Neuronal Mechanisms for Fear Memory Generalization in PTSD and Anxiety Disorders

描述(申请人提供)：创伤后应激障碍(PTSD)和其他一些焦虑症表现为恐惧记忆的过度泛化，这些记忆源于创伤经历，但现在适用于非危险情况。决定记忆精确度和概括性程度的神经机制在很大程度上是未知的，这种理解的缺乏阻碍了有效治疗的发展。在此之前，我观察到在内侧前额叶皮质或海马体的功能性操作后，过度泛化的背景恐惧记忆。此外，我还发现，在解剖上连接前额叶皮质和海马体的丘脑中线核团也起着至关重要的作用。投射到统一核的前额叶神经元的选择性失活或联合核内神经元的直接失活会产生过度泛化，而联合核内神经元活动的增加则会减少恐惧的泛化。这些观察得出了我的假设：在大脑中，有一个双向调节恐惧记忆泛化水平的调节系统，这个系统由前额叶皮质、重新连接核和海马体之间的回路组成。前额叶皮质和联合核的低活动减少了海马区对与特定恐惧记忆相关的细节的表征，并导致过度泛化，如创伤后应激障碍和焦虑；而增加前额叶皮质和联合核的活动水平将下调恐惧泛化水平，并提供治疗益处。在这项建议的指导阶段，我将系统地研究这三个大脑结构在决定恐惧概化水平方面的作用，以及这些大脑结构之间在编码或提取恐惧记忆方面的功能关系。因为我的初步数据表明，恐惧泛化是由一个子集而不是整个前额叶神经元组成的，所以我将确定与恐惧泛化调控有关的特定前额叶神经元亚群，并用高通量RNA测序技术揭示它们的遗传身份。基于上述信息，在独立的阶段，I将对特定的前额神经元群进行详细的功能表征，包括它们的解剖联系、电生理特性和基因表达谱。我将测试这些属性的变化是否会导致恐惧、记忆过度泛化和焦虑。这项拟议中的研究的成功完成将为一种深刻的认知功能--记忆精确度/概括性的确定--提供一个机械的解释，从而为缓解焦虑的有效疗法开辟新的途径。就事业而言，我对一家学术机构的神经科学研究感兴趣，该机构的长期目标是揭示基本认知功能背后的神经机制，并利用由此获得的信息来治疗大脑疾病。我将主要关注但不限于内存功能的各个方面。到目前为止，神经科学在细胞和分子神经生物学以及人类认知神经科学领域已经取得了长足的进步；然而，连接这两个末端的研究却落后了。我认为，对负责认知功能的神经元回路进行详细的功能剖析，是当今神经科学的关键。因此，我未来5-10年的近期目标将是详细描述前额叶皮质-丘脑通路的连通性和功能特性，并阐明它们在各种认知功能中的作用，如本文提出的那些。我最初接受的是临床医学方面的培训，然后接受了神经科学方面的科学培训。我在分子和细胞神经生物学方法和系统神经科学技术方面都有丰富的经验，这使我成为拟议研究的理想人选。目前提案的第一阶段将在斯坦福大学托马斯·苏德霍夫博士和伊恩·戈特利布博士的指导下进行。苏德霍夫博士是研究突触功能和相关精神障碍的领先神经生物学家；戈特利布博士是世界著名的认知科学家，在焦虑和抑郁研究方面拥有专业知识。在他们的指导下，我提出的研究将在科学价值和技术合理性方面得到保证。斯坦福大学一直是基础神经科学发现和创新神经科学方法的摇篮，并将为研究提供最佳环境。

DESCRIPTION (provided by applicant): Post-traumatic stress disorder (PTSD) and some other anxiety disorders manifest as overgeneralization of fear memories that are derived from traumatic experiences but now applied to nonhazardous situations. The neuronal mechanisms determining the degree of memory precision versus generalization are largely unknown, and this lack of understanding impedes the development of effective therapies. Previously, I observed over- generalized contextual fear memory following functional manipulations of the medial prefrontal cortex or the hippocampus. Moreover, I discovered that nucleus reuniens of the midline thalamus which anatomically connects the prefrontal cortex to the hippocampus also plays an essential role. Selective inactivation of prefrontal neurons projecting to nucleus reuniens or direct inactivation of neurons in nucleus reuniens produced overgeneralization, while increasing neuronal activity in nucleus reuniens reduced fear generalization. These observations lead to my hypothesis that in the brain there is a tuning system bi-directionally adjusting the generalization level of fear memories, and this system is composed of the circuits between the prefrontal cortex, nucleus reuniens and the hippocampus. Low activity of the prefrontal cortex and nucleus reuniens decreases hippocampal representation of the details associated with a particular fear memory and leads to overgeneralization as seen in PTSD and anxiety; while increasing the activity level of the prefrontal cortex and nucleus reuniens will downregulate fear generalization level and provides therapeutic benefits. In the mentored phase of this proposal, I will systematically examine the roles of these three brain structures in determining fear generalization level and the functional relationship between these brain structures in encoding or retrieval of fear memories. Because my preliminary data indicate that a subset rather than the whole prefrontal neuronal population contributes to fear generalization, I will identify the particular prefrontal subpopulations of neurons which are specifically involved i the regulation of fear generalization and reveal their genetic identities with high throughput RNA sequencing techniques. Based on the above information, in the independent phase I will then perform detailed functional characterization of the specific prefrontal neuronal groups including their anatomical connections, electrophysiological properties and gene expression profiles. I will test if changes in these properties result in fear memory overgeneralization and anxiety. Successful completion of the proposed studies will offer a mechanistic account of a profound cognitive function - the determination of memory precision/generalization - and thus open up novel avenues for effective therapies to abate anxiety. Careerwise, I am interested in neuroscience research in an academic institute with a long-term goal to uncover the neuronal mechanisms underlying basic cognitive functions and to utilize the information thus obtained to treat brain disorders. I will primarily focus on but not limit my topics to various aspects of memory functions. To date, great strides have been made in neuroscience in the fields of cellular and molecular neurobiology as well as in human cognitive neuroscience; however, research bridging these two ends is lagging behind. I believe that detailed functional dissection of the neuronal circuits responsible for cognitive functions is pivotal to neuroscience now. Therefore, my immediate objective for the next 5-10 years will be to characterize in detail the connectivity and functional properties of the prefrontal cortex-thalamus pathways and to elucidate their roles in various cognitive functions such as those proposed here. I was initially trained in clinical medicine and then received scientific training in neuroscience. I have had extensive experience in both molecular and cellular neurobiology approaches and systems neuroscience techniques, which make me ideal for the proposed studies. The first phase of the current proposal will be conducted with mentoring from Dr. Thomas Sudhof and Dr. Ian Gotlib at Stanford University. Dr. Sudhof is a leading neurobiologist in studying synaptic functions and related mental disorders; Dr. Gotlib, a world renowned cognitive scientist with expertise in anxiety and depression research. With their guidance, my proposed studies shall be ensured in both scientific value and technical soundness. Stanford University has been the cradle of fundamental neuroscience findings and innovative neuroscience approaches and will furnish the best environment for the studies.