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

Kristen L. Zuloaga, Lance A. Johnson, Natalie E. Roese, Tessa Marzulla, Wenri Zhang, Xiao Nie, Farah N. Alkayed, Christine Hong, Marjorie R. Grafe, Martin M. Pike, Jacob Raber, Nabil J. Alkayed

Research output: Contribution to journalArticlepeer-review

67 Scopus citations


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.

Original languageEnglish
Pages (from-to)1257-1270
Number of pages14
JournalJournal of Cerebral Blood Flow and Metabolism
Issue number7
StatePublished - Jul 1 2016

Bibliographical note

Funding Information:
This work was supported by R21AG043857 (N.J.A.), R01NS070837 (N.J.A.), F32NS082017 (K.L.Z.) National Science Foundation, SMA-1408653 (LAJ), T32-HL094294 (L.A.J.), Oregon Tax Check-off Grant Alzheimer's Research Fund (L.A.J.), the Collins Medical Trust (L.A.J.), and the development account of J.R.

Publisher Copyright:
© The Author(s) 2015.


  • Vascular cognitive impairment
  • cerebral blood flow
  • chronic cerebral hypoperfusion
  • cognitive impairment
  • diabetes
  • high-fat diet
  • vascular dementia

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology
  • Cardiology and Cardiovascular Medicine


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