High fat diet-induced diabetes in mice exacerbates cognitive deficit due to chronic hypoperfusion

J Cereb Blood Flow Metab. 2016 Jul;36(7):1257-70. doi: 10.1177/0271678X15616400. Epub 2015 Nov 11.


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.

Keywords: Vascular cognitive impairment; cerebral blood flow; chronic cerebral hypoperfusion; cognitive impairment; diabetes; high-fat diet; vascular dementia.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Behavior, Animal / physiology
  • Brain / blood supply*
  • Brain / diagnostic imaging
  • Brain / pathology
  • Carotid Artery, Common / physiopathology
  • Carotid Stenosis / complications
  • Carotid Stenosis / diagnostic imaging
  • Carotid Stenosis / physiopathology*
  • Cerebrovascular Circulation / physiology*
  • Cognition Disorders / etiology*
  • Cognition Disorders / physiopathology
  • Cognition Disorders / psychology
  • Diabetes Mellitus, Experimental / complications
  • Diabetes Mellitus, Experimental / diagnostic imaging
  • Diabetes Mellitus, Experimental / physiopathology*
  • Diet, High-Fat / adverse effects*
  • Endothelium, Vascular / physiopathology
  • Image Processing, Computer-Assisted
  • Magnetic Resonance Imaging
  • Male
  • Maze Learning / physiology
  • Mice, Inbred C57BL