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Zhao Y, Jiang H, Shang H, Xia Z. Thyroid-stimulating Hormone Inhibition Drives Hippocampal 5-HT Loss and Notch Activation, Disrupting Neurogenesis–apoptosis Balance and Inducing Mood-related Behaviors in Rats. BCN 2026; 17 (2) :309-322
URL: http://bcn.iums.ac.ir/article-1-3374-fa.html

Introduction: Therapeutic suppression of thyroid-stimulating hormone (TSH) is widely used after thyroidectomy, but its neurobehavioral impact remains unclear. 
Methods: We investigated emotion-related behaviors and hippocampal mechanisms in rats assigned to the blank control, TSH replacement, or TSH inhibition groups following total thyroidectomy with graded levothyroxine. Open-field and tail suspension tests (TSTs) indexed behavior; ELISA quantified serum FT3/FT4/TSH and hippocampal 5-HT levels; BrdU with Nestin/NeuN/GFAP assessed neurogenesis; and qPCR/Western blot measured Notch1, HES1/HES5, Jagged-1, and Bax/Bcl-2 expression levels.
Results: Compared with control/replacement groups, TSH inhibition produced anxiety-/depression-like phenotypes, elevated FT3/FT4 with reduced TSH levels, and decreased hippocampal 5-HT levels. Notably, Notch signaling was upregulated and functionally linked to behavior by biasing neural stem-cell fate away from neurons toward astrocytes and curtailing neurogenesis, a cellular change that maps corresponds to the observed anxiety- and depression-like outcomes. Concomitantly, an increased Bax/Bcl-2 ratio indicated a pro-apoptotic shift that undermines hippocampal plasticity, providing an additional mechanistic bridge to the behavioral phenotype. Together, reduced 5-HT (upstream) levels, Notch-driven suppression of neuronal differentiation, and heightened apoptosis converge to impair hippocampal circuit integrity, offering a coherent molecular-to-behavioral pathway for mood-related effects under TSH suppression.
Conclusion: These findings suggest that long-term TSH inhibition may carry neuropsychiatric risks and support routine monitoring of mood and cognition in patients receiving suppressive regimens.