Investigating the Effects of Alcohol Dependence on the Neural Circuitry Supporting Decision-Making Behavior

研究酒精依赖对支持决策行为的神经回路的影响

• 批准号: 10371046
• 负责人: Christian Cazares
• 金额: $ 3.17万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-03 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10371046
• 关键词: Address; Affect; Alcohol dependence; Alcohols; Animal Model; Award; Behavior; Behavioral; Behavioral Genetics; Biological; Brain; Brain region; Cells; Chronic; Cluster Analysis; Cognitive deficits; Complex; Data; Decision Making; Dependence; Disease; Electrophysiology (science); Environment; Etiology; Evaluation; Fluorescence; Future; Genetic Identity; Goals; Heterogeneity; Image; Individual; Information Theory; Investigation; Life; Light; Measurement; Mental disorders; Modeling; Movement; Mus; Neurobiology; Neurologic; Neurons; Neurosciences; Obsessive-Compulsive Disorder; Outcome; Output; Performance; Phase; Photons; Population; Population Dynamics; Process; Publications; Relapse; Research; Research Project Grants; Resolution; Rodent Model; Surface; Techniques; Testing; Therapeutic; Training; Work; addiction; alcohol effect; alcohol exposure; alcohol use disorder; analytical method; analytical tool; dynamic system; experience; experimental study; extracellular; flexibility; gray matter; in vivo; in vivo imaging; insight; interdisciplinary approach; interdisciplinary collaboration; large scale data; microendoscope; miniaturize; mouse model; neural circuit; neuromechanism; novel; patient population; problem drinker; rabies viral tracing; relating to nervous system; spatiotemporal

Project Summary Daily life involves making flexible and adaptive decisions to achieve desired goals. Disorders of decision- making, such as those associated with alcohol use disorder, can surface when the underlying neurobiology of decision-making goes awry. Difficulties in parsing the effects of alcohol dependence on decision-making processes arise from a fundamental lack of structural and functional input-output mapping of the highly complex neural circuits that support decision-making. While neurobiological investigations have identified a key role for orbitofrontal cortex (OFC) computations in decision-making, the specific neural mechanisms underlying these computations and their disruption in alcohol addiction are unknown. Thus, the goal of Christian Cazares’s F99-phase is to apply unbiased and circuit specific techniques in parallel to unveil the long-lasting structural and functional toll that alcohol dependence places on OFC circuitry. Christian’s work submitted for publication used extracellular recording techniques to establish how OFC representations of decision-making actions are significantly altered following induction of alcohol dependence using an instrumental lever pressing task. However, the biological mechanisms for these functional changes remain unknown. Given the vast complexity of the circuit mechanisms that support decision-making, unbiased approaches can pose an advantage for identifying the dependence-induced changes that result in aberrant decision-making behavior. To this end, Christian proposes to utilize an exploratory monosynaptic rabies tracing technique on a well- validated animal model of alcohol dependence to identify changes in whole-brain inputs to the OFC. A greater understanding of how alcohol-dependence results in decision-making deficits also requires the use of in vivo techniques that take into consideration the genetic identity of cells involved. Thus, Christian will utilize miniaturized fluorescence microendoscopes to capture large-scale, spatiotemporal neural activity from genetically identified OFC subpopulations during decision-making. By clustering activity in relation to decision- making behavior, Christian will be able to train and test decoders on each of these neuron clusters to assess the extent to which OFC subpopulations reflect behavioral performance, as well as investigate if alcohol- dependence effects on OFC function are specific to excitatory or inhibitory sub-populations. In the K00-phase, Christian plans to use large-scale datasets in conjunction with information theory to draw relationships between brain activity and behavior that might otherwise have gone unobserved. Capturing these subtle relationships will open avenues for investigating otherwise unobservable information that guides decision-making behavior. By conducting experiments only achievable by an interdisciplinary approach, Christian will not only shed light on the connections between neurobiology and decision-making, but also on how these connections may break down in a psychiatric disease in which decision-making is aberrant.

项目摘要 日常生活包括做出灵活和适应性的决定，以实现预期的目标。决策障碍- 制造，如与酒精使用障碍有关的，当潜在的神经生物学 决策出了问题。分析酒精依赖对决策的影响的困难 过程产生于根本缺乏高度的结构和功能输入-产出映射 支持决策的复杂神经回路。虽然神经生物学研究已经确定了一个关键 眼眶额叶皮质(OFC)计算在决策中的作用，具体的神经机制 这些计算和它们在酒精成瘾中的破坏是未知的。因此，克里斯蒂安的目标 卡萨雷斯的F99阶段是并行应用无偏和电路特定的技术，以揭开长效 酒精依赖对OFC电路造成的结构和功能损失。克里斯蒂安的作品提交给 出版使用细胞外记录技术来建立OFC如何表示决策 在诱导酒精依赖后，使用仪器性杠杆按压，动作会发生显著变化 任务。然而，这些功能变化的生物学机制仍不清楚。鉴于广袤的 支持决策的电路机制的复杂性、不偏不倚的方法可能会造成 有助于识别导致异常决策行为的依赖引起的变化。 为此，克里斯蒂安建议在一口井上使用一种探索性的单突触狂犬病追踪技术- 验证酒精依赖的动物模型，以确定OFC的全脑输入的变化。一个更伟大的 要了解酒精依赖是如何导致决策缺陷的，还需要在体内使用 考虑到相关细胞的遗传特性的技术。因此，克里斯蒂安将利用 微型荧光显微内窥镜捕捉大范围的时空神经活动 在决策过程中对OFC亚群进行遗传识别。通过将与决策相关的活动聚集在一起- 做出行为，克里斯蒂安将能够训练和测试这些神经元簇上的解码器，以评估 OFC亚群反映行为表现的程度，以及调查酒精是否- 对OFC功能的依赖效应是兴奋性或抑制性亚群特有的。在K00阶段， 克里斯蒂安计划将大规模数据集与信息论结合起来，以绘制出 大脑活动和行为，否则可能不会被观察到。捕捉这些微妙的关系 将为调查原本无法观察到的指导决策行为的信息开辟道路。 通过进行只能通过跨学科方法实现的实验，克里斯蒂安不仅将阐明 神经生物学和决策之间的联系，以及这些联系可能如何断开 患上了一种决策异常的精神疾病。