Neural encoding of associative learning by orbitofrontal cortex circuits

项目概要/摘要|利用眶额皮层回路进行联想学习的神经编码 眶额皮质（OFC）的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、重性抑郁症、注意力 缺陷多动症和精神分裂症。尽管如此，OFC神经回路的功能，以及它们如何在大脑中发挥作用， 与这些疾病有关的损害是未知的。冲动性决策的特点是无法 根据预测结果优化决策。因此，它可能是由于巴甫洛夫神经元和神经元的功能障碍引起的。 学习刺激-结果关联的系统，以及学习刺激-行动的工具系统， 结果关联。眶额皮层被认为传递这两种类型的联系，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中这些学习系统的差异畸变。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揭示其健康功能的基础， 疾病为了理解遗传或投射定义的神经元如何学习和维持信息， 必须纵向跟踪他们在学习期间和学习之后的活动演变。最新技术水平 成像和遗传/病毒方法现在使这成为可能。使用这些技术，我提出试点数据 这表明我已经纵向追踪了数千个眶额皮层神经元的活动，包括那些 投射到腹侧被盖区，因为小鼠学习了刺激和奖励之间的联系。然而，活动是否 在这些实验中发现的模式是从其他地方传递到这些OFC输出神经元上的，或者是一种 局部计算的乘积是未知的。因此，我首先建议研究来自内侧丘脑的输入， 被示出为编码关联信息的结构被OFC电路集成以影响输出活动。作为 这一部分的目标，我将培训，以执行膜片钳电生理学的第一个目标，建立功能 这种输入与OFC内特定的遗传和投影定义的细胞类型的连接性。在第二 目的是，我将光遗传学沉默内侧丘脑-OFC通路，同时纵向跟踪响应 VTA投射OFC神经元在学习刺激-奖励关联过程中的进化。最后，我建议 将我的独立研究转移到研究OFC中的特定细胞类型如何学习工具性关联， 通过一个经常用来衡量冲动性的延迟折扣任务来指导决策。鉴于我的毕业 大鼠工具行为的训练和跨期决策的理论背景，这些 提出的目标将帮助我建立一个独特的研究路线。此外，技术和管理培训 在K99阶段聚集的各位，以及我的顾问委员会和机构的支持，将帮助我过渡 在学术研究中获得独立教职

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.