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

Cell Death and Disease, 2025 · DOI: https://doi.org/10.1038/s41419-025-07542-y · Published: March 17, 2025

Simple Explanation

Spinal cord injury can lead to cognitive and emotional problems. This study found that after spinal cord injury, there's an increase in GFAP signals in a specific brain region called the frontal association cortex (FrA). This increase is linked to nerve cells (neurons) undergoing programmed cell death (apoptosis) that also have increased levels of a protein called SGK1. Further experiments suggest that SGK1 may protect these neurons from apoptosis. The researchers suggest that targeting SGK1 in neurons of the limbic system (involved in emotions) could be a potential treatment for the cognitive and emotional problems that can occur after spinal cord injuries.

Study Duration

Not specified

Participants

C57BL/6 mice

Evidence Level

Not specified

Key Findings

1
Spinal cord transection (SCT) surgery led to increased bioluminescence in the brain, particularly in the frontal association cortex (FrA).
2
GFAP signals were intensified in the FrA due to apoptotic neurons with SGK1 upregulation, induced by sustained high glucocorticoid levels after SCT.
3
SGK1 upregulation in FrA neurons exerted anti-apoptotic effects through NRF2/HO-1 signaling, and SGK1 knockdown aggravated post-SCI depressive-like behaviors.

Research Summary

This study investigates the mechanisms underlying cognitive deficits and emotional disorders after spinal cord injury (SCI). The researchers used a GFAP-IRES-Venus-AkaLuc knock-in mouse model to study astrocyte activation after SCI. They found that complete spinal cord transection (SCT) led to increased bioluminescence in the brain, specifically in the frontal association cortex (FrA), an area involved in learning and memory. Further investigation revealed that increased GFAP signals in the FrA were due to apoptotic neurons with SGK1 upregulation, which had anti-apoptotic effects through NRF2/HO-1 signaling. Knockdown of SGK1 in FrA neurons worsened depressive-like behaviors post-SCI.

Practical Implications

Therapeutic Target

Ectopic SGK1 expression designated for limbic neurons could serve as a therapeutic target for treatments for spinal cord injuries.

Understanding SCI Complications

The study enhances understanding of the encephalic region involvement in cognitive and emotional disorders post-SCI.

Glucocorticoid Management

Managing glucocorticoid levels post-SCI may reduce neuronal apoptosis in the FrA and improve outcomes.

Study Limitations

1
Whether GFAP-positive neurons in encephalic regions other than FrA are apoptotic remains unknown.
2
The phenotypes and functions of apoptotic GFAP-positive neurons in the FrA are unclear.
3
The exact mechanisms underlying their sensitivity to high-level glucocorticoids are largely elusive.

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