A Role for Peroxisome Proliferator-Activated Receptor Gamma Coactivator-1α in Nucleus Accumbens Neuron Subtypes in Cocaine Action.
A Role for Peroxisome Proliferator-Activated Receptor Gamma Coactivator-1α in Nucleus Accumbens Neuron Subtypes in Cocaine Action.
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DOI：
10.1016/j.biopsych.2016.10.024
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发表时间：
2017-04-01
影响因子：
10.6
通讯作者：
Lobo MK
中科院分区：
文献类型：
--
作者：
Chandra R;Engeln M;Francis TC;Konkalmatt P;Patel D;Lobo MK
已知可卡因行为可塑性中关键参与的分子调节过氧化物酶体增殖物激活受体γ辅激活因子-1 α（PGC-1α）并与之相互作用。此外，PGC-1α启动子具有早期生长反应3（Egr 3）的结合位点，Egr 3在多巴胺受体D1与D2富集的中脑核（NAc）中型多刺神经元（MSN）亚型中的可卡因作用中发挥动态作用。然而，NAc中PGC-1α在可卡因作用中的作用尚不清楚。重复可卡因暴露后，检测NAc中PGC-1α mRNA和蛋白的表达。在重复使用可卡因后，使用染色质免疫沉淀（ChIP）检测NAc中Egr 3与PGC-1α启动子的结合和组蛋白甲基化。使用D1-Cre-RiboTag和D2-Cre-RiboTag细胞系在重复可卡因后评估MSN亚型中的PGC-1α核糖体相关mRNA。最后，在可卡因条件性位置偏爱和可卡因诱导的运动过程中，使用Cre诱导的AAV和Cre系在NAc D1-MSNs和D2-MSNs中表达PGC-1α。重复可卡因增加NAc中PGC-1α水平，并增加PGC-1α启动子处的Egr 3结合和H3 K4 me 3。PGC-1α在D1-MSNs中表达增加，而D2-MSNs则表达降低。病毒介导的PGC-1α在D1-MSNs中的表达增强了对可卡因的行为反应，而在D2-MSNs中的表达减弱了这些行为。我们证明了PGC-1α在可卡因作用中的新作用。PGC-1α在NAc D1-MSNs中增强，特别是在可卡因暴露后。这些数据与PGC-1α启动子处活性甲基化和Egr 3结合增加一致。最后，我们证明了PGC-1α通过D1-MSNs与D2-MSNs介导可卡因行为可塑性的双向作用。
Molecules critically involved in cocaine behavioral plasticity are known to regulate and interact with peroxisome proliferator-activated receptor gamma coactivator-1alpha, PGC-1α. Additionally, the PGC-1α promoter has binding sites for early growth response 3 (Egr3), which plays a dynamic role in cocaine action in nucleus accumbens (NAc) medium spiny neurons (MSN) subtypes, those enriched in dopamine receptor D1 vs. D2. However, the role of PGC-1α in NAc in cocaine action is unknown. PGC-1α mRNA and protein were examined in NAc after repeated cocaine exposure. Binding of Egr3 to and histone methylation at the PGC-1α promoter was examined in NAc, using chromatin immunoprecipitation (ChIP), after repeated cocaine. PGC-1α ribosome-associated mRNA in MSN subtypes was assessed after repeated cocaine using D1-Cre-RiboTag and D2-Cre-RiboTag lines. Finally, PGC-1α was expressed in NAc D1-MSNs vs. D2-MSNs using a Cre-inducible AAV and Cre lines during cocaine conditioned place preference and cocaine-induced locomotion. Repeated cocaine increased PGC-1α levels, and increased Egr3 binding and H3K4me3 at the PGC-1α promoter in NAc. Increased PGC-1α occurred in D1-MSNs, while D2-MSNs showed reduced levels. Viral mediated expression of PGC-1α in D1-MSNs enhanced behavioral responses to cocaine, while expression in D2-MSNs blunted these behaviors. We demonstrate a novel role for PGC-1α in NAc in cocaine action. PGC-1α is enhanced in NAc D1-MSNs specifically after cocaine exposure. These data are consistent with increased active methylation and Egr3 binding at the PGC-1α promoter. Finally, we demonstrate a bidirectional role for PGC-1α in mediating behavioral plasticity to cocaine through D1-MSNs vs. D2-MSNs.