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Locomotor mal-performance and gait adaptability deficits in sickle cell mice are associated with vascular and white matter abnormalities and oxidative stress in cerebellum
Journal article   Open access   Peer reviewed

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

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, …
Brain research, Vol.1746, pp.146968-146968
11/01/2020
DOI: 10.1016/j.brainres.2020.146968
PMCID: PMC7483603
PMID: 32533970
url
https://doi.org/10.1016/j.brainres.2020.146968View
Published (Version of record) Open Access

Abstract

•Sickle cell disease (SCD) patients can have abnormal cerebellum on imaging studies.•SCD mice have evidence of cerebellar behavior deficits as described in SCD patients.•Cerebellar behavior deficits in SCD mice are associated with white matter abnormalities.•The deficits are associated with oxidative stress and vascular injury in cerebellum.•SCD mice are valid models for studies of cerebellar injury in SCD. 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.
 Anemia Cerebellum Balance Behavior Erasmus ladder Sickle

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