Alcohol Use Disorder and Associated Neurological Symptoms of Cognitive Dysfunction and Pain

摘要LSUHSC CARC研究组成部分3：酒精使用障碍及相关神经系统疾病 认知功能障碍和疼痛的症状 酒精使用障碍（AUD）的特征是神经功能缺损，消极的情感状态和深刻的情感障碍。 喝酒的升级。与过量饮酒相关的认知和行为缺陷归因于 神经元回路的功能性和持续性变化。慢性酒精诱发的认知障碍是 与选择性的中枢神经系统损伤有关，如前额叶皮层（PFC）。 过量的酒精暴露也会损害周围神经系统产生一种特征 神经病变，并由此产生的痛觉过敏（增加疼痛敏感性）被假设为加强负性 强化过程，以增加酒精的动机。饮酒也是导致病情严重的一个因素 人类免疫缺陷病毒（HIV）疾病的因素。即使在后抗逆转录病毒治疗（ART）时代， 神经认知缺陷在艾滋病毒感染者（PLWH）中仍然普遍存在。hiv相关神经认知 疾病（HAND）和共同发生的AUD可以加剧这些缺陷。PLWH还患有慢性疼痛， 这会破坏身体和情感功能，干扰ART的坚持，并使 病毒学失败PLWH的疼痛症状与大脑的特定变化相关，相应地 与这一人群中的许多心理社会因素有关，包括抑郁症。虽然认知缺陷 和疼痛在PLWH中密切相关，很少有研究检查与压力相关的神经生物学因素， 或者酒精和艾滋病毒如何促进这一过程。PFC代表并执行 目标导向行为的最高形式，其功能在诸如AUD的动机障碍中受到损害。 作为PLWH中疼痛和认知障碍的潜在神经生物学相关因素，我们的临床前研究 研究小组和其他人已经暗示了糖皮质激素受体（GR）信号传导的功能增强， 与过度饮酒、认知功能障碍和慢性疼痛有关。增强的GR信号 因此，与认知和疼痛相关的大脑区域（如PFC）的易受伤害的兴奋性改变可能代表了 导致这些病理的统一机制。最后，新的证据表明，西方饮食 在美国通常食用的维生素E会使神经认知和疼痛症状恶化。因此 西方饮食背景下过量饮酒、认知和疼痛的神经生物学相互作用 消费是艾滋病毒研究的一个严重不足的公共利益领域。我们的总体 一种假设是，过量饮酒和艾滋病毒/抗逆转录病毒药物暴露的个人消费西方饮食添加剂 在PLWH中产生认知缺陷和痛觉过敏，与增加的糖皮质激素信号传导有关， PFC内的超兴奋性。我们将使用双向平移实验来检查这些因素 设计结合了人类和非人类灵长类动物模型。

Abstract LSUHSC CARC Research Component 3: Alcohol Use Disorder & Associated Neurological Symptoms of Cognitive Dysfunction and Pain Alcohol use disorder (AUD) is characterized by neurological deficits, negative affective states, and a profound escalation of drinking. The cognitive and behavioral deficits associated with excessive drinking are attributed to functional and persistent changes to neuronal circuitry. Chronic alcohol induced-cognitive impairments are associated with selective central nervous system damage in areas such as the prefrontal cortex (PFC). Excessive alcohol exposure also damages the peripheral nervous system to produce a characteristic neuropathy, and the resulting hyperalgesia (increased pain sensitivity) is hypothesized to potentiate negative reinforcement processes to increase motivation for alcohol. Alcohol use also represents a major exacerbating factor for human immunodeficiency virus (HIV) disease. Even in the post-antiretroviral therapy (ART) era neurocognitive deficits remain prevalent in persons living with HIV (PLWH). HIV-associated neurocognitive disorder (HAND) and co-occurring AUD can exacerbate these deficits. PLWH also suffer from chronic pain, which disrupts physical and emotional function, interferes with ART adherence, and doubles the chance of virologic failure. Pain symptoms in PLWH are associated with specific changes in the brain and correspondingly associates with numerous psychosocial factors in this population, including depression. While cognitive deficits and pain are closely linked in PLWH, few studies have examined the stress-related neurobiological factors that drive these interactions or how alcohol and HIV promote this process. The PFC represents and executes the highest forms of goal-directed behavior, and its function is compromised in motivational disorders such as AUD. As a potential neurobiological correlate of pain and cognitive impairment in PLWH, preclinical studies from our group and others have implicated a functional potentiation of glucocorticoid receptor (GR) signaling in association with excessive alcohol drinking, cognitive dysfunction, and chronic pain. Heightened GR signaling and altered excitability of vulnerable cognition- and pain-related brain areas such as the PFC may thus represent a unifying mechanism contributing to these pathologies. Finally, emerging evidence suggests that Western diets commonly consumed in the United States worsen both neurocognitive and pain symptomatology. Thus, the neurobiological interaction of excessive alcohol drinking, cognition, and pain in the context of Western diet consumption represents a critically underexplored area of HIV research in the public interest. Our overarching hypothesis is that excessive drinking and HIV/ART exposure in individuals consuming a Western diet additively produce cognitive deficits and hyperalgesia in PLWH in association with increased glucocorticoid signaling and hyperexcitability within the PFC. We will examine these factors using a bidirectional translational experimental design incorporating human and nonhuman primate models.