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

项目总结 酗酒和抑郁症等其他精神疾病之间的共病是非常常见的。 确定这些条件的回路如何重叠对于靶向治疗的发展至关重要 酒精中毒患者的特定人群。我们小组最近确定了一种双向关系，即 酒精暴露和压力敏感性，这一点将在本提案中进一步研究。 近几十年来，神经免疫系统因参与精神疾病而受到关注， 表明其信号转导过程有望成为治疗共病障碍的靶点。对我们的 实验室是转录因子核因子κ轻链增强子活化的B细胞(NFkB)。NFkB是 在酒精暴露后被激活，并与消费和奖励等行为过程有关。 NFkB也参与了抑郁样症状的发展，这些症状是由于暴露在社交失败中而产生的 应激(SDS)，抑郁症的主要临床前模型。因此，NFkB的多方面角色表明，这 转录因子可能影响酒精滥用和酒精滥用的潜在回路。 抑郁症。 为了进一步研究NFkB在这些过程中的作用，目标1将研究十二烷基硫酸钠对酒精奖赏的影响 在NFkB-LacZ报告小鼠中通过条件性位置偏爱(CPP)。我们预计容易被击败的老鼠 压力会表现出酒精奖励的增强，这种奖励的增加将与NFkB活性的增加相关联 在感兴趣的区域，如伏隔核。在已确定的区域中选择性抑制NFkB 使用新型前体药物Daun02，我们怀疑易感动物的奖赏增加将会减弱。 目的2将探索相反的现象，即酒精暴露增加了对亚阈值抑郁的敏感性。 我们预计，长期酒精暴露会刺激特定感兴趣区域的NFkB活性，例如 基底外侧核和中央杏仁核，用Daun02选择性阻断这些区域的NFkB将减弱 对十二烷基硫酸钠敏感。我们还怀疑内毒素，神经免疫系统的有效诱导剂和 NFkB活性，将模拟这些影响，并增加对SDS的敏感性。 这些研究将促进我们目前对酒精奖励和压力背后的机制的了解。 灵敏度以及NFkB在这些电路中的参与。从这项提议中获得的结果将 进一步证实了靶向NFkB的有前景的治疗潜力，其关键参与证明了这一点 在许多重要的行为过程中将酒精中毒和应激敏感联系在一起。

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.