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<p>The suprachiasmatic nucleus (SCN) is the central circadian clock in mammals, and its dysregulation is linked to various circadian disorders. Vasopressin signaling is a primary regulator of SCN synchronicity and functional output. We investigated the effect of the V1a receptor (V1aR) antagonist, balovaptan (30 mg/kg), on locomotor activity rhythms in mice following a 6-hour phase advance of the light-dark cycle. We found that a single administration significantly accelerated resynchronization of locomotor rhythms. To investigate the underlying mechanism, we developed a mathematical framework simulating the SCN and its control of biomarkers, including melatonin and core body temperature. Our model successfully captures the accelerated synchronization observed under V1aR antagonism and replicates well-established SCN behaviors, such as the phase response curve and forced desynchronization. Mechanistically, the model suggests that weakening vasopressin signaling strengthens the SCN’s resistance to internal desynchronization. Furthermore, we show a strong link between the endogenous period and the phase of circadian biomarkers. The model predicts that V1aR antagonism induces a phase advance proportional to the endogenous period, suggesting that individuals with longer endogenous periods may experience more substantial therapeutic benefits. This framework establishes a computational foundation for designing clinical trials evaluating V1aR antagonism for circadian rhythm disorders.</p>

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Modelling the effect of V1a receptor antagonism and its potential therapeutic effect in circadian disorders

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月3日

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  • Marcelo Boareto,
  • Jorge Mendoza,
  • Sebastian C. Holst,
  • Andries Kalsbeek,
  • Eric Prinssen,
  • Christophe Grundschober

摘要

The suprachiasmatic nucleus (SCN) is the central circadian clock in mammals, and its dysregulation is linked to various circadian disorders. Vasopressin signaling is a primary regulator of SCN synchronicity and functional output. We investigated the effect of the V1a receptor (V1aR) antagonist, balovaptan (30 mg/kg), on locomotor activity rhythms in mice following a 6-hour phase advance of the light-dark cycle. We found that a single administration significantly accelerated resynchronization of locomotor rhythms. To investigate the underlying mechanism, we developed a mathematical framework simulating the SCN and its control of biomarkers, including melatonin and core body temperature. Our model successfully captures the accelerated synchronization observed under V1aR antagonism and replicates well-established SCN behaviors, such as the phase response curve and forced desynchronization. Mechanistically, the model suggests that weakening vasopressin signaling strengthens the SCN’s resistance to internal desynchronization. Furthermore, we show a strong link between the endogenous period and the phase of circadian biomarkers. The model predicts that V1aR antagonism induces a phase advance proportional to the endogenous period, suggesting that individuals with longer endogenous periods may experience more substantial therapeutic benefits. This framework establishes a computational foundation for designing clinical trials evaluating V1aR antagonism for circadian rhythm disorders.