Grant: Operating Grant

Each year, more than 234 million patients undergo anesthesia and surgery worldwide. It is widely assumed that cognitive function rapidly returns to baseline in the early postoperative period. However, postoperative cognitive dysfunction, particularly long-term memory loss, is a frequent but poorly understood neurological complication after surgery. Postoperative memory loss is associated with a reduction in quality of life, early retirement, as well as premature death. Our goal is to understand the mechanisms underlying postoperative memory deficits and to develop treatment and prevention strategies. In our previous CIHR-supported studies, we identified a "memory-blocking" receptor that, when activated, prevents the formation of new memories. Overactivation of these receptors disrupts communication in a region of the brain that regulates memory processes. General anesthetics can cause such overactivation, leading to profound memory blockade. The prolonged time course of postoperative memory loss prompted us to look for an endogenous factor that activates the memory-blocking receptors. We discovered that one of the most important pro-inflammatory cytokines, interleukin 1 beta (IL-1b), increases receptor activity. This result is exciting because it is already known that IL-1b causes memory deficits, via mechanisms that remain unclear. Also, the levels of IL-1b in the brain increase after surgery. Thus, we hypothesize that IL-1b increases the activity of memory-blocking receptors, thereby causing postoperative memory deficits. Using a mouse model, we will determine how IL-1b increases the activity of memory-blocking receptors. We will also determine whether inhibiting these receptors reduces the severity and/or incidence of postoperative memory deficits. If so, we anticipate developing a strategy for preventing postoperative cognitive dysfunction. Our results may have implications for the memory loss associated with anesthesia and inflammatory disease