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.

项目概要日常生活涉及做出灵活和适应性的决定以实现预期目标。当潜在的神经生物学问题出现时，诸如与酒精使用障碍相关的那些因素就会浮出水面。难以分析酒精依赖对决策的影响。过程的产生是由于高度缺乏结构性和功能性的输入-输出映射。支持决策的复杂神经回路，而神经生物学研究已经确定了一个关键。眶额皮层（OFC）计算在决策中的作用，其背后的具体神经机制因此，这些计算及其对酒精成瘾的破坏是未知的。 Cazares 的 F99 阶段将并行应用无偏和电路特定技术，以揭示持久的依赖 OFC 电路的结构和功能酒精。该出版物使用细胞外记录技术来确定 OFC 如何表示决策使用工具杠杆按压诱发酒精依赖后，行动显着然而，考虑到这些功能变化的生物学机制仍然未知。由于支持决策的电路机制的复杂性，无偏见的方法可能会造成识别依赖引起的导致异常决策行为的变化的优势。为此，克里斯蒂安建议在良好的环境中利用探索性单突触狂犬病追踪技术验证了酒精依赖的动物模型，以确定 OFC 的全脑输入变化。了解酒精依赖如何导致决策缺陷还需要使用体内因此，克里斯蒂安将利用考虑到所涉及细胞的遗传特性的技术。微型荧光显微内窥镜可捕获大规模的时空神经活动通过对与决策相关的活动进行聚类，对 OFC 亚群进行基因识别。做出行为，克里斯蒂安将能够在每个神经集群上训练和测试解码器以评估 OFC 亚群反映行为表现的程度，以及调查酒精如果- OFC 功能的依赖性效应特定于兴奋性或抑制性亚群。 Christian 计划结合使用大规模数据集和信息论来绘制之间的关系捕捉这些微妙的关系可能会被忽视。将为调查指导决策行为的其他不可观察信息开辟途径。通过进行只有通过跨学科方法才能实现的实验，克里斯蒂安不仅会阐明关于神经生物学和决策之间的联系，以及这些联系如何被打破患有精神疾病，决策出现异常。