Improving memory after hippocampal cell loss

描述（由申请人提供）：这是一份新的R15区域（学术研究促进奖）拨款申请的重新提交。原申请已于2005年10月覆核。一致的文献表明，在精神分裂症和阿尔茨海默病（AD）等神经精神疾病中存在海马异常，并且在这两种疾病中，海马功能和结构的变化与记忆障碍有关。但据我们所知，海马体积减少的动物模型还没有被用于测试记忆缺陷的新疗法。这种模型的开发和使用是很重要的，因为现有的涉及乙酰胆碱或谷氨酸功能全身性下降的记忆丧失动物模型可能无法充分模拟由海马功能障碍引起的记忆缺陷的病理生理学。本研究的目的是开发和使用中度兴奋性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，兴奋性毒性损伤海马背侧产生持久的空间工作记忆缺陷。自最初应用以来，我们还在初步研究中表明，硫哌丁胺是一种高度选择性的组胺H3受体拮抗剂，可明显减轻损伤引起的空间工作记忆缺陷。基于这些数据，我们假设硫哌丁胺和相关的H3拮抗剂可以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。本研究的具体目的是为了回答以下问题：1)H3拮抗剂能否缓解成年发病海马损伤大鼠的空间工作记忆缺陷？ 2)H3拮抗剂直接注入前额叶皮层能否改善成年发病海马损伤大鼠的记忆？ 3)H3拮抗剂能否缓解新生儿发病海马损伤大鼠的空间工作记忆、脉冲前抑制和运动活动的变化？这些研究的结果将提高我们对记忆缺陷的理解，特别是与海马功能障碍相关的记忆缺陷，并为神经精神疾病的这种缺陷提供新的治疗策略。这项申请的资金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的学生——一个传统上在生物医学科学方面代表性不足的州——成功地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的缩小有关。拟议的研究旨在研究具有类似区域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。研究结果可能为记忆障碍的治疗指明了新的方向，而且这项工作也将加强肯塔基州大学本科生的生物医学研究教育。

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.