CRF regulation of BNST target control in alcohol withdrawal

描述(申请人提供)：酒精使用障碍(AUD)是一种慢性复发性疾病，对个人健康和美国的社会经济福祉有很大影响，据估计，每年在与AUD相关的问题上花费1840亿美元。因此，寻找缓解AUDS的药物治疗靶点具有重要意义。最近的研究表明，过度饮酒的最初动机可能依赖于大脑的正强化系统的激活，该系统主要由腹侧被盖区释放的多巴胺(DA)介导。在AUDS发展的某个时间点，人们认为会发生一种转变，使得过度饮酒的动机从依赖积极强化系统转变为消极强化系统。杏仁核是调节焦虑和应激反应的重要大脑区域，而促肾上腺皮质激素释放因子(CRF)是一种被认为参与应激反应的神经递质，它们被认为与AUD发生所需的负强化通路密切相关。然而，在AUDS的发展过程中，积极和消极强化系统之间的切换所涉及的确切性质和神经回路尚不清楚。我们实验室最近的研究表明，正性和负性强化系统之间存在潜在的直接联系，由此DA可以提高终纹床核(BNST)中CRF的水平，终纹床核是延伸的杏仁核的一个组成部分，通常被描述为正向和负向强化通路中的信息中间管理者。长期以来，酒精暴露会增加包括BNST在内的许多大脑区域的DA水平，这表明酒精暴露也会增加BNST CRF的水平。CRF已被证明可以增加BNST神经元的兴奋性，这进一步被证明在许多啮齿动物模型中增加了焦虑样行为。此外，戒酒还被证明会增加BNST中CRF的水平，并增加焦虑。此外，反复刺激CRF受体可引起BNST调节的焦虑样行为的敏感化。因此，反复的酒精暴露和戒酒预计会导致BNST中CRF水平的增加，这既是通过酒精暴露期间DA的间接调节，也是通过在戒断期间直接增加CRF的释放。酒精DA和CRF之间的这种相互作用被认为是导致BNST CRF受体敏化的原因，因此是AUD发生中从阳性强化到阴性强化的最初转折点。这项建议将结合电生理、药理学、行为学和荧光成像技术来确定BNST CRF在慢性间歇性酒精暴露后是否敏化，以及哪些BNST输出神经元受到这种敏化的影响。这些研究的成功完成可能会揭示对AUD发展的新见解，并可能发现未来治疗这种衰弱疾病的药物干预的新靶点。 与公共健康相关：酒精中毒是一种破坏性的、代价高昂的疾病，假定由于导致最初过度饮酒和后来依赖的神经回路的转变而发展起来。一个潜在的过渡性成分可能是终纹床核中的一条独特的通路，终纹床核是参与调节不同奖赏和压力系统的大脑区域，可能对长期酒精暴露和戒酒造成的侮辱特别敏感。这项建议旨在研究这一独特的途径，并确定它在反复接触酒精和戒酒后可能发生的变化，目的是揭示开发新的更好的酒精中毒治疗方法的新靶点。

DESCRIPTION (provided by applicant): Alcohol use disorder (AUD) is a chronic relapsing disease that has a great impact on individual health as well as the socio-economic well-being of the US as an estimated $184 billion dollars are spent annually on AUD related problems. Therefore, finding pharmacotherapeutic targets to alleviate AUDs is of great importance. Recent research shows that the initial motivation to excessively consume alcohol may be reliant upon activation of the brain's positive reinforcement system which is predominantly mediated by dopamine (DA) release from the ventral tegmental area. At some point in the development of AUDs a transition is thought to occur such that motivation to excessively consume alcohol switches from reliance on positive reinforcement to negative reinforcement systems. The extended amygdala, a brain region important in mediating anxiety and stress responses, and corticotrophin releasing factor (CRF), a neurotransmitter thought to be involved in stress reactivity, are thought to be heavily involved in the negative reinforcement pathways required for AUD development. However, the exact nature and neurocircuitry involved in the switch between utilizing positive and negative reinforcement systems during the development of AUDs is not yet known. Recent work from our lab has shown a potentially direct connection between positive and negative reinforcement systems whereby DA can elevate CRF levels in the bed nucleus of the stria terminalis (BNST), a component of the extended amygdala that is often described as a middle manager of information in both the positive and negative reinforcement pathways. Alcohol exposure has long been shown to increase DA levels in many brain regions, including the BNST, which suggests that alcohol exposure would also increase BNST CRF levels. CRF has been shown to increase the excitability of BNST neurons, which has further been shown to increase anxiety-like behaviors in many rodent models. In addition, withdrawal from alcohol exposure has also been shown to increase CRF levels in the BNST and increase anxiety. Furthermore, repeated CRF receptor stimulation has been shown to cause a sensitization of anxiety-like behaviors regulated by the BNST. Therefore, repeated alcohol exposures and withdrawals would be expected to cause increased levels of CRF in the BNST, both via indirect modulation via DA during alcohol exposure and by directly increasing CRF release during withdrawal. This interaction between alcohol DA and CRF is hypothesized to cause a sensitization of BNST CRF receptors and therefore be the initial transition point between positive and negative reinforcement in AUD development. This proposal will integrate electrophysiological, pharmacological, behavioral, and fluorescent imaging techniques to determine if BNST CRF sensitize following chronic intermittent alcohol exposure and which BNST output neurons are affected by this sensitization. Successful completion of these studies may reveal new insights into AUD development and possibly uncover novel targets for future pharmacological interventions in the treatment of this debilitating disease. PUBLIC HEALTH RELEVANCE: Alcoholism is a devastating and costly disease hypothesized to develop due a transition in the neurocircuitry responsible for initial excessive alcohol drinking and latter dependency. One potential transitional component may be a unique pathway in the bed nucleus of the stria terminalis, a brain region involved in the regulation of the separate reward and stress systems, which may be especially sensitive to insults by chronic alcohol exposures and withdrawals. This proposal aims to examine this unique pathway and determine how it may change following repeated alcohol exposures and withdrawals with the goal of revealing novel targets for the development of new and better treatments for alcoholism.