Neural encoding of associative learning by orbitofrontal cortex circuits

眶额皮层回路联想学习的神经编码

• 批准号: 10249362
• 负责人: Vijay Mohan K Namboodiri
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10249362
• 关键词: Address; Advisory Committees; Affect; Animals; Anxiety; Attention deficit hyperactivity disorder; Axon; Behavior; Behavioral; Brain; Cues; Data; Decision Making; Disease; Distal; Electrophysiology (science); Elements; Evolution; Faculty; Functional disorder; Future; Goals; Head; Health; Image; Impairment; Impulsivity; Institution; Interneurons; Learning; Light; Major Depressive Disorder; Maps; Measures; Medial; Mediating; Methods; Mus; Nature; Neurons; Obsessive compulsive behavior; Obsessive-Compulsive Disorder; Operant Conditioning; Outcome; Output; Parvalbumins; Pathway interactions; Pattern; Phase; Positioning Attribute; Prefrontal Cortex; Rattus; Research; Rest; Rewards; Role; Schizophrenia; Somatostatin; Stimulus; Structure; Synapses; System; Techniques; Thalamic structure; Training; Ventral Tegmental Area; addiction; base; cell type; classical conditioning; discounting; experimental study; flexibility; imaging genetics; insight; neural circuit; neuropsychiatric disorder; optogenetics; outcome prediction; patch clamp; relating to nervous system; response; virus genetics

Project Summary/Abstract | Neural encoding of associative learning by orbitofrontal cortex circuits Dysfunction of the orbitofrontal cortex (OFC) can cause impulsive decision-making, and is implicated in neuropsychiatric disorders including addiction, obsessive compulsive disorder, major depression, attention deficit hyperactivity disorder and schizophrenia. Nevertheless, the function of OFC neural circuits, and how their impairment relates to these disorders is unknown. Impulsive decision-making is characterized by an inability to optimize decisions based on their predicted outcome. It may thus arise due to the dysfunction of both Pavlovian systems, which learn stimulus-outcome associations, and instrumental systems, which learn stimulus-action- outcome associations. OFC is thought to convey both these types of associations, including to the ventral tegmental area (VTA)—a key regulator of learning. Thus, impulsive decision-making may be a consequence of differential aberrations in these learning systems within OFC. Hence, understanding how these associations are learned and maintained by OFC neural circuits may be fundamental to unraveling its function in health and disease. To understand how genetically or projection-defined neurons learn and maintain information, it is imperative to longitudinally track the evolution of their activity during and after learning. Recent state-of-the-art imaging and genetic/viral methods have now made this possible. Using these techniques, I present pilot data demonstrating that I have longitudinally tracked the activity of thousands of OFC neurons, including those projecting to VTA, as mice learned the associations between stimuli and rewards. However, whether the activity patterns uncovered in these experiments are relayed onto these OFC output neurons from elsewhere, or are a product of local computation is unknown. Hence, I first propose to study how input from the medial thalamus, a structure shown to encode associative information, is integrated by the OFC circuit to affect output activity. As part of this goal, I will train to perform patch-clamp electrophysiology in the first aim to establish functional connectivity of this input with specific genetically and projection-defined cell types within OFC. In the second aim, I will optogenetically silence the medial thalamus-to-OFC pathway while longitudinally tracking response evolution of VTA projecting OFC neurons during the learning of stimulus-reward associations. Lastly, I propose to transition my independent research to study how specific cell-types in OFC learn instrumental associations to guide decision-making, through a delay discounting task often used to measure impulsivity. Given my graduate training in rat instrumental behavior and theoretical background in intertemporal decision-making, these proposed aims will help me establish a unique line of research. Further, the technical and managerial training gathered during the K99 phase, and the support of my advisory committee and institution, will help me transition to an independent faculty position in academic research.

项目摘要/摘要|眼眶前额叶回神经编码的联想学习 眼眶前额叶皮质(OFC)功能障碍可导致冲动决策，并与 神经精神障碍包括成瘾、强迫症、严重抑郁、注意力 缺陷多动障碍和精神分裂症。然而，OFC神经回路的功能以及它们是如何 与这些障碍相关的损害尚不清楚。冲动决策的特征是不能 根据预测结果优化决策。因此，它可能是由于两个巴甫洛夫人的功能障碍引起的 学习刺激-结果关联的系统，以及学习刺激-行动的工具性系统- 结果关联。OFC被认为传递了这两种类型的联系，包括腹侧 被盖区(VTA)--学习的关键调节器。因此，冲动的决策可能是 OFC内这些学习系统中的差动像差。因此，了解这些关联是如何 OFC神经回路的学习和维持可能是解开其健康和健康功能的基础 疾病。为了了解基因或投射定义的神经元是如何学习和维护信息的， 必须纵向跟踪他们在学习过程中和学习后活动的演变。最新最先进的技术 成像和遗传/病毒方法现在已经使这成为可能。使用这些技术，我展示了试点数据 证明我已经纵向跟踪了数千个OFC神经元的活动，包括那些 投射到VTA，因为小鼠学会了刺激和奖励之间的联系。然而，无论活动是否 在这些实验中发现的模式被从其他地方传递到这些OFC输出神经元上，或者是一个 局部计算的乘积未知。因此，我首先提议研究来自内侧丘脑的输入是如何 显示为编码关联信息的结构由OFC电路集成以影响输出活动。AS 作为这个目标的一部分，我将训练执行膜片钳电生理学的第一个目标是建立功能 这一输入与OFC内特定的遗传和投影定义的细胞类型的连接性。在第二个 目的：在纵向追踪反应的同时，我将光基因沉默丘脑内侧到OFC的通路 VTA投射OFC神经元在学习刺激-奖赏联系过程中的演变。最后，我建议 将我的独立研究转变为研究OFC中特定的细胞类型如何学习工具性联系 通过通常用来衡量冲动程度的延迟贴现任务来指导决策。考虑到我的毕业生 训练大鼠的工具性行为和跨期决策的理论背景 提议的AIMS将帮助我建立一条独特的研究路线。此外，技术和管理培训 在K99阶段收集的，以及我的咨询委员会和机构的支持，将帮助我过渡 在学术研究中担任独立的教职。