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

BackgroundSpinal 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. MethodsWe 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 (|log2FC| > 1, Padj < 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. ResultsIn the discovery cohort, high-thoracic SCI produced a lesion-level-dependent neuroendocrine surge in the hypothalamus: Avp (fold change 7.23; Padj = 0.002), Oxt (fold change 14.25; Padj = 2.3 x 10-7), and Ucn3 (fold change 9.22; Padj = 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 Padj > 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. ConclusionsThese 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.