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Sexually Dimorphic Changes of Hypocretin (Orexin) in Depression

机译：抑郁症中促胰泌素（Orexin）的性二态性变化

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Highlights ? Hypocretin (orexin) changes were studied in human postmortem brain in depression. ? A clear sex-related change was found in the hypothalamic hypocretin-1-immunoreactivity in depression. ? A rat depression model did not reflect the changes in the hypocretin system in the human brain in depression. The stress systems of depressed patients are put into a higher gear by genetic and developmental factors. Over-reaction of these systems to stressful environmental situations makes people vulnerable to depression and suicide. This is the first postmortem study on changes in a relatively novel stress system in depression, consisting of the hypothalamic hypocretin neurons and hypocretin receptors in the prefrontal cortex. A clear sex-related change was found in the hypothalamic hypocretin-1-immunoreactivity in depression. Evaluation of the hypocretin system in a frequently used depression animal model, i.e. chronic unpredictable mild stress rats, did not replicate changes found in the hypocretin systems in the human brain in depression. BackgroundNeurophysiological and behavioral processes regulated by hypocretin (orexin) are severely affected in depression. However, alterations in hypocretin have so far not been studied in the human brain. We explored the hypocretin system changes in the hypothalamus and cortex in depression from male and female subjects.MethodsWe quantified the differences between depression patients and well-matched controls, in terms of hypothalamic hypocretin-1 immunoreactivity (ir) and hypocretin receptors (Hcrtr-receptors)-mRNA in the anterior cingulate cortex (ACC) and dorsolateral prefrontal cortex. In addition, we determined the alterations in the hypocretin system in a frequently used model for depression, the chronic unpredictable mild stress (CUMS) rat.Resultsi) Compared to control subjects, the amount of hypocretin-immunoreactivity (ir) was significantly increased in female but not in male depression patients; ii) hypothalamic hypocretin-ir showed a clear diurnal fluctuation, which was absent in depression; iii) male depressive patients who had committed suicide showed significantly increased ACC Hcrt-receptor-2-mRNA expression compared to male controls; and iv) female but not male CUMS rats showed a highly significant positive correlation between the mRNA levels of corticotropin-releasing hormone and prepro-hypocretin in the hypothalamus, and a significantly increased Hcrt-receptor-1-mRNA expression in the frontal cortex compared to female control rats.ConclusionsThe clear sex-related change found in the hypothalamic hypocretin-1-ir in depression should be taken into account in the development of hypocretin-targeted therapeutic strategies.
机译：强调 ？在抑郁症的人死后大脑中研究了降钙素（orexin）的变化。 ？在抑郁症的下丘脑hypocretin-1免疫反应性中发现了明显的性别相关变化。 ？大鼠抑郁模型不能反映抑郁症中人脑降钙素系统的变化。遗传和发育因素使抑郁症患者的压力系统处于较高水平。这些系统对压力环境的过度反应使人们容易遭受抑郁和自杀。这是关于抑郁症中相对较新的压力系统变化的首次事后研究，该系统由下丘脑前额叶皮层的下丘脑降钙素神经元和降钙素受体组成。在抑郁症的下丘脑hypocretin-1免疫反应性中发现了明显的性别相关变化。在经常使用的抑郁症动物模型（即慢性不可预测的轻度应激大鼠）中对降钙素系统的评估没有在抑郁症的人脑中复制在降钙素系统中发现的变化。背景在抑郁症中，受降钙素（orexin）调节的神经生理和行为过程受到严重影响。然而，迄今为止尚未在人脑中研究过降钙素的改变。我们探讨了男性和女性抑郁症患者下丘脑和皮层的降钙素系统变化。方法我们根据下丘脑的hypercretin-1免疫反应性（ir）和降钙素受体（Hcrtr-receptors）量化了抑郁症患者与相匹配的对照组之间的差异。扣带回皮层（ACC）和背外侧前额叶皮层中的）-mRNA。此外，我们确定了在经常使用的抑郁模型慢性慢性不可预知轻度应激（CUMS）大鼠中降钙素系统的变化。结果）与对照组相比，雌性降钙素免疫反应（ir）的量显着增加但不适用于男性抑郁症患者; ii）下丘脑hypercretin-ir表现出明显的昼夜波动，而在抑郁症中则没有。 iii）与男性对照者相比，自杀的男性抑郁症患者的ACC Hcrt-receptor-2-mRNA表达显着增加; iv）雌性而不是雄性CUMS大鼠在下丘脑中的促肾上腺皮质激素释放激素与促胰降血糖素原mRNA水平之间呈高度显着正相关，与额叶皮质相比，Hcrt-receptor-1-mRNA表达显着增加。结论在下丘脑靶向治疗策略的制定中应考虑到在丘脑下丘脑hypocretin-1-ir中发现的明显的性别相关变化。

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