Signaling models for dopamine-dependent temporal contiguity in striatal synaptic plasticity
Signaling models for dopamine-dependent temporal contiguity in striatal synaptic plasticity
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DOI：
10.1371/journal.pcbi.1008078
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发表时间：
2020-07-01
影响因子：
4.3
通讯作者：
Ishii, Shin
中科院分区：
文献类型：
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作者：
Urakubo, Hidetoshi;Yagishita, Sho;Ishii, Shin
动物会记住它们的行为和随后的奖励之间的时间联系。我们先前在纹状体表达D1R的棘突投射神经元(D1SPN)中发现了支持这种奖赏学习的突触机制。在配对的突触前和突触后(前-后配对)，多巴胺(DA)的爆发在几秒钟的时间窗口内促进树突棘增大，这被称为强化可塑性(RP)。先前的研究也确定了潜在的信号通路；然而，信号动力学如何导致RP仍不清楚。在本研究中，我们首先建立了D1SPN信号动力学的计算模型。D1RP模型成功地复制了实验观察到的蛋白激酶A(PKA)活性，包括其关键时间窗。在这个模型中，棘突/细树突中的腺苷环化酶1(AC1)在对抗前后配对和DA猝发的符合检测中起着关键作用。特别是，前后配对(Ca~(2+)信号)延迟地刺激AC1，并且在不对称的时间窗内，由DA猝发激活由Ca~(2+)刺激的AC1。此外，刺/细树突的细小对于PKA活动的短时间窗口至关重要。然后，我们建立了D2 SPN的RP模型，该模型还预测了RP的关键时间窗口，该时间窗口取决于前-后配对和DA相位下降的时间。AC1也适用于D2RP模型中的符合探测器。我们进一步模拟了导致钙/钙调蛋白依赖的蛋白激酶II(CaMKII)激活的信号通路，并阐明了AC1下游分子作为整合因子的作用，将瞬时输入信号转化为持续的脊柱增大。最后，我们讨论了这种时间窗口如何指导动物的奖赏学习。
Animals remember temporal links between their actions and subsequent rewards. We previously discovered a synaptic mechanism underlying such reward learning in D1 receptor (D1R)-expressing spiny projection neurons (D1 SPN) of the striatum. Dopamine (DA) bursts promote dendritic spine enlargement in a time window of only a few seconds after paired pre- and post-synaptic spiking (pre-post pairing), which is termed as reinforcement plasticity (RP). The previous study has also identified underlying signaling pathways; however, it still remains unclear how the signaling dynamics results in RP. In the present study, we first developed a computational model of signaling dynamics of D1 SPNs. The D1 RP model successfully reproduced experimentally observed protein kinase A (PKA) activity, including its critical time window. In this model, adenylate cyclase type 1 (AC1) in the spines/thin dendrites played a pivotal role as a coincidence detector against pre-post pairing and DA burst. In particular, pre-post pairing (Ca2+ signal) stimulated AC1 with a delay, and the Ca2+-stimulated AC1 was activated by the DA burst for the asymmetric time window. Moreover, the smallness of the spines/thin dendrites is crucial to the short time window for the PKA activity. We then developed a RP model for D2 SPNs, which also predicted the critical time window for RP that depended on the timing of pre-post pairing and phasic DA dip. AC1 worked for the coincidence detector in the D2 RP model as well. We further simulated the signaling pathway leading to Ca2+/calmodulin-dependent protein kinase II (CaMKII) activation and clarified the role of the downstream molecules of AC1 as the integrators that turn transient input signals into persistent spine enlargement. Finally, we discuss how such timing windows guide animals' reward learning.