The ?7 nAChRs has emerged as a potential target in the treatment of many neurodegenerative disorders, which have been found to be associated with an inflammatory response. The ?7 nAChRs are expressed in macrophages where they play a key role in the cholinergic anti-inflammatory pathway, were they have proven to be an effective target in the treatment of sepsis, myocardial ischemia, and rheumatoid arthritis. However little is known about the role that ?7 nAChRs play on brain inflammation. Interestingly, it has been shown that a high fat diet on wild-type mice causes the activation of microglia resulting in impairments on working memory and in humans an elevated serum cholesterol is a risk factor for mild cognitive impairment and dementia. Suggesting that dietary fat content affects the function of the brain. Using electrophysiology and pharmacological manipulation of lipids, we demonstrated that changes in lipid levels in the plasma membrane causes dramatic changes in the function of the ?7 nAChRs. To dissect the role that ?7 nAChR plays on the high fat diet mediated microglia activation and subsequent development of neuroinflammation, we will generate microglia specific ?7 nAChR knockout mice and compare them with control, fed either a normal or high fat diet. We will look at the activation of inflammatory responses over time, the function of neuronal ?7 nAChRs, and the susceptibility of neuronal cell death caused by dietary induced changes in inflammatory response. The results will help us discern the role of ?7nAChR in both microglia activation and subsequent neuronal cell death, and shed light in the possibility of targeting ?7 nAChRs therapeutically in the prevention of obesity induced dementia.
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