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.

项目摘要/摘要 决策既是成瘾的原因又是结果。轨道额的功能障碍 Cortex（OFC）被认为是成瘾者决策缺陷的基础，基于电路的机制尚未 由于压倒性的功能异质性而识别。初步逆行标签实验表明 该单独的OFC投影神经元选择性地靶向皮质下结构，但未知是否 解剖学分离反映了功能划分和基本的亚皮质分类原理。 整合功能遗传学和电生理学的最新技术，目的 建议是将决策变量直接映射到OFC中的不同单元格类型。拟议的目标将 测试中心假设，即不同的OFC输出神经元与更多的劳动 具体而言，OFC到VTA投影神经元代表了一个独特的输出道，可有选择地路由选择 价值。在AIM 1中，我将确定单个神经元处OFC-to-VTA投影神经元的靶标选择性 解决。在AIM 2中，我将确定OFC-VTA投影神经元是否代表了遗传学的细胞类型。在 AIM 3，我将在执行丰富的，感知的决策任务的大鼠中提供细胞类型的录音 确定C-VTA投影神经元在支持选择行为中的作用。这些研究有助于 对决策的计算方式的机械理解，揭示了总体，基本的 在OFC中控制皮质皮质信息分布的原理。拟议的研究是 鉴定成瘾和将来的细胞类型特定功能障碍的基础 更有效的基于电路的疗法。最终，该建议为我做好准备 独立的医师科学家。我将获得一个独特而多学科的技能，将来会启用 我更好地弥合了实验性神经科学和临床实践之间的差距。