Age-associated impaired executive function: Rescue by NMDA receptor upregulation

与年龄相关的执行功能受损：通过 NMDA 受体上调来挽救

• 批准号: 10033493
• 负责人: Ashok Kumar
• 金额: $ 41.94万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-01 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10033493
• 关键词: Affinity; Age; Age-Years; Age-associated memory impairment; Aging; Agonist; Alzheimer' s Disease; Alzheimer' s disease risk; Animals; Applications Grants; Astrocytes; Attention; Attentional deficit; Bathing; Behavior; Behavioral; Binding; Binding Sites; Brain; Calcium; Calmodulin; Characteristics; Cognition; Cognitive; Cognitive aging; Cognitive deficits; Collection; Complex; Data; Effectiveness; Elderly; Electrophysiology (science); Enzymes; Executive Dysfunction; Family; Female; Genes; Glial Fibrillary Acidic Protein; Glycine; Goals; Health; Hippocampus (Brain); Human; Impaired cognition; Impairment; In Vitro; Individual; Injections; Interneurons; Intervention; Learning; Link; Longevity; Measures; Medial; Mediating; Memory; Memory impairment; Mental disorders; Modification; Molecular; N-Methyl-D-Aspartate Receptors; NMDA receptor A1; Neurodegenerative Disorders; Neuroglia; Neurons; Performance; Phosphotransferases; Prefrontal Cortex; Preparation; Problem Solving; Process; Pyramidal Cells; RNA; Rattus; Reaction Time; Receptor Activation; Recovery; Risk Factors; Rodent; Rodent Model; Schizophrenia; Serine; Short-Term Memory; Slice; Societies; Source; Structure; Synapses; Synapsins; Synaptic plasticity; Techniques; Testing; Therapeutic; Training; Up-Regulation; Viral Vector; Western Blotting; Work; age related; aged; aging population; cognitive ability; cognitive function; cognitive performance; combat; daily functioning; executive function; expression vector; flexibility; hippocampal pyramidal neuron; improved; male; middle age; multidisciplinary; novel; promoter; receptor expression; receptor function; receptor upregulation; relating to nervous system; response; senescence; serine racemase; sex; spatial memory; synaptic function; vector

Project Summary/Abstract The number of elderly individuals over 65 years of age is projected to increase exponentially over the next several decades. Neurodegenerative diseases including Alzheimer’s and dementia are expected to pose a significant health and financial concern for aging individuals, their families, and society. In order to therapeutically combat neurodegenerative diseases, we have to understand age-associated alterations and delineate the mechanisms causing cognitive deficiency. Cognitive impairment in the form of reduced executive function, including attentional abilities and cognitive flexibility, is a characteristic of several psychiatric and neurodegenerative diseases as well as of cognitive aging. N-methyl-D-aspartate receptor (NMDAR) hypofunction contributes to impaired attention in schizophrenia. Furthermore, electrophysiological evidence has shown that NMDAR hypofunction in the medial prefrontal cortex (mPFC) emerges during middle age and is associated with a decline in attentional ability. Results indicate that like older humans, serine racemase RNA (SRR) declines in the mPFC of older rats with impaired cognition. Serine racemase generates D-serine, a co- agonist that regulates NMDAR function. The overall goal of this proposal is to test the hypothesis that enhancing NMDAR function through 1) upregulation of the GluN2B NMDAR subunit or 2) increased expression of SRR, in the mPFC, will restore NMDAR-mediated synaptic function and ameliorate attention and cognitive flexibility. Aim 1 will test the hypothesis that upregulation of the GluN2B subunit of NMDAR in the mPFC will restore NMDAR- mediated synaptic function and improve cognitive function. By employing specific expression vectors, we will limit the expression of the GluN2B subunit of NMDAR either to mPFC pyramidal neurons alone or in conjunction with interneurons. Behavioral performance of animals will be tested on the 5-choice serial reaction time task and the set-shifting task, and upregulation will be confirmed using electrophysiological, immunohistochemical, Western blotting, and RT-qPCR analyses. It is predicted that upregulation of GluN2B expression in the mPFC will restore NMDAR-mediated synaptic function and improve executive function. Aim 2 will test the hypothesis that a viral vector mediated increase in the expression of serine racemase, specific to pyramidal neurons or astrocytes will enhance NMDAR function and reverse cognitive deficits associated with senescence. Augmented expression, specific to pyramidal cells or astrocytes in the mPFC will be confirmed. We predict that upregulation of serine racemase will enhance NMDAR function and ameliorate attention and cognitive flexibility. The proposed studies will employ an array of powerful multidisciplinary techniques to modify specific components of mPFC circuitry testing two novel and independent hypothesis both directed at improving age-related cognitive dysfunction.

项目摘要/摘要 预计65岁以上的基本个人的数量将在下一个中成倍增加 几十年。包括阿尔茨海默氏症和痴呆在内的神经退行性疾病有望构成A 老龄化个人，他们的家庭和社会的重大健康和财务关注。为了治疗 战斗神经退行性疾病，我们必须了解与年龄相关的改变并描述 导致认知缺陷的机制。认知障碍以减少执行功能的形式， 包括注意力和认知灵活性，是几种精神病的特征 神经退行性疾病以及认知衰老。 N-甲基-D-天冬氨酸受体（NMDAR） 功能障碍导致精神分裂症的注意力受损。此外，电生理证据具有 表明内侧前额叶皮层（MPFC）中的NMDAR功能功能不全 与注意力能力的下降有关。结果表明，像老年人一样，丝氨酸种族酶RNA （SRR）在认知受损的老鼠的MPFC中下降。丝氨酸种族酶产生D-serine，一个共同 调节NMDAR功能的激动剂。该提议的总体目标是检验以下假设 NMDAR函数通过1）上调Glun2b NMDAR亚基或2）SRR的表达增加，在 MPFC将恢复NMDAR介导的突触功能，并改善注意力和认知灵活性。目的 1将检验以下假设：MPFC中NMDAR的Glun2b亚基上调将恢复NMDAR- 介导的突触功能并改善认知功能。通过使用特定的表达向量，我们将 将NMDAR的Glun2b亚基的表达限制为单独或单独或连接的MPFC锥体神经元 与中间神经元。动物的行为表现将在5个选择的串行反应时间任务上进行测试，并且 设置转移任务和上调将使用电生理，免疫组织化学， 蛋白质印迹和RT-QPCR分析。据预测，MPFC中Glun2b表达的上调 将恢复NMDAR介导的突触功能并改善执行功能。 AIM 2将检验假设 病毒载体介导的丝氨酸种族酶表达的增加，特异于锥体神经元或 星形胶质细胞将增强NMDAR功能，并反向认知定义与感应相关。增强 将确认针对MPFC中锥体细胞或星形胶质细胞的表达。我们预测该更新 丝氨酸种族酶将增强NMDAR功能，并改善注意力和认知灵活性。提议 研究将采用一系列强大的多学科技术来修改MPFC的特定组成部分 电路测试两个新颖和独立的假设，均旨在改善与年龄相关的认知 功能障碍。