# High-Fat-Diet-Induced Metabolic Disorders: An Original Cause for Neurovascular Uncoupling Through the Imbalance of Glutamatergic Pathways

## TL;DR

A high-fat diet causes brain blood vessel dysfunction in mice by disrupting glutamate pathways, leading to cognitive decline.

## Contribution

Identifies glutamatergic pathways as a novel mechanism for high-fat-diet-induced neurovascular uncoupling.

## Key findings

- A 70% alteration in myogenic tone of the basilar artery occurs after 6 months of HFD.
- A 77% reduction in glutamate-induced vasodilation appears after 12 months of HFD.
- Enzyme contributions in glutamatergic pathways shift with HFD duration.

## Abstract

Backgrounds/Objective: The impact of metabolic disturbances induced by an unbalanced diet on cognitive decline in mid-life is now widely observed, although the mechanisms are not well identified. Here we report that glutamatergic vasoactive pathways are a key feature of high-fat-diet (HFD)-induced neurogliovascular uncoupling in mice. Methods: C57Bl6/J mice are fed either with normal diet (ND) or high-fat diet (HFD) during 6 or 12 months and characterized for metabolic status. Cerebral vascular tree from pial to intraparenchymal arteries, is investigated with Halpern’s arteriography and with differential interference contrast infrared imaging of brain slices. Results: A 70% alteration in the myogenic tone of the basilar artery is observed as early as 6 months (M6) after the HFD. Infrared imaging revealed a 77% reduction in the glutamate-induced vasodilation of intraparenchymal arterioles appearing after 12 months (M12) of the HFD. The respective contributions of enzymes involved in glutamatergic pathways were altered as a function of HFD and time. The decrease in astrocytic COX I observed at M6 was followed by a loss of neuronal COX II and a compensatory action of NOS at M12. Conclusions: This HFD-induced neurogliovascular uncoupling pathway offers therapeutic targets to consider for improving cerebral vasoactive functions while preventing peripheral metabolic disturbances.