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.

镰状细胞病 (SCD) 患者可能会发生中风，并因此出现神经和神经认知缺陷。然而，最近的研究表明，即使在影像学检查中没有可检测到的脑实质异常，SCD 患者也可能有严重的认知和运动功能障碍，这可能早在婴儿时期就出现。由于小脑在运动和非运动功能（包括感觉运动处理和学习）中起着关键作用，我们使用伊拉斯谟阶梯检查了人源化 SCD 小鼠的小脑行为。纯合子（镰状）小鼠有明显的运动障碍，其特征是协调不良和运动步态/步态适应性受损。相反，Townes 纯合小鼠在运动学习方面没有总体缺陷，因为他们能够将条件刺激（高音警告音）与障碍物的出现联系起来，并学会减少步进时间从而提高速度以避免它。虽然这些动物没有小脑中风，但这些运动和适应性步态/步态缺陷与氧化应激、小脑血管内皮和白质异常以及血脑屏障破坏有关，提示缺血性损伤。综上所述，这些观察结果表明 SCD 小鼠的运动和适应性运动缺陷反映了 SCD 患者中描述的一些缺陷，并且白质和血管内皮的缺血性变化和氧化应激是这些缺陷的生物学相关性。