A new approach to the role of prefrontal-limbic circuits in anxiety disorders

前额叶边缘环路在焦虑症中作用的新方法

• 批准号: 9461437
• 负责人: Peter Rudebeck
• 金额: $ 6.2万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9461437
• 关键词: Adult; Affect; Amygdaloid structure; Anatomy; Animal Model; Anxiety; Anxiety Disorders; Behavior; Behavioral; Biological; Brain; Cognition; Data; Event; Foundations; Functional disorder; Goals; Human; Individual; Knowledge; Lead; Limbic System; Link; Macaca; Mental Health; Mental disorders; Methods; Monkeys; Neural Pathways; Neurons; Neurosciences Research; Outcome; Pathway interactions; Physiological; Population; Prefrontal Cortex; Primates; Probability; Psychiatric therapeutic procedure; Research; Rewards; Role; Signal Pathway; Signal Transduction; Specificity; Stimulus; Structure; Techniques; Testing; Translating; Translational Research; Translations; Uncertainty; Work; base; density; experimental study; improved; innovation; insight; neural patterning; neuroimaging; neuromechanism; nonhuman primate; novel strategies; relating to nervous system; response; translational impact; visual stimulus

Project summary Dysfunction within the circuits connecting the prefrontal cortex (PFC) and limbic system is the cause of nearly every psychiatric condition, including anxiety disorders. Determining how individual pathways within these circuits function to drive specific aspects of cognition and affect would revolutionize our understanding of the biological bases of psychiatric disorders and provide the critical foundation for pathway-specific treatments in humans. In order to establish the function of these circuits, we must be able to characterize and manipulate the activity of distinct neural pathways that connect the prefrontal and limbic system. The ability to do this in monkeys would be a major advance in basic neuroscience research and would also have significant translational impact. This is because the macaque PFC is more similar, in both its cytoarchitecture and its connections, to the human PFC than that of any other available animal model. What we discover in macaques can be directly translated to humans and have the greatest possible bearing on the understanding and treatment of psychiatric disorders. Our goal here is to develop the use of pathway specific manipulations of neural activity in monkeys and to combine them with recordings of single neurons to answer a fundamental question relating to the pathophysiology of anxiety disorders. Neuroimaging studies of people with anxiety disorders have observed dysfunction between the ventrolateral PFC and amygdala, but little is know about the specific contribution of this circuit to behavior and the role of specific pathways within this circuit. We hypothesize that the ventrolateral PFC-amygdala circuit is vital for encoding the probability that an event will occur. Furthermore, we theorize that dysfunction within the specific pathway from amygdala to ventrolateral PFC heightens anxiety related to the likelihood that a negative outcome will occur. To test our hypothesis we will use an innovative combination of single-neuron recordings, field potential recordings, and pathway specific chemogenetic silencing, analyzing the timing of reward-related neural responses (Aim1) and the LFP synchrony (Aim 2) within this circuit under normal physiological conditions and when neurons in the amygdala that specifically project to the ventrolateral prefrontal cortex are transiently inhibited (Aim 3). Completing the aims of this project will fundamentally advance our understanding of the neural pathways and mechanisms involved in representing uncertainty as well as providing a pathway specific understanding of how amygdala influences outcome probability representations. In addition, achieving the aims of this project will not only provide unique insights into the pathophysiology of anxiety disorders, but it will also lay the foundation for pathway specific manipulations of neural activity in the monkey brain. Given the close correspondence between the human and monkey brains, these experiments in monkeys are a necessary first step to refining and evaluating the potential use of these techniques to treat humans with anxiety disorders.

项目概要 连接前额皮质 (PFC) 和边缘系统的回路功能障碍是近乎 各种精神疾病，包括焦虑症。确定这些路径中的各个路径如何 电路的功能是驱动认知和情感的特定方面，这将彻底改变我们对事物的理解 精神疾病的生物学基础，并为路径特异性治疗提供关键基础 人类。为了建立这些电路的功能，我们必须能够表征和操纵 连接前额叶和边缘系统的不同神经通路的活动。有能力做到这一点 猴子将是基础神经科学研究的重大进步，也将具有重大意义 翻译影响。这是因为猕猴 PFC 在细胞结构和结构上都更加相似。 与人类 PFC 的连接优于任何其他可用的动物模型。我们在猕猴身上发现了什么 可以直接翻译给人类，并对理解和理解产生最大可能的影响 精神疾病的治疗。我们的目标是开发路径特异性操作的使用 猴子的神经活动，并将其与单个神经元的记录相结合，以回答一个基本问题 有关焦虑症病理生理学的问题。焦虑症患者的神经影像学研究 已经观察到腹外侧 PFC 和杏仁核之间存在功能障碍，但人们对其中的机制知之甚少。 该回路对行为的具体贡献以及该回路内特定路径的作用。我们 假设腹外侧 PFC-杏仁核回路对于编码事件发生的概率至关重要 发生。此外，我们推测从杏仁核到腹外侧的特定通路内的功能障碍 PFC 会加剧与发生负面结果的可能性相关的焦虑。为了检验我们的假设，我们 将使用单神经元记录、场电位记录和特定通路的创新组合 化学遗传学沉默，分析奖励相关神经反应 (Aim1) 和 LFP 的时间 在正常生理条件下以及当杏仁核中的神经元 专门投射到腹外侧前额叶皮层的神经元被暂时抑制（目标 3）。完成 该项目的目标将从根本上增进我们对神经通路和机制的理解 参与表示不确定性以及提供对杏仁核如何进行特定途径的理解 影响结果概率表示。此外，实现该项目的目标不仅 为焦虑症的病理生理学提供了独特的见解，但也将为 猴脑神经活动的通路特异性操作。鉴于密切的对应关系 在人类和猴子的大脑之间，这些在猴子身上进行的实验是完善大脑的必要的第一步 并评估这些技术治疗人类焦虑症的潜在用途。