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

利用病毒载体研究慢性炎症对执行功能的影响

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.