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

项目摘要 连接前额叶皮层（PFC）和边缘系统的回路功能障碍是导致几乎 包括焦虑症在内的所有精神疾病确定其中的各个途径 电路的功能，以驱动特定方面的认知和影响，将彻底改变我们的理解， 精神疾病的生物学基础，并为特定途径治疗提供关键基础， 人类为了建立这些电路的功能，我们必须能够表征和操纵这些电路。 连接前额叶和边缘系统的不同神经通路的活动。能够在 猴子将是基础神经科学研究的一个重大进展， 翻译影响这是因为猕猴前额叶皮层在细胞结构和 连接，人类PFC比任何其他可用的动物模型。我们在猕猴身上发现的 可以直接翻译给人类，并有最大可能的影响， 精神疾病的治疗。我们的目标是开发使用的途径特异性操纵的 神经活动，并将其与单个神经元的记录相结合，以回答一个基本的问题。 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学研究 已经观察到腹外侧PFC和杏仁核之间的功能障碍，但对 该回路对行为的特定贡献以及该回路中特定通路的作用。我们 我假设腹外侧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，我们的理论认为，从杏仁核到腹外侧核的特定通路中的功能障碍 前额叶皮层会加剧与消极结果发生的可能性相关的焦虑。为了验证我们的假设， 将使用单神经元记录，场电位记录和通路特异性的创新组合， 化学基因沉默，分析奖励相关神经反应（Aim 1）和LFP的时间 在正常生理条件下，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推进我们对神经通路和机制的理解 参与代表不确定性，以及提供一个具体的途径，了解如何杏仁核 影响结果概率表征。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了独特的见解，但它也将奠定基础， 猴子大脑中神经活动的特定途径操纵。考虑到他们之间 在人类和猴子的大脑之间，这些在猴子身上的实验是必要的第一步， 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.