Genetic targeting of hippocampal CA2 pyramidal neurons

海马 CA2 锥体神经元的基因靶向

• 批准号: 8764349
• 负责人: STEVEN A SIEGELBAUM
• 金额: $ 40万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-11 至 2019-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8764349
• 关键词: Acute; Address; Adult; Alzheimer' s Disease; Animals; Area; Attention; Autistic Disorder; Behavior; Behavioral; Bipolar Disorder; Brain; Brain region; Cations; Cell Nucleus; Cognitive; Cognitive deficits; Complex; Cues; Data; Discrimination; Disease; Epilepsy; Exhibits; Fiber; Gap Junctions; Genetic; Genetic Markers; Health; Hippocampus (Brain); Hypothalamic Hormones; Hypothalamic structure; Individual; Interneurons; Label; Laboratories; Learning; Lesion; Light; Link; Location; Maps; Measures; Mediating; Memory; Mental Processes; Mental disorders; Molecular; Mus; Neurons; Neurosciences; Output; Pattern; Performance; Pharmacogenetics; Process; Property; Relative (related person); Reporting; Rodent; Role; Route; Schizophrenia; Social Behavior; Social Interaction; Synapses; Techniques; Tetanus Toxin; Time; Vasopressin Receptor; Vasopressins; base; cell type; conditioned fear; dentate gyrus; entorhinal cortex; granule cell; hippocampal pyramidal neuron; insight; interdisciplinary approach; interest; learned behavior; memory encoding; memory recall; morris water maze; mossy fiber; neglect; nervous system disorder; neural circuit; neuromechanism; neuropsychiatry; novel; object recognition; postsynaptic; prevent; public health relevance; receptor; recombinase; relating to nervous system; research study; response; social

DESCRIPTION (provided by applicant): This project examines the neural circuitry of the CA2 region of the hippocampus and its role in hippocampal-dependent learning and behavior. Although the hippocampus has been one of the most intensively studied brain areas, based on its importance for declarative memory, relatively little is known about the CA2 region since its initial description by Lorente de N¿ in 1934. In contrast there is a wealth of information about th functional properties and synaptic connections of the other major regions of hippocampus including dentate gyrus, CA3 and CA1. The lack of attention paid to CA2 has been largely due to experimental and technical difficulties in studying this relatively small region that occupies a transitional zone between CA3 and CA1. This situation has impeded our understanding of how hippocampus encodes memories and how alterations in hippocampal function contribute to psychiatric and neurological disorders as CA2 has been implicated schizophrenia and bipolar disorder, as well as in epilepsy. Moreover, CA2 pyramidal neurons exhibit some of the highest levels of expression in the brain of the vasopressin 1b receptor, which has been implicated in both normal social behavior and autism. Over the past several years it has become increasingly clear that CA2 does indeed form a separate region with its own molecular identity and distinct electrophysiological properties (as shown, in part, by recent data from our laboratory). These molecular studies have enabled us to generate a mouse line that expresses Cre recombinase in CA2 pyramidal neurons, thereby allowing us to selectively label and manipulate CA2 excitatory output. Our initial experiments have used this mouse to identify some of the major inputs and outputs of the CA2 pyramidal neurons. Moreover by expressing tetanus toxin selectively in CA2 we have been able to inactivate its synaptic output and explore the behavioral consequences of CA2 silencing. Surprisingly, we find that inactivation of CA2 has little effect on a number of mouse behaviors, with no significant change in hippocampal-dependent spatial memory (Morris water maze), contextual fear conditioning, or novel object recognition. In stark contrast, silencing of CA2 results in a profound loss of social memory, the ability of a mouse to recognize a previously encountered mouse. Here we propose to employ this mouse line to examine in more detail both the anatomical and functional synaptic connectivity of CA2 pyramidal neurons and to explore more deeply the role of CA2 in various social and non-social forms of hippocampal-dependent learning and memory. Given the changes in social behavior associated with various neurological and psychiatric disorders, some of which have been linked to CA2, our experiments offer potential insights into both basic mechanisms of memory storage and the neural bases of altered cognitive processing important for social interactions.

描述（由申请人提供）：该项目检查海马 CA2 区域的神经回路及其在海马依赖性学习和行为中的作用。尽管海马体一直是研究最深入的大脑区域之一，但由于其对陈述性记忆的重要性，自 1934 年 Lorente de N¿ 首次描述以来，人们对 CA2 区域的了解相对较少。相比之下，关于海马体其他主要区域（包括齿状回、CA3 和 CA1）的功能特性和突触连接的信息丰富。 CA2 缺乏关注很大程度上是由于研究这个相对较小的区域的实验和技术困难，该区域占据了 CA3 和 CA1 之间的过渡区。这种情况阻碍了我们对海马体如何编码记忆以及海马体功能的改变如何导致精神和神经系统疾病的理解，因为 CA2 与精神分裂症和双相情感障碍以及癫痫有关。此外，CA2 锥体神经元在大脑中表现出一些最高水平的加压素 1b 受体表达，该受体与正常社会行为和自闭症有关。 在过去的几年中，越来越清楚的是，CA2 确实形成了一个独立的区域，具有自己的分子特性和独特的电生理特性（如我们实验室的最新数据部分所示）。这些分子研究使我们能够产生在 CA2 锥体神经元中表达 Cre 重组酶的小鼠品系，从而使我们能够选择性地标记和操纵 CA2 兴奋性输出。我们最初的实验使用这只小鼠来识别 CA2 锥体神经元的一些主要输入和输出。此外，通过在 CA2 中选择性表达破伤风毒素，我们已经能够使其突触输出失活并探索 CA2 沉默的行为后果。令人惊讶的是，我们发现 CA2 失活对小鼠的许多行为几乎没有影响，海马依赖性空间记忆（莫里斯水迷宫）、情境恐惧调节或新物体识别没有显着变化。与此形成鲜明对比的是，CA2 的沉默会导致社交记忆的严重丧失，即小鼠识别先前遇到的小鼠的能力。在这里，我们建议利用该小鼠系来更详细地检查 CA2 锥体神经元的解剖学和功能性突触连接，并更深入地探索 CA2 在海马依赖性学习和记忆的各种社会和非社会形式中的作用。 鉴于与各种神经和精神疾病相关的社会行为变化，其中一些与 CA2 有关，我们的实验为记忆存储的基本机制和对社交互动重要的认知处理改变的神经基础提供了潜在的见解。