Selective human tau protein expression in different clock circuits of the Drosophila brain disrupts different aspects of sleep and circadian rhythms
Selective human tau protein expression in different clock circuits of the Drosophila brain disrupts different aspects of sleep and circadian rhythms
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DOI：
10.1101/2020.12.14.422675
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发表时间：
2020-12
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影响因子：
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通讯作者：
David Jaciuch;J. Munns;S. Chawla;S. Davis;M. Juusola
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文献类型：
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作者：
David Jaciuch;J. Munns;S. Chawla;S. Davis;M. Juusola
昼夜行为缺陷，如白天小睡增加和夜间睡眠减少，在阿尔茨海默病和其他tau蛋白病中很常见。但目前尚不清楚这些昼夜节律异常是否源于主起搏器或下游神经元中的tau病理学。在这里，我们通过在特定的果蝇脑回路中选择性地表达不同的人类tau蛋白，并在明-暗（LD）和“自由运行”的暗-暗（DD）条件下监测运动活动来研究这个问题。我们表明，在苍蝇大脑中表达人类tau蛋白忠实地再现了tau蛋白病中发现的几种行为变化。我们确定离散的神经元亚群内的时钟网络的主要目标，不同的昼夜节律行为紊乱在不同的环境条件。具体来说，我们发现，PDF阳性起搏神经元的主要网站夜间活动增益和睡眠损失，而非PDF时钟神经元的主要网站减少的内在行为节律。生物发光测量显示，尽管行为心律失常，分子钟是完整的。我们的研究结果表明，中枢时钟和传入时钟神经元的功能障碍共同导致表达人类tau蛋白的果蝇昼夜运动活动节律中断。该研究将特定区域果蝇时钟神经元中的体内人类tau蛋白表达与由此产生的睡眠和昼夜节律缺陷直接联系起来，以提取关于阿尔茨海默病和其他tau蛋白病如何扰乱活动和睡眠平衡的新知识。我们预计，这种新的方法将为模型生物中神经退行性疾病的其他研究提供一个有用的通用模板，旨在剖析神经退行性疾病对昼夜节律行为的影响，并进一步加深我们对时钟神经元网络如何工作的理解。
Circadian behavioural deficits, such as increased daytime naps and reduced night-time sleep, are common in Alzheimer’s disease and other tauopathies. But it has remained unclear whether these circadian abnormalities arise from tau pathology in either the master pacemaker or downstream neurons. Here we study this question by selectively expressing different human tau proteins in specific Drosophila brain circuits and monitoring locomotor activity under light-dark (LD) and in “free-running” dark-dark (DD) conditions. We show that expressing human tau proteins in the fly brain recapitulates faithfully several behavioural changes found in tauopathies. We identify discrete neuronal subpopulations within the clock network as the primary target of distinct circadian behavioural disturbances in different environmental conditions. Specifically, we show that the PDF-positive pacemaker neurons are the main site for night-activity gain and -sleep loss, whereas the non-PDF clock-neurons are the main site of reduced intrinsic behavioural rhythmicity. Bioluminescence measurements revealed that the molecular clock is intact despite the behavioural arrhythmia. Our results establish that dysfunction in both the central clock- and afferent clock-neurons jointly contribute to the circadian locomotor activity rhythm disruption in Drosophila expressing human tau. Significance Statement This study directly links in vivo human tau protein expression in region-specific Drosophila clock-neurons with the resulting sleep and circadian rhythm deficits to extract new knowledge of how Alzheimer’s disease and other tauopathies perturb the balance of activity and sleep. We anticipate that this novel approach will provide a useful general template for other studies of neurodegeneration in model organisms, seeking to dissect the impact of neurodegenerative disease on circadian behaviour, and further deepening our understanding of how the clock-neuron network works.