Mao Yunfeng, Zhang Mingjun, Peng Xiaoqi, Liu Yi, Liu Yehao, Xia Qianhui, Luo Bin, Chen Lin, Zhang Zhi, Wang Yuanyin, Wang Haitao
Department of Anesthesiology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei 230026, China.
College & Hospital of Stomatology, Anhui Medical University, Key Laboratory of Oral Diseases Research of Anhui Province, Hefei 230022, China; School of Basic Medical Sciences, Anhui Medical University, Hefei 230022, China.
Curr Biol. 2025 Feb 24;35(4):831-842.e5. doi: 10.1016/j.cub.2024.12.044. Epub 2025 Jan 30.
Hyperacusis, exaggerated sensitivity to sound, frequently accompanies chronic pain in humans, suggesting interactions between different sensory systems in the brain. However, the neural mechanisms underlying this comorbidity remain largely unexplored. In this study, behavioral tests measuring sound-evoked pupil dilation and reaction times to lick water following auditory stimuli showed hyperacusis-like behaviors in neuropathic pain model mice. Through viral tracing, fiber photometry, and multi-electrode recordings, we identified glutamatergic projections from primary somatosensory cortex (S1HL) to the auditory cortex (ACx) that participate in amplifying sound-evoked neuronal activity following spared nerve injury in the hindlimb. Chemo- or optogenetic manipulation and electrophysiology recordings confirmed that the S1HL → ACx pathway is essential for this heightened response to sound. Specifically, activating this pathway intensified glutamatergic neuronal activity in the ACx and induced hyperacusis-like behaviors, while chemogenetic suppression reversed these effects in neuropathic pain model mice. These findings illustrate the mechanism by which central gain increases in the ACx of neuropathic pain mice, improving our understanding of cross-modal sensory system interactions and suggesting circuit pathway targets for developing interventions to treat pain-associated hyperacusis in clinic.
听觉过敏，即对声音过度敏感，在人类中常伴随慢性疼痛，这表明大脑中不同感觉系统之间存在相互作用。然而，这种共病的神经机制在很大程度上仍未得到探索。在本研究中，通过行为测试测量声音诱发的瞳孔扩张以及听觉刺激后舔水的反应时间，发现在神经性疼痛模型小鼠中存在类似听觉过敏的行为。通过病毒示踪、纤维光度测定法和多电极记录，我们确定了从初级躯体感觉皮层（S1HL）到听觉皮层（ACx）的谷氨酸能投射，这些投射在下肢 spared 神经损伤后参与放大声音诱发的神经元活动。化学或光遗传学操作以及电生理记录证实，S1HL→ACx 通路对于这种对声音的增强反应至关重要。具体而言，激活该通路会增强 ACx 中的谷氨酸能神经元活动并诱发类似听觉过敏的行为，而化学遗传学抑制则可逆转神经性疼痛模型小鼠中的这些效应。这些发现阐明了神经性疼痛小鼠 ACx 中中枢增益增加的机制，增进了我们对跨模态感觉系统相互作用的理解，并为开发治疗临床上与疼痛相关的听觉过敏的干预措施提供了回路通路靶点。
