Background Medium spiny neurons (MSNs) comprise the main body (95% in mouse) of the dorsal striatum neurons and represent dopaminoceptive GABAergic neurons. The cAMP (cyclic Adenosine MonoPhosphate)—mediated cascade of excitation and inhibition responses observed in MSN intracellular signal transduction is crucial for neuroscience research due to its involvement in the motor and behavioral functions. In particular, all types of addictions are related to MSNs. Shedding the light on the mechanics of the above-mentioned cascade is of primary importance for this research domain. Results A mouse model of chronic social conflicts in daily agonistic interactions was used to analyze dorsal striatum neurons genes implicated in cAMP-mediated phosphorylation activation pathways specific for MSNs. Based on expression correlation analysis, we succeeded in dissecting Drd1- and Drd2-dopaminoceptive neurons (D1 and D2, correspondingly) gene pathways. We also found that D1 neurons genes clustering are split into two oppositely correlated states, passive and active ones, the latter apparently corresponding to D1 firing stage upon protein kinase A (PKA) activation. We observed that under defeat stress in chronic social conflicts the loser mice manifest overall depression of dopamine-mediated MSNs activity resulting in previously reported reduced motor activity, while the aggressive mice with positive fighting experience (aggressive mice) feature an increase in both D1-active phase and D2 MSNs genes expression leading to hyperactive behavior pattern corresponded by us before. Based on the alternative transcript isoforms expression analysis, it was assumed that many genes ( Drd1, Adora1, Pde10, Ppp1r1b, Gnal ), specifically those in D1 neurons, apparently remain transcriptionally repressed via the reversible mechanism of promoter CpG island silencing, resulting in alternative promoter usage following profound reduction in their expression rate. Conclusion Based on the animal stress model dorsal striatum pooled tissue RNA-Seq data restricted to cAMP related genes subset we elucidated MSNs steady states exhaustive projection for the first time. We correspond the existence of D1 active state not explicitly outlined before, and connected with dynamic dopamine neurotransmission cycles. Consequently, we were also able to indicate an oscillated postsynaptic dopamine vs glutamate action pattern in the course of the neurotransmission cycles.

中文翻译：

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从基因表达的角度观察背侧纹状体 MSN 中的多巴胺反应基因通路：cAMP 介导的基因网络


背景 中型多棘神经元 (MSN) 构成背侧纹状体神经元的主体（小鼠中的 95%），代表多巴胺感受 GABA 能神经元。在 MSN 细胞内信号转导中观察到的 cAMP（环磷酸腺苷）介导的兴奋和抑制反应级联对于神经科学研究至关重要，因为它涉及运动和行为功能。特别是，所有类型的成瘾都与MSN有关。阐明上述级联的机制对于该研究领域至关重要。结果 使用日常竞争性互动中慢性社会冲突的小鼠模型来分析背侧纹状体神经元基因，这些基因涉及 cAMP 介导的 MSN 特异性磷酸化激活途径。基于表达相关性分析，我们成功剖析了 Drd1 和 Drd2 多巴胺感受神经元（相应的 D1 和 D2）基因通路。我们还发现 D1 神经元基因簇分为两种相反相关的状态，即被动状态和主动状态，后者显然对应于蛋白激酶 A (PKA) 激活时的 D1 放电阶段。我们观察到，在慢性社会冲突中的失败压力下，失败者小鼠表现出多巴胺介导的 MSN 活性整体抑制，导致先前报道的运动活动减少，而具有积极战斗经验的攻击性小鼠（攻击性小鼠）的特征是 D1 活性增加阶段和 D2 MSNs 基因表达导致我们之前对应的过度活跃行为模式。 基于替代转录亚型表达分析，假设许多基因（Drd1、Adora1、Pde10、Ppp1r1b、Gnal），特别是 D1 神经元中的基因，显然通过启动子 CpG 岛沉默的可逆机制保持转录抑制，从而导致替代转录亚型表达率大幅降低后启动子的使用。结论 基于仅限于 cAMP 相关基因子集的动物应激模型背侧纹状体汇集组织 RNA-Seq 数据，我们首次阐明了 MSN 稳态详尽预测。我们对应了之前未明确概述的 D1 活跃状态的存在，并与动态多巴胺神经传递周期相关。因此，我们还能够指出神经传递周期过程中振荡的突触后多巴胺与谷氨酸的作用模式。