EPH FAMILY RECEPTORS IN THE HIPPOCAMPOSEPTAL SYSTEM

海马中隔系统中的 EPH 家族受体

基本信息

批准号：
6108486
负责人：
RENPING ZHOU
金额：
$ 14.52万
依托单位：
UNIV OF MED/DENT NJ-R W JOHNSON MED SCH
依托单位国家：
美国
项目类别：
财政年份：
1999
资助国家：
美国
起止时间：
1999-04-01 至 2000-03-31
项目状态：
已结题

项目摘要

Topographic projection is a general feature of brain architecture, and appears to be critical for appropriate coding and processing of information. The hippocampus and septum, which have been the focus of intense interest, since these structures play a central roles in learning and memory, are interconnected topographically. Although their topographic connections have been known for nearly two decades, and the topography may be critical for cognitive functions, the molecular basis for the topographic projection is unknown. The long term goal of this study is to elucidate the molecular mechanisms of axonal targeting in the hippocamposeptal system. It has been proposed by Roger Sperry that topographic mapping is accomplished by matching gradients of chemoaffinity labels on the pre-synaptic and postsynaptic neurons. Consistent with this proposal, we have shown that Bsk, an eph family receptor, and its ligands are expressed in complementary gradients in the hippocampus and the target, lateral septum in the adult brain. Furthermore, we have shown that, one of the ligands, Elf-1, selectively inhibited the growth of topographically incorrect but allowed the growth of hippocampal neurites. These observations led to the hypothesis that eph family receptors and ligands serve as chemoaffinity labels for the hippocamposeptal topographic mapping. Several predictions can be made based on this hypothesis: 1, the eph family ligands and receptors are expressed in proper gradients at the time of topographic mapping; 2, the ligands inhibit or support the growth of axons from appropriate regions of the hippocampus in vitro; 3. changing the gradients of expression disturbs the topographic projection in vivo. to test these predictions, we propose to examine the spatial and temporal patterns of expression of eph ligands and receptors in the hippocamposeptal system, and study the biological actions of the ligands on the hippocampal neurons in vitro. In additions, as critical tests for the roles of expression gradients of the eph molecules, we plan to take two complementary approaches to alter Bsk expression and function in vivo. First, we will inject a soluble eph ligand, A1-1/rags, which serves as an inhibitor for Bsk or related receptors, into developing mouse brains; Second, we will over-express Bsk using Talpha1 neuron-specific tubulin promoter, which generates high levels of uniform expression, in transgenic mice. The effect of these alterations on the hippocamposeptal topographic projection will be examined using axonal tracing techniques. These studies will help to understand how the output pathways of the hippocampus are organized and may shed light on the mechanism of learning and memory, as well as diseases affecting these processes.

地形投影是大脑结构的一般特征，并且似乎对于适当的编码和处理至关重要信息。海马体和隔膜，一直是研究的重点强烈的兴趣，因为这些结构在学习中发挥着核心作用和记忆，在拓扑上是相互关联的。尽管他们的地形近二十年来人们已经知道这些联系，并且地形可能对于认知功能至关重要，这是认知功能的分子基础地形投影未知。这项研究的长期目标是阐明轴突靶向的分子机制海马间隔系统。罗杰·斯佩里 (Roger Sperry) 提出地形图是通过匹配化学亲和力梯度来完成的突触前和突触后神经元上的标签。与此一致提议，我们已经证明了 Bsk，一种 eph 家族受体，及其配体在海马体和目标，成人大脑中的侧隔膜。此外，我们还展示了配体之一 Elf-1 选择性抑制地形上不正确，但允许海马神经突的生长。这些观察结果得出这样的假设：eph 家族受体和配体作为海马间隔地形的化学亲和标记映射。根据这个假设，可以做出以下几个预测： 1、 eph家族配体和受体以适当的梯度表达地形测绘时间； 2、配体抑制或支持生长体外海马体适当区域的轴突； 3、改变表达梯度扰乱了体内的地形投影。为了测试这些预测，我们建议检查空间和时间 eph配体和受体的表达模式海马间隔系统，并研究配体的生物学作用对体外海马神经元的影响。此外，作为关键测试 eph分子表达梯度的作用，我们计划采取两种改变 Bsk 体内表达和功能的互补方法。首先，我们将注射可溶性 eph 配体 A1-1/rags，它作为 Bsk 或相关受体的抑制剂，进入发育中的小鼠大脑；其次，我们将使用 Talpha1 神经元特异性微管蛋白过度表达 Bsk 启动子，在转基因中产生高水平的均匀表达老鼠。这些改变对海马间隔地形的影响将使用轴突追踪技术检查投影。这些研究将有助于了解海马体的输出路径是如何的组织起来并可能阐明学习和记忆的机制，如以及影响这些过程的疾病。