Motivational valence is determined by striatal melanocortin 4 receptors
Motivational valence is determined by striatal melanocortin 4 receptors
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DOI：
10.1172/jci97854
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发表时间：
2018-07-02
影响因子：
15.9
通讯作者：
Engblom, David
中科院分区：
文献类型：
--
作者：
Klawonn, Anna Mathia;Fritz, Michael;Engblom, David
以正确的方式为显着刺激分配正价或负价对于生存至关重要。因此，以扰乱体内平衡为特征的有害刺激和内部状态会伴随着不适、不安和厌恶。厌恶信号会在慢性疾病期间造成广泛的痛苦，包括炎症、癌症和抑郁症。在这里，我们使用转基因小鼠研究了黑皮质素 4 受体 (MC4R) 在厌恶处理中的作用，并进行了一项行为测试，在该测试中，小鼠避开它们已经学会与厌恶刺激相关的环境。在正常小鼠中，强烈的厌恶是由全身炎症、恶心、疼痛等引起的。阿片受体引起的烦躁不安。与此形成鲜明对比的是，缺乏 MC4R 的小鼠对厌恶刺激表现出偏好或冷漠。缺乏 MC4R 的小鼠从厌恶到奖赏的异常转变是多巴胺依赖性的，并且与多巴胺系统活性从减少到增加的变化有关。当 MC4R 在多巴胺 D1 受体表达细胞或缺乏 MC4R 的小鼠纹状体中重新表达时，对厌恶刺激的反应就会正常化。此外，投射到腹侧纹状体的弓状核原阿黑皮素神经元的激活以MC4R依赖性方式增加了纹状体神经元的活性并引起厌恶。我们的研究结果表明，通过纹状体 MC4R 的黑皮质素信号传导对于将负面动机效价分配给有害刺激至关重要。
It is critical for survival to assign positive or negative valence to salient stimuli in a correct manner. Accordingly, harmful stimuli and internal states characterized by perturbed homeostasis are accompanied by discomfort, unease, and aversion. Aversive signaling causes extensive suffering during chronic diseases, including inflammatory conditions, cancer, and depression. Here, we investigated the role of melanocortin 4 receptors (MC4Rs) in aversive processing using genetically modified mice and a behavioral test in which mice avoid an environment that they have learned to associate with aversive stimuli. In normal mice, robust aversions were induced by systemic inflammation, nausea, pain, and. opioid receptorinduced dysphoria. In sharp contrast, mice lacking MC4Rs displayed preference or indifference toward the aversive stimuli. The unusual flip from aversion to reward in mice lacking MC4Rs was dopamine dependent and associated with a change from decreased to increased activity of the dopamine system. The responses to aversive stimuli were normalized when MC4Rs were reexpressed on dopamine D1 receptor-expressing cells or in the striatum of mice otherwise lacking MC4Rs. Furthermore, activation of arcuate nucleus proopiomelanocortin neurons projecting to the ventral striatum increased the activity of striatal neurons in an MC4R-dependent manner and elicited aversion. Our findings demonstrate that melanocortin signaling through striatal MC4Rs is critical for assigning negative motivational valence to harmful stimuli.