Physiology and information processing of the OCD circuit

强迫症回路的生理学和信息处理

• 批准号: 10594000
• 负责人: Ilya E. Monosov
• 金额: $ 34.09万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-06-01 至 2027-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10594000
• 关键词: Adaptive Behaviors; Agonist; Algorithms; Anatomy; Animal Model; Animals; Anxiety; Area; Axon; Behavior; Behavior Control; Behavioral; Brain; Brain region; Clinical; Collaborations; Computer Analysis; Data; Decision Making; Dedications; Desire for food; Development; Electrophysiology (science); Event; Grant; Histologic; Human; Image Analysis; Incentives; Insula of Reil; Internal Capsule; Laboratories; Magnetic Resonance Imaging; Maps; Measures; Mediating; Mental disorders; Methods; Monkeys; Muscimol; Negative Reinforcements; Neurobiology; Neurons; Obsessive-Compulsive Disorder; Outcome; Pathology; Pathway interactions; Patients; Physiology; Play; Prefrontal Cortex; Procedures; Process; Property; Psyche structure; Psychological reinforcement; Publications; Rewards; Risk; Role; Symptoms; Uncertainty; Work; design; expectation; experimental study; in vivo; information processing; maladaptive behavior; mind control; motivated behavior; neural; neural circuit; neurotransmission; nonhuman primate; novel; novel therapeutics; optogenetics; therapy development; willingness

Project Summary (P2). The control of adaptive behavior, at its most fundamental level, relies on appropriately weighting the rewards and aversive outcomes, and deciding when to take a risk to maximize reward, and when to play it safe. Malfunctions in these processes are associated with psychiatric disorders and maladaptive behavioral states, such Obsessive-Compulsive Disorder (OCD) and anxiety. But despite their importance in everyday decision making and clinical settings, little is known about how aversive outcomes influence value- based decision making. In particular, in non-human primates, the closest animal model to humans, the neuronal mechanisms of how the brain evaluates and anticipates aversive events is poorly understood. P2 will (1) assess how the brain controls decision making under the risk and uncertainty of aversive outcomes in non- human primates and (2) in collaboration with other projects in the Conte Center, will utilize this information to shed light on the circuit mechanisms of, and novel therapies for, OCD and related pathologies. Aim 1 will utilize functionally targeted in-vivo anterograde tracing to identify regions within vlPFC, insula, and other regions that receive inputs from an area in ACC that has been functionally implicated in processing value and uncertainty of aversive outcomes. In the same animals, we will perform electrophysiological examinations of newly identified brain regions and assess whether and how they contribute to the processing of valuation, uncertainty, and receipt of aversive reinforcements. With P1, we will understand the relationship between functional properties of the OCD related brain areas and their anatomic connectivity. With P3-P5, we will relate single neuron data in non-human primates to ongoing therapy development and circuit mapping efforts in humans. Aim 2. will utilize a combination of computational and experimental methods to assess how the neural encoding of information about aversive reinforcements could give rise to OCD-like maladaptive behavior under aversive-outcome uncertainty. This Aim will utilize the probabilistic approach-avoidance task (PAAT), that we developed with P3, to determine the mental algorithms involved in aversive decision making under uncertainty and derive their neural underpinnings in the ACC-vlPFC-insula circuit. It will then disrupt the neural activity in identified sub regions of the circuit to obtain causal evidence for their contributions to specific aspects of behavioral control in PAAT. The unprecedented precision of single neuron recordings in this Aim will inform the interpretation of imaging data in other Projects. Furthermore, a wide range of direct manipulation methods for mediating OCD-related circuitry will be explored to facilitate the development of novel treatments for OCD in P5. In sum, these Center-integrated Aims represent crucial steps for our understanding of the neurobiology of OCD and more generally will broaden our understanding of the mechanisms of decision making. Particularly, in collaboration with other projects of the Center, they will shed light on how brain areas known to be crucially involved in OCD mediate our everyday decision making.

项目总结(P2)。对适应行为的控制，在其最基本的层面上，依赖于适当的 权衡回报和厌恶的结果，并决定何时冒险以最大化回报，以及何时 为了安全起见。这些过程中的故障与精神障碍和适应不良有关 行为状态，如强迫症(OCD)和焦虑。但尽管它们在 日常决策和临床环境中，人们对厌恶结果如何影响价值知之甚少。 基于决策的决策。特别是，在非人类灵长类动物中，最接近人类的动物模型 大脑如何评估和预测厌恶事件的神经机制还知之甚少。P2将 (1)评估在风险和不确定性的情况下，大脑是如何控制决策的 人类灵长类动物和(2)与孔特中心的其他项目合作，将利用这些信息 阐明了强迫症和相关病理的电路机制和新的治疗方法。目标1将 利用功能靶向的体内顺行追踪来识别VLPFC、岛和其他区域 从ACC中的某个区域接收输入的区域，该区域在功能上与处理价值和 令人厌恶的结果的不确定性。在相同的动物身上，我们将进行电生理检查 新识别的大脑区域，并评估它们是否以及如何对估值过程做出贡献， 不确定性，以及收到令人厌恶的增援部队。有了P1，我们将了解到 强迫症相关脑区的功能特性及其解剖连接。通过P3-P5，我们将与 非人灵长类动物的单个神经元数据对正在进行的治疗开发和电路映射的努力 人类。目标2.将利用计算和实验相结合的方法来评估 对厌恶强化信息的神经编码可能导致类似强迫症的适应不良行为 在令人厌恶的结果不确定性下。该目标将利用概率接近-避免任务(PAAT)， 这是我们用P3开发的，用来确定在以下情况下涉及厌恶决策的心理算法 不确定性，并推导出它们在ACC-VLPFC-IASI电路中的神经基础。然后它会扰乱神经 在已确定的巡回分区中的活动，以获得其对特定区域贡献的因果证据 帕特的行为控制方面。在这个目标上，单个神经元记录的前所未有的精确度将 通知其他项目中成像数据的解释。此外，广泛的直接操纵 将探索调节强迫症相关回路的方法，以促进新治疗方法的开发 对于P5中的强迫症。总而言之，这些与中心整合的目标是我们理解 强迫症的神经生物学以及更广泛的意义将拓宽我们对决策机制的理解 制作。特别是，与该中心的其他项目合作，他们将阐明大脑区域是如何 众所周知，强迫症是我们日常决策的中介人。