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）：这是重新提交新的 R15 AREA（学术研究增强奖）资助申请。最初的申请于 2005 年 10 月进行了审查。一致的文献表明，神经精神疾病中存在海马异常，例如精神分裂症和阿尔茨海默病 (AD)，并且在这两种疾病中，海马功能和结构的变化与记忆有关损害。但据我们所知，海马体积缩小的动物模型尚未用于检测记忆缺陷的新疗法。这种模型的开发和使用非常重要，因为现有的涉及乙酰胆碱或谷氨酸功能系统性降低的记忆丧失动物模型可能无法充分模拟海马功能障碍引起的记忆缺陷的病理生理学。拟议研究的目标是开发和使用中度兴奋毒性海马损伤模型来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，背侧海马的兴奋性毒性损伤会导致空间工作记忆的持久缺陷。我们在最初应用以来进行的初步研究中还表明，硫哌丁胺（一种高度选择性的组胺 H3 受体拮抗剂）可以明显减轻损伤引起的空间工作记忆缺陷。根据这些数据，我们假设硫哌丁胺和相关的 H3 拮抗剂将改善成年和新生儿海马兴奋性毒性损伤大鼠的空间工作记忆。该提案的具体目标是回答以下问题：1）H3拮抗剂能否减轻成年海马损伤大鼠的空间工作记忆缺陷，2）直接将H3拮抗剂注入前额叶皮层可以改善患有成年海马损伤的大鼠的记忆力吗？成人发病的海马损伤，&3) H3 拮抗剂能否减轻新生儿发病的海马损伤大鼠的空间工作记忆、前脉冲抑制和运动活动的变化？这些研究的结果应该提高我们对与海马功能障碍特别相关的记忆缺陷的理解，并为神经精神疾病中的此类缺陷提出新的治疗策略。该申请的资助还将扩大学生在行为神经科学和精神药理学方面的研究，并更好地使肯塔基州（该州传统上在生物医学科学领域代表性不足）的学生能够成功进入生物医学研究生课程。与阿尔茨海默病或精神分裂症等临床疾病相关的记忆丧失与特定大脑区域尺寸的减小有关。拟议的研究旨在研究具有类似区域大脑大小变化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治疗方法。研究结果可能会揭示记忆障碍治疗的新方向，拟议的工作也将加强肯塔基州本科生的生物医学研究教育。