Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel.
Mol Syst Biol. 2020 Jul;16(7):e9510. doi: 10.15252/msb.20209510.
Stress activates a complex network of hormones known as the hypothalamic-pituitary-adrenal (HPA) axis. The HPA axis is dysregulated in chronic stress and psychiatric disorders, but the origin of this dysregulation is unclear and cannot be explained by current HPA models. To address this, we developed a mathematical model for the HPA axis that incorporates changes in the total functional mass of the HPA hormone-secreting glands. The mass changes are caused by HPA hormones which act as growth factors for the glands in the axis. We find that the HPA axis shows the property of dynamical compensation, where gland masses adjust over weeks to buffer variation in physiological parameters. These mass changes explain the experimental findings on dysregulation of cortisol and ACTH dynamics in alcoholism, anorexia, and postpartum. Dysregulation occurs for a wide range of parameters and is exacerbated by impaired glucocorticoid receptor (GR) feedback, providing an explanation for the implication of GR in mood disorders. These findings suggest that gland-mass dynamics may play an important role in the pathophysiology of stress-related disorders.
压力会激活一个被称为下丘脑-垂体-肾上腺（HPA）轴的复杂激素网络。HPA 轴在慢性压力和精神障碍中失调，但这种失调的起源尚不清楚，无法用当前的 HPA 模型来解释。为了解决这个问题，我们开发了一个 HPA 轴的数学模型，该模型纳入了 HPA 激素分泌腺总功能质量的变化。质量变化是由 HPA 激素引起的，这些激素是轴中腺体的生长因子。我们发现，HPA 轴表现出动态补偿的特性，即腺体质量在数周内进行调整，以缓冲生理参数的变化。这些质量变化解释了酒精中毒、厌食症和产后皮质醇和 ACTH 动力学失调的实验发现。失调发生在广泛的参数范围内，并且由于糖皮质激素受体（GR）反馈受损而加剧，这为 GR 在情绪障碍中的作用提供了一个解释。这些发现表明，腺体质量动态可能在与压力相关的疾病的病理生理学中发挥重要作用。
