Understanding the Role of Brain Insulin Levels and Signaling in Post Stroke Cognitive Impairment

Stroke is the leading cause of long term disability and has the potential to impact a person’s activities of daily life on a physical and cognitive level. Insulin resistance has been linked to increased risk of stroke recurrence, death, and poor outcome following stroke. Insulin resistance leads to decreased insulin transport into the brain. Insulin was thought to be primarily important for peripheral bodily function, however brain insulin has proven to improve memory and cognition as well as having neuroprotective properties. Brain insulin levels and increasing insulin in the brain has not been examined as a therapeutic model for improving stroke recovery. This dissertation introduced a way to bypass the blood brain barrier and administered insulin as a therapeutic directly to the brain, through intranasal administration. The first dissertation chapter provided background of stroke, populations that experience worse stroke outcome, importance of insulin, and a potential therapeutic avenue, the second chapter detailed the experimental methods used to answer the questions. The third chapter explored the impact diet-induced brain insulin deficiency had on cognition. Brain insulin deficiency mimicked by inducing hyperinsulinemia though a high fat diet (HFD) in male and female mice. Brain insulin was demonstrated by observing brain insulin levels, signaling, and cognition was observed by having the mice perform cognitive tasks. HFD males had reduced brain insulin, and impaired performance on cognitive tasks. To account for the impact of diet on cognition chapter four focused on the impact pharmacologically induced brain insulin deficiency had on cognition in male and female mice on a standard diet (STD). Insulin signaling, and cognition were assessed. Male mice demonstrated reduced downstream insulin signaling in the brain and impaired performance on cognitive tasks. The fifth chapter explored the impact increasing brain insulin had on stroke recovery in a STD and HFD mouse model. Following stroke, male and female mice received intranasal insulin treatment then survival, neurological deficits, cognitive and motor deficits were assessed. Intranasal insulin improved functional stroke recovery in male mice. These studies provide insight into the impact brain insulin deficiency has on cognition and the importance of brain insulin on stroke recovery