场景调节恐惧焦虑行为的神经机理

Extinction is a behavior phenomenon that allows for adaptive decreases in conditioned responses. It is an active form of learning such that conditioned responses to a conditional stimulus (CS) decrease because of the omission of an unconditional stimulus (US). This kind of adaptive control in behaviors is necessary to constantly update the perception for the danger, safety and reward in the environment and is essential for individual’s survival. It has been studied for almost a century since Pavlov’s classic study of conditioned responses in dogs. To date, fear extinction is being extensively studied as an animal behavioral model because of its huge clinical relevance. Extinction-based exposure therapies are indeed effective for the treatment of post-traumatic stress disorder (PTSD) but it often relapses in different environments (contexts) because fear extinction is context specific. Therefore, it is of high importance to investigate neural circuit mechanisms underlying context specificity of fear extinction, with aim to enhance current therapeutic treatments of anxiety disorders..The extinction memory is believed to be distributed across a large-scale networks of brain structures such as amygdala, hippocampus and prefrontal cortex. The hippocampus is a key brain structure processing the contextual information and interacting with amygdala and other brain areas involved in the fear learning and memory. The synaptic connections between neurons in the neural circuits are the key to understand the circuit mechanism, and the recently developed viral-mediated trans-synaptic tracing technique is instrumental to selectively reveal these circuit elements based on their connectivity in the neural network. My prior work demonstrated that hippocampal projection cells directly target output neurons in central amygdala by using rabies-mediated trans-synaptic tracing. These findings suggest that the projection from hippocampus to central amygdala could play an important role for contextual modulation of fear responses during fear extinction. Therefore, I propose to address these questions by combining state-of-art in vivo imaging techniques, viral-mediated trans-synaptic tracing and the behavioral model of fear extinction. The core idea of this proposal is to record the activity of the same population of neurons (defined by trans-synaptic tracing) simultaneously across different contexts and behavior sessions. I will combine GCamP6-based Ca2+ imaging with retrograde trans-synaptic tracing from central amygdala to hippocampus. On top of that, I will employ miniscope to perform in vivo imaging in hippocampus in order to dissect circuit mechanisms for context specificity of fear extinction. Eventually, I want to exploit this approach in order to explore methods to strengthen or generalize extinction memory and hope to shed light onto current therapeutic treatments of anxiety disorders.

现代社会的很多人在工作生活中不堪压力而表现出焦虑抑郁症状，其中突发性事件带来的影响尤为巨大，甚至导致创伤后遗症。暴露疗法广泛应用于对创伤后遗症的临床治疗，但当患者处在治疗场景之外时，恐惧症状常会复发。因此场景如何调节恐惧行为是一个亟需解答的科学问题，也具有重要的临床意义。申请人在以往的工作中运用恐惧复发的小鼠行为学范式，发现海马脑区到杏仁核脑区的通路发挥着重要作用，揭示了海马到杏仁核的神经环路在场景对恐惧焦虑的行为调控中的重要性。本项目将运用恐惧消退(Fear Extinction)的行为学范式，研究海马投射到杏仁核的神经环路在恐惧消退过程中的功能作用。我们将结合现代的跨突触的环路追踪技术、光遗传、光学成像和电生理技术，精细解析相关的神经环路结构和功能。我们还会探索人工改变这个神经环路的突触联系的方法，从而扩大恐惧消退训练的效果。这些研究将为临床治疗创伤后遗症提供新的靶点和思路。

现代社会的人在工作生活中面临压力，很多表现出焦虑抑郁症状；其中突发性事件带来的影响尤为巨大，甚至导致创伤后遗症。暴露疗法广泛应用于对创伤后遗症的临床治疗，但当患者处在治疗场景之外时，恐惧症状常会复发。因此场景如何调节恐惧行为是一个亟需解答的科学问题，也具有重要的临床意义。海马脑区被认为处理场景信息的关键脑区，但海马内环路处理场景信息的机制并不清楚。综上，本项目从几下方面进行研究并取得了重要进展：.（A）精细解析海马脑区投射神经元的输入和输出。(B)解析海马内环路（dCA3-vCA1长轴环路）在场景恐惧学习记忆当中的功能作用。 (C) 建立场景认知相关的自由活动和VR两大类的行为范式。（D）建立使用超微显微镜大规模记录海马神经元的技术方法，运用超微显微镜大批量记录CA1神经活动。（E）研究海马脑区调节恐惧记忆形成、消退和复发的神经机制。.我们发现：（1）CA1主要的中间神经元类型都接收CA3的输入，锥体细胞接收更多来自于感觉皮层信息的输入。（2）海马长轴环路dCA3-vCA1是连接背腹侧海马的重要环路，在恐惧记忆形成过程中发挥着重要功能，并且是场景信息与恐惧关联的起点。（3）在VR精确控制场景单一信息的缺失时，动物对场景认知具有很强的模式补全特性。（4）海马vCA1细胞在声音恐惧记忆当中对声音等基本感觉信息的编码受到场景调节的神经机制。即vCA1细胞对同一声音的信号编码在不同场景下截然不同。.本项目所支持的研究不仅开发了新的VR实验系统，还首次鉴定和解析了海马长轴内环路在场景记忆形成当中的环路机制，并且阐明了海马vCA1细胞编码恐惧记忆当中场景依赖特性的神经机制。这为临床治疗创伤后遗症等病症提供了新的靶点和思路。