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

眶额皮层 - 腹侧被盖区投影神经元：将功能映射到解剖学和分子上不同的神经亚群

• 批准号: 10405473
• 负责人: Suelynn Ren
• 金额: $ 5.18万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10405473
• 关键词: Affinity Chromatography; Anatomy; Architecture; Automobile Driving; Characteristics; Choice Behavior; Clinical; Complex Variables; Decision Making; Development; Electrophysiology (science); Foundations; Functional disorder; Future; Genetic; Genetic Markers; Goals; Heterogeneity; Individual; Information Distribution; Label; Learning; Maps; Mental disorders; Molecular; Multiplexed Analysis of Projections by Sequencing; Neurons; Neurosciences; Neurotransmitter Receptor; Optics; Output; Physicians; Population; Population Projection; Positioning Attribute; Process; Psychiatry; Rattus; Resolution; Rewards; Ribosomes; Role; Route; Satiation; Scientist; Sensory; Site; Sorting - Cell Movement; Source; Stream; Structure; System; Techniques; Testing; Tracer; Training; Translating; Uncertainty; Update; Ventral Tegmental Area; addiction; barrier to care; base; career; cell cortex; cell type; classical conditioning; clinical practice; dopamine system; dopaminergic neuron; drug of abuse; experimental study; fluorophore; molecular phenotype; multidisciplinary; neuroeconomics; neuroregulation; relating to nervous system; skills; sobriety; therapeutic development; therapeutic target; treatment adherence; uptake

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.

项目概要/摘要 糟糕的决策既是成瘾的原因，也是成瘾的结果。虽然眶额功能障碍 皮层（OFC）被认为是成瘾者决策缺陷的根源，但基于电路的机制尚未被证实 由于压倒性的功能异质性而被识别。初步逆行标记实验表明 单个 OFC 投射神经元选择性地针对皮层下结构，但尚不清楚这是否 解剖学上的分离反映了功能上的分工和基本的皮质下分类原则。 整合功能遗传学和电生理学的最先进技术，该项目的目标 建议是将决策变量直接映射到 OFC 中的不同细胞类型。拟议的目标将 检验中心假设，即不同 OFC 输出神经元之间存在分工等等 具体来说，OFC 到 VTA 的投射神经元代表了一个独特的输出束，可以选择性地路由选择 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目标选择性 解决。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，我将提供执行丰富的感知决策任务的大鼠的细胞类型特异性记录，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 对决策如何计算的机械理解，并可能揭示一个总体的、基本的 控制 OFC 中皮质-皮质下信息分布的原则。拟议的研究奠定了 为识别成瘾中细胞类型特异性功能障碍奠定了基础，并在未来开发 更有效的基于回路的疗法。最终，这个建议有助于我为职业生涯做好准备 独立医师科学家。我将获得独特的多学科技能，将来能够 我更好地弥合实验神经科学和临床实践之间的差距。