Role of the thioredoxin system in chronic corticosterone treatment- impaired neuronal differentiation and degeneration
Bibliographic record
Abstract
During the stress response, the hypothalamic-pituitary-adrenal (HPA) axis releases glucocorticoids into the bloodstream, targeting different organs including the brain. Chronic stress is a major risk factor for depression. Thioredoxin (Trx) is an oxidoreductase that reverses protein cysteine thiol oxidation, inhibits apoptosis signal-regulating kinase 1 (ASK1) and has been shown to promote cAMP response element-binding protein (CREB) activation. Trx reductase (TrxR) maintains Trx in a reduced state, while Trx interacting protein (Txnip) acts as an endogenous Trx inhibitor. Studies from our lab showed that chronic stress and chronic corticosterone (CORT) treatment upregulated Txnip and induced oxidative damage in cultured mouse neurons and mouse brain, suggesting that Trx system mediates CORT-induced neuronal damage. The objective of this work is to investigate the role of Trx system in chronic CORT-impaired neuronal differentiation and CORT-enhanced neurodegeneration. First, we found that Trx and TrxR protein levels increased during differentiation, while Txnip increased during neurodegeneration of primary mouse cortical neurons. Blocking Trx with CRISPR/Cas9 or the Trx inhibitor PX12 reduced neurite outgrowth. PX12 treatment also reduced the expression of synaptic proteins vGLUT1 and PSD95. Second, we found that CREB phosphorylation increased during neuronal differentiation and that blocking Trx reduced CREB phosphorylation in primary cortical neurons. In SH-SY5Y cells, we found that H2O2 reduced CREB phosphorylation and promoted CREB cysteine oxidation, while treatment with Trx mimetic peptide CB3 reversed H2O2 effect. We also found in primary mouse cortical neurons that ASK1 phosphorylation was increased during neurodegeneration and that PX12 increased ASK1 phosphorylation. Third, we found that CORT treatment elevated Txnip protein levels, reduced CREB phosphorylation, enhanced ASK1 phosphorylation, and impaired neurite outgrowth in primary neurons. Knocking down Txnip prevented CORT-impaired neurite outgrowth. Fourth, we found that chronic CORT injections induced depressive-like behaviors in mice, which was reversed by knocking down Txnip in the frontal cortex. Our findings suggest that Trx can facilitate neuronal differentiation by preserving the cellular redox balance, inhibiting CREB cysteine oxidation and maintaining CREB activation. Trx can also inhibit ASK1 apoptotic signaling and produce a neuroprotective effect. Chronic CORT treatment can upregulate Txnip, which may further inhibit Trx activity, inhibiting neurite outgrowth and promoting depressive-like behaviors in mice.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.001 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".