Bethea Thelma, Adegbenro Temitope, Martin John H
Department of Molecular, Cellular, and Biomedical Sciences, Center for Discovery and Innovation, City University of New York School of Medicine, New York, NY, USA; Neuroscience Program, Graduate Center of the City University of New York, New York, NY, USA.
Department of Molecular, Cellular, and Biomedical Sciences, Center for Discovery and Innovation, City University of New York School of Medicine, New York, NY, USA.
Exp Neurol. 2025 Jul 31;394:115401. doi: 10.1016/j.expneurol.2025.115401.
Hyperreflexia is a consequence of spinal cord injury (SCI) and motor system lesions in the brain. Two major mechanisms underpinning hyperreflexia have been reported: proprioceptive afferent (PA) circuit changes produced by 1 A fiber sprouting, which could enhance reflex signaling, together with reduced GABAergic inhibitory presynaptic regulation (GABApre); and increased intrinsic motor neuron excitability, for example, produced by reduced motor neuron membrane-bound potassium-chloride co-transporter2 (KCC2). Here we examine how selective unilateral CST injury in the medullary pyramid (PTX), which eliminates the CST from one hemisphere, allows investigation of different mechanisms to determine their contributions to hyperreflexia. We used rate-dependent depression (RDD) of the Hoffmann (H)-reflex for the forelimb and hindlimb 5th-digit abductor muscles to assess hyperreflexia on both the contra- and ipsilesional sides. We compared RDD longitudinally in intact rats and after unilateral-PTX rats at 7-dpi and 42-dpi, supplemented with additional timepoints to examine hyperreflexia development. Immunohistochemistry was used to identify PA synapses (VGlut1), GABA presynaptic boutons (GABApre), motor neurons (ChAT), and to measure motor neuronal KCC2. Following unilateral PTX, we observed significant hyperreflexia in the contralesional forelimb only. Membrane-bound KCC2 was unchanged in contralesional cervical motor neurons. Whereas both cervical and lumbar motor neurons showed increased PA sprouting contralesionally, there was a concomitant increase in GABApre terminals for the lumbar not cervical cord, which associated with a normal hindlimb H-reflex. Our findings show that KCC2 is disassociated from hyperreflexia in the uniPTX model. Instead, forelimb hyperreflexia can be explained by cervical motor neuron PA sprouting and an uncompensated GABApre regulation.
反射亢进是脊髓损伤（SCI）和大脑运动系统损伤的结果。据报道，反射亢进的两个主要机制如下：由ⅠA类纤维芽生产生的本体感觉传入（PA）回路变化，这可能增强反射信号，同时γ-氨基丁酸（GABA）能抑制性突触前调节（GABApre）降低；以及内在运动神经元兴奋性增加，例如，由运动神经元膜结合的氯化钾共转运体2（KCC2）减少所致。在这里，我们研究了延髓锥体（PTX）中的选择性单侧皮质脊髓束（CST）损伤，该损伤消除了一个半球的CST，如何能够研究不同机制以确定它们对反射亢进的作用。我们使用霍夫曼（H）反射对前肢和后肢第5指展肌的频率依赖性抑制（RDD）来评估对侧和损伤同侧的反射亢进。我们在完整大鼠以及单侧PTX大鼠在7天和42天损伤后纵向比较了RDD，并补充了额外的时间点来研究反射亢进的发展。免疫组织化学用于识别PA突触（VGlut1）、GABA突触前终末（GABApre）、运动神经元（ChAT），并测量运动神经元的KCC2。单侧PTX后，我们仅在对侧前肢观察到明显的反射亢进。对侧颈段运动神经元中膜结合的KCC2没有变化。虽然颈段和腰段运动神经元在对侧均显示PA芽生增加，但腰段而非颈段脊髓的GABApre终末伴随增加，这与后肢H反射正常相关。我们的数据表明，在单侧PTX模型中，KCC2与反射亢进无关。相反，前肢反射亢进可以通过颈段运动神经元PA芽生和未得到补偿的GABApre调节来解释。
