Science2014-06-10 5:10 PM

增加大脑钾离子通道的电流会让抑郁消失 Enhancing Depression Mechanisms in Midbrain Dopamine Neurons Achieves Homeostatic Resilience

论文摘要 

过去的研究显示,当小鼠体内阳离子通道的电流增加时,其脑中腹侧被盖区 (VTA) 中的多巴胺神经元会变得过度活跃,并转而使这些小鼠变得抑郁。然而,Allyson Friedman及其同事现在发现,增加这些离子通道的电流甚至会进一步导致一种令人惊讶的效应:它会完全消除小鼠的抑郁症。

据研究人员说,这一意外的发现可能最终会带来可促进人类从抑郁状态中自然恢复的新疗法。Friedman及她的团队对小鼠的抑郁症模型进行了研究并证实,在易感(即抑郁)小鼠中,阳离子通道电流增加,而其VTA中的多巴胺神经元过度活跃。

但是,尽管有回复能力(非抑郁的)小鼠的VTA多巴胺神经元是正常的,但它们的离子通道电流比它们对等的易感小鼠及对照小鼠中的离子通道的电流增加得更多。当研究人员用实验药物手段进一步增加易感小鼠中阳离子通道的电流时,他们发现,这些小鼠在几天的时间之内就摆脱了抑郁症。

据研究人员说,这些易感小鼠——它们通常会避开同笼内的其它小鼠——会突然花更多的时间与其笼伴互动。他们说,这些小鼠的VTA多巴胺神经元也变得正常了。鉴于他们的发现,Friedman与其他研究人员提出,钾离子通道驱动了这一与直觉相悖的现象。

Abstract 

Typical therapies try to reverse pathogenic mechanisms. Here, we describe treatment effects achieved by enhancing depression-causing mechanisms in ventral tegmental area (VTA) dopamine (DA) neurons. In a social defeat stress model of depression, depressed (susceptible) mice display hyperactivity of VTA DA neurons, caused by an up-regulated hyperpolarization-activated current (Ih). Mice resilient to social defeat stress, however, exhibit stable normal firing of these neurons. Unexpectedly, resilient mice had an even larger Ih, which was observed in parallel with increased potassium (K+) channel currents. Experimentally further enhancing Ih or optoGENEtically increasing the hyperactivity of VTA DA neurons in susceptible mICE completely reversed depression-related behaviors, an antidepressant effect achieved through resilience-like, projection-specific homeostatic plasticity. These results indicate a potential therapeutic path of promoting natural resilience for depression treatment.

Editor's Summary

Resilient Hyperpolarization

Despite constant exposure to all sorts of stressors, most people are resilient and do not develop depression, but we do not understand the neurophysiological underpinnings of stress resilience. Friedman et al. (p. 313) studied this phenomenon in a mouse model of social-defeat stress depression. In the mice they found that, despite apparently pathological levels of hyperpolarization and elevated potassium channel currents in the ventral tegmental area (a structure known to be involved in depression), resilient mice showed normal activity in dopaminergic neurons. Thus, if “depressed” mice were experimentally provoked into hyperpolarization—unexpectedly, they completely reversed depression-related behaviors.

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