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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要日常生活涉及做出灵活和适应性决策以实现所需的目标。决策的疾病当与酒精使用障碍相关的诸如与酒精疾病相关的制造可能会浮出水面决策变得不好。解析酒精对决策的影响的困难过程是由于缺乏高度的结构和功能输入输出映射而产生的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关键眶额皮层（OFC）计算在决策中的作用，这是基础的特定神经机制这些计算及其在酒精成瘾中的破坏是未知的。那是基督徒的目标 Cazares的F99阶段是平行应用公正和电路的特定技术，以揭示长期的持久酒精依赖置于OFC电路上的结构和功能性损失。克里斯蒂安的工作提交出版物使用细胞外记录技术来确定OFC的决策方式使用仪器杠杆施加诱导酒精依赖后，作用发生了重大改变任务。但是，这些功能变化的生物学机制仍然未知。给定新支持决策的电路机制的复杂性，公正的方法可能构成识别依赖性引起的变化的优势，导致异常决策行为。为此，基督教的提议利用探索性的单突触狂犬病追踪技术经过验证的酒精依赖动物模型，以识别OFC全脑输入的变化。更大了解酒精依赖性如何导致决策定义也需要使用体内考虑到涉及细胞的遗传认同的技术。那是基督徒会利用微型荧光微型镜检查以捕获大规模的时空神经活动在决策过程中，基因鉴定了OFC亚群。通过与决策有关的聚类活动 - 采取行为，基督徒将能够对这些神经元簇中的每个群集进行训练和测试解码器，以评估 OFC亚群的反映行为表现的程度，以及研究是否酒精对OFC功能的依赖性影响特定于兴奋性或抑制性亚群。在k00期间，基督徒计划将大规模数据集与信息理论结合在一起，以在否则可能没有观察到的大脑活动和行为。捕捉这些微妙的关系将开放途径，以调查指导决策行为的其他不可观察的信息。通过进行仅通过跨学科方法来实现的实验，基督徒不仅会亮着关于神经生物学和决策之间的联系，以及这些连接可能如何打破在决策异常的精神疾病中倒下。