Analyzing the Sex-Dependent Effects of Intranasal Insulin on Memory Impairment Secondary to High-Fat Diet

Abstract

Purpose: Insulin can improve memory by enhancing the intrinsic excitability of hippocampal CA1 pyramidal neurons during memory consolidation. Chronic high-fat diet (HFD), however, can significantly impair spatial memory via reduction in excitability of these same neurons in both male and female rodent models. Interestingly, sex-dependent experimentation in these models has also shown that CA1 neurons from HFD females retain insulin-sensitivity while those from HFD males do not. Combining these findings from previous studies, it can be hypothesized that insulin therapy would improve memory deficits in females but not males fed a HFD. The following study aims to explore these sex-dependent responses to insulin therapy, as well as the use of intranasal insulin as an alternative and novel method of insulin administration that could potentially eliminate the harmful peripheral side effects of insulin via injection. Methods: Spatial memory of male and female Long-Evans rats fed control vs high-fat diet (HFD) was assessed in a spontaneous alternation task (SAT) using a four-arm radial maze (plus maze). Normally, rats will remember which arm of the maze they last visited and will attempt to sequentially explore new arms. The ability of the rats to do this is scored, with a low score indicating hippocampal impairment. Following behavioral experimentation, insulin tolerance testing was performed in order to rule-out peripheral presence of elevated insulin. Results: Intranasal delivery of insulin reversed memory impairments secondary to high-fat diet in both male and female rats. This was demonstrated by improvement in SAT scores of HFD rats treated with intranasal insulin therapy vs saline. These results were not as expected, but may be explained by the lack of a significant difference in fasting blood glucose levels of control vs high-fat diet animals. This indicates that high-fat diet animals were not showing symptoms of diabetes. It is possible then, that the animals in this experiment were in a pre-disease state where impairments were more readily reversible in both sexes and not just females. Additionally, lack of a decrease in peripheral glucose levels following intranasal insulin administration indicates that intranasal insulin did not have peripheral effects. Conclusions: This study highlights the possibility of the intranasal route as a novel method of insulin administration. Further studies should be conducted to explore the viability of this option compared to the current method of injecting insulin. For example, CSF extraction could be performed to confirm the presence of elevated insulin levels in the brain following intranasal insulin administration, as well as studies that provide further evidence that intranasal delivery bypasses the harmful peripheral side-effects of injected insulin. Lastly, although this study failed to reproduce diabetic responses, future experimentation in aged animals that have been on a HFD for [greater than] 12 weeks could better elucidate whether sex-dependent responses to chronic HFD would have an effect on insulin therapy and reversal of memory impairment.