SUN-240 Female Mice Lacking Brain Insulin Production Exhibit Learning Deficits, Anxiety, and Reduced Hippocampal Cyclin D1 Expression

Insulin dysregulation independently underlies diabetes and Alzheimer’s Disease (AD) pathology. However, the former has also been shown to be a risk factor for the latter. The ancestral insulin gene (Ins2), but not the pancreas-specific Ins1gene, is transcribed locally within the brain in mice. We confirmed that neuronal expression of Ins2 is most prominent within the hippocampus, a brain region with established roles in learning and memory, and that it was reduced by a diet known to promote neuronal dysfunction. It is not yet clear, however, how insulin produced locally within the brain influences hippocampal function, learning and memory. To eliminate brain-derived insulin, we used young and old mice with germline Ins2knockout (Ins2(-/-)) and their normal complement of wildtype Ins1 alleles, which had equivalent pancreatic insulin and normal glucose homeostasis. Using the Morris water maze, we found that learning and memory performance of female Ins2(-/-)mice was significantly impaired relative to wild-type mice, whereas the performance of male Ins2(-/-)and wild-type mice did not differ. During acquisition training, the swim-speed in female Ins2(-/-)was faster than wild-type mice, suggesting increased stress reactivity and motivation to escape from water. Indeed, anxiety-like behavior was increased in female mice as assessed by the open-field test. Using RNA sequencing to profile isolated hippocampi, we found that femaleIns2(-/-)mice had a significant reduction in Cyclin D1 (Ccnd1) compared with littermate controls. This observation points to a possible defect in hippocampal neurogenesis, a physiological hallmark of impaired memory and emotionality implicated in both, diabetes and AD. Together these data suggest that Ins2plays sex- and brain region-specific roles in neuronal function and perhaps adult neurogenesis.