Orbitofrontal Cortex - Ventral Tegmental Area Projection Neurons: Mapping Function to an Anatomically and Molecularly Distinct Neural Subpopulation

项目总结/摘要 糟糕的决策既是成瘾的原因，也是成瘾的后果。虽然眶额功能障碍 尽管人们认为大脑皮层（OFC）是成瘾者决策缺陷的基础，但基于回路的机制还没有被证实。 由于压倒性的功能异质性而被识别。初步的逆行标记实验表明， 单个眶额皮层投射神经元选择性地靶向皮层下结构，但尚不清楚这是否 解剖分离反映了劳动的功能分工和基本的皮层下分类原则。 结合功能遗传学和电生理学的最新技术，本研究的目的是 建议是将决策变量直接映射到OFC中的不同小区类型。拟议的目标将 测试中心假设，即不同的OFC输出神经元之间存在劳动分工，以及更多 具体地说，OFC到VTA投射神经元代表了一个有选择地路由选择不同输出通道 值在目标1中，我将确定单个神经元上OFC到VTA投射神经元的靶选择性 分辨率在目标2中，我将确定OFC-VTA投射神经元是否代表遗传上不同的细胞类型。在 目标3，我将在大鼠执行丰富的感知决策任务时提供细胞类型特异性记录， 确定OFC-VTA投射神经元在支持选择行为中的作用。这些研究有助于 对决策是如何计算的机械理解，并可能揭示出一个总体的，基本的 控制眶额皮层-皮层下信息分布的原则。拟议的研究奠定了 为成瘾中细胞类型特异性功能障碍的鉴定奠定了基础， 更有效的循环疗法最终，这个建议有助于我为职业生涯做好准备， 独立的物理学家和科学家我将获得一个独特的和多学科的技能，在未来， 我更好地弥合实验神经科学和临床实践之间的差距。

PROJECT SUMMARY/ABSTRACT Poor decision-making is both a cause and a consequence of addiction. Though dysfunction of the orbitofrontal cortex (OFC) is thought to underlie decision-making deficits in addicts, a circuit-based mechanism has not been identified due to overwhelming functional heterogeneity. Preliminary retrograde labelling experiments suggest that individual OFC projection neurons selectively target subcortical structures, but it is unknown if this anatomical separation mirrors a functional division-of-labor and a fundamental subcortical sorting principle. Integrating state-of-the-art techniques from functional genetics and electrophysiology, the objective of this proposal is to directly map a decision-making variable to a distinct cell-type in the OFC. The proposed aims will test the central hypothesis that that there is a division-of-labor between different OFC output neurons and more specifically, that OFC-to-VTA projection neurons represent a distinct output tract that selectively routes choice value. In Aim 1, I will determine the target selectivity of OFC-to-VTA projection neurons at a single neuron resolution. In Aim 2, I will determine if OFC-VTA projection neurons represent a genetically-distinct cell-type. In Aim 3, I will provide cell-type specific recordings in rats performing a rich, perceptual decision-making task and determine the role of OFC-VTA projection neurons in supporting choice behavior. These studies contribute to a mechanistic understanding of how decisions are computed and potentially, reveal an overarching, fundamental principle that governs cortical-subcortical information distribution in the OFC. The proposed studies lay the foundation for the identification of cell-type specific dysfunction in addiction and in future, the development of more effective, circuit-based therapies. Ultimately, this proposal serves to prepare me for a career as an independent physician-scientist. I will obtain a unique and multi-disciplinary skill-set that, in the future, will enable me to better bridge the gap between experimental neuroscience and clinical practice.