Lesion-Level-Dependent Neuroendocrine Surge Precedes Neuroinflammation and Endoplasmic Reticulum Stress in the Hypothalamus After Spinal Cord Injury: Dual-Cohort Transcriptomic Evidence for a Temporally Ordered AVP Cascade
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Background
Spinal cord injury (SCI) triggers remote pathological changes in supraspinal regions, including neuroendocrine dysfunction that manifests clinically as hyponatremia and central diabetes insipidus. Clinical observations of lesion-level dependency and sequential transformation between these disorders suggest a temporally ordered hypothalamic cascade in which a compensatory arginine vasopressin (AVP)-driven neuroendocrine surge may precede a later neuroinflammation and endoplasmic reticulum (ER) stress-mediated neuronal exhaustion. Direct transcriptomic evidence for the temporal ordering of these events, however, has been lacking.
Methods
We performed a dual-cohort transcriptomic analysis. A discovery cohort (NCBI Sequence Read Archive PRJNA953752) comprised hypothalamic tissue from adult male Sprague-Dawley rats subjected to high-thoracic (T3) SCI, low-thoracic (T10) SCI, or sham surgery, sampled at post-injury day 7 and analyzed with edgeR/DESeq2 (|log 2 FC| > 1, P adj < 0.05). An independent chronic-phase validation cohort (Gene Expression Omnibus GSE297887) of hippocampal tissue from SCI and sham mice was interrogated as a sensitive supraspinal proxy for remote neuroinflammatory and ER-stress signatures. Pre-defined gene panels covered neuroendocrine, neuroinflammation, and ER-stress/unfolded-protein-response categories.
Results
In the discovery cohort, high-thoracic SCI produced a lesion-level-dependent neuroendocrine surge in the hypothalamus: Avp (fold change 7.23; P adj = 0.002), Oxt (fold change 14.25; P adj = 2.3 × 10 −7 ), and Ucn3 (fold change 9.22; P adj = 0.002) were among the most significantly upregulated genes genome-wide, whereas low-thoracic SCI failed to reach significance for any of these targets. Classical neuroinflammation markers and canonical ER-stress effectors remained transcriptionally silent (all P adj > 0.69). The PERK-pathway sentinel genes Trib3 and Ppp1r15a/GADD34 exhibited coordinated sub-threshold trends indicative of early activation, and Avp expression was tightly correlated with Mmp9 (r = 0.833; P = 0.0004). In the chronic-phase validation cohort, microglial P2ry12 and ferroptosis signatures were significantly upregulated ( P2ry12 fold change 1.33; P = 0.008) suggesting a primed microglial state, while ER-stress effectors remained silent.
Conclusions
These data support a temporally ordered hypothalamic cascade after SCI in which an early compensatory neuroendocrine surge precedes — and may precipitate, through biosynthetic overload and blood–brain-barrier disruption — a subsequent neuroinflammation and ER-stress crisis. The defined molecular window between neuroendocrine activation and inflammatory/ER-stress engagement identifies a candidate therapeutic window for early neuroprotective intervention in acute SCI.
