Tauopathy severely disrupts homeostatic set-points in emergent neural dynamics but not in the activity of individual neurons.
Tauopathy severely disrupts homeostatic set-points in emergent neural dynamics but not in the activity of individual neurons.
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Tau蛋白病严重破坏了新兴神经动力学的稳态设定点，但不会破坏单个神经元的活动。
DOI：
10.1101/2023.09.01.555947
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Hengen,KeithB
中科院分区：
文献类型：
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作者：
McGregor,JamesN;Farris,ClaytonA;Ensley,Sahara;Schneider,Aidan;Wang,Chao;Liu,Yuqi;Tu,Jianhong;Elmore,Halla;Ronayne,KeenanD;Wessel,Ralf;Dyer,EvaL;Bhaskaran-Nair,Kiran;Holtzman,DavidM;Hengen,KeithB
神经元活动的稳态调节对于鲁棒计算至关重要；关键设定点（例如发射率）会主动稳定以补偿扰动。从这个角度来看，神经退行性疾病中枢的大脑功能的破坏应该反映了计算基本设定点的损害。尽管神经退行性变与功能结果有关，但疾病对神经元活动设定点的影响尚不清楚。在这里，我们对 tau 介导的神经变性对神经元活动稳态设定点的影响进行了全面的、理论驱动的研究。在 tau 蛋白病小鼠模型中，我们检查了整个疾病进展期间自由行为期间 27,000 小时的海马记录。与我们最初的假设相反，即 tau 蛋白病会影响尖峰率和方差的设定点，我们发现细胞水平设定点甚至对疾病的最新阶段也有弹性。相反，我们发现 tau 蛋白病会破坏网络水平的神经元活动，我们使用神经元相互作用的成对测量以及网络接近临界点的测量来量化神经元活动，这是一种理想的计算机制，被称为稳态设定点。我们发现网络关键性的变化 1) 跟踪症状，2) 预测潜在的解剖学和分子病理学，3) 以睡眠/觉醒依赖性方式发生，4) 可用于可靠地对动物的基因型进行分类。我们的数据表明，关键设定点完好无损，但稳态机制逐渐无法稳定海马网络，尤其是在清醒时。这项工作说明了神经退行性过程如何影响神经生物系统的计算能力，并提出了分子病理学、电路功能和动物行为之间的重要联系。
The homeostatic regulation of neuronal activity is essential for robust computation; key set-points, such as firing rate, are actively stabilized to compensate for perturbations. From this perspective, the disruption of brain function central to neurodegenerative disease should reflect impairments of computationally essential set-points. Despite connecting neurodegeneration to functional outcomes, the impact of disease on set-points in neuronal activity is unknown. Here we present a comprehensive, theory-driven investigation of the effects of tau-mediated neurodegeneration on homeostatic set-points in neuronal activity. In a mouse model of tauopathy, we examine 27,000 hours of hippocampal recordings during free behavior throughout disease progression. Contrary to our initial hypothesis that tauopathy would impact set-points in spike rate and variance, we found that cell-level set-points are resilient to even the latest stages of disease. Instead, we find that tauopathy disrupts neuronal activity at the network-level, which we quantify using both pairwise measures of neuron interactions as well as measurement of the network’s nearness to criticality, an ideal computational regime that is known to be a homeostatic set-point. We find that shifts in network criticality 1) track with symptoms, 2) predict underlying anatomical and molecular pathology, 3) occur in a sleep/wake dependent manner, and 4) can be used to reliably classify an animal’s genotype. Our data suggest that the critical set-point is intact, but that homeostatic machinery is progressively incapable of stabilizing hippocampal networks, particularly during waking. This work illustrates how neurodegenerative processes can impact the computational capacity of neurobiological systems, and suggest an important connection between molecular pathology, circuit function, and animal behavior.