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: 10411708
• 负责人: Ilya E. Monosov
• 金额: $ 35.33万
• 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/10411708
• 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; Desire for food; Development; Electrophysiology (science); Event; Grant; Histologic; Human; Image Analysis; Incentives; Insula of Reil; Internal Capsule; Laboratories; Light; Magnetic Resonance Imaging; Measures; Mediating; Mental disorders; Methods; Monkeys; Muscimol; Negative Reinforcements; Neurobiology; Neurons; Obsessive-Compulsive Disorder; Outcome; Pathology; Pathway interactions; Patients; Physiology; Play; Procedures; Process; Property; Psyche structure; Psychological reinforcement; Publications; Rewards; Risk; Role; Signal Transduction; Sum; Symptoms; Uncertainty; Weight; Work; base; design; expectation; experimental study; in vivo; information processing; maladaptive behavior; mind control; motivated behavior; neural circuit; nonhuman primate; novel; novel therapeutics; optogenetics; relating to nervous system; 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.

项目摘要（P2）。在最基本的层面上，对适应性行为的控制依赖于适当的 加重奖励和厌恶结果，并决定何时冒险以最大化奖励，以及何时 要安全起见。这些过程中的故障与精神疾病和适应不良有关 行为状态，这种强迫症（OCD）和焦虑。但是尽管它们的重要性 每天的决策和临床环境，关于厌恶结果如何影响价值 - 基于决策。特别是，在非人类灵长类动物中，最接近人类的动物模型， 大脑如何评估和预期厌恶事件的神经元机制知之甚少。 P2会 （1）评估大脑如何控制非厌恶结果的风险和不确定性的决策 人类灵长类动物和（2）与孔戴中心的其他项目合作，将使用此信息来 阐明了OCD和相关病理的电路机理和新型疗法。目标1意志 利用具有功能的靶向体内迁移跟踪来识别VLPFC，Insula和其他内部的区域 从ACC领域接收输入的区域在功能上与处理值有关 厌恶结果的不确定性。在同一动物中，我们将进行电生理检查 新确定的大脑区域并评估它们是否以及如何贡献估值的处理， 不确定性和厌恶增强的接收。使用P1，我们将了解 强迫症相关的大脑区域的功能特性及其解剖连通性。使用P3-P5，我们将与 非人类灵长类动物中的单个神经元数据，用于正在进行的治疗开发和电路映射工作 人类。 AIM 2。将利用计算和实验方法的组合来评估如何评估 有关厌恶增强的信息的神经编码可能导致OCD样不良适应性行为 在厌恶的不确定性下。这个目标将利用概率避免方法任务（PAAT）， 我们使用P3开发的，以确定在厌恶决策中所涉及的心理算法 不确定性并在ACC-VLPFC-insula电路中得出其神经基础。然后会破坏神经 电路的确定子区域的活动，以获得其对特定的贡献的因果证据 PAAT行为控制的各个方面。在此目标中，单个神经元记录的前所未有的精度 告知其他项目中成像数据的解释。此外，多种直接操作 将探索介导与强迫症相关电路的方法，以促进新治疗的发展 对于P5中的强迫症。总而言之，这些中心集成的目标代表了我们对人的理解的关键步骤 强迫症的神经生物学以及更广泛的神经生物学将扩大我们对决策机制的理解 制作。特别是，与中心其他项目合作，他们将阐明大脑区域 众所周知，在强迫症中至关重要的是调解我们的日常决策。