Genetic targeting of hippocampal CA2 pyramidal neurons

描述(由申请人提供)：本项目研究海马区CA2区的神经回路及其在海马体依赖的学习和行为中的作用。尽管海马区一直是研究最深入的大脑区域之一，基于其对陈述性记忆的重要性，但自1934年Lorente de N�首次描述以来，人们对CA2区知之甚少。相比之下，关于海马齿状回、CA3和CA1等其他主要区域的TH功能特性和突触连接的信息丰富。对CA2缺乏关注在很大程度上是因为在研究这个相对较小的区域时遇到了实验和技术上的困难 CA3和CA1之间的过渡带。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变化如何导致精神和神经疾病的理解，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加压素1b受体的一些最高水平的表达，该受体与正常的社会行为和自闭症有关。在过去的几年里，越来越清楚的是，CA2确实形成了一个独立的区域，具有自己的分子同一性和独特的电生理特性(部分地，正如我们实验室最近的数据所表明的那样)。这些分子研究使我们能够建立一个在CA2锥体神经元中表达Cre重组酶的小鼠系，从而使我们能够选择性地标记和操纵CA2兴奋性输出。我们的初步实验已经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中选择性地表达破伤风毒素，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的失活对小鼠的一些行为几乎没有影响，在海马区依赖的空间记忆(Morris水迷宫)、上下文恐惧条件反射或新对象识别方面没有显著变化。与之形成鲜明对比的是，CA2的沉默会导致严重丧失社会记忆，即老鼠识别以前遇到的老鼠的能力。在这里，我们建议利用这个小鼠系来更详细地研究CA2锥体神经元的解剖和功能突触连接，并更深入地探索CA2在各种社会性和非社会性形式的海马体依赖的学习和记忆中的作用。考虑到与各种神经和精神障碍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会互动重要的认知过程改变的神经基础提供了潜在的见解。

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.