SGK1 upregulation in GFAP+ neurons in the frontal association cortex protects against apoptosis after spinal cord injury

Spinal cord injury (SCI) casts devastating and long-lasting impacts on the well-being of patients. Cognitive deficits and emotional disorders are common in individuals with SCI, yet the underlying mechanisms are not completely understood. Astrogliosis and glial scar formation occur during the subacute phase post injury, playing complicated roles in remyelination and neurite regrowth. Therefore, we constructed a GFAP-IRES-Venus-AkaLuc knockin mouse model for the corresponding studies. Surprisingly, complete spinal cord transection (SCT) surgery led to earlier and more prominent augmentation of bioluminescence in the brain than in the spinal cord. Bulk RNA-sequencing revealed the activation of apoptotic signaling and upregulation of serum and glucocorticoid-regulated kinase 1 (SGK1). Tissue clearing and immunostaining revealed that the pattern of GFAP signals changed throughout the brain. Specifically, GFAP signals were intensified in the frontal association cortex (FrA), an encephalic region involved in associative learning and recognition memory processes. Further exploration indicated that intensified GFAP signals in FrA came from neurons with SGK1 upregulation and ongoing apoptosis. SGK1 upregulation was induced by sustained high glucocorticoid levels. The introduction of SGK1 silencing vectors confirmed that SGK upregulation exerted anti-apoptotic effects through the NRF2-HO1 signaling. Thus, ectopic SGK1 expression designated for limbic neurons could serve as a promising therapeutic target for the future development of treatments for spinal cord injuries.