NFkB: A critical link between alcohol abuse and stress-sensitivity

NFkB：酗酒和压力敏感性之间的关键联系

• 批准号: 9765119
• 负责人: Sadie Elizabeth Nennig
• 金额: $ 1.36万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-13 至 2019-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9765119
• 关键词: Alcohol abuse; Alcohol consumption; Alcohol dependence; Alcoholism; Alcohols; Amygdaloid structure; Anhedonia; Animals; Anxiety; Attention; Attenuated; B-Lymphocytes; Behavioral; Brain; Cell Nucleus; Cell Wall; Chronic; Clinical; Comorbidity; Complement; Consumption; Control Animal; DNA Binding; Data; Development; Disease; Enhancers; Exposure to; Gram-Negative Bacteria; High Prevalence; Hour; Immune response; Individual; Knowledge; Laboratories; LacZ Genes; Light; Link; Lipopolysaccharides; Measures; Mediating; Mediator of activation protein; Mental Depression; Mental disorders; Molecular; Mus; National Institute on Alcohol Abuse and Alcoholism; Neuroimmune; Neuroimmune system; Nuclear; Nucleus Accumbens; Patients; Phenotype; Physiological; Population; Pre-Clinical Model; Predisposition; Process; Prodrugs; Property; Protocols documentation; Reporter; Rewards; Risk Factors; Role; Signal Transduction; Social Interaction; Stress; Symptoms; Techniques; Therapeutic; Water; Work; alcohol exposure; alcohol involvement; alcohol response; alcohol reward; cohort; comorbid depression; depression model; depressive symptoms; interest; neurophysiology; novel; preference; prevent; problem drinker; regional difference; response; social; social defeat; stressor; therapeutic development; therapeutic target; transcription factor

PROJECT SUMMARY Comorbidity between alcoholism and other psychiatric disorders such as depression is extremely common. Determining how the circuitries of these conditions overlap is critical for the development of therapeutics targeting specific populations of alcoholic patients. Our group has recently determined a bidirectional relationship between alcohol exposure and stress-sensitivity which will be further investigated in this proposal. The neuroimmune system has gained attention in recent decades for its involvement in psychiatric conditions, indicating its signaling processes as promising targets for treating comorbid disorders. Of specific interest to our laboratory is the transcription factor nuclear factor κ light chain enhancer of activated B cells (NFkB). NFkB is activated following alcohol exposure and is implicated in behavioral processes such as consumption and reward. NFkB is also involved in the development of depressive-like symptoms that arise from exposure to social defeat stress (SDS), a major preclinical model of depression. As such, the multifaceted roles of NFkB suggest that this transcription factor may influence the circuitries underlying the development of both alcohol abuse and depression. To further study the role of NFkB in these processes, Aim 1 will examine the effects of SDS on alcohol reward via conditioned place preference (CPP) in NFkB-LacZ reporter mice. We expect that mice susceptible to defeat stress will display enhanced alcohol reward, and this elevated reward will associate with increased NFkB activity in regions of interest such as the nucleus accumbens. With selective inhibition of NFkB in the regions identified using the novel prodrug Daun02, we suspect that the increase in reward in susceptible animals will be attenuated. Aim 2 will explore the opposite phenomenon, that alcohol exposure increases sensitivity to subthreshold SDS. We expect that chronic alcohol exposure stimulates NFkB activity in specific regions of interest such as the basolateral and central amygdala, and selectively blocking NFkB in these regions with Daun02 will diminish sensitivity to SDS. We also suspect that lipopolysaccharide, a potent inducer of the neuroimmune system and NFkB activity, will mimic these effects and increase sensitivity to SDS. These studies will advance our current knowledge of the mechanisms underlying alcohol reward and stress- sensitivity as well as the involvement of NFkB in these circuitries. The results obtained from this proposal will further corroborate the promising therapeutic potential of targeting NFkB, as evidenced by its pivotal involvement in many important behavioral processes linking alcoholism and stress-sensitivity.

项目概要 酗酒和抑郁症等其他精神疾病之间的共病极为常见。 确定这些条件的电路如何重叠对于开发靶向治疗至关重要 我们的小组最近确定了特定人群的酗酒者之间的双向关系。 酒精暴露和压力敏感性将在本提案中进一步研究。 近几十年来，神经免疫系统因其与精神疾病的关系而受到关注， 表明其信号传导过程是我们特别感兴趣的治疗共病疾病的有希望的目标。 实验室的转录因子是活化B细胞核因子κ轻链增强子(NFkB)。 酒精暴露后被激活，并与消费和奖励等行为过程有关。 NFkB 还参与因暴露于社交失败而引起的抑郁样症状的发展 应激（SDS）是抑郁症的一种主要临床前模型，因此，NFkB 的多方面作用表明这一点。 转录因子可能影响酒精滥用和酗酒发展的潜在电路 沮丧。 为了进一步研究 NFkB 在这些过程中的作用，目标 1 将检查 SDS 对酒精奖励的影响 通过 NFkB-LacZ 报告小鼠的条件位置偏好（CPP），我们预计小鼠容易被击败。 压力会增加酒精奖励，而这种增加的奖励将与增加的 NFkB 活性相关 在感兴趣的区域，例如伏隔核，在确定的区域中选择性抑制 NFkB。 使用新型前药 Daun02，我们怀疑易感动物的奖励增加将会减弱。 目标 2 将探索相反的现象，即酒精暴露会增加对阈下 SDS 的敏感性。 我们预计，长期接触酒精会刺激特定感兴趣区域的 NFkB 活性，例如 基底外侧和中央杏仁核，并且用 Daun02 选择性阻断这些区域的 NFkB 将减弱 我们还怀疑脂多糖是神经免疫系统的有效诱导剂， NFkB 活性将模拟这些效应并增加对 SDS 的敏感性。 这些研究将增进我们目前对酒精奖赏和压力背后机制的了解。 灵敏度以及 NFkB 在这些电路中的参与将从该提案中获得的结果。 进一步证实了靶向 NFkB 的治疗潜力，正如其关键参与所证明的那样 在许多与酗酒和压力敏感有关的重要行为过程中。