Engagement of novel noradrenergic and CRF circuit interactions by chronic alcohol

慢性酒精参与新型去甲肾上腺素能和 CRF 回路相互作用

基本信息

批准号：
8870234
负责人：
Yuval Silberman
金额：
$ 13.9万
依托单位：
VANDERBILT UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-06-15 至 2016-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8870234
关键词：
Accounting Acute Adrenergic Agents Adrenergic Receptor Alcohol consumption Alcohol withdrawal syndrome Alcoholism Alcohols American Amygdaloid structure Architecture Behavior Biomedical Research Brain region Cells Cessation of life Chronic Chronic stress Corticotropin-Releasing Hormone Dendrites Dendritic Spines Development Disease Drug Exposure Electrophysiology (science)Equilibrium Ethanol Functional disorder Glutamates Goals Health Image Institution Lead Learning Maintenance Maps Mediating Mentors Modeling Morphology Mus Negative Reinforcements Neuroanatomy Neurons Neurosciences Norepinephrine Nucleus solitarius Opiates Pathway interactions Peripheral Pharmaceutical Preparations Phase Play Population Positioning Attribute Predisposition Receptor Activation Receptor Signaling Recruitment Activity Regulation Relapse Reporter Research Rewards Risk Factors Role Signal Transduction Site Source Staging Stress Structure of terminal stria nuclei of preoptic region Symptoms System Techniques Testing Time Transgenic Organisms United States Universities Vertebral column Withdrawal Woman Work adrenergic alcohol effect alcohol exposure alcohol seeking behavior alcoholism therapy alpha-adrenergic receptor base beta-adrenergic receptor binge drinker career drinking glutamatergic signaling medical schools men neuropathology noradrenergic novel optogenetics preference problem drinker programs research study skills stressor tool transmission process treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Alcoholism is a vexing health problem accounting for 2.5 million deaths per year around the world, representing the third largest risk factor for global disease. Alcoholism is the number one leading risk factor for disease in the United States, as an estimated 43% of men and 28% of women can be classified as binge drinkers and about 7% of Americans are considered alcoholics. One of the major issues facing the treatment of alcoholism is the high rate (50-90%) of relapse. Finding new strategies for the treatment of alcoholism is my major long-term career goal. Long-term stress vulnerability and reduced capacity to control drinking are hallmarks of alcoholism and determining the causes of these symptoms may lead to better treatments strategies. These enduring dysfunctions likely result from equally enduring changes in key neuronal pathways involved in stress and reward signaling, such as the bed nucleus of the stria terminalis (BNST). Corticotropin releasing factor (CRF) signaling within the BNST plays a key role in negative reinforcement-based enhancement of alcohol drinking induced by chronic alcohol exposure. This system may also play an important role in the inability of alcoholics to limit drinking and in their propensity for relapse However, the mechanism by which chronic alcohol recruits this important pathway at the intersection of stress and reward signaling remains unclear. Determining the mechanisms by which chronic alcohol exposure alters BNST signaling in my current short-term goal. In this proposal we will use a combination of cutting edge neuroscience techniques to determine how BNST-CRF neurocircuitry is integrated with alcohol sensitive brain regions in the naive state and examine how chronic alcohol exposures disrupts this connectivity. Accumulating evidence suggests that increased norepinephrine transmission in the BNST may play a critical role in the enhancement of BNST-CRF signaling during alcohol withdrawal. Our previous findings indicate that alpha- adrenergic receptors activation generally decreases BNST excitability while beta-adrenergic receptors activation can depolarize BNST-CRF neurons and promote increased BNST excitability. Therefore, alpha- and beta-adrenergic receptors may balance the overall effect of norepinephrine on BNST activity. In a related brain region, the basolateral amygdala, alpha/beta-adrenergic receptors also balance norepinephrine modulation of neuronal activity and stress can shift this balance towards increased beta-adrenergic receptor excitation. Since chronic alcohol exposure is a stress, chronic alcohol may shift the alpha/beta -adrenergic balance to promote norepinephrine mediated excitation of BNST-CRF neurons during withdrawal. We will explore this hypothesis in Aim 1 of this proposal in a novel transgenic CRF reporter mouse using a combination of optogenetic, electrophysiological, and pharmacologic approaches. Dendritic spines play a key role in the regulation of afferent-specific plasticity and chronic drug exposure can alter dendritic spine morphology. However little is known about how chronic alcohol may alter BNST-CRF neuron dendritic spines. We propose that chronic alcohol may induce long-term adaptations in the dendritic architecture of BNST-CRF neurons that may "lock in" enduring BNST-CRF neuron excitability. This hypothesis will be examined in Aim 2 using a novel combination of electrophysiological and neuroanatomical approaches. These two aims will involve the development of new scientific skills "marrying" the selective examination of regulatory influences onto BNST-CRF neurons with studies examining the form and function of this neuronal population critical to the development of alcoholism. This work will be mentored by leaders in the fields of alcoholism (Dr. Danny Winder) and neuroanatomy (Dr. Ariel Deutch) at Vanderbilt University School of Medicine, a world-renowned biomedical research institution. While these two aims will allow for a better understanding of how norepinephrine transmission may recruit BNST-CRF circuitry during chronic alcohol, little is known about how chronic alcohol modulates the source of this norepinephrine signaling. Recent evidence suggests that neurons in the nucleus of the tractus solitarius (NTS) are the main source of norepinephrine transmission in the BNST, but these neurons have yet to be directly examined in the context of alcoholism. The independent phase of this proposal will determine if norepinephrine neurons in the NTS, particularly those neurons that project to the BNST, are modulated by acute and chronic alcohol. This work will set the stage for independent research program aimed at determining how BNST-projecting NTS- norepinephrine neurons regulate alcohol seeking during the development of alcoholism. This integrative approach is a novel way to examine mechanisms of neuropathology in alcoholism and may lead to the development of better treatment strategies to alleviate this debilitating disease.

