title: Cognitive and behavior deficits in sickle cell mice are associated with profound neuropathologic changes in hippocampus and cerebellum.
abstract: Strokes are perhaps the most serious complications of sickle cell disease (SCD) and by the fifth decade occur in approximately 25% of patients. While most patients do not develop strokes, mounting evidence indicates that even without brain abnormalities on imaging studies, SCD patients can present profound neurocognitive dysfunction. We sought to evaluate the neurocognitive behavior profile of humanized SCD mice (Townes, BERK) and to identify hematologic and neuropathologic abnormalities associated with the behavioral alterations observed in these mice. Heterozygous and homozygous Townes mice displayed severe cognitive deficits shown by significant delays in spatial learning compared to controls. Homozygous Townes also had increased depression- and anxiety-like behaviors as well as reduced performance on voluntary wheel running compared to controls. Behavior deficits observed in Townes were also seen in BERKs. Interestingly, most deficits in homozygotes were observed in older mice and were associated with worsening anemia. Further, neuropathologic abnormalities including the presence of large bands of dark/pyknotic (shrunken) neurons in CA1 and CA3 fields of hippocampus and evidence of neuronal dropout in cerebellum were present in homozygotes but not control Townes. These observations suggest that cognitive and behavioral deficits in SCD mice mirror those described in SCD patients and that aging, anemia, and profound neuropathologic changes in hippocampus and cerebellum are possible biologic correlates of those deficits. These findings support using SCD mice for studies of cognitive deficits in SCD and point to vulnerable brain areas with susceptibility to neuronal injury in SCD and to mechanisms that potentially underlie those deficits.
authors.affiliation: The Sheikh Zayed Institute for Pediatric Surgical Innovation, Children's Research Institute, United States.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.affiliation: The Sheikh Zayed Institute for Pediatric Surgical Innovation, Children's Research Institute, United States.
authors.forename: Luis E F
authors.initials: LEF
authors.lastname: Almeida
authors.affiliation: Department of Nutritional Sciences, Howard University, Washington DC 20059, United States.
authors.forename: Celia M
authors.initials: CM
authors.lastname: de Souza Batista
authors.affiliation: The Sheikh Zayed Institute for Pediatric Surgical Innovation, Children's Research Institute, United States.
authors.forename: Alfia
authors.initials: A
authors.lastname: Khaibullina
authors.affiliation: The Sheikh Zayed Institute for Pediatric Surgical Innovation, Children's Research Institute, United States.
authors.forename: Nuo
authors.initials: N
authors.lastname: Xu
authors.affiliation: The Sheikh Zayed Institute for Pediatric Surgical Innovation, Children's Research Institute, United States.
authors.forename: Sarah
authors.initials: S
authors.lastname: Albani
authors.affiliation: The Sheikh Zayed Institute for Pediatric Surgical Innovation, Children's Research Institute, United States.
authors.forename: Kira A
authors.initials: KA
authors.lastname: Guth
authors.affiliation: The Sheikh Zayed Institute for Pediatric Surgical Innovation, Children's Research Institute, United States.
authors.forename: Ji Sung
authors.initials: JS
authors.lastname: Seo
authors.affiliation: Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, United States.
authors.forename: Martha
authors.initials: M
authors.lastname: Quezado
authors.affiliation: The Sheikh Zayed Institute for Pediatric Surgical Innovation, Children's Research Institute, United States; Divisions of Anesthesiology and Pain Medicine, Children's National Health System, United States; Center for Neuroscience Research, Children's Research Institute, Children's National Health System, School of Medicine and Health Sciences, George Washington University, Washington, DC 20010, United States. Electronic address: zquezado@childrensnational.org.
authors.forename: Zenaide M N
authors.initials: ZMN
authors.lastname: Quezado
mesh_terms: D000375:Aging / Q000473:pathology / Q000502:physiology / Q000523:psychology; D000755:Anemia, Sickle Cell / Q000473:pathology* / Q000503:physiopathology* / Q000523:psychology; D000818:Animals; D002531:Cerebellum / Q000473:pathology* / Q000503:physiopathology; D003072:Cognition Disorders / Q000209:etiology / Q000473:pathology* / Q000503:physiopathology*; D015331:Cohort Studies; D003430:Cross-Sectional Studies; D003863:Depression / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D005260:Female; D005838:Genotype; D006624:Hippocampus / Q000473:pathology* / Q000503:physiopathology; D007501:Iron / Q000378:metabolism; D008297:Male; D018782:Maze Learning / Q000502:physiology; D008822:Mice, Transgenic; D009043:Motor Activity / Q000502:physiology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D012193:Reversal Learning / Q000502:physiology; D012727:Sex Characteristics
chemical_list: D007501:Iron
keywords: Anemia; Anxiety; Cerebellum; Depression; Hippocampus; Learning; Memory; Neuronal injury; Pain