Excision of the endothelial blood–brain barrier insulin receptor does not alter spatial cognition in mice fed either a chow or high-fat diet

Insulin is transported across the blood–brain barrier (BBB) endothelium to regulate aspects of metabolism and cognition. Brain insulin resistance often results from high-fat diet (HFD) consumption and is thought to contribute to spatial cognition deficits. To target BBB insulin function, we used Cre-LoxP genetic excision of the insulin receptor (InsR) from endothelial cells in adult male mice. We hypothesized that this excision would impair spatial cognition, and that high-fat diet consumption would exacerbate these effects. Excision of the endothelial InsR did not impair performance in two spatial cognition tasks, the Y-Maze and Morris Water Maze, in tests held both before and after 14 weeks of access to high-fat (or chow control) diet. The HFD increased body weight gain and induced glucose intolerance but did not impair spatial cognition. Endothelial InsR excision tended to increase body weight and reduce sensitivity to peripheral insulin, but these metabolic effects were not associated with impairments to spatial cognition and did not interact with HFD exposure. Instead, all mice showed intact spatial cognitive performance regardless of whether they had been fed chow or a HFD, and whether the InsR had been excised or not. Overall, the results indicate that loss of the endothelial InsR does not impact spatial cognition, which is in line with pharmacological evidence that other mechanisms at the BBB facilitate insulin transport and allow it to exert its pro-cognitive effects.