Bao A-M, Meynen G, Swaab D F
Netherlands Institute for Neuroscience, Meibergdreef 47, 1105 BA Amsterdam, The Netherlands.
Brain Res Rev. 2008 Mar;57(2):531-53. doi: 10.1016/j.brainresrev.2007.04.005. Epub 2007 Apr 27.
The stress response is mediated by the hypothalamo-pituitary-adrenal (HPA) system. Activity of the corticotropin-releasing hormone (CRH) neurons in the hypothalamic paraventricular nucleus (PVN) forms the basis of the activity of the HPA-axis. The CRH neurons induce adrenocorticotropin (ACTH) release from the pituitary, which subsequently causes cortisol release from the adrenal cortex. The CRH neurons co-express vasopressin (AVP) which potentiates the CRH effects. CRH neurons project not only to the median eminence but also into brain areas where they, e.g., regulate the adrenal innervation of the autonomic system and affect mood. The hypothalamo-neurohypophysial system is also involved in stress response. It releases AVP from the PVN and the supraoptic nucleus (SON) and oxytocin (OXT) from the PVN via the neurohypophysis into the bloodstream. The suprachiasmatic nucleus (SCN), the hypothalamic clock, is responsible for the rhythmic changes of the stress system. Both centrally released CRH and increased levels of cortisol contribute to the signs and symptoms of depression. Symptoms of depression can be induced in experimental animals by intracerebroventricular injection of CRH. Depression is also a frequent side effect of glucocorticoid treatment and of the symptoms of Cushing's syndrome. The AVP neurons in the hypothalamic PVN and SON are also activated in depression, which contributes to the increased release of ACTH from the pituitary. Increased levels of circulating AVP are also associated with the risk for suicide. The prevalence, incidence and morbidity risk for depression are higher in females than in males and fluctuations in sex hormone levels are considered to be involved in the etiology. About 40% of the activated CRH neurons in mood disorders co-express nuclear estrogen receptor (ER)-alpha in the PVN, while estrogen-responsive elements have been found in the CRH gene promoter region, and estrogens stimulate CRH production. An androgen-responsive element in the CRH gene promoter region initiates a suppressing effect on CRH expression. The decreased activity of the SCN is the basis for the disturbances of circadian and circannual fluctuations in mood, sleep and hormonal rhythms found in depression. Neuronal loss was also reported in the hippocampus of stressed or corticosteroid-treated rodents and primates. Because of the inhibitory control of the hippocampus on the HPA-axis, damage to this structure was expected to disinhibit the HPA-axis, and to cause a positive feedforward cascade of increasing glucocorticoid levels over time. This 'glucocorticoid cascade hypothesis' of stress and hippocampal damage was proposed to be causally involved in age-related accumulation of hippocampal damage in disorders like Alzheimer's disease and depression. However, in postmortem studies we could not find the presumed hippocampal damage of steroid overexposure in either depressed patients or in patients treated with synthetic steroids.
应激反应由下丘脑 - 垂体 - 肾上腺（HPA）系统介导。下丘脑室旁核（PVN）中促肾上腺皮质激素释放激素（CRH）神经元的活动构成了HPA轴活动的基础。CRH神经元诱导垂体释放促肾上腺皮质激素（ACTH），随后导致肾上腺皮质释放皮质醇。CRH神经元共表达血管加压素（AVP），其可增强CRH的作用。CRH神经元不仅投射到正中隆起，还投射到大脑其他区域，例如在这些区域它们调节自主神经系统的肾上腺神经支配并影响情绪。下丘脑 - 神经垂体系统也参与应激反应。它通过神经垂体从PVN和视上核（SON）释放AVP，并从PVN释放催产素（OXT）进入血液循环。视交叉上核（SCN），即下丘脑生物钟，负责应激系统的节律性变化。中枢释放的CRH和皮质醇水平升高均导致抑郁的体征和症状。通过脑室内注射CRH可在实验动物中诱发抑郁症状。抑郁也是糖皮质激素治疗和库欣综合征症状的常见副作用。下丘脑PVN和SON中的AVP神经元在抑郁时也会被激活，这导致垂体释放ACTH增加。循环中AVP水平升高也与自杀风险相关。女性抑郁的患病率、发病率和发病风险高于男性，性激素水平的波动被认为与病因有关。在情绪障碍中，约40%被激活的CRH神经元在PVN中共表达核雌激素受体（ER） - α，而在CRH基因启动子区域发现了雌激素反应元件，并且雌激素刺激CRH的产生。CRH基因启动子区域的雄激素反应元件对CRH表达产生抑制作用。SCN活动减少是抑郁中发现的昼夜节律和年节律波动紊乱、情绪、睡眠和激素节律紊乱的基础。在应激或接受皮质类固醇治疗的啮齿动物和灵长类动物的海马中也报道了神经元丢失。由于海马对HPA轴具有抑制性控制，预计该结构的损伤会解除对HPA轴的抑制，并随着时间的推移导致糖皮质激素水平呈正反馈级联增加。应激和海马损伤的这种“糖皮质激素级联假说”被认为与阿尔茨海默病和抑郁症等疾病中与年龄相关的海马损伤积累存在因果关系。然而，在尸检研究中，我们在抑郁症患者或接受合成类固醇治疗的患者中均未发现类固醇过度暴露所推测的海马损伤。
