title: High fat diet-induced diabetes in mice exacerbates cognitive deficit due to chronic hypoperfusion.
abstract: Diabetes causes endothelial dysfunction and increases the risk of vascular cognitive impairment. However, it is unknown whether diabetes causes cognitive impairment due to reductions in cerebral blood flow or through independent effects on neuronal function and cognition. We addressed this using right unilateral common carotid artery occlusion to model vascular cognitive impairment and long-term high-fat diet to model type 2 diabetes in mice. Cognition was assessed using novel object recognition task, Morris water maze, and contextual and cued fear conditioning. Cerebral blood flow was assessed using arterial spin labeling magnetic resonance imaging. Vascular cognitive impairment mice showed cognitive deficit in the novel object recognition task, decreased cerebral blood flow in the right hemisphere, and increased glial activation in white matter and hippocampus. Mice fed a high-fat diet displayed deficits in the novel object recognition task, Morris water maze and fear conditioning tasks and neuronal loss, but no impairments in cerebral blood flow. Compared to vascular cognitive impairment mice fed a low fat diet, vascular cognitive impairment mice fed a high-fat diet exhibited reduced cued fear memory, increased deficit in the Morris water maze, neuronal loss, glial activation, and global decrease in cerebral blood flow. We conclude that high-fat diet and chronic hypoperfusion impair cognitive function by different mechanisms, although they share commons features, and that high-fat diet exacerbates vascular cognitive impairment pathology.
authors.affiliation: Department of Anesthesiology and Perioperative Medicine, Oregon Health and Science University, Portland, OR, USA.
authors.forename: Kristen L
authors.initials: KL
authors.lastname: Zuloaga
authors.affiliation: The Knight Cardiovascular Institute, Portland, OR, USA Department of Behavioral Neuroscience, Portland, OR, USA.
authors.forename: Lance A
authors.initials: LA
authors.lastname: Johnson
authors.affiliation: Department of Anesthesiology and Perioperative Medicine, Oregon Health and Science University, Portland, OR, USA.
authors.forename: Natalie E
authors.initials: NE
authors.lastname: Roese
authors.affiliation: Department of Behavioral Neuroscience, Portland, OR, USA.
authors.forename: Tessa
authors.initials: T
authors.lastname: Marzulla
authors.affiliation: Department of Anesthesiology and Perioperative Medicine, Oregon Health and Science University, Portland, OR, USA.
authors.forename: Wenri
authors.initials: W
authors.lastname: Zhang
authors.affiliation: Department of Anesthesiology and Perioperative Medicine, Oregon Health and Science University, Portland, OR, USA.
authors.forename: Xiao
authors.initials: X
authors.lastname: Nie
authors.affiliation: Department of Anesthesiology and Perioperative Medicine, Oregon Health and Science University, Portland, OR, USA.
authors.forename: Farah N
authors.initials: FN
authors.lastname: Alkayed
authors.affiliation: Department of Anesthesiology and Perioperative Medicine, Oregon Health and Science University, Portland, OR, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Hong
authors.affiliation: Department of Anesthesiology and Perioperative Medicine, Oregon Health and Science University, Portland, OR, USA Department of Pathology, Portland, OR, USA.
authors.forename: Marjorie R
authors.initials: MR
authors.lastname: Grafe
authors.affiliation: Advanced Imaging Resource Center, Oregon Health and Science University, Portland, OR, USA.
authors.forename: Martin M
authors.initials: MM
authors.lastname: Pike
authors.affiliation: The Knight Cardiovascular Institute, Portland, OR, USA Department of Behavioral Neuroscience, Portland, OR, USA Departments of Neurology and Radiation Medicine, Division of Neuroscience, ONPRC, Oregon Health and Science University, Portland, OR, USA.
authors.forename: Jacob
authors.initials: J
authors.lastname: Raber
authors.affiliation: Department of Anesthesiology and Perioperative Medicine, Oregon Health and Science University, Portland, OR, USA The Knight Cardiovascular Institute, Portland, OR, USA alkayedn@ohsu.edu.
authors.forename: Nabil J
authors.initials: NJ
authors.lastname: Alkayed
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000502:physiology; D001921:Brain / Q000098:blood supply* / Q000000981:diagnostic imaging / Q000473:pathology; D017536:Carotid Artery, Common / Q000503:physiopathology; D016893:Carotid Stenosis / Q000150:complications / Q000000981:diagnostic imaging / Q000503:physiopathology*; D002560:Cerebrovascular Circulation / Q000502:physiology*; D003072:Cognition Disorders / Q000209:etiology* / Q000503:physiopathology / Q000523:psychology; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000000981:diagnostic imaging / Q000503:physiopathology*; D059305:Diet, High-Fat / Q000009:adverse effects*; D004730:Endothelium, Vascular / Q000503:physiopathology; D007091:Image Processing, Computer-Assisted; D008279:Magnetic Resonance Imaging; D008297:Male; D018782:Maze Learning / Q000502:physiology; D008810:Mice, Inbred C57BL
keywords: Vascular cognitive impairment; cerebral blood flow; chronic cerebral hypoperfusion; cognitive impairment; diabetes; high-fat diet; vascular dementia