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

项目摘要/摘要 糟糕的决策既是上瘾的原因，也是上瘾的后果。尽管眼眶前额功能障碍 大脑皮质(OFC)被认为是成瘾者决策缺陷的基础，但基于电路的机制尚未得到证实 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OFC投射神经元选择性地以皮质下结构为靶点，但尚不清楚这是否 解剖分离反映了功能分工和基本的皮质下分选原则。 结合功能遗传学和电生理学的最新技术，这项研究的目标是 建议将决策变量直接映射到OFC中的不同单元类型。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分工等 具体地说，OFC到VTA投射神经元代表选择性地路由选择的不同的输出区域 价值。在目标1中，我将确定OFC到VTA投射神经元在单个神经元上的靶点选择性 决议。在目标2中，我将确定OFC-VTA投射神经元是否代表一种遗传上不同的细胞类型。在……里面 目标3，我将提供执行丰富的知觉决策任务的大鼠的细胞类型特定记录，并 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 机械地理解决策是如何计算的，并潜在地揭示了一个总体的、基本的 管理OFC中皮质-皮质下信息分布的原则。拟议的研究奠定了 成瘾中细胞类型特异性功能障碍的识别基础和未来的发展 更有效的、基于电路的疗法。最终，这项提议为我的职业生涯做好了准备 独立的医生兼科学家。我将获得一套独特的多学科技能，在未来，这将使 我希望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.