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首页> 外文学位 >The Role of C3-C4 Propriospinal Interneurons on Reaching and Grasping Behaviors Pre- and Post-cervical Spinal Cord Injury
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The Role of C3-C4 Propriospinal Interneurons on Reaching and Grasping Behaviors Pre- and Post-cervical Spinal Cord Injury

机译：C3-C4颈前中枢神经元在颈髓损伤前后触及行为中的作用

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摘要

Greater than 50% of all spinal cord injuries (SCIs) in humans occur at the cervical level and the biggest desire of quadriplegic patients is recovery of hand and digit function. Several weeks after spinal cord injury, re-organization and re-modeling of spared endogenous pathways occurs and plasticity of both supraspinal and interneuronal networks are believed to mediate functional recovery. Propriospinal interneurons (PNs) are neurons found entirely in the spinal cord with axons projecting to different spinal segments. PNs function by modulating locomotion, integrating supraspinal motor pathways and peripheral sensory afferents. Recent studies have postulated that if PNs are spared following SCI, these neurons can contribute to functional recovery by establishing synaptic connections onto motor neurons. However, to what extent cervical PNs are involved in recovery of reaching behavior is not known.;In our first study, we generated a lentiviral vector that permits highly efficient retrograde transport (HiRet) upon uptake at synaptic terminals in order to map supraspinal and interneuronal populations terminating near forelimb motoneurons (MNs) innervating the limb. With this vector, we found neurons labeled within the C3-C4 spinal cord and in the red nucleus, two major populations which are known to modulate forelimb reaching behavior. We also proceeded to use a novel two-viral vector method to specifically label ipsilateral C3-C4 PNs with tetracycline-inducible GFP. Histological analysis showed detailed labeling of somas, dendrites along with axon terminals. Based on this data, we proceeded to determine the contribution of C3-C4 PNs and rubrospinal neurons on forelimb reaching and grasping before and after cervical SCI.;In our second study, we have examined a double-infection technique for shutdown of PNs and rubrospinal neurons (RSNs) in adult rats. Adult rats were microinjected with a lentiviral vector expressing tetracycline-inducible inhibitory DREADDs into C6-T1 spinal levels. Adeno-associated viral vectors (AAV2) expressing TetON mixed with GIRK2 were injected into the red nucleus and C3-C4 spinal levels respectively. Rats were tested for deficits in reaching behaviors upon application of doxycycline and clozapine-n-oxide (CNO) administration. No behavioral deficits were observed pre-injury. Rats then received a C5 spinal cord lesion to sever cortical input to forelimb motoneurons and were allowed four weeks to spontaneously recover. Upon re-administration of CNO to activate inhibitory DREADDs, deficits were observed in forelimb reaching. Histological analysis of the C3-C4 spinal cord and red nucleus showed DREADD+ neurons co-expressing GIRK2 in somas and dendrites of PNs and RSNs. PN terminals expressing DREADD were observed near C6-T1 motoneurons and in the brainstem. Control animals did not show substantial deficits with CNO administration. These results indicate both rubro- and propriospinal pathways are necessary for recovery of forelimb reaching.;In a separate study, we sought to determine if promoting severed CST sprouting rostral to a C5 lesion near C3-C4 PNs could improve behavioral recovery post SCI. Past studies have examined sprouting and regeneration of corticospinal tract (CST) fibers post-cervical SCI through viral upregulation of key components of the PI3K/Akt/mTOR cascade. We examined the regenerative growth potential of CST fibers that are transduced with AAV2 expressing constituively active Akt3 or STAT3 both separately and in combination (Akt3 + STAT3). We have observed significant increases in CST axonal sprouting and regeneration in Akt3 and Akt3 + STAