靶向运动皮层区域的重复经颅磁刺激在Rett综合征非人灵长类模型中诱导细胞类型特异的转录重编程与行为恢复
Repetitive transcranial magnetic stimulation targeting motor cortical region induces cell-type-specific transcriptional reprogramming and behavioral recovery in non-human primate model of Rett syndrome
Rett 综合征（RTT）是一种由 MECP2 基因突变引起的严重神经发育障碍，目前缺乏有效治疗手段。运动皮层是 RTT 与孤独症谱系障碍中的关键枢纽，其功能受损会导致运动、社交和认知缺陷。本研究在 RTT 非人灵长类模型（MECP2 突变猴）中考察了靶向运动区的重复经颅磁刺激（rTMS）的效果，并探究了治疗效果背后的神经分子基础。我们确定了 RTT 的一个新治疗靶点——腹侧前运动皮层（PMv），并发现经过 20 天 rTMS 疗程后，若干行为学与功能连接指标出现了方向性变化。神经影像分析证实，rTMS 诱导了大尺度功能连接的重组，表现为躯体运动网络与突显网络之间的功能整合增强，并使运动皮层与丘脑及前扣带皮层之间的耦合恢复正常。值得注意的是，单核 RNA 测序揭示 rTMS 触发了细胞类型特异性的转录重编程：它通过恢复即刻早期基因（如 FOS、EGR1）的表达与调控网络，逆转了兴奋性神经元的病理性过度活跃，并纠正了失调的细胞间信号传导（如 NRG、WNT）。这些发现表明，以脑刺激靶向运动皮层区域可能治疗 RTT，值得进一步开展临床验证。
在 MECP2 突变猴中把 rTMS 的行为、功能连接与单核转录组变化放在同一条证据链上，为刺激运动皮层改善 RTT 症状提供了跨层次数据。
Rett syndrome (RTT), a severe neurodevelopmental disorder caused by mutations in the MECP2 gene, currently lacks effective treatments. The motor cortex is a pivotal hub in RTT and autism spectrum disorders, and its impairments contribute to motor, social, and cognitive deficits. Here we examined the effects of repetitive transcranial magnetic stimulation (rTMS) targeting motor area in non-human primate of RTT (MECP2-mutant monkey) and investigated neuromolecular basis underlying therapeutic effects. We identified a new treatment target, ventral premotor cortex (PMv), for RTT and found that following a 20-day rTMS course, several behavioral and functional connectivity measures showed directional changes. Neuroimaging analyses confirmed that rTMS induced reorganization of large-scale functional connectivity with enhanced functional integration between the somatomotor and the salience networks and normalized coupling between the motor cortex and both the thalamus and the anterior cingulate cortex. Notably, single-nucleus RNA sequencing revealed that rTMS triggered cell-type-specific transcriptional reprogramming: it rescued pathological hyperactivity of excitatory neurons by restoring the expression and regulatory networks of immediate early genes (e.g., FOS, EGR1) and corrected dysregulated intercellular signaling (e.g., NRG, WNT). These findings indicate that targeting motor cortical areas with brain stimulation may treat RTT, which warrants further clinical validation.
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来源：bioRxiv · Neuroscience · biorxiv.org