The effects of brain-derived insulin loss on adult neurogenesis in aged male and female Ins2 knockout mice

Insulin resistance in the brain is associated with Alzheimer’s disease, the most common form of dementia with women being more affected than men. Diabetes is a metabolic disorder signified by dysfunctional insulin release and action, and it is a risk factor for Alzheimer’s Disease. Interestingly, administration of insulin to the brain is an effective experimental treatment to improve learning and memory impairments in Alzheimer’s Disease patients. This suggests an important role of insulin action local to the brain. Increasingly more research reports that insulin can be synthesized in the hippocampus, the brain region responsible for learning and memory, and one of the only areas in which new neurons can form throughout adulthood. However, not much is known about how brain-derived insulin effects adult neurogenesis and what factors modulate its expression. This study aimed to confirm insulin production in the hippocampus, assess its modulation by diet and exercise, and identify how brain-derived insulin loss affects adult neurogenesis in female and male mice. I hypothesized that insulin expression is most abundant in the hippocampus, that a high carbohydrate diet decreases insulin expression while exercise increases its expression, and that brain-derived insulin loss decreases adult neurogenesis. To examine these aims I utilized a genetically engineered mouse model with deletion of the Ins2 gene (expressed in the brain) while leaving the Ins1 gene (expressed only in the pancreas), and thus normal glucose homeostasis, intact. In line with my prediction, Ins2 mRNA was high in the hippocampus compared to other regions. Ins2 mRNA was expressed at higher levels in hippocampi of females than males. Contrary to my prediction, Ins2 expression was higher in females eating a high carbohydrate diet and exercise blunted this effect. Surprisingly, the deletion of Ins2 alleles led to increased cell proliferation and this effect was sexually dimorphic. Overall, these results suggest brain-derived insulin differs between sexes and influences adult neurogenesis in mice, highlighting the potential of brain-derived insulin for therapeutic research of Alzheimer’s Disease.Medicine, Faculty ofGraduat