Neuroinflammation underlies the development of social stress induced cognitive deficit in sickle cell disease.
Cognitive deficit is a debilitating complication of SCD with a 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. Overall design: To test whether exposure of sickle cell mice to repeated social defeat results intotal transipt tomics changes and whether treatment with minocycline will ameliorate this changes. We performed bulk RNA-sequencing on cortical and hippocampal samples from mice that were exposed to repeated social defeat (RSD), mice treated with minocycline and simultaneously exposed to repeated social disease and animals treated with our exposure to RSD and animals that were neither treated or exposed to RSD.