Neuroinflammation underlies the development of social stress induced cognitive deficit in sickle cell disease.

Cognitive deficit is a debilitating complication of SCD with multifactorial pathobiology. Here we show that neuroinflammation and dysregulation in lipidomics and transcriptomics profiles are major underlying mechanisms of social stress-induced cognitive deficit in SCD. Townes sickle cell (SS) mice and controls (AA) were exposed to social stress using the repeat social defeat (RSD) paradigm concurrently with or without treatment with minocycline. Mice were tested for cognitive deficit using novel object recognition (NOR) and fear conditioning (FC) tests. SS mice exposed to RSD without treatment had worse performance on cognitive tests compared to SS mice exposed to RSD with treatment or to AA controls, irrespective of their RSD or treatment disposition. Additionally, compared to SS mice exposed to RSD with treatment, SS mice exposed to RSD without treatment had significantly more cellular evidence of neuroinflammation coupled with a significant shift in the differentiation of neural progenitor cells towards astrogliogenesis. Additionally, brain tissue from SS mice exposed to RSD was significantly enriched for genes associated with blood-brain barrier dysfunction, neuron excitotoxicity, inflammation, and significant dysregulation in sphingolipids important to neuronal cell processes. We demonstrate in this study that neuroinflammation and lipid dysregulation are potential underlying mechanisms of social stress-related cognitive deficit in SS mice. Key PointsO_LINeuroinflammation and lipid dysfunction are potential underlying mechanisms of social stress-related cognitive deficit in SCD patients. C_LIO_LIMitigating or ameliorating the impact of cognitive deficits in SCD needs to consider the biological changes already created by exposure to social stress. C_LI Novelty of our FindingsWe show for the first time, that neuroinflammation along with changes in the brain lipidome and transcriptome, are underlying biological mechanism contributing to the development and potentially progression of cognitive impairment among sickle cell patients. These findings also provide for the first time, a mechanistic basis for an earlier reported observation of a higher likelihood of having lower intelligence quotient scores among children with sickle cell disease exposed to social stress in the form of low parental socioeconomic status.