214-LB: Brain Mitochondrial Function and Cognition Are Impaired in Brain Insulin Receptor Knockout Mice

Insulin resistance has been linked to cognitive dysfunction and increased risk for Alzheimer’s disease and other dementias. It is unclear if cognitive decline during insulin resistance is due to systemic or brain-specific insulin resistance. Previous studies demonstrated that brain mitochondrial function is reduced concurrent to diminished insulin signaling in high fat-fed mice. However, it remains to be determined whether insulin signaling in the brain directly impacts brain mitochondrial function and cognition. Therefore, we developed a tamoxifen inducible brain-specific insulin receptor knockout (BIRKO) mouse by breeding C57/BL6J mice with a floxed insulin receptor gene with mice that express a tamoxifen-inducible Nestin-Cre. These BIRKO mice were used to identify if brain insulin signaling is required for maintenance of brain mitochondrial function and cognition. Four weeks after tamoxifen administration, we confirmed using western blotting that the insulin receptor was completely absent in all regions of the brain, but not the muscle, heart, liver, kidney, or adipose from the BIRKO mice. Spatial learning was reduced (P<0.05; n=8 so far) and short-term memory trended to be reduced (P=0.18; n=8 so far) in BIRKO mice compared to controls. Further, ATP production rate was reduced (64 vs. 42 pmols/s/mg tissue; P<0.005; n=9) and reactive oxygen species production was increased (33 vs. 58 pmols/s/g tissue; P<0.005; n=9) in isolated mitochondria from the cerebrum in BIRKO mice versus controls. These changes were not accompanied by altered body weight, fat mass or lean body mass. Because the clearly pronounced mitochondrial deficits in the brain of BIRKO mice are accompanied by cognitive decline, our results suggest a link between cognition and brain mitochondrial function. Thus, these novel and important findings warrant further studies to provide molecular insights into the mechanisms governing the link of brain insulin resistance to Alzheimer’s disease and other dementias.