Prefrontal dopamine regulates fear reinstatement through the downregulation of extinction circuits.
Prefrontal dopamine regulates fear reinstatement through the downregulation of extinction circuits.
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DOI：
10.7554/elife.08274
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发表时间：
2015-07-30
期刊：
影响因子：
7.7
通讯作者：
Nomura H
中科院分区：
文献类型：
--
作者：
Hitora-Imamura N;Miura Y;Teshirogi C;Ikegaya Y;Matsuki N;Nomura H
预防复发是治疗焦虑症的主要挑战。恐惧的恢复可能会导致复发，尽管通过基于消退的暴露疗法成功地减少了恐惧。通过利用小鼠的情景恐惧条件反射任务，我们发现，恢复恐惧伴随着下缘皮质(IL)c-Fos表达的减少和突触输入的减少，以及杏仁中央核(CEM)内侧细分的c-Fos表达的增强。此外，我们发现白介素多巴胺在恢复过程中起着关键作用。恢复性提示电击诱导腹侧被盖区投射IL的多巴胺能神经元c-Fos表达，阻断IL-D1信号通路可阻止突触输入减少、CEM c-Fos表达和恐惧恢复。这些发现表明，依赖于多巴胺的消退回路失活是恐惧恢复的基础，并可能解释物质使用障碍和焦虑症的共病。DOI：http://dx.doi.org/10.7554/eLife.08274.001焦虑症影响全球数以百万计的人。虽然许多焦虑症患者通过适当的治疗可以康复，但其中约40%的人会遇到病情复发的情况。研究人员可以通过建立相关过程的动物模型来调查复发的原因。例如，如果一只老鼠每次进入特定的笼子时都受到一个小电击，它将学会将该笼子与电击联系起来。一旦创建了这种关联，就可以使用一种称为消亡的程序来“撤销”它。在笼子的例子中，这可以通过将鼠标放在笼子中很长时间来执行，但不给它任何电击。随着时间的推移，动物了解到笼子不再与不愉快的结果联系在一起。然而，如果老鼠在灭绝后被给予提醒电击，那么笼子和电击之间的原始关联就会重新建立起来。这被称为恐惧恢复，类似于旧病复发。许多大脑区域被认为与恐惧的恢复有关。杏仁核就是这样一个与恐惧反应密切相关的区域。据认为，大脑的另一部分，内侧前额叶皮质(MPFC)可以抑制杏仁核的反应，从而减少动物的焦虑。虽然我们很清楚大脑的哪些部分参与了恐惧的处理，但我们还不知道它们是如何共同作用造成复发的。Hitora-Imamura等人。使用前述方法，当小鼠进入笼子时，选择性地给予小鼠小电击，以诱导恐惧、灭绝和恢复恐惧，并研究这如何影响小鼠的大脑活动。正如预期的那样，恐惧可能与杏仁核的活动有关。在物种灭绝期间，内侧前额叶皮质的高水平活动抑制了杏仁核的反应。当小鼠经历提醒电击时，一种名为多巴胺的化学物质被释放。当多巴胺进入内侧前额叶皮质时，该区域的活动就会减少，杏仁核的“刹车”被移除，小鼠的恐惧情绪又会恢复。多巴胺参与了恐惧的恢复，这一发现尤其重要，因为众所周知，许多经常滥用的药物会增加大脑中的多巴胺水平。多巴胺在恢复恐惧中的作用可能解释了为什么药物滥用与焦虑症密切相关。DOI：http://dx.doi.org/10.7554/eLife.08274.002
Prevention of relapses is a major challenge in treating anxiety disorders. Fear reinstatement can cause relapse in spite of successful fear reduction through extinction-based exposure therapy. By utilising a contextual fear-conditioning task in mice, we found that reinstatement was accompanied by decreased c-Fos expression in the infralimbic cortex (IL) with reduction of synaptic input and enhanced c-Fos expression in the medial subdivision of the central nucleus of the amygdala (CeM). Moreover, we found that IL dopamine plays a key role in reinstatement. A reinstatement-inducing reminder shock induced c-Fos expression in the IL-projecting dopaminergic neurons in the ventral tegmental area, and the blocking of IL D1 signalling prevented reduction of synaptic input, CeM c-Fos expression, and fear reinstatement. These findings demonstrate that a dopamine-dependent inactivation of extinction circuits underlies fear reinstatement and may explain the comorbidity of substance use disorders and anxiety disorders. DOI: http://dx.doi.org/10.7554/eLife.08274.001 Anxiety disorders affect millions of people worldwide. While many people with anxiety disorders can recover with appropriate treatment, about 40% of these individuals will encounter a relapse of their condition. Researchers can investigate the causes of relapses by creating animal models of the processes involved. For example, if a mouse receives a small shock every time it enters a particular cage, it will learn to associate that cage with the shock. Once this association has been created, it can be ‘undone’ using a procedure called extinction. In the cage example, this may be performed by placing the mouse in the cage for a long time, but without giving it any shocks. Over time, the animal learns that the cage is no longer linked to an unpleasant outcome. However, if a mouse is given a reminder shock after extinction has occurred, the original association between the cage and the shock is re-established. This is known as fear reinstatement and is similar to a relapse. A number of brain regions are thought to be involved in fear reinstatement. One such region, the amygdala, is heavily involved in fear responses. It is thought that another part of the brain, the medial prefrontal cortex (mPFC), can suppress the amygdala's responses, consequently reducing the animal's anxiety. While we have a good idea of which parts of the brain are involved in fear processing, we don't yet know how they work together to create a relapse. Hitora-Imamura et al. used the aforementioned method of selectively giving mice small shocks when they entered cages to induce fear, extinction, and fear reinstatement and examined how this affected the mice's brain activity. As expected, fear could be linked to activity in the amygdala. During extinction, high levels of activity in the medial prefrontal cortex suppressed the amygdala's response. When the mice experienced the reminder shock, a chemical called dopamine was released. When dopamine entered the medial prefrontal cortex, the region's activity was reduced, removing the ‘brakes’ from the amygdala and reinstating the mice's fear. The finding that dopamine is involved in fear reinstatement is particularly important, as many commonly abused drugs are known to increase levels of dopamine in the brain. Dopamine's role in fear reinstatement may explain why substance abuse is so closely linked to anxiety disorders. DOI: http://dx.doi.org/10.7554/eLife.08274.002