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

项目摘要 日常生活涉及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那些，当潜在的神经生物学， 决策就会出错解析酒精依赖对决策的影响的困难 过程的产生是由于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。虽然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， 这些计算和它们对酒精成瘾的破坏是未知的。因此，基督教的目标 Cazares的F99阶段是并行应用无偏和电路特定技术，以揭示持久的 酒精依赖对眶额皮层回路造成结构和功能损害。Christian的作品 一份出版物使用细胞外记录技术来确定OFC如何代表决策 在使用仪器杠杆按压诱导酒精依赖后， 任务然而，这些功能变化的生物学机制仍然未知。鉴于 支持决策的电路机制的复杂性，无偏见的方法可以构成一个 这有利于识别导致异常决策行为的依赖性诱导的变化。 为此，克里斯蒂安建议利用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。更大 了解酒精依赖如何导致决策缺陷也需要使用体内 这些技术考虑了所涉及细胞的遗传特性。因此，克里斯蒂安将利用 微型荧光显微内窥镜捕捉大规模，时空神经活动， 在决策过程中基因识别的OFC亚群。通过对与决策相关的活动进行聚类- 克里斯蒂安将能够在每个神经元簇上训练和测试解码器， OFC亚群在多大程度上反映了行为表现，以及调查酒精- 对OFC功能的依赖性效应对于兴奋性或抑制性亚群是特异性的。在K 00阶段， 克里斯蒂安计划使用大规模数据集与信息理论相结合，以绘制 大脑活动和行为，否则可能无法观察到。捕捉这些微妙的关系 将为调查指导决策行为的其他不可观察的信息开辟途径。 通过进行实验，只有通过跨学科的方法才能实现，克里斯蒂安不仅会阐明 神经生物学和决策之间的联系，以及这些联系如何断裂 在精神疾病中，决策是异常的。

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.