title: Role of PKA signaling in D2 receptor-expressing neurons in the core of the nucleus accumbens in aversive learning.
abstract: 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.
authors: Department of Systems Biology, Osaka Bioscience Institute, Osaka 565-0874, Japan;
authors: Takashi
authors: T
authors: Yamaguchi
authors: Laboratory for Memory Mechanisms, Brain Science Institute, RIKEN, Saitama 351-0198, Japan;
authors: Akihiro
authors: A
authors: Goto
authors: Department of Systems Biology, Osaka Bioscience Institute, Osaka 565-0874, Japan; Laboratory of Molecular Cell Biology and Development, Graduate School of Biostudies, Kyoto University, Kyoto 606-8315, Japan;
authors: Ichiro
authors: I
authors: Nakahara
authors: Department of Systems Biology, Osaka Bioscience Institute, Osaka 565-0874, Japan;
authors: Satoshi
authors: S
authors: Yawata
authors: Department of Systems Biology, Osaka Bioscience Institute, Osaka 565-0874, Japan; Department of Research and Drug Discovery, Medical Innovation Center, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan;
authors: Takatoshi
authors: T
authors: Hikida
authors: Laboratory of Bioimaging and Cell Signaling, Graduate School of Biostudies, Kyoto University, Kyoto 606-8315, Japan.
authors: Michiyuki
authors: M
authors: Matsuda
authors: Department of Systems Biology, Osaka Bioscience Institute, Osaka 565-0874, Japan; Laboratory of Molecular Cell Biology and Development, Graduate School of Biostudies, Kyoto University, Kyoto 606-8315, Japan; funabiki@ent.kuhp.kyoto-u.ac.jp snakanis@obi.or.jp.
authors: Kazuo
authors: K
authors: Funabiki
authors: Department of Systems Biology, Osaka Bioscience Institute, Osaka 565-0874, Japan; funabiki@ent.kuhp.kyoto-u.ac.jp snakanis@obi.or.jp.
authors: Shigetada
authors: S
authors: Nakanishi
mesh_terms: D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects / Q000502:physiology*; D017868:Cyclic AMP-Dependent Protein Kinases / Q000235:genetics / Q000378:metabolism*; D004724:Endoscopy / Q000379:methods; D031541:Fluorescence Resonance Energy Transfer / Q000379:methods; D008297:Male; D008568:Memory / Q000187:drug effects / Q000502:physiology; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009474:Neurons / Q000378:metabolism*; D009714:Nucleus Accumbens / Q000166:cytology / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D013744:Tetanus Toxin / Q000494:pharmacology
chemical_list: D017448:Receptors, Dopamine D2; D013744:Tetanus Toxin; D017868:Cyclic AMP-Dependent Protein Kinases
keywords: aversive behavior; basal ganglia; cAMP-PKA signal; in vivo FRET imaging; transmission blockade