol use disorders by reducing cognitive control over drinking and maintenance of abstinence. Here we examined effects of combined ethanol and stress exposure on prefrontal cortex (PFC)-dependent cognition. METHODS Adult male C57BL/6J mice were trained to drink ethanol (15%, v/v) on a 1hr/day 1-bottle schedule. Once stable, mice were exposed to cycles of chronic intermittent ethanol (CIE) or air-control vapor exposure (Air), followed by test cycles of 1hr/day ethanol drinking. During test drinking mice received no-stress (NS) or 10 minutes of forced swim stress (FSS) 4 hours before each test. This schedule produced four experimental groups: control, Air/NS; ethanol-dependent no stress, CIE/NS; non-dependent stress, Air/FSS; or ethanol-dependent stress, CIE/FSS. After two cycles of CIE and FSS exposure we assessed PFC-dependent cognition using object/context recognition and attentional set-shifting. At the end of the study mice were perfused and brains collected for measurement of c-Fos activity in PFC and locus coeruleus (LC). RESULTS CIE/FSS mice escalated ethanol intake faster than CIE/NS and consumed more ethanol than Air/NS across all test cycles. After two cycles of CIE/FSS, mice showed impairments in contextual learning and extra-dimensional set shifting relative to other groups. In addition to cognitive dysfunction, CIE/FSS mice demonstrated widespread reductions in c-Fos activity within prelimbic and infralimbic PFC as well as LC. CONCLUSION Together, these findings show that interactions between ethanol and stress exposure rapidly lead to disruptions in signaling across cognitive networks and impairments in PFC-dependent cognitive function.

Kcnn3 as a target for treating aberrant behaviors in stressed, ethanol-dependent mice

“…Previous evidence has revealed excessive ethanol intake and deficits in executive cognitive function in mice exposed to chronic intermittent ethanol and forced swim stress (28)(29)(30)(31). Here, we found that this model of ethanol and stress co-exposure also produced anxiety-like behaviors in a novel environment without affecting food consumption in the home cage.…”

“…Stressful life events can precipitate the onset of major depressive disorder and are a major risk factor for developing mood disorders (24,25), and the relationship between stress and mood disorders is influenced by gene-environment interactions (26,27). In this study, we evaluated the extent to which chronic ethanol and stress co-exposure produces excessive drinking (28)(29)(30) and cognitive impairments (31), as well as the covariance to affective and anxiety-like behaviors. Next, we used a deep phenome and gene expression data set acquired over the past decade for many members of the BXD family of mice (32) to identify K + channel genes in the basolateral amygdala (BLA) that are associated with anxiety-like behaviors.…”

Transcriptome Analysis of Alcohol Drinking in Non-Dependent and Dependent Mice Following Repeated Cycles of Forced Swim Stress Exposure

“…Identifying the shared and unshared biological systems impacted for these conditions represents an important step in understanding the pathophysiology of diseases associated with AUD and stress. The current studies sought to test the hypothesis that nondependent alcohol consumption (CTL), chronic intermittent ethanol (CIE) vapor-induced dependence, repeated forced swim stress (FSS), and the combination of CIE and FSS produce distinct transcriptomic signatures within the prefrontal cortex, a critical brain-region involved in stress and alcohol addiction [23,24]. RNA-seq analysis was conducted on total RNA isolated from the medial prefrontal cortex (referred to as CTX throughout the manuscript) to identify transcriptome-wide gene expression changes in four treatment groups compared to naive subjects: CTL, CIE, FSS, and CIE + FSS.…”

Contribution of Dynorphin and Orexin Neuropeptide Systems to the Motivational Effects of Alcohol

“…The PFC may be another area where the DYN/KOR system interacts with alcohol. KORs modulate neurotransmission in the PFC, and this brain region is implicated in the role of stress in the transition to alcohol dependence (Margolis et al 2006;Tejeda et al 2013Tejeda et al , 2015Lu and Richardson 2014;Rodberg et al 2017). Chronic alcohol exposure increases prodynorphin expression in the PFC, and a comparison of postmortem human brain tissue in alcoholic and control subjects revealed greater expression of prodynorphin and KOR mRNA in the dorsolateral PFC and orbitofrontal cortex (Bazov et al 2013;D'Addario et al 2013).…”