EPH FAMILY RECEPTORS IN THE HIPPOCAMPOSEPTAL SYSTEM

地形投影是大脑结构的一般特征， 似乎是关键的适当编码和处理 信息.海马体和隔膜，这一直是重点， 强烈的兴趣，因为这些结构在学习中起着核心作用 和内存，在拓扑学上是相互连接的。虽然他们的地形 近二十年来，人们已经知道了这种联系， 对认知功能至关重要，这是 地形投影未知。本研究的长期目标是 阐明轴突靶向的分子机制， 前房中隔系统。罗杰·斯佩里（Roger Sperry）提出， 通过匹配化学亲和性的梯度， 突触前和突触后神经元上的标记。符合本 我们已经证明，Bsk，一个Eph家族受体，及其配体， 在海马体和海马体中以互补梯度表达， 目标成人大脑的外侧隔此外，我们还表明， 其中一种配体Elf-1选择性地抑制了 地形不正确，但允许海马神经突的生长。 这些观察结果导致了一种假设，即Eph家族受体和 配体作为化学亲和性标记物， 映射.基于这一假设可以做出几个预测：1， eph家族配体和受体以适当的梯度表达在 2、配体抑制或支持生长 体外海马适当区域的轴突; 3.改变 表达的梯度干扰了体内的拓扑投影。 为了验证这些预测，我们建议检查空间和时间 Eph配体和受体的表达模式 研究配体的生物学作用 对海马神经元的影响此外，作为关键测试， 的作用的表达梯度的eph分子，我们计划采取 两种互补的方法来改变体内Bsk表达和功能。 首先，我们将注射一种可溶性的Eph配体A1-1/rags， 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Talpha 1神经元特异性微管蛋白过表达Bsk 启动子，其在转基因中产生高水平的均匀表达， 小鼠这些改变对前房间隔地形的影响 将使用轴突追踪技术检查投射。这些研究 将有助于理解海马体的输出通路 组织，并可能阐明学习和记忆的机制， 以及影响这些过程的疾病。

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.