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

项目摘要/摘要 65岁以上的老年人人数预计将在接下来的一年里呈指数级增长。 几十年了。包括阿尔茨海默氏症和痴呆症在内的神经退行性疾病预计会造成 对老年人、他们的家庭和社会的重大健康和经济问题。为了在治疗上 与神经退行性疾病作斗争，我们必须了解与年龄相关的变化并描绘出 导致认知缺陷的机制。以执行功能减退为形式的认知障碍， 包括注意力能力和认知灵活性，是几个精神病学和 神经退行性疾病以及认知老化。N-甲基-D-天冬氨酸受体 功能减退是精神分裂症患者注意力受损的原因之一。此外，电生理学证据表明 研究表明，NMDAR功能低下的内侧前额叶皮质(MPFC)出现在中年和 与注意力能力下降有关。结果表明，像老年人一样，丝氨酸消旋酶RNA 认知受损的老年大鼠的mPFC(SRR)下降。丝氨酸外消旋酶产生D-丝氨酸，是一种辅酶. 调节NMDAR功能的激动剂。这项提议的总体目标是检验这样一个假设，即增强 NMDAR功能通过1)上调GluN2B NMDAR亚单位或2)增加SRR，在 MPFC，将恢复NMDAR介导的突触功能，改善注意力和认知灵活性。目标 1将检验这样的假设，即在mPFC中上调NMDAR的GluN2B亚单位将恢复NMDAR- 调节突触功能，改善认知功能。通过使用特定的表达载体，我们将 限制NMDAR的GluN2B亚单位单独或联合表达mPFC锥体神经元 有中间神经元。动物的行为表现将在5个选择的系列反应时间任务和 将使用电生理、免疫组织化学、 Western blotting和RT-qPCR分析。据预测，mPFC中GluN2B的表达上调 将恢复NMDAR介导的突触功能并改善执行功能。目标2将检验这一假设 病毒载体介导的丝氨酸外消旋酶的表达增加，这种酶是锥体神经元或 星形胶质细胞将增强NMDAR功能，逆转与衰老相关的认知缺陷。增强的 MPFC中锥体细胞或星形胶质细胞的特异性表达将得到证实。我们预测，这种上调 丝氨酸消旋酶可增强NMDAR功能，改善注意力和认知灵活性。建议数 研究将使用一系列强大的多学科技术来修改mPFC的特定组件 电路测试两个新的独立假设均旨在改善与年龄相关的认知 功能障碍。

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.