Dopamine D2 receptors gate generalization of conditioned threat responses through mTORC1 signaling in the extended amygdala.
Dopamine D2 receptors gate generalization of conditioned threat responses through mTORC1 signaling in the extended amygdala.
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DOI：
10.1038/mp.2015.210
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发表时间：
2016-11
影响因子：
11
通讯作者：
Valjent, E.
中科院分区：
文献类型：
--
作者：
De Bundel, D.;Zussy, C.;Espallergues, J.;Gerfen, C. R.;Girault, J-A;Valjent, E.
条件性威胁反应的过度概括是焦虑症的一个强有力的临床标志。在过度概括中，适合威胁预测线索的反应是由感知上相似的安全预测线索引起的。因此，对条件性威胁反应的不适当学习可能构成焦虑症的病因学基础。多巴胺 (DA) 在记忆编码中的作用已得到充分证实。事实上，通过发出显着性和效价信号，DA 被认为可以促进代表安全或威胁的刺激之间的区分学习。然而，DA 调节威胁反应过度概括的神经解剖学和生化底物仍然知之甚少。在这里，我们报道了 DA D2 受体 (D2R) 信号的调节双向调节恐惧反应的巩固。虽然 D2R 的封锁会引起普遍的恐惧反应，但它的刺激有助于区分代表安全或威胁的刺激之间的学习。此外，我们发现受控恐惧泛化需要终纹床核（BNST）和中央杏仁核（CEA）中 D2R 的协调激活。最后，我们将 mTORC1 级联激活确定为 D2R 介导其作用的重要分子事件。这些数据表明，扩展杏仁核中的 D2R 信号传导构成了一个重要的检查点，DA 通过该检查点参与威胁处理的控制和过度概括的恐惧反应的出现。
Overgeneralization of conditioned threat responses is a robust clinical marker of anxiety disorders. In overgeneralization, responses that are appropriate to threat-predicting cues are evoked by perceptually similar safety-predicting cues. Inappropriate learning of conditioned threat responses may thus form an etiological basis for anxiety disorders. The role of dopamine (DA) in memory encoding is well established. Indeed by signaling salience and valence, DA is thought to facilitate discriminative learning between stimuli representing safety or threat. However, the neuroanatomical and biochemical substrates through which DA modulates overgeneralization of threat responses remain poorly understood. Here we report that the modulation of DA D2 receptor (D2R) signaling bidirectionally regulates the consolidation of fear responses. While the blockade of D2R induces generalized fear responses, its stimulation facilitates discriminative learning between stimuli representing safety or threat. Moreover, we show that controlled fear generalization requires the coordinated activation of D2R in the bed nucleus of the stria terminalis (BNST) and the central amygdala (CEA). Finally, we identify the mTORC1 cascade activation as an important molecular event by which D2R mediates its effects. These data reveal that D2R signaling in the extended amygdala constitutes an important checkpoint through which DA participates in the control of threat processing and the emergence of overgeneralized fear responses.
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在大鼠和人类中持续的恐惧：恐惧与焦虑中的杏仁核的作用。
DOI：
10.1038/npp.2009.109
发表时间：
2010-01
期刊：
Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology
影响因子：
--
作者：
通讯作者：
--
影响因子：
3.3
作者：
BOUTHENET, ML;MARTRES, MP;SCHWARTZ, JC
通讯作者：
SCHWARTZ, JC
影响因子：
2.5
作者：
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通讯作者：
Pare, Denis
DOI：
10.1111/j.1749-6632.1999.tb09312.x
发表时间：
1999-01-01
期刊：
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影响因子：
--
作者：
Guarraci, FA;Frohardt, RJ;Karp, BS
通讯作者：
Karp, BS
影响因子：
64.8
作者：
Ciocchi, Stephane;Herry, Cyril;Luethi, Andreas
通讯作者：
Luethi, Andreas