Characterizing the role of fronto-striatal connectivity in value-based decision-making

项目摘要 基于价值的决策是评估环境中的选项以告知最佳课程的过程 的行动。大量的行为证据表明，以价值为基础的决策是受损的， 成瘾更好地理解基于价值的决策是如何计算和执行的， 细胞类型对于识别和最终治疗导致适应不良的电路干扰至关重要 成瘾的决策。到目前为止，绝大多数研究都是关于价值的神经相关性- 基于行为的决策已经在行为灵长类动物中进行了。虽然灵长类动物有能力 复杂的认知任务，我们目前缺乏灵长类兼容的工具来记录和操纵活动 精确定义的神经元群体。这就限制了灵长类动物的研究能告诉我们多少 我们关于解剖学和遗传学定义的细胞类型在基于价值的决策中的作用。这 该提案通过开发一项新任务来研究大鼠基于价值的决策来克服这一障碍。大鼠 能够执行复杂的认知任务，但他们也可以接受现代技术， 记录和操纵定义的细胞类型的活动。初步数据显示，老鼠 能够做出适当的基于价值的决策，并证明基于价值的决策是 严重依赖于眶额皮层的活动本提案的目标是描述 眶额皮层中的神经元与下游神经回路相互作用， 决策的在K99指导阶段，候选人将在光遗传学上抑制眶额轴突 动物不同脑区的终端做出基于价值的决定，以确定关键的输出途径 通过它来实现在眶额皮层中计算的选择。初步调查显示， 从眶额皮质到背侧纹状体的投射可能是关键的输出途径， 基于价值的决策是中介的。然后，候选人会问信息是如何转换的， 通过结合轴突的光遗传学抑制从眶额皮质传递到背侧纹状体 终端与在体内细胞外电生理记录在大鼠执行基于值的决策- 制作任务。拟议中的K99研究不仅将确定眶额皮质中的神经元如何 与下游神经回路相互作用，以调解选择，但也将为候选人提供关键的 在体内电生理学和降维技术方面进行培训，以分析世界各地的大数据- 斯坦福大学的课堂实验室。在R 00独立阶段，申请人将应用此培训， 不同的决策相关参数如何映射到背侧纹状体的不同细胞类型。统称 拟议中的研究将提供一些关于如何以价值为基础的决策是由 解剖学和遗传学定义的细胞类型。这有望阐明新的治疗策略， 成瘾，同时也为申请人作为独立调查员提供了许多新的调查途径。

Project Summary Value-based decision-making is the process of evaluating options in the environment to inform the best course of action. Abundant behavioral evidence demonstrates that value-based decision-making is impaired in addiction. An improved understanding of how value-based decisions are computed and executed by defined cell types is critical to identifying and ultimately treating the circuit disturbances that underlie maladaptive decision-making in addiction. To date, the vast majority of studies examining the neural correlates of value- based decision-making have been conducted in behaving primates. While primates are capable of performing complex cognitive tasks, we currently lack primate-compatible tools for recording and manipulating the activity of precisely defined populations of neurons. This has placed limitations on how much primate studies can tell us about the role of anatomically and genetically defined cell types in value-based decision-making. This proposal overcomes this obstacle by developing a new task to study value-based decision-making in rats. Rats are capable of performing complex cognitive tasks, but they are also amenable to modern techniques for recording and manipulating the activity of defined cell types. Preliminary data demonstrate that rats are capable of making appropriate value-based decisions, and demonstrate that value-based decision-making is critically dependent on activity in the orbitofrontal cortex. The goal of this proposal is to characterize how neurons in the orbitofrontal cortex interact with downstream neural circuits to mediate value-based decision-making. In the K99 mentored phase, the candidate will optogenetically inhibit orbitofrontal axon terminals in distinct brain areas in animals making value-based decisions to identify the critical output pathway through which choices computed in the orbitofrontal cortex are implemented. Preliminary efforts reveal that the projection from the orbitofrontal cortex to the dorsal striatum is likely the key output pathway through which value-based decisions are mediated. The candidate will then ask how information is transformed as it is transmitted from the orbitofrontal cortex to the dorsal striatum by combining optogenetic inhibition of axon terminals with in vivo extracellular electrophysiological recordings in rats performing the value-based decision- making task. The proposed K99 research will not only determine how neurons in the orbitofrontal cortex interact with downstream neural circuits to mediate choice, but will also provide the candidate with critical training in in vivo electrophysiology and dimensionality reduction techniques for analysing big data in world- class labs at Stanford University. In the R00 independent phase, the applicant will apply this training to ask how different decision-related parameters map onto distinct cell types in the dorsal striatum. Collectively, the proposed research will provide some of the first insights into how value-based decisions are mediated by anatomically and genetically defined cell types. This promises to illuminate new therapeutic strategies for addiction, while also generating many new lines of enquiry for the applicant as an independent investigator.