EPH MOLECULES IN HIPPOCAMPAL TOPOGRAPHIC PROJECTIONS

这项研究的长期目标是阐明分子 海马隔系统中轴突靶向的机制。它 由罗杰·斯佩里提出的地形图是 通过将化学亲和力标记的梯度匹配到 突触前和突触后神经元。与这一提议相一致， 海盗研究人员已经表明，Eph家族的受体BSK， 和它的配体在互补的梯度中表达 海马体和靶区，即成人大脑的外侧隔膜。 此外，他还选择性地展示了其中一种配体Elf-1 抑制了不正确的神经突起生长，但允许 正确的海马神经纤维的生长。这些观察结果导致了 Eph家族受体和配体作为 化学亲和性标记物用于海马隔区地形图标测。 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 地形图绘制时间；2)配体抑制或支持 海马区适当区域轴突的体外生长； 3)改变表情的梯度会干扰地形 体内投射。为了验证这些预测，研究人员建议 研究Eph表达的空间和时间模式 海马间隔系统中的配体和受体，并研究 配体对体外培养的海马神经元的生物学作用。 此外，作为对表达梯度的作用的关键测试， EPH分子，申请者计划服用两个互补的 在体内改变BSK表达和功能的方法。首先，他会 注射可溶的Eph配体A1-1/RAGS，作为抑制剂 用于BSK或相关受体，进入发育中的小鼠大脑。第二，他 将使用Talphal神经元特异性微管蛋白启动子过表达BSK， 在转基因小鼠中产生高水平的统一表达。 这些改变对海马区地形图的影响 投射将使用轴突追踪技术进行检查。这些 研究将有助于理解细胞的输出途径如何 海马体是有组织的，并可能有助于阐明 学习和记忆，以及影响这些过程的疾病。

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 presynaptic and postsynaptic neurons. Consistent with this proposal, the pirncipal investigator has shown that Bsk, an eph family receptor, and its ligand are expressed in complementary gradients in the hippocampus and the target, lateral septum in the adult brain. Furthermore, he has shown one of these ligands, Elf-1, selectively inhibited the growth of topographically incorrect neurites, but allowed the growth of correct hippocampal neurites. These observation sled to the hypothesis that eph family receptors and ligands serve as chemoaffinity labels for the hippocamposeptal topograph mapping. Several predictions can be made based on this hypothesis: 1) the eph family ligands and receptors are expressed in propoer gradients at the time of topographic maping; 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, the investigator proposed 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 addition, as critical tests for the roles of expression gradients of the eph molecules, the applicant plans to take two complementary approaches to alter Bsk expression and function in vivo. First, he will inject a soluble eph ligand, A1-1/RAGS, which serves as an inhibitor for Bsk or related receptors, into developing mouse brain. Second, he will overexpress Bsk using Talphal neuron-specific tublin promoter, which generates high levels of uniform expression, in transgenic mice. The effects of these alterations on the hippocampal 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 mechanisms of learning and memory, as well as diseases affecting these processes.