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

项目总结 连接前额叶皮质(PFC)和边缘系统的回路内的功能障碍是导致 所有精神疾病，包括焦虑症。确定这些路径中的各个路径如何 驱动认知和情感的特定方面的电路功能将彻底改变我们对 精神障碍的生物学基础，并为精神障碍的特定途径治疗提供关键基础 人类。为了确定这些电路的功能，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。能够在中实现这一点 猴子将是基础神经科学研究的重大进步，也将有重大意义 翻译影响。这是因为猕猴PFC在细胞结构和 与人类PFC的联系，比任何其他可用的动物模型都要好。我们在猕猴身上发现的东西 可以直接翻译给人类，并对理解和 治疗精神疾病。我们在这里的目标是开发通路特定操作的使用 猴子的神经活动，并结合单个神经元的记录回答一个基本问题 与焦虑症的病理生理学有关的问题。焦虑症患者的神经影像研究 已观察到前额叶腹外侧区和杏仁核之间的功能障碍，但对此知之甚少 此回路对行为的特定贡献以及此回路内特定通路的作用。我们 假设PFC-杏仁核腹外侧部回路对于编码事件的概率是至关重要的 发生。此外，我们推测从杏仁核到腹外侧部的特定通路中的功能障碍。 PFC加剧了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、场电位记录和特定路径的创新组合 化学沉默，分析奖赏相关神经反应的时序(Aim1)和LFP 在正常生理条件下和杏仁核中神经元的同步性(目标2) 投射到腹外侧额叶皮质的神经元暂时受到抑制(目标3)。完成 这个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，以及提供杏仁核如何 影响结果概率表示。此外，实现该项目的目标不仅将 为焦虑症的病理生理学提供独特的见解，但它也将为 猴子大脑中神经活动的特定路径操纵。考虑到密切的通信 在人类和猴子的大脑之间，这些在猴子身上的实验是改进的必要的第一步 并评估这些技术在治疗人类焦虑症方面的潜在用途。

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.