期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：36
页码：11383-11388
DOI：10.1073/pnas.1514731112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceThe 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 Forster 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.
关键词：basal ganglia ; in vivo FRET imaging ; transmission blockade ; cAMP-PKA signal ; aversive behavior
