Cherniak Meir, Anglister Lili, Lev-Tov Aharon
Department of Medical Neuroscience, Institute for Medical Research, Israel-Canada, the Hebrew University-Hadassah Medical School, Jerusalem, 9112102 Israel.
Department of Medical Neuroscience, Institute for Medical Research, Israel-Canada, the Hebrew University-Hadassah Medical School, Jerusalem, 9112102 Israel
J Neurosci. 2017 Feb 1;37(5):1294-1311. doi: 10.1523/JNEUROSCI.2213-16.2016. Epub 2016 Dec 26.
The ability to improve motor function in spinal cord injury patients by reactivating spinal central pattern generators (CPGs) requires the elucidation of neurons and pathways involved in activation and modulation of spinal networks in accessible experimental models. Previously we reported on adrenoceptor-dependent sacral control of lumbar flexor motoneuron firing in newborn rats. The current work focuses on clarification of the circuitry and connectivity involved in this unique modulation and its potential use. Using surgical manipulations of the spinal gray and white matter, electrophysiological recordings, and confocal microscopy mapping, we found that methoxamine (METH) activation of sacral networks within the ventral aspect of S2 segments was sufficient to produce alternating rhythmic bursting (0.15-1 Hz) in lumbar flexor motoneurons. This lumbar rhythm depended on continuity of the ventral funiculus (VF) along the S2-L2 segments. Interrupting the VF abolished the rhythm and replaced it by slow unstable bursting. Calcium imaging of S1-S2 neurons, back-labeled via the VF, revealed that ∼40% responded to METH, mostly by rhythmic firing. All uncrossed projecting METH responders and ∼70% of crossed projecting METH responders fired with the concurrent ipsilateral motor output, while the rest (∼30%) fired with the contralateral motor output. We suggest that METH-activated sacral CPGs excite ventral clusters of sacral VF neurons to deliver the ascending drive required for direct rhythmic activation of lumbar flexor motoneurons. The capacity of noradrenergic-activated sacral CPGs to modulate the activity of lumbar networks via sacral VF neurons provides a novel way to recruit rostral lumbar motoneurons and modulate the output required to execute various motor behaviors.
Spinal central pattern generators (CPGs) produce the rhythmic output required for coordinating stepping and stabilizing the body axis during movements. Electrical stimulation and exogenous drugs can reactivate the spinal CPGs and improve the motor function in the absence of descending supraspinal control. Since the body-stabilizing sacral networks can activate and modulate the limb-moving lumbar circuitry, it is important to clarify the functional organization of sacral and lumbar networks and their linking pathways. Here we decipher the ascending circuitry linking adrenoceptor-activated sacral CPGs and lumbar flexor motoneurons, thereby providing novel insights into mechanisms by which sacral circuitry recruits lumbar flexors, and enhances the motor output during lumbar afferent-induced locomotor rhythms. Moreover, our findings might help to improve drug/electrical stimulation-based therapy to accelerate locomotor-based rehabilitation.
通过重新激活脊髓中枢模式发生器（CPG）来改善脊髓损伤患者运动功能的能力，需要在可及的实验模型中阐明参与脊髓网络激活和调节的神经元及通路。此前我们报道了新生大鼠中肾上腺素能受体依赖的骶部对腰屈肌运动神经元放电的控制。当前工作聚焦于阐明这种独特调节所涉及的神经回路和连接及其潜在用途。通过对脊髓灰质和白质进行手术操作、电生理记录以及共聚焦显微镜绘图，我们发现甲氧明（METH）激活S2节段腹侧的骶部网络足以在腰屈肌运动神经元中产生交替的节律性爆发（0.15 - 1赫兹）。这种腰部节律依赖于腹侧索（VF）沿S2 - L2节段的连续性。中断VF会消除节律并代之以缓慢不稳定的爆发。通过VF逆向标记的S1 - S2神经元的钙成像显示，约40%的神经元对METH有反应，大多表现为节律性放电。所有未交叉投射的对METH有反应的神经元以及约70%交叉投射的对METH有反应的神经元与同侧运动输出同步放电，而其余（约30%）与对侧运动输出同步放电。我们认为METH激活的骶部CPG会兴奋骶部VF神经元的腹侧簇，以传递直接节律性激活腰屈肌运动神经元所需的上行驱动。去甲肾上腺素能激活的骶部CPG通过骶部VF神经元调节腰部网络活动的能力，为募集上位腰运动神经元并调节执行各种运动行为所需输出提供了一种新途径。
脊髓中枢模式发生器（CPG）产生协调运动和稳定身体轴线在运动过程中所需的节律性输出。电刺激和外源性药物可以在没有下行上位脊髓控制的情况下重新激活脊髓CPG并改善运动功能。由于稳定身体的骶部网络可以激活和调节肢体运动的腰部回路，阐明骶部和腰部网络的功能组织及其连接通路很重要。在这里我们解读了连接肾上腺素能受体激活的骶部CPG和腰屈肌运动神经元的上行回路，从而为骶部回路募集腰屈肌以及在腰部传入诱导的运动节律期间增强运动输出的机制提供了新见解。此外，我们的发现可能有助于改进基于药物/电刺激的疗法以加速基于运动的康复。
