کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
8684662 | 1580134 | 2018 | 12 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Cell-type specific expression of constitutively-active Rheb promotes regeneration of bulbospinal respiratory axons following cervical SCI
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کلمات کلیدی
AAV2mTORCMAPhemagglutinin tagCTBNMJTSC1/2RHEBrVRGSpinal cord injury - آسیب نخاعیCervical spinal cord injury - آسیب نخاعی گردنیaxon - آکسون Neuromuscular junction - اتصال عصبی عضلانیEMG - الکترومیوگرافیelectromyography - الکترومیوگرافیRegeneration - باززاییRespiratory - تنفسیCNS - دستگاه عصبی مرکزیDiaphragm - دیافراگم Ras homolog enriched in brain - رایحه همولوگ در مغز غنی شده استRegrowth - رشد سریعcentral nervous system - سیستم عصبی مرکزیGAP - شکافsci - علمیphosphatase and tensin homolog - فسفاتاز و تنسین همولوگBreathing - نفس کشیدنMechanistic target of rapamycin - هدف مکانیکی رپامایسینcompound muscle action potential - پتانسیل عمل عضله مرکبGTPase-activating protein - پروتئین فعال GTPasePten - ژن PTENcholera toxin subunit B - کلسترول توکسین Brostral ventral respiratory group - گروه تنفسی شکمی روسترول
موضوعات مرتبط
علوم زیستی و بیوفناوری
علم عصب شناسی
عصب شناسی
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
Damage to respiratory neural circuitry and consequent loss of diaphragm function is a major cause of morbidity and mortality in individuals suffering from traumatic cervical spinal cord injury (SCI). Repair of CNS axons after SCI remains a therapeutic challenge, despite current efforts. SCI disrupts inspiratory signals originating in the rostral ventral respiratory group (rVRG) of the medulla from their phrenic motor neuron (PhMN) targets, resulting in loss of diaphragm function. Using a rat model of cervical hemisection SCI, we aimed to restore rVRG-PhMN-diaphragm circuitry by stimulating regeneration of injured rVRG axons via targeted induction of Rheb (ras homolog enriched in brain), a signaling molecule that regulates neuronal-intrinsic axon growth potential. Following C2 hemisection, we performed intra-rVRG injection of an adeno-associated virus serotype-2 (AAV2) vector that drives expression of a constitutively-active form of Rheb (cRheb). rVRG neuron-specific cRheb expression robustly increased mTOR pathway activity within the transduced rVRG neuron population ipsilateral to the hemisection, as assessed by levels of phosphorylated ribosomal S6 kinase. By co-injecting our novel AAV2-mCherry/WGA anterograde/trans-synaptic axonal tracer into rVRG, we found that cRheb expression promoted regeneration of injured rVRG axons into the lesion site, while we observed no rVRG axon regrowth with AAV2-GFP control. AAV2-cRheb also significantly reduced rVRG axonal dieback within the intact spinal cord rostral to the lesion. However, cRheb expression did not promote any recovery of ipsilateral hemi-diaphragm function, as assessed by inspiratory electromyography (EMG) burst amplitudes. This lack of functional recovery was likely because regrowing rVRG fibers did not extend back into the caudal spinal cord to synaptically reinnervate PhMNs that we retrogradely-labeled with cholera toxin B from the ipsilateral hemi-diaphragm. Our findings demonstrate that enhancing neuronal-intrinsic axon growth capacity can promote regeneration of injured bulbospinal respiratory axons after SCI, but this strategy may need to be combined with other manipulations to achieve reconnection of damaged neural circuitry and ultimately recovery of diaphragm function.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Experimental Neurology - Volume 303, May 2018, Pages 108-119
Journal: Experimental Neurology - Volume 303, May 2018, Pages 108-119
نویسندگان
Mark W. Urban, Biswarup Ghosh, Laura R. Strojny, Cole G. Block, Sara M. Blazejewski, Megan C. Wright, George M. Smith, Angelo C. Lepore,