Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease, characterized by the death of upper (UMN) and lower motor neurons (LMN) in the motor cortex, brainstem, and spinal cord. Despite decades of research, ALS remains incurable, challenging to diagnose, and of extremely rapid progression. A unifying feature of sporadic and familial forms of ALS is cortical hyperexcitability, which precedes symptom onset, negatively correlates with survival, and is sufficient to trigger neurodegeneration in rodents. Using electrocorticography in the Sod1 G86R and Fus Δ NLS/+ ALS mouse models and standard electroencephalography recordings in patients with sporadic ALS, we demonstrate a deficit in theta-gamma phase-amplitude coupling (PAC) in ALS. In mice, PAC deficits started before symptom onset, and in patients, PAC deficits correlated with the rate of disease progression. Using mass spectrometry analyses of CNS neuropeptides, we identified a presymptomatic reduction of noradrenaline (NA) in the motor cortex of ALS mouse models, further validated by in vivo two-photon imaging in behaving SOD1 G93A and Fus Δ NLS/+ mice, that revealed pronounced reduction of locomotion-associated NA release. NA deficits were also detected in postmortem tissues from patients with ALS, along with transcriptomic alterations of noradrenergic signaling pathways. Pharmacological ablation of noradrenergic neurons with DSP-4 reduced theta-gamma PAC in wild-type mice and administration of a synthetic precursor of NA augmented theta-gamma PAC in ALS mice. Our findings suggest theta-gamma PAC as means to assess and monitor cortical dysfunction in ALS and warrant further investigation of the NA system as a potential therapeutic target.

中文翻译：

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小鼠模型和肌萎缩侧索硬化症患者的皮质过度兴奋与去甲肾上腺素缺乏有关

肌萎缩侧索硬化症 (ALS) 是一种毁灭性的神经退行性疾病，其特征是运动皮层、脑干​​和脊髓的上运动神经元 (UMN) 和下运动神经元 (LMN) 死亡。尽管经过数十年的研究，ALS 仍然无法治愈，诊断具有挑战性，而且进展极其迅速。散发性和家族性 ALS 的一个共同特征是皮质过度兴奋，它先于症状出现，与生存呈负相关，并且足以引发啮齿类动物的神经退行性变。使用皮层电图描记术SOD1G86R 和福斯 Δ非线性LS/+ ALS 小鼠模型和散发性 ALS 患者的标准脑电图记录，我们证明了 ALS 中 θ-γ 相位振幅耦合 (PAC) 的缺陷。在小鼠中，PAC 缺陷在症状出现之前就开始出现，而在患者中，PAC 缺陷与疾病进展速度相关。通过对中枢神经系统神经肽的质谱分析，我们发现 ALS 小鼠模型运动皮层中去甲肾上腺素 (NA) 的症状前减少，并通过行为中的体内双光子成像进一步验证超氧化物歧化酶1G93A 和福斯 Δ非线性LS/+ 小鼠中，运动相关的 NA 释放显着减少。在 ALS 患者的死后组织中也检测到 NA 缺陷，以及去甲肾上腺素信号通路的转录组改变。在野生型小鼠中，用 DSP-4 药理学消融去甲肾上腺素能神经元可减少 θ-γ PAC，而在 ALS 小鼠中施用 NA 的合成前体可增强 θ-γ PAC。我们的研究结果表明，theta-gamma PAC 可以作为评估和监测 ALS 皮质功能障碍的手段，并值得进一步研究 NA 系统作为潜在的治疗靶点。