Differentially timed extracellular signals synchronize pacemaker neuron clocks.
Differentially timed extracellular signals synchronize pacemaker neuron clocks.
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DOI：
10.1371/journal.pbio.1001959
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发表时间：
2014-09
期刊：
影响因子：
9.8
通讯作者：
Blau J
中科院分区：
文献类型：
--
作者：
Collins B;Kaplan HS;Cavey M;Lelito KR;Bahle AH;Zhu Z;Macara AM;Roman G;Shafer OT;Blau J
果蝇中的昼夜节律起搏神经元由两个同步信号调节，这两个同步信号在一天中相反的时间释放，产生细胞内环AMP的节律。同步的神经元活动对于行为等复杂过程至关重要。昼夜节律起搏神经元提供了一个不寻常的机会来研究同步性，因为它们的分子时钟在延长的时间范围内（24小时）同相振荡。为了确定同步信号在哪里，何时以及如何被感知，我们首先研究了果蝇幼虫的最小时钟神经回路，操纵四个主起搏神经元（LNvs）或两个背时钟神经元（DN 1）。出乎意料的是，我们发现PDF受体（PdfR）在LNvs和DN 1中都需要保持同步的LNv时钟。我们还发现，谷氨酸是第二个同步信号，从DN 1 s释放，并通过代谢型谷氨酸受体（mGluRA）在LNvs感知。由于同时减少LNvs中的Pdfr和mGluRA表达严重抑制了Timeless时钟蛋白振荡，我们得出结论，主起搏器LNvs需要细胞外信号才能正常工作。这两个同步信号在一天中相反的时间释放，并驱动LNvs中的cAMP振荡。最后，我们发现PdfR和mGluRA也有助于同步成人s-LNvs中的时间振荡。我们建议，差分定时信号驱动cAMP振荡和同步起搏神经元的昼夜神经回路将跨物种保存。昼夜节律分子钟对于动物行为的日常周期是必不可少的，我们对这些时钟在单个起搏神经元中的工作方式有很好的了解。然而，这些单独的时钟的准确性是毫无意义的，除非它们彼此同步。在这项研究中，我们表明，同步的主要起搏器LNv神经元在果蝇幼虫需要两个细胞外信号，在一天中的相反时间收到：即，神经肽PDF从LNvs本身在黎明和谷氨酸释放背时钟神经元在黄昏。LNvs通过分别增加或减少细胞内cAMP的G蛋白偶联受体感知PDF和谷氨酸。PDF和谷氨酸释放的交替阶段在细胞内环AMP中产生振荡。除了保持LNvs之间的同步，这种节奏也需要在个别幼虫LNvs的分子钟振荡。我们发现PDF和谷氨酸信号的中断也降低了成人LNvs的同步性。这损害了生物钟蛋白的振荡，苍蝇推迟了睡眠的开始。我们的数据突出了细胞间信号传导在确保昼夜节律网络内时钟神经元之间同步的重要性。我们的发现有助于将果蝇和哺乳动物之间的时钟特性的保守性扩展到时钟基因之外，包括时钟电路。
Circadian pacemaker neurons in Drosophila are regulated by two synchronizing signals that are released at opposite times of day, generating a rhythm in intracellular cyclic AMP. Synchronized neuronal activity is vital for complex processes like behavior. Circadian pacemaker neurons offer an unusual opportunity to study synchrony as their molecular clocks oscillate in phase over an extended timeframe (24 h). To identify where, when, and how synchronizing signals are perceived, we first studied the minimal clock neural circuit in Drosophila larvae, manipulating either the four master pacemaker neurons (LNvs) or two dorsal clock neurons (DN1s). Unexpectedly, we found that the PDF Receptor (PdfR) is required in both LNvs and DN1s to maintain synchronized LNv clocks. We also found that glutamate is a second synchronizing signal that is released from DN1s and perceived in LNvs via the metabotropic glutamate receptor (mGluRA). Because simultaneously reducing Pdfr and mGluRA expression in LNvs severely dampened Timeless clock protein oscillations, we conclude that the master pacemaker LNvs require extracellular signals to function normally. These two synchronizing signals are released at opposite times of day and drive cAMP oscillations in LNvs. Finally we found that PdfR and mGluRA also help synchronize Timeless oscillations in adult s-LNvs. We propose that differentially timed signals that drive cAMP oscillations and synchronize pacemaker neurons in circadian neural circuits will be conserved across species. Circadian molecular clocks are essential for daily cycles in animal behavior and we have a good understanding of how these clocks work in individual pacemaker neurons. However, the accuracy of these individual clocks is meaningless unless they are synchronized with one another. In this study we show that synchronizing the principal pacemaker LNv neurons in Drosophila larvae require two extracellular signals that are received at opposite times of day: namely, the neuropeptide PDF released from LNvs themselves at dawn and glutamate released from dorsal clock neurons at dusk. LNvs perceive both PDF and glutamate via G-protein coupled receptors that increase or decrease intracellular cAMP, respectively. The alternating phases of PDF and glutamate release generate oscillations in intracellular cyclic AMP. In addition to maintaining synchrony between LNvs, this rhythm is also required for molecular clock oscillations in individual larval LNvs. We show that disruption of PDF and glutamate signaling also reduces synchrony in adult LNvs. This impairs the oscillations of clock proteins and flies have delayed onset of sleep. Our data highlight the importance of intercellular signaling in ensuring synchrony between clock neurons within the circadian network. Our findings help extend the conservation of clock properties between Drosophila and mammals beyond clock genes to include clock circuitry.
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影响因子：
16.2
作者：
Evans JA;Leise TL;Castanon-Cervantes O;Davidson AJ
通讯作者：
Davidson AJ
影响因子：
64.8
作者：
Grima, B;Chèlot, E;Rouyer, F
通讯作者：
Rouyer, F
DOI：
10.1523/jneurosci.2688-09.2010
发表时间：
2010-04-28
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Blanchard FJ;Collins B;Cyran SA;Hancock DH;Taylor MV;Blau J
通讯作者：
Blau J
影响因子：
16.6
作者：
Doi, Masao;Ishida, Atsushi;Miyake, Akiko;Sato, Miho;Komatsu, Rie;Yamazaki, Fumiyoshi;Kimura, Ikuo;Tsuchiya, Soken;Kori, Hiroshi;Seo, Kazuyuki;Yamaguchi, Yoshiaki;Matsuo, Masahiro;Fustin, Jean-Michel;Tanaka, Rina;Santo, Yasuko;Yamada, Hiroyuki;Takahashi, Yukari;Araki, Michihiro;Nakao, Kazuki;Aizawa, Shinichi;Kobayashi, Masaki;Obrietan, Karl;Tsujimoto, Gozoh;Okamura, Hitoshi
通讯作者：
Okamura, Hitoshi
影响因子：
16.2
作者：
Dahdal D;Reeves DC;Ruben M;Akabas MH;Blau J
通讯作者：
Blau J