Liu Yuntao, Liu Haiwei, Lu Yingwen, Yin Xiangping, Lu Weilin, Lian Xiaoyue, Wang Ke, Shi Chennan, Yao Zhimo, Chen Jiang-Fan, Li Zhihui
The Molecular Neuropharmacology Laboratory and the Eye-Brain Research Center, The State Key Laboratory of Ophthalmology, Optometry and Vision Science, Wenzhou Medical University, Wenzhou, China.
The Molecular Neuropharmacology Laboratory and the Eye-Brain Research Center, The State Key Laboratory of Ophthalmology, Optometry and Vision Science, Wenzhou Medical University, Wenzhou, China; Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), China.
Exp Neurol. 2023 Jun;364:114396. doi: 10.1016/j.expneurol.2023.114396. Epub 2023 Mar 31.
Parkinson's disease (PD) is characterized by dopaminergic neuron loss and α-synuclein (α-Syn) aggregates, but lacks effective treatments for the disease progression and non-motor symptoms. Recently, combined 40 Hz auditory and visual stimulation is emerging as a promising non-invasive method to decrease amyloid and improve cognition in Alzheimer's disease (AD), but whether this treatment can modify α-Syn-induced PD pathology remains unclear. Here we evaluated the effects of chronic exposure to 40 Hz and 80 Hz auditory and visual stimulation on α-Syn accumulation and the functional effects of 40 Hz stimulation on motor, cognitive and mood dysfunctions in PD mice. We found that 40 Hz and 80 Hz auditory and visual stimulation activated multiple cortical regions, entrained gamma oscillations and markedly attenuated p-α-Syn deposition in neurons, but not astrocytes, microglial cells in the primary and secondary motor cortex (M1, M2), medial prefrontal cortex (mPFC) and the striatum. Moreover, 40 Hz stimulation significantly reduced cell apoptosis in M1, increased the neuromuscular strength selectively in PD mice, which correlated with p-α-Syn reduction in the motor cortex. In addition, 40 Hz stimulation improved spatial working memory and decreased depressive-like behaviors specifically in PD mice, which correlated with p-α-Syn reduction in mPFC, but promoted anxiety-like behaviors and increased stress-related adreno-cortico-tropic-hormone (ACTH), corticosterone levels in the plasma of normal mice. Collectively, we demonstrated that chronic multisensory gamma stimulation (40 Hz and 80 Hz) significantly attenuates α-Syn deposition in neurons of the interconnected cortex and 40 Hz stimulation improved neuromuscular strength, spatial working memory, and reduced depressive behaviors, which support its non-invasive therapeutic potential for modifying PD progression and treating non-motor symptoms.
帕金森病（PD）的特征是多巴胺能神经元丢失和α-突触核蛋白（α-Syn）聚集，但对于疾病进展和非运动症状缺乏有效的治疗方法。最近，40赫兹的听觉和视觉联合刺激正成为一种有前景的非侵入性方法，可减少阿尔茨海默病（AD）中的淀粉样蛋白并改善认知，但这种治疗是否能改变α-Syn诱导的PD病理仍不清楚。在这里，我们评估了长期暴露于40赫兹和80赫兹听觉和视觉刺激对α-Syn积累的影响，以及40赫兹刺激对PD小鼠运动、认知和情绪功能障碍的功能影响。我们发现，40赫兹和80赫兹的听觉和视觉刺激激活了多个皮质区域，夹带了γ振荡，并显著减弱了初级和次级运动皮层（M1、M2）、内侧前额叶皮层（mPFC）和纹状体中神经元而非星形胶质细胞、小胶质细胞中的p-α-Syn沉积。此外，40赫兹刺激显著减少了M1中的细胞凋亡，选择性地增加了PD小鼠的神经肌肉力量，这与运动皮层中p-α-Syn的减少相关。此外，40赫兹刺激改善了PD小鼠的空间工作记忆并特异性地减少了抑郁样行为，这与mPFC中p-α-Syn的减少相关，但促进了正常小鼠的焦虑样行为并增加了血浆中与应激相关的促肾上腺皮质激素（ACTH）、皮质酮水平。总体而言，我们证明了慢性多感觉γ刺激（40赫兹和80赫兹）显著减弱了相互连接的皮层神经元中的α-Syn沉积，并且40赫兹刺激改善了神经肌肉力量、空间工作记忆并减少了抑郁行为，这支持了其在改变PD进展和治疗非运动症状方面的非侵入性治疗潜力。
