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

• 批准号: 9215075
• 负责人: Yuval Silberman
• 金额: $ 24.9万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9215075
• 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; 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

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）：酗酒是一个令人烦恼的健康问题，每年导致全球 250 万人死亡，是全球第三大风险因素 疾病。酗酒是美国第一大疾病风险因素，估计 43% 的男性和 28% 的女性属于酗酒者，约 7% 的美国人被视为酗酒者。酗酒治疗面临的主要问题之一是高复发率（50-90%）。寻找治疗酗酒的新策略是我主要的长期职业目标。长期的压力脆弱性和控制饮酒的能力下降是酗酒的标志，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参与压力和奖励信号传导的关键神经元通路（例如终纹床核（BNST））的同样持久的变化引起的。 BNST 内的促肾上腺皮质激素释放因子 (CRF) 信号在慢性酒精暴露引起的基于负强化的饮酒增强中发挥着关键作用。该系统也可能在酗酒者无法限制饮酒和酗酒倾向中发挥重要作用。然而，慢性酒精在压力和奖励信号交叉点上招募这一重要途径的机制仍不清楚。我当前的短期目标是确定长期酒精暴露改变 BNST 信号传导的机制。在本提案中，我们将结合使用尖端神经科学技术来确定 BNST-CRF 神经回路如何与幼稚状态下的酒精敏感大脑区域整合，并研究长期酒精暴露如何破坏这种连接。越来越多的证据表明，BNST 中去甲肾上腺素传输的增加可能在酒精戒断期间 BNST-CRF 信号传导的增强中发挥关键作用。我们之前的研究结果表明，α-肾上腺素能受体激活通常会降低 BNST 兴奋性，而 β-肾上腺素能受体激活可以使 BNST-CRF 神经元去极化并促进 BNST 兴奋性增加。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，基底外侧杏仁核中，α/β-肾上腺素受体也平衡去甲肾上腺素对神经元活动的调节，而压力可以将这种平衡转向增加β-肾上腺素受体的兴奋。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，从而在戒断期间促进去甲肾上腺素介导的 BNST-CRF 神经元兴奋。我们将结合光遗传学、电生理学和药理学方法，在新型转基因 CRF 报告小鼠中探索本提案目标 1 中的这一假设。树突棘在传入特异性可塑性的调节中发挥关键作用，长期药物暴露可以改变树突棘形态。然而，人们对长期饮酒如何改变 BNST-CRF 神经元树突棘知之甚少。我们认为，长期饮酒可能会诱导 BNST-CRF 神经元树突结构的长期适应，从而“锁定”持久的 BNST-CRF 神经元兴奋性。这一假设将在目标 2 中使用电生理学和神经解剖学方法的新颖组合进行检验。这两个目标将涉及新科学技能的发展，将选择性检查对 BNST-CRF 神经元的调节影响与检查对酗酒的发展至关重要的神经元群的形式和功能的研究“结合”起来。这项工作将由世界著名生物医学研究机构范德比尔特大学医学院酗酒领域（Danny Winder 博士）和神经解剖学（Ariel Deutch 博士）领域的领导者指导。虽然这两个目标将有助于更好地了解去甲肾上腺素传输如何在长期饮酒期间招募 BNST-CRF 回路，但人们对长期饮酒如何调节去甲肾上腺素信号来源知之甚少。最近的证据表明，孤束核（NTS）中的神经元是 BNST 中去甲肾上腺素传输的主要来源，但这些神经元尚未在酗酒的情况下进行直接检查。该提案的独立阶段将确定 NTS 中的去甲肾上腺素神经元，特别是那些投射到 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基础，旨在确定 BNST 投射的 NTS-去甲肾上腺素神经元如何在酗酒的发展过程中调节酒精寻求。这种综合方法是检查酒精中毒神经病理学机制的一种新方法，并可能导致开发更好的治疗策略来减轻这种使人衰弱的疾病。