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.

Characterization of a mouse model of sickle cell trait: parallels to human trait and a novel finding of cutaneous sensitization

“…As chronic pain is not typically considered a common outcome of SCT, these findings may inform future clinical follow‐up or may alternatively indicate that even Berk AS mice generate an exaggerated sickle‐like phenotype, perhaps owing in part to differential regulation of haemoglobin subunits on the transgene compared to undisrupted regulation in naïve mice. Of note, some similar behavioural phenotypes have been reported in heterozygous Townes AS mice, which display normal haemoglobin levels and haematocrits (Wang et al , ) (data not shown). Of note, there are subtle differences between the Berk SS and Townes SS mice, including their respective pain phenotypes (Lei et al , ).…”

“…Several groups have characterized Berk hemizygous mice as having an intermediate sickle-like phenotype (Kohli et al, 2010;Szczepanek et al, 2012;Wang et al, 2016). However, these mice contain chimeric haemoglobin due to heterozygous expression of murine b globin as well as expression of one or two copies of the transgene containing the sickle variant of human b globin [Tg(Hu-miniLCRa1 Gc A cdb S ) Hba 0 //Hba 0 Hbb + //Hbb 0 ] (Manci et al, 2007;Kohli et al, 2010;Wang et al, 2016). This chimeric haemoglobin (human a globin paired with mouse b globin) has impaired oxygen affinity, leading to increased tissue hypoxia and renal pathology in these hemizygous mice (Noguchi et al, 2001).…”

Neurochemical and Behavior Deficits in Rats with Iron and Rotenone Co-treatment: Role of Redox Imbalance and Neuroprotection by Biochanin A

“…Insufficient iron supplement also results in a number of neurological and psychiatric conditions such as pediatric restless leg syndrome and attention deficit hyperactivity disorder (Millichap, 2008 ; Benton, 2010 ). In addition, anemia due to iron deficiency in infants contributes to cognitive and social impairments (Carter et al, 2010 ; Wang L. et al, 2016 ). Because of the essential role of iron in neurological as well as overall development, it has been recommended that breast milk which contains iron nutrition is preferred benefit for infants and may be replaced with iron-fortified formula to those who cannot receive breastfeed.…”

The corticosteroid compounds prednisolone and vamorolone do not alter the nociception phenotype and exacerbate liver injury in sickle cell mice

“…We conducted a preclinical trial of vamorolone, a dissociative, and of prednisolone, a conventional corticosteroid, to test the hypotheses that in humanized SCD mice 27 – 30 dissociative corticosteroids would improve the nociception phenotype, decrease signs of inflammation, and improve organ dysfunction. We designed a preclinical trial of vamorolone and prednisolone enrolling humanized Townes sickle cell male and female mice of all genotypes [controls, heterozygotes, and homozygotes (sickling)].…”

“…We designed a preclinical trial of vamorolone and prednisolone enrolling humanized Townes sickle cell male and female mice of all genotypes [controls, heterozygotes, and homozygotes (sickling)]. Homozygotes in this mouse strain are known to recapitulate hematologic and nociception phenotypes of human SCD 27 – 32 .…”