Neuroimmune mechanisms of adult chronic ethanol consumption

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ABSTRACT Excessive alcohol consumption has risen during the ongoing COVID 19 pandemic, and there is an urgent need to improve treatment options. Individuals with alcohol use disorder (AUD) struggle with inhibitory control, decision making and emotional processing, and these cognitive symptoms reduce treatment adherence, worsen clinical outcomes, and promote relapse. The neuroimmune system is a key player in the pathophysiology of AUD, and targeting this modulatory system is less likely to produce unwanted side effects compared to directly targeting neurotransmitter dysfunction. Of particular interest, the cytokine interleukin-1β (IL-1β) is implicated in the cognitive symptoms of AUD. There are strong genetic associations among the IL-1 system, AUD and cognitive decline, and individuals with AUD have elevated postmortem brain and peripheral levels of IL-1β. The IL-1 signaling complex typically contains AcP, which generates neuroinflammatory responses. However, neurons also express AcPb, a second accessory protein that is neuroprotective and curbs the canonical AcP neuroinflammatory response. Aging increases the ratio of AcP to AcPb, leading to a stronger neuroinflammatory response, impaired synaptic plasticity and spatial memory deficits. Since individuals with AUD show signs of premature cortical aging, we hypothesize that chronic ethanol exposure produces a similar proinflammatory bias in IL-1β/AcP signaling within the medial prefrontal cortex (mPFC), thereby contributing to deficits in cognitive function. Therefore, here we will examine IL-1β synaptic regulation in early withdrawal and protracted abstinence in male and female mice. We will also test the hypothesis that early withdrawal and protracted abstinence lead to AcP-mediated cognitive impairment. Thus, the overarching goal of this proposal is to determine the neuroimmune mechanisms by which chronic ethanol produces long-lasting changes in mPFC function. The proposed studies will (i) fill critical gaps in our knowledge regarding IL-1β/neuroimmune regulation of basal mPFC function, (ii) provide essential information about how the consequences of chronic ethanol on the IL-1/neuroimmune system manifest in males and females, and (iii) potentially identify AcP as a novel pharmaceutical target for treating the cognitive symptoms of AUD. These studies will have important implications for our understanding of how persistent neuroinflammation can lead to the pathophysiology of AUD, and will promote the development of a new class of pharmacotherapeutics.