Loss of brain insulin production impairs learning and memory in female mice

Abstract Aims/hypothesis Diabetes is characterised by dysfunctional insulin release and action, and it is a risk factor for Alzheimer’s disease, the most common form of dementia. Alterations in brain insulin signalling and metabolism have been linked with Alzheimer’s disease. We hypothesised that loss of brain insulin might alter learning and memory performance. Methods We used qPCR, immunofluorescence and western blot analysis to confirm that the ancestral insulin gene, Ins2 , is transcribed within the brain, including in the hippocampus. To determine how locally produced insulin influences hippocampal function, we used mice with germline Ins2 knockout ( Ins2 −/− ) and the normal complement of wild-type Ins1 alleles. Compensation from the Ins1 gene ensured normal glucose tolerance, normal insulin sensitivity, normal fasting insulin and normal body weight under these diet and housing conditions. We analysed visuo-spatial learning and memory performance using the Morris water maze. We used RNA sequencing to provide unbiased analysis of gene expression in isolated hippocampi. Results Hippocampal Ins2 mRNA was higher in female mice than in males, and was modulated by diet. Learning and memory were significantly impaired in female Ins2 −/− mice relative to wild-type mice, while the performance of male Ins2 −/− and wild-type mice did not differ. RNA sequencing showed that cyclin D1 ( Ccnd1 ) was significantly reduced in Ins2 −/− mice. Conclusions/interpretation Our data point to female-specific roles for brain-derived Ins2 in learning and memory function in mice. Graphical Abstract