描述（由申请人提供）：酒精中毒是全球每年250万人死亡的烦人的健康问题，这是全球第三大风险因素疾病。酒精中毒是美国疾病的第一大危险因素，因为估计有43％的男性和28％的女性可以归类为暴饮暴食者，而约7％的美国人被认为是酗酒者。酒精中毒治疗面临的主要问题之一是复发的率很高（50-90％）。寻找治疗酒精中毒的新策略是我的重要长期职业目标。长期的压力脆弱性和控制饮酒能力的减少是酒精中毒的标志，确定这些症状的原因可能会导致更好的治疗策略。这些持久的功能障碍可能是由于与压力和奖励信号传导所涉及的关键神经元途径的持久变化所致，例如Stria末端的床核（BNST）。 BNST内的皮质激素释放因子（CRF）信号传导在基于阴性增强的增强饮酒诱导的饮酒中起着关键作用。该系统也可能在酗酒者限制饮酒及其复发的倾向中起着重要作用，但是，在压力和奖励信号传导相交时，慢性酒精招募了这一重要途径的机制尚不清楚。确定慢性酒精暴露在我当前的短期目标中改变BNST信号的机制。在此提案中，我们将结合使用尖端神经科学技术的组合来确定BNST-CRF神经记录如何与天真状态下的酒精敏感大脑区域集成在一起，并检查慢性酒精暴露如何破坏这种连接性。积累的证据表明，BNST中的去甲肾上腺素传播的增加可能在提高酒精期间BNST-CRF信号传导的增强中起关键作用。我们以前的发现表明，α-肾上腺素能受体的激活通常会降低BN的兴奋性，而β-肾上腺素能受体的激活可以使BNST-CRF神经元去极化并促进BNST兴奋性的增加。因此，α-和β-肾上腺素能受体可能平衡去甲肾上腺素对BNST活性的总体影响。在相关的大脑区域，基底外侧杏仁核，α/β-肾上腺素能受体也平衡了神经元活性的去甲肾上腺素调节，而应力可以将这种平衡转向增加的β-肾上腺素能受体激发。由于慢性酒精暴露是一种压力，因此慢性酒精可能会改变α/β-肾上腺素能平衡，以促进去甲肾上腺素介导的BNST -CRF神经元的激发。我们将使用光学遗传学，电生理学和药理方法的组合在新的转基因CRF报告小鼠中的AIM 1中探讨这一假设。树突状棘在调节传入特异性可塑性中起关键作用，而慢性药物暴露会改变树突状棘的形态。然而，对于慢性酒精如何改变BNST-CRF神经元树突状刺的知之甚少。我们建议慢性酒精可能会在BNST-CRF神经元的树突状结构中引起长期适应，这些神经元可能会“锁定”持久的BNST-CRF神经元兴奋性。该假设将在AIM 2中使用电生理学和神经解剖学方法的新型组合进行检查。这两个目标将涉及新的科学技能“结合”调查对BNST-CRF神经元的选择性检查，研究研究对酒精中毒发展至关重要的这种神经元种群的形式和功能。这项工作将由酒精中毒（Danny Winder博士）和神经解剖学领域的领导人（Ariel Deutch博士）的领导人，范德比尔特大学医学院（Vanderbilt University School of Medicine）是一家世界知名的生物医学研究机构。虽然这两个目标将可以更好地理解慢性酒精期间的去甲肾上腺素传播如何募集BNST-CRF电路，但对于慢性酒精如何调节这种去甲肾上腺素信号的来源，几乎不知道。最近的证据表明，索拉氏菌（NTS）核中的神经元是BNST中去甲肾上腺素传播的主要来源，但是在酒精中毒的背景下，这些神经元尚未直接检查。该提案的独立阶段将确定NTS中的去甲肾上腺素神经元，尤其是那些投射到BNST的神经元是否受到急性和慢性酒精的调节。这项工作将为独立研究计划奠定阶段，旨在确定BNST项目如何调节酒精中毒期间的酒精寻求。这种综合方法是检查酒精中毒中神经病理学机制的一种新型方法，并可能导致制定更好的治疗策略以减轻这种使人衰弱的疾病。