Project 460602

Chronic systemic inflammation increases with age and is associated with a variety of late-life diseases and infection outcomes. It has been previously shown that higher inflammation is a risk factor for cognitive decline; however, the mechanisms by which this occurs are not understood. The main characteristic of age-associated inflammation is chronic low levels of inflammatory cytokines in the circulation and tissues. Tumour necrosis factor (TNF) is one of the drivers of age-associated inflammation. We previously discovered that the absence of TNF protected against unhealthy aging and decreased mortality rates in mice (>18 months). In the Central Nervous System (CNS), TNF is mainly produced by activated microglia, which are glial cells and resident macrophages. This research project aims to uncover the mechanisms by which age-associated inflammation contributes to the dysfunction of microglia in CNS that leads to an increase in cognitive decline. I will be on the hippocampal region of the mouse brain because its main functions are learning and memory consolidation. I plan to show that changes in the microglial density of this region are a result of age-associated inflammation and dysfunctional microglia. For this project, I will use wild-type mice and TNF knockout to compare at a young age (<6 months) and older age (>18 months). I will be using immunohistochemistry techniques to confirm structural changes in the brain. To examine functional changes of the brain, I am using traditional behavioural tests, such as rotarod, open field test, and novel object recognition to assess mice learning and memory performance. Additionally, I will be implementing a novel automated system, Intellicage, to measure changes in learning and memory. Overall, a reduction of age-associated inflammation could be a new non-invasive approach to counteract the effects of cognitive decline as a function of aging.