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）：这是一个新的R15区域（学术研究增强奖）补助金的申请重新提交。2005年10月审查了最初的申请。一致的文献表明，海马异常的神经精神疾病，如精神分裂症和阿尔茨海默病（AD）的存在，在这两种疾病，海马功能和结构的变化已被链接到记忆障碍。但据我们所知，海马体积减少的动物模型还没有被用来测试记忆缺陷的新治疗方法。这种模型的开发和使用是重要的，因为涉及乙酰胆碱或谷氨酸功能的全身性降低的记忆丧失的现有动物模型可能不能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，兴奋性毒性损伤背海马产生持久的空间工作记忆的赤字。我们还表明，在初步研究中进行的，因为最初的申请，硫代哌丁胺，一个高度选择性的组胺H3受体拮抗剂，明确地消除损伤诱导的空间工作记忆的缺陷。作为这些数据的结果，我们假设，硫代哌丁胺和相关的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。本建议的具体目标是回答以下问题：1）H3拮抗剂能否减轻成年发作海马损伤大鼠的空间工作记忆缺陷，2）将H3拮抗剂直接输注到前额皮质能否改善成年发作海马损伤大鼠的记忆，& 3）H3拮抗剂能否减轻空间工作记忆、前脉冲抑制、和自发活动的关系？这些研究的结果应该提高我们的理解，记忆缺陷，特别是海马功能障碍，并提出新的治疗策略，这种赤字在神经精神疾病。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，并更好地使来自肯塔基州（传统上在生物医学科学领域代表性不足的州）的学生能够成功晋级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的大小减少有关。拟议的研究旨在研究实验室大鼠的记忆，这些大鼠的局部大脑大小发生了类似的变化，并确定了与这些大小变化相关的记忆障碍的新治疗方法。研究结果可能会为记忆障碍的治疗提供新的方向，而这项研究也将加强肯塔基州大学本科生的生物医学研究教育。