MOLECULAR BASIS OF LEARNING AND MEMORY

学习和记忆的分子基础

基本信息

批准号：
12210007
负责人：
MISHINA Masayoshi
金额：
$ 99.84万
依托单位：
UNIVERSITY OF TOKYO
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research on Priority Areas
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2004
项目状态：
已结题

项目摘要

Tolerance and physical dependence caused by chronic treatment of narcotics are good models to study basic neuronal plasticity. NMDA receptor GluRel mutant mice showed a marked loss of the analgesic tolerance after repeated morphine treatments. Region-specific rescue of GluRel by electroporation in the periaqueductal gray matter and the ventral tegmental area significantly reversed morphine analgesic tolerance liability. Similarly, nucleus accumbens-specific rescue reversed the loss of naloxone-precipitated physical dependence in GluRel mutant mice.Classical eyeblink conditioning, a simple form of associative learning, provides an experimental system to solve the complex relationships of molecules, neural signaling, synaptic plasticity, neural circuits and behaviors. There are two paradigms of eyeblink conditioning depending on the temporal relationship between the conditioned and unconditioned stimuli. In delay conditioning, cerebellar Purkinje cell-specific GluRd2 mutant mice exhibite … More d a severe impairment in learning. However, in the trace paradigm, GluRd2 mutant mice learned as successfully as the wild-type mice. In contrast, N-methyl-D-aspartate (NMDA) receptor GluRel mutant mice attained a normal level of learning in delay conditioning, but exhibited severe impairment in trace conditioning. These findings suggest that neural substrates underlying eyeblink conditioning are distinct depending on the temporal relationships of the conditioned and unconditioned stimuli.GluRd2 selectively expressed in cerebellar Purkinje cells plays a central role in cerebellar long-term depression, motor learning and formation of parallel fiber synapses. By yeast two- hybrid screening, we identified Delphilin and Shank scaffold proteins as GluRd2-interacting molecules. Anti-GluRd2 antibodies immunoprecipitated Shank1, Shank2, Homer and metabotropic GluRla proteins from the synaptosomal membrane fractions of cerebella. Furthermore, Shank2 interacted with GRIP1 in the cerebellum. These results suggest that through Shank1 and Shank2, GluRd2 interacts with the metabotropic GluRla, the AMPA-type GluR and the inositol 1,4,5-trisphosphate receptor (IP3R) that are essential for cerebellar long- term depression. Less

长期麻醉药物治疗引起的耐受性和身体依赖性是研究基本神经元可塑性的良好模型。通过导水管周围灰质中的电穿孔重复吗啡治疗后，GluRel 突变小鼠表现出明显的镇痛耐受性丧失。腹侧被盖区显着逆转吗啡镇痛耐受性，类似地，伏隔核特异性救援逆转了吗啡镇痛耐受性的丧失纳洛酮在 GluRel 突变小鼠中引发身体依赖性。经典的眨眼条件反射是一种简单的联想学习形式，提供了一个实验系统来解决分子、神经信号、突触可塑性、神经回路和行为的复杂关系。眨眼有两种范例。在延迟条件反射中，小脑浦肯野细胞特异性 GluRd2 突变小鼠表现出严重的条件反射。然而，在跟踪范式中，GluRd2 突变小鼠的学习能力与野生型小鼠一样成功，相反，N-甲基-D-天冬氨酸 (NMDA) 受体 GluRel 突变小鼠在延迟条件反射中达到了正常的学习水平。，但在微量条件反射中表现出严重损伤。这些发现表明，眨眼条件反射的神经底物是不同的，具体取决于条件刺激和非条件刺激的时间关系。GluRd2 在小脑浦肯野细胞中选择性表达，起着重要作用。通过酵母双杂交筛选，我们将 Delphilin 和 Shank 支架蛋白鉴定为 GluRd2 相互作用分子，抗 GluRd2 抗体免疫沉淀 Shank1、Shank2、Homer 和代谢型。来自小脑突触体膜部分的 GluRla 蛋白此外，Shank2 与 GRIP1 相互作用。这些结果表明，GluRd2 通过 Shank1 和 Shank2 与小脑长期抑郁所必需的代谢型 GluRla、AMPA 型 GluR 和肌醇 1,4,5-三磷酸受体 (IP3R) 相互作用。