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: 9912827
• 负责人: Peter Rudebeck
• 金额: $ 42.38万
• 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 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9912827
• 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.

项目摘要 连接前额叶皮层（PFC）和边缘系统的电路中的功能障碍是几乎 每种精神病病，包括焦虑症。确定在这些中的单个途径 电路的功能来推动认知和影响的特定方面，将彻底改变我们对 精神疾病的生物学基础，为途径特定治疗的关键基础 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性。这样做的能力 猴子将是基本神经科学研究的重大进步，也将具有重要的 翻译影响。这是因为猕猴PFC在其细胞结构及其 与任何其他可用动物模型相比，与人类PFC的联系。我们在猕猴中发现了什么 可以直接转化为人类，并且对理解和 精神疾病的治疗。我们的目标是开发使用途径的特定操作 猴子的神经活动，并将它们与单个神经元的录音相结合以回答基本 与焦虑症的病理生理有关的问题。神经影像学研究焦虑的人 疾病已经观察到腹外侧PFC和杏仁核之间的功能障碍，但对此一无所知 该电路对行为的特定贡献以及该电路中特定途径的作用。我们 假设腹外侧PFC-Amygdala电路对于编码事件的可能性至关重要 发生。此外，我们将从杏仁核到腹外侧的特定途径内的功能障碍理论化 PFC增加了与发生负面结果的可能性有关的焦虑。为了检验我们的假设我们 将使用单神经元记录，现场潜在记录和特定途径的创新组合 化学发生沉默，分析与奖励相关的神经反应的时间（AIM1）和LFP 在正常生理条件下和杏仁核中的神经元时，该电路内的同步（目标2） 该专门向腹外侧前额叶皮层的投射被瞬时抑制（AIM 3）。完成 该项目的目的将从根本上促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的途径的特定理解 影响结果概率表示。此外，实现该项目的目标不仅将 提供有关焦虑症的病理生理学的独特见解，但也将为 途径对猴子大脑神经活动的特定操纵。给定紧密的通信 在人类和猴子的脑之间，猴子中的这些实验是精炼的必要第一步 并评估这些技术的潜在用途来治疗焦虑症的人。

项目成果

Interaction between decision-making and interoceptive representations of bodily arousal in frontal cortex.

• DOI: 10.1073/pnas.2014781118
• 发表时间: 2021-08-31
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Fujimoto A;Murray EA;Rudebeck PH
• 通讯作者: Rudebeck PH

Specialized Representations of Value in the Orbital and Ventrolateral Prefrontal Cortex: Desirability versus Availability of Outcomes.

眼眶和腹外侧前额叶皮层价值的专门表示：结果的可取性与可用性。

• DOI: 10.1016/j.neuron.2017.07.042
• 发表时间: 2017
• 期刊: Neuron
• 影响因子: 16.2
• 作者: Rudebeck,PeterH;Saunders,RichardC;Lundgren,DawnA;Murray,ElisabethA
• 通讯作者: Murray,ElisabethA

Trust, but verify: A cautionary tale of translating chemogenetic methods (A commentray on Galvan et al).

信任，但要验证：转化化学遗传学方法的警示故事（Galvan 等人的评论）。

• DOI: 10.1111/ejn.14496
• 发表时间: 2019
• 期刊: The European journal of neuroscience
• 作者: Fredericks,JMegan;Fujimoto,Atsushi;Rudebeck,PeterH
• 通讯作者: Rudebeck,PeterH

Specializations for reward-guided decision-making in the primate ventral prefrontal cortex.

• DOI: 10.1038/s41583-018-0013-4
• 发表时间: 2018-07
• 期刊: Nature reviews. Neuroscience
• 作者: Murray EA;Rudebeck PH
• 通讯作者: Rudebeck PH

Heightened Defensive Responses Following Subtotal Lesions of Macaque Orbitofrontal Cortex.

猕猴眶额皮质次全损伤后防御反应增强。

• DOI: 10.1523/jneurosci.2812-18.2019
• 发表时间: 2019
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Pujara,MaiaS;Rudebeck,PeterH;Ciesinski,NicoleK;Murray,ElisabethA
• 通讯作者: Murray,ElisabethA