TRANSCRIPTION FACTOR/REGULATION IN LEARNING AND MEMORY

描述(改编自应用程序)：本研究的总体目标是 研究转录基因调控在习得和治疗中的作用 空间记忆的保持。空间记忆在本质上是联想的， 与个人在空间中的方位和运动有关 到周围环境中对象的位置。A基本的 了解空间记忆是如何形成的将使设计 针对各种疾病的适当和有效的治疗和预防策略 表现为记忆改变的神经学和神经精神病学状况 处理，如阿尔茨海默病(AD)和中风。基因调控 表情被认为是建立持久的 构成长期记忆形成基础的细胞变化。这个 Hzf-3/Nurr1基因是可诱导孤儿核家族的一员。 受体(ONRs)，由即刻早期转录因子组成，被认为是 参与突触的可塑性。PI最近的研究表明， 大鼠海马区hzf-3基因表达水平的变化 海马苔藓纤维-CA3突触的长时程增强 获取洞板食物搜索任务的空间记忆。结果 提示hzf-3基因在海马区的表达密切相关。 与空间学习的习得和保持有关。这个 研究人员假设hzf-3蛋白产物是正常所必需的。 学习习得，并调节其基因的转录 控制对于适当的空间记忆形成很重要。这项建议 将研究hzf-3/Nurr1蛋白产物在血管形成中的作用。 长期空间记忆，并将识别在获取过程中表达的基因 和保留空间记忆，包括那些需要hzf-3产品的记忆 用于转录激活。具体目标1将检查以下各项的影响 序列特异性反义寡核苷酸，旨在阻断 HZF-3蛋白产物的翻译，关于孔板的获取 用于空间记忆的食物搜索任务。寡脱氧核苷酸被微量注入 在训练洞板食物搜索任务之前的海马区 确定了对获取和保留的影响。的有效性。 Hzf-3/Nurr1基因的翻译中断将通过 免疫印迹和免疫组织化学方法，并与行为学效果进行比较 HZF-3反义寡核苷酸。在特异性靶基因2中，cDNA2 微阵列用于定义空间转录表达谱 在洞板食物搜索任务中学习。商品化的cDNA 最初用于选择候选学习和记忆成绩单的微阵列 将用于在玻璃载玻片上制备宏阵列，这些宏阵列将用于 进一步的分析和验证。将这些阵列与大鼠海马区杂交 在食物搜索迷宫中训练的大鼠制备的cdna探针。最后， 在特定目标3的研究将定义hzf-3依赖的转录。 反义治疗与cDNA联合应用对空间学习的影响 微阵列分析。DNA阵列将与制备的cDNAs探针杂交 在海马区注射生理盐水后，在迷宫中训练的动物， HZF-3反义或对照寡核苷酸。建议的一套 实验将提供新的基础知识，这些知识涉及 分子机制辅助大脑中的信息存储，这是 对于制定适当的神经管理策略是必要的 在内存处理中显示问题的条件。

Description (Adapted from Application): The overall goal of this research is to examine the role of transcriptional gene regulation in acquisition and retention of spatial memory. Spatial memory is associative in nature and relates to the orientation and movement of an individual in space in relation to the location of objects in the surrounding environment. A basic understanding of how spatial memories are formed will enable the design of appropriate and effective treatment and prevention strategies for the various neurologic and neuropsychiatric conditions that display alterations in memory processing, such as Alzheimer's disease (AD) and stroke. Regulation of gene expression is considered essential for the establishment of long-lasting cellular changes that underlie the formation of long-term memory. The hzf-3/nurr1 gene is a member of the family of inducible orphan nuclear receptors (ONRs), comprised by immediate-early transcription factors thought to be involved in synaptic plasticity. Recent studies by the PI have shown that the mRNA levels of hzf-3 increase in the rat hippocampus following induction of long-term potentiation at the hippocampal mossy fiber-CA3 synapse and during acquisition of the hole board food search task for spatial memory. Results suggest that the expression of the hzf-3 gene in the hippocampus is closely associated with acquisition and retention of spatial learning. The investigators hypothesize that the hzf-3 protein product is required for normal learning acquisition and that it regulates the transcription of genes whose control is important for appropriate spatial memory formation. This proposal will examine the role of the hzf-3/nurr1 protein product in the formation of long-term spatial memory and will identify genes expressed during acquisition and retention of spatial memory including those that require the hzf-3 product for transcriptional activation. Specific aim 1 will examine the effects of sequence specific antisense oligodeoxynucleotides, designed to block translation of the hzf-3 protein product, on the acquisition of the hole board food search task for spatial memory. Oligodeoxynucleotides are microinfused intrahippocampally prior to training in the hole board food search task and the effects on acquisition and retention are determined. The effectiveness of translational disruption of the hzf-3/nurr1 gene will be determined with Western blots and immunohistochemistry and compared with the behavioral effects of the hzf-3 antisense oligodeoxynucleotides. In specific aim 2, cDNA microarrays are used to define a transcripts expression profile of spatial learning in the Hole Board Food Search Task. Commercially available cDNA microarrays used initially to select candidate learning and memory transcripts will be used to prepare macroarrays on glass slides that will be used for further analysis and validation. The arrays are hybridized with rat hippocampal cDNA probes prepared from rats trained in the food search maze. Finally, studies in specific aim 3 will define an hzf-3 dependent transcriptional profile of spatial learning by combining antisense treatments with cDNA microarray analysis. DNA arrays will be hybridized with cDNA probes prepared from animals trained in the maze after hippocampal injection of either saline, hzf-3 antisense or control oligodeoxynucleotides. The proposed set of experiments will provide new and fundamental knowledge which concerns the molecular mechanisms subserving information storage in the brain and which is necessary for the development of proper management strategies of neural conditions that display problems in memory processing.