Gradual Cerebral Hypoperfusion Impairs Fear Conditioning and Object Recognition Learning and Memory in Mice: Potential Roles of Neurodegeneration and Cholinergic Dysfunction

J Alzheimers Dis. 2018;61(1):283-293. doi: 10.3233/JAD-170635.

Abstract

In the present study, male C57BL/6J mice were subjected to gradual cerebral hypoperfusion by implanting an ameroid constrictor (AC) on the left common carotid artery (CCA) and a stenosis on the right CCA. In the sham group, all surgical procedures were kept the same except no AC was implanted and stenosis was not performed. One month following the surgical procedures, fear conditioning and object recognition tests were conducted to evaluate learning and memory functions and motor functions were assessed using a balance beam test. At the experimental endpoint, mice were perfused and brains were collected for immunostaining and histology. Learning and memory as well as motor functions were significantly impaired in the hypoperfusion group. The immunoreactivity to choline acetyltransferase was decreased in dorsal striatum and basal forebrain of the hypoperfusion group indicating that cholinergic tone in these brain regions was compromised. In addition, an increased number of Fluoro-Jade positive neurons was also found in cerebral cortex, dorsal striatum and hippocampus indicating neurodegeneration in these brain regions. Based on this pattern of data, we argued that this mouse model would be a useful tool to investigate the therapeutic interventions for the treatment of vascular dementia. Additionally, this model could be employed to exploit the effect of microvascular occlusions on cognitive impairment in the absence and presence of Alzheimer's disease pathology.

Keywords: Ameroid constrictor; balance beam test; choline acetyltransferase; fear conditioning test; gradual hypoperfusion; neurodegeneration; novel object recognition test; vascular dementia.

MeSH terms

  • Animals
  • Brain / metabolism
  • Brain / pathology
  • Carotid Stenosis / complications*
  • Carotid Stenosis / psychology
  • Cerebrovascular Circulation / physiology
  • Choline O-Acetyltransferase / metabolism*
  • Conditioning, Psychological / physiology*
  • Disease Models, Animal
  • Fear*
  • Fluoresceins / metabolism
  • Learning Disabilities / etiology*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Phosphopyruvate Hydratase / metabolism
  • Postural Balance / physiology
  • Recognition, Psychology / physiology*

Substances

  • Fluoresceins
  • fluoro jade
  • Choline O-Acetyltransferase
  • Phosphopyruvate Hydratase