Use of viral-vectors for studying effects of chronic inflammation on executive function

应用病毒载体研究慢性炎症对执行功能的影响 摘要 这项拟议工作的目标是提供一种慢性炎症的病毒载体模型，以研究慢性炎症在衰老和阿尔茨海默病期间认知能力下降中的作用。已经建立了一种全身炎症模型，包括肌肉表达IL-6，从而升高血清IL-6，诱导脑星形胶质细胞增生和小胶质细胞激活。依赖内侧前额叶皮质(MPFC)的执行功能受损是认知功能下降的早期指标，其原因是突触功能受损，与N-甲基-D-天冬氨酸受体(NMDAR)功能低下有关。这一机制涉及活性氧物种(ROS)，可能来自激活的小胶质细胞，在系统性炎症和认知受损的出现之间提供了潜在的联系。有证据表明，皮质NMDAR突触活性降低导致的转录变化类似于与年龄相关的认知能力下降和阿尔茨海默病相关的变化，这表明由于慢性炎症，NMDAR突触活性降低，改变了神经营养、神经保护和突触特异性基因的转录。目的1将验证外周炎症特异性影响mPFC介导的执行功能的假说。研究将采用5项连续反应时任务(5-CSRTT)，它对mPFC功能(警觉性)很敏感，可以检测运动功能或动机的变化。生物学措施将包括血清细胞因子和细胞因子、神经胶质细胞激活、氧化应激以及mPFC中NMDAR功能的氧化还原调节。我们预测，炎症的诱导(如IL-6的病毒表达)将增加血清中的炎症标志物，这些标志物可以预测警觉性受损的出现，并将与炎症标志物和mPFC中NMDAR功能受损有关。目的2研究慢性低水平全身性炎症引起的mPFC转录和认知功能下降。我们预测，长期(3个月)血清细胞因子的增加将削弱警觉性，并导致氧化还原介导的NMDAR功能低下和mPFC中的转录谱衰老。目的3将检验这一想法，即mPFC中抗氧化酶的上调将在保护NMDAR功能、促进年轻的转录模式和挽救认知方面具有选择性作用。

Use of viral-vectors for studying effects of chronic inflammation on executive function Abstract The goal of the proposed work is to provide a viral vector model of chronic inflammation to study the role of chronic inflammation in cognitive decline during aging and Alzheimer’s disease. A systemic inflammation model has been developed and involves muscle expression of IL-6, which elevates serum IL-6 and induces brain astrogliosis and microglia activation. Impaired medial prefrontal cortex (mPFC)-dependent executive function, an early indicator of cognitive decline, is due to impaired synaptic function associated with hypofunction of N-methyl-D-aspartate receptors (NMDARs). The mechanism involves reactive oxygen species (ROS), possibly from activated microglia, providing a potential link between systemic inflammation and the emergence of impaired cognition. Evidence indicates that decreased cortical NMDAR synaptic activity results in transcriptional changes similar to that associated with age-related cognitive decline and Alzheimer’s disease suggesting that a decrease in NMDAR synaptic activity, due to chronic inflammation, alters transcription of neurotrophic, neuroprotective, and synapse specific genes. Aim 1 will test the hypothesis that peripheral inflammation specifically influences executive function mediated by the mPFC. Studies will employ the 5-choice serial reaction time task (5-CSRTT), which is sensitive to mPFC function (vigilance), and can detect changes in motor function or motivation. Biological measures will include serum cytokines and cytokines, glial activation, oxidative stress, and redox regulation of NMDAR function in the mPFC. We predict that induction of inflammation (e.g. viral expression of IL-6) will increase inflammatory markers in the serum, which are predictive of the emergence of impaired vigilance and will be associated with inflammation markers and impaired NMDAR function in the mPFC. Aim 2 examines mPFC transcription and cognitive decline due to chronic low-level systemic inflammation. We predict that a long-term (3 months) increase in serum cytokines will impair vigilance and result in a redox-mediated NMDAR hypofunction and a senescent transcription profile in the mPFC. Aim 3 will examine the idea that upregulation of antioxidant enzymes in the mPFC will have a selective effect in protecting NMDAR function, promoting a youthful transcriptional profile, and rescue cognition.