System Maintenance Notice

Please note that maintenance work is scheduled between 4 AM and 5 AM - CET. During this time, you may experience reduced performance. Thanks for your patience.

Publications

Journal Article Research Support, N.I.H., Intramural Ppublish 5 citations

PubMed: 32533970 DOI: 10.1016/j.brainres.2020.146968

Locomotor mal-performance and gait adaptability deficits in sickle cell mice are associated with vascular and white matter abnormalities and oxidative stress in cerebellum.

Brain Res 1746:146968

Authors: Luis E F Almeida, Li Wang, Sayuri Kamimura, Patricia M Zerfas, Meghann L Smith, Osorio L Abath Neto, Ticiana Vale, Martha M Quezado, Iren Horkayne-Szakaly, Paul Wakim, Zenaide M N Quezado

Affiliations

  • Department of Perioperative Medicine, National Institutes of Health Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA.
  • Center for Neuroscience Research and The Sheikh Zayed Institute for Pediatric Surgical Innovation, Children's Research Institute, School of Medicine and Health Sciences, George Washington University, Washington, DC 20010, USA.
  • Office of Research Services, Office of the Director, National Institutes of Health, Bethesda, MD 20892, USA.
  • Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
  • Neuropathology and Ophthalmic Pathology, Joint Pathology Center, Defense Health Agency, Silver Spring, MD 20910, USA.
  • Biostatistics and Clinical Epidemiology Service, National Institutes of Health Clinical Center, Bethesda, MD 20892, USA.
  • Department of Perioperative Medicine, National Institutes of Health Clinical Center, National Institutes of Health, Bethesda, MD 20892, USA.

Abstract

Patients with sickle cell disease (SCD) can develop strokes and as a result, present neurologic and neurocognitive deficits. However, recent studies show that even without detectable cerebral parenchymal abnormalities on imaging studies, SCD patients can have significant cognitive and motor dysfunction, which can present as early as during infancy. As the cerebellum plays a pivotal role in motor and non-motor functions including sensorimotor processing and learning, we examined cerebellar behavior in humanized SCD mice using the Erasmus ladder. Homozygous (sickling) mice had significant locomotor malperformance characterized by miscoordination and impaired locomotor gait/stepping pattern adaptability. Conversely, Townes homozygous mice had no overall deficits in motor learning, as they were able to associate a conditioning stimulus (high-pitch warning tone) with the presentation of an obstacle and learned to decrease steptimes thereby increasing speed to avoid it. While these animals had no cerebellar strokes, these locomotor and adaptive gait/stepping patterns deficits were associated with oxidative stress, as well as cerebellar vascular endothelial and white matter abnormalities and blood brain barrier disruption, suggestive of ischemic injury. Taken together, these observations suggest that motor and adaptive locomotor deficits in SCD mice mirror some of those described in SCD patients and that ischemic changes in white matter and vascular endothelium and oxidative stress are biologic correlates of those deficits. These findings point to the cerebellum as an area of the central nervous system that is vulnerable to vascular and white matter injury and support the use of SCD mice for studies of the underlying mechanisms of cerebellar dysfunction in SCD.

MeSH

Stroke, Oxidative Stress, Stress, Physiological, Cells, Gait, Neurology, Blood-Brain Barrier, Learning, Cerebellum, White Matter

Cited by