Mechanism of Social Stress Mediated Cognitive Deficit in Sickle Cell Disease

Cognitive and behavioral deficits comprise understudied aspects of sickle cell disease (SCD)-related neurological complications. Recent evidence suggests that social stress is associated with impaired cognitive and neurobehavioral function in non-SCD populations.[1-3] Our hypothesis is that cognitive impairment associated with stress in sickle cell disease is modulated by neuroinflammation and/or alterations in the brain lipidomic profile compared to controls, based on published studies showing a dysregulation of sphingolipid(SL) metabolism in RBCs due to sickle cell mutation and a resultant change in the expression of inflammatory factors, including EVs that induce inflammatory phenotypes in myeloid cells[4]. Additionally, SLs are critical to the remodeling of dendritic spines and activation of microglia. The repeat social defeat (RSD) paradigm will be used to model social stress in the Townes humanized sickle cell (HbSS) and control (HbAA) mice. Mice will be randomized based on genotype and RSD disposition to be used for brain lipidomic profiling, immunohistochemistry for assessing neuroinflammation, and Golgi-Cox impregnation for the assessment of neuronal morphology. We performed LC/MS analysis of brain samples selected from the cerebrum and hippocampus after exposure to social stress in the form of RSD. Preliminary data suggests that changes in concentration of bioactive lipids in the brain in SS mice may result in significant impairment in learning and memory.

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4. Botchwey, E.A., et al., Sphingolipid dysregulation in erythrocytes during sickle cell disease contributes to pro-inflammatory microparticle generation and subsequent inflammatory cell activation. 2016.