Role of PKA signaling in D2 receptor-expressing neurons in the core of the nucleus accumbens in aversive learning
Role of PKA signaling in D2 receptor-expressing neurons in the core of the nucleus accumbens in aversive learning
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DOI：
10.1073/pnas.1514731112
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发表时间：
2015-08
期刊：
影响因子：
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通讯作者：
Takashi Yamaguchi;Akihiro Goto;Ichiro Nakahara;Satoshi Yawata;T. Hikida;M. Matsuda;K. Funabiki;
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文献类型：
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作者：
Takashi Yamaguchi;Akihiro Goto;Ichiro Nakahara;Satoshi Yawata;T. Hikida;M. Matsuda;K. Funabiki;
中脑核（nucleus reverbens，NAc）是通过表达D1受体的直接通路神经元和表达D2受体的间接通路神经元控制厌恶性学习的关键神经基质。我们探讨了厌恶性学习是如何控制的细胞内PKA信号在这两种类型的神经元在NAc。我们不仅通过直接或间接通路神经元中PKA的通路特异性抑制来解决这个问题，而且还通过在两种类型的神经元中明确表达的PKA生物传感器的FRET响应的显微内窥镜分析来解决这个问题。我们从这两种不同的方法中获得了一致的发现，并证明间接通路神经元中PKA的激活在厌恶记忆的形成和保持中发挥着关键作用。丘脑核（NAc）是厌恶性学习的关键神经基质，由两个不同的中型多刺神经元（MSN）亚群组成。直接途径（dMSN）和间接途径（iMSN）的MSN分别主要表达多巴胺（DA）D1和D2受体，并且分别通过Gs-和Gi-偶联的cAMP依赖性蛋白激酶A（PKA）信号级联被DA递质正向和负向调节。在这项研究中，我们解决了细胞内PKA信号是如何参与厌恶学习的细胞类型特异性的方式。当传递阻断破伤风毒素的通路特异性表达单方面阻断dMSNs或iMSNs的传递时，将PKA抑制剂注入NAc核心的完整侧废除了间接通路阻断小鼠对电击的被动回避学习，但在直接通路阻断小鼠中没有。然后，我们检查PKA活性的时间变化，在dMSN和iMSN行为小鼠通过监测Förster共振能量转移响应的PKA生物传感器的帮助下，显微内窥镜。在厌恶记忆形成和提取过程中，iMSNs中PKA活性增加，dMSNs中PKA活性降低。重要的是，当通过将小鼠保持在条件反射装置中来防止厌恶性记忆时，iMSN中增加的PKA活性消失。此外，在iMSNs的PKA活性的增加，由厌恶刺激反映了厌恶记忆保持的促进。这些结果表明，PKA信号在iMSNs中起着至关重要的作用，在厌恶记忆的形成和保持。
Significance The nucleus accumbens (NAc) is a key neural substrate that controls aversive learning through D1 receptor-expressing direct pathway neurons and D2 receptor-expressing indirect pathway neurons. We explored how aversive learning is controlled by intracellular PKA signaling in these two types of neurons in the NAc. We approached this issue not only by pathway-specific inhibition of PKA in either direct or indirect pathway neurons, but also by microendoscopic analysis of FRET responses of the PKA biosensor distinctly expressed in the two types of neurons. We obtained consistent findings from these two different approaches, and demonstrate that activation of PKA in the indirect pathway neurons plays a pivotal role in both the formation and the retention of aversive memory. The nucleus accumbens (NAc) serves as a key neural substrate for aversive learning and consists of two distinct subpopulations of medium-sized spiny neurons (MSNs). The MSNs of the direct pathway (dMSNs) and the indirect pathway (iMSNs) predominantly express dopamine (DA) D1 and D2 receptors, respectively, and are positively and negatively modulated by DA transmitters via Gs- and Gi-coupled cAMP-dependent protein kinase A (PKA) signaling cascades, respectively. In this investigation, we addressed how intracellular PKA signaling is involved in aversive learning in a cell type-specific manner. When the transmission of either dMSNs or iMSNs was unilaterally blocked by pathway-specific expression of transmission-blocking tetanus toxin, infusion of PKA inhibitors into the intact side of the NAc core abolished passive avoidance learning toward an electric shock in the indirect pathway-blocked mice, but not in the direct pathway-blocked mice. We then examined temporal changes in PKA activity in dMSNs and iMSNs in behaving mice by monitoring Förster resonance energy transfer responses of the PKA biosensor with the aid of microendoscopy. PKA activity was increased in iMSNs and decreased in dMSNs in both aversive memory formation and retrieval. Importantly, the increased PKA activity in iMSNs disappeared when aversive memory was prevented by keeping mice in the conditioning apparatus. Furthermore, the increase in PKA activity in iMSNs by aversive stimuli reflected facilitation of aversive memory retention. These results indicate that PKA signaling in iMSNs plays a critical role in both aversive memory formation and retention.