Genetic targeting of hippocampal CA2 pyramidal neurons

描述（由申请人提供）：本项目研究海马体CA2区域的神经回路及其在海马体依赖性学习和行为中的作用。尽管海马体是研究最深入的大脑区域之一，基于它对陈述性记忆的重要性，但自从Lorente de N在1934年首次描述CA2区域以来，人们对它的了解相对较少。相比之下，关于海马其他主要区域（包括齿状回、CA3和CA1）的功能特性和突触连接的信息却非常丰富。对CA2缺乏关注主要是由于研究这个相对较小的区域存在实验和技术上的困难

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.