Improving memory after hippocampal cell loss

海马细胞丢失后改善记忆

• 批准号: 7251719
• 负责人: MARK Edward BARDGETT
• 金额: $ 19.67万
• 依托单位: NORTHERN KENTUCKY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7251719
• 关键词: Academic Research Enhancement Awards; Acetylcholine; Adult; Alzheimer' s Disease; Animal Model; Animals; Behavioral; Biological Assay; Biomedical Research; Brain region; Chronic; Clinical; Cognitive; Data; Development; Disease; Dorsal; Education; Functional disorder; Funding; Glutamates; Goals; Grant; Hippocampus (Brain); Histamine H3 Receptors; Infusion procedures; Injury; Institution; Kentucky; Knowledge; Laboratory Rat; Light; Link; Literature; Medial; Memory; Memory Disorders; Memory Loss; Memory impairment; Modeling; Motor Activity; Neonatal; Nerve Degeneration; Neurosciences; Performance; Pilot Projects; Prefrontal Cortex; Psychopharmacology; Purpose; Radial; Rattus; Research; Research Design; Rewards; Role; Schizophrenia; Science; Short-Term Memory; Structure; Students; Testing; Training; United States National Institutes of Health; Universities; Upper arm; Work; base; brain size; ciproxifan; college; day; drug testing; hippocampal cell loss; human study; improved; neurodevelopment; neuropsychiatry; postnatal; prepulse inhibition; programs; size; thioperamide

DESCRIPTION (provided by applicant): This is a resubmission of an application for a new R15 AREA (Academic Research Enhancement Award) grant. The original application was reviewed in October 2005. A consistent literature has demonstrated the presence of hippocampal abnormalities in neuropsychiatric disorders, such as schizophrenia and Alzheimer's disease (AD), and, in both disorders, changes in hippocampal function and structure have been linked to memory impairment. But to our knowledge, an animal model of reduced hippocampal volume has not been used to assay new treatments for memory deficits. The development and use of such a model is important since existing animal models of memory loss involving systemic decreases in acetylcholine or glutamate function may not adequately emulate the pathophysiology of memory deficits caused by hippocampal dysfunction. The goal of the proposed research is to develop and use models of modest excitotoxic hippocampal injury to assess the cognitive enhancing ability of specific candidate compounds. Our preliminary data demonstrate that excitotoxic injury to the dorsal hippocampus produces enduring deficits in spatial working memory. We have also shown in preliminary studies performed since the original application that thioperamide, a highly selective antagonist at histamine H3 receptors, clearly alleviates injury-induced deficits in spatial working memory. As a result of this data, we hypothesize that thioperamide and related H3 antagonists will improve spatial working memory in rats with adult and neonatal excitotoxic injury to the hippocampus. The specific aims of this proposal are intended to answer the following questions: 1) Can H3 antagonists alleviate spatial working memory deficits in rats with adult-onset hippocampal injury, 2) Can direct infusion of H3 antagonists into the prefrontal cortex improve memory in rats with adult-onset hippocampal injury, & 3) Can H3 antagonists alleviate changes in spatial working memory, prepulse inhibition, and locomotor activity in rats with neonatal-onset hippocampal injury? The results of these studies should improve our understanding of memory deficits specifically linked to hippocampal dysfunction and suggest new treatment strategies for such deficits in neuropsychiatric disorders. The funding of this application will also expand student research in behavioral neuroscience and psychopharmacology and better enable students from Kentucky, a state traditionally underrepresented in biomedical sciences, to successfully advance into biomedical graduate programs. Memory loss associated with clinical disorders, such as Alzheimer's Disease or schizophrenia, has been linked to reductions in the size of specific brain regions. The proposed studies are designed to study memory in laboratory rats with similar changes in regional brain size and to identify new treatments for the memory impairment associated with these size changes. The results may shed light on new directions in the treatment of memory disorders, and the proposed work will also enhance education in biomedical research among college undergraduates in Kentucky.

描述（由申请人提供）：这是对新R15领域（学术研究增强奖）拨款的申请的重新提交。最初的应用在2005年10月进行了审查。一致的文献证明了神经精神疾病中的海马异常存在，例如精神分裂症和阿尔茨海默氏病（AD），并且在这两种疾病中，海马功能和结构的变化都与记忆障碍联系起来。但是据我们所知，尚未使用减少海马体积的动物模型来分析记忆缺陷的新治疗方法。这种模型的开发和使用很重要，因为现有的记忆丧失动物模型涉及乙酰胆碱或谷氨酸功能的全身性降低的动物模型可能无法充分模仿由海马功能障碍引起的记忆缺陷的病理生理学。拟议的研究的目的是开发和使用适度的兴奋性海马损伤模型，以评估特定候选化合物的认知增强能力。我们的初步数据表明，背侧海马的兴奋性损伤会导致空间工作记忆的持久缺陷。我们还在自最初应用以来进行的初步研究表明，硫代酰胺是组胺H3受体的高度选择性拮抗剂，显然可以减轻损伤引起的空间工作记忆中的缺陷。由于这些数据，我们假设硫代酰胺和相关的H3拮抗剂将改善成人和新生儿兴奋性毒性损伤对海马的大鼠的空间工作记忆。该提案的具体目的旨在回答以下问题：1）H3拮抗剂能否缓解患有成年人发作的海马损伤的大鼠的空间工作记忆缺陷，2）可以直接将H3拮抗剂注入前额叶前的皮质中，以改善成人型抗体抗体的大鼠的记忆力，又可以改善H3型H3型H3型H3型抗体，并可以替代H3的动力学，并可以替代H3的动力学家，并可以将H3的变化为H3及其替代，并可以改善H3的动力学家，并可以使H3型抗体变化，并可以改善H3抗体的变化。新生儿发作的海马损伤的大鼠运动活动？这些研究的结果应提高我们对与海马功能障碍特别相关的记忆缺陷的理解，并提出有关神经精神疾病中这种缺陷的新治疗策略。该应用程序的资金还将扩大学生在行为神经科学和心理药理学方面的研究，并更好地使来自肯塔基州的学生能够在生物医学科学领域的传统人数不足，以成功地进入生物医学研究生课程。与临床疾病相关的记忆丧失，例如阿尔茨海默氏病或​​精神分裂症，与特定大脑区域大小的减少有关。拟议的研究旨在研究区域脑大小相似的实验室大鼠的记忆，并确定与这些大小变化相关的记忆障碍的新疗法。结果可能会揭示记忆障碍治疗的新方向，拟议的工作还将增强肯塔基大学大学本科生生物医学研究的教育。