两篇Nature：学习压力分子机制

　　

生物通报道：来自加拿大卡尔加里大学（University of Calgary）霍奇基斯脑研究所（Hotchkiss Brain Institute）的研究人员发现大脑中的压力环路（stress circuits）在生命早期经过了复杂的学习过程。研究人员采用了多种尖端的技术，包括光遗传学，指出在单个应激后，压力环路能自我调整，这表明大脑在生命早期利用压力经验，为后续的挑战做准备。

领导这一研究的是加拿大卡尔加里大学Jaideep Bains博士，他和他的同事发现了在增加或减少学习的过程中所产生的短压力独特时间窗口。他们通过操控特殊的细胞途径，揭示出了一种动物模型中学习在压力环路中的关键作用。

这些发现公布在世界顶级神经系统科学期刊Nature Neuroscience的4月7在线版上。

“这些新研究结果表明，之前被认为是‘硬件’的大脑神经系统实际上很灵活，尤其是在生命早期，”卡尔加里大学生理和药理系教授Bains说，“利用这些信息，研究人员现在可以进一步探索早期生命压力和压力应激易感，或后期反弹之间的精密细胞和分子联系。”

压力应激易感（Stress vulnerability），也就是对压力的敏感性，出现在许多健康问题中，蔽日心血管疾病，肥胖，糖尿病和抑郁症等。虽然最新这些研究采用的是动物模型，但是在人体中也存在相似的病理机制。

“我们的研究为设计更有效的预防和治疗减轻压力作用，或者迎接社会健康挑战的新方法，奠定了重要的基础。”

此前Bains教授研究组曾在大鼠体内发现了压力诱导食欲的机制。通常条件下，大脑会分泌一种名为内源性大麻素（一种负责大脑中细胞间通信的化学分子）的神经传递素控制人的食欲。Bains教授等人发现在缺乏食物时，大脑会发生一种压力应答，它会导致脑部功能临时性的改变。而这种改变会损害内源性大麻素调节食物摄取的正常功能，诱发非正常的强烈食欲。研究还发现，如果抑制大脑中的这种压力应激激素效应时，缺乏食物也不会导致神经系统的发生任何变化。

这项研究确认了压力对神经系统的重要影响，缺乏食物形成的压力会导致大鼠神经系统的细胞间通信异常。并且，这些实验也可以用来解释为何在人们承受较大压力时容易食欲大增。（生物通：张迪）

原文摘要：

Noradrenaline is a stress-associated metaplastic signal at GABA synapses
Exposure to a stressor sensitizes behavioral and hormonal responses to future stressors. Stress-associated release of noradrenaline enhances the capacity of central synapses to show plasticity (metaplasticity). We found noradrenaline-dependent metaplasticity at GABA synapses in the paraventricular nucleus of the hypothalamus in rat and mouse that controls the hypothalamic-pituitary-adrenal axis. In vivo stress exposure was required for these synapses to undergo activity-dependent long-term potentiation (LTPGABA). The activation of β-adrenergic receptors during stress functionally upregulated metabotropic glutamate receptor 1 (mGluR1), allowing for mGluR1-dependent LTPGABA during afferent bursts. LTPGABA was expressed postsynaptically and manifested as the emergence of new functional synapses. Our findings provide, to the best of our knowledge, the first demonstration that noradrenaline release during an in vivo challenge alters information storage capacity at GABA synapses. Because these GABA synapses become excitatory following acute stress, this metaplasticity may contribute to neuroendocrine sensitization to stress.

Glucocorticoid feedback uncovers retrograde opioid signaling at hypothalamic synapses
Stressful experience initiates a neuroendocrine response culminating in the release of glucocorticoid hormones into the blood. Glucocorticoids feed back to the brain, causing adaptations that prevent excessive hormone responses to subsequent challenges. How these changes occur remains unknown. We found that glucocorticoid receptor activation in rodent hypothalamic neuroendocrine neurons following in vivo stress is a metaplastic signal that allows GABA synapses to undergo activity-dependent long-term depression (LTDGABA). LTDGABA was unmasked through glucocorticoid receptor–dependent inhibition of Regulator of G protein Signaling 4 (RGS4), which amplified signaling through postsynaptic metabotropic glutamate receptors. This drove somatodendritic opioid release, resulting in a persistent retrograde suppression of synaptic transmission through presynaptic μ receptors. Together, our data provide new evidence for retrograde opioid signaling at synapses in neuroendocrine circuits and represent a potential mechanism underlying glucocorticoid contributions to stress adaptation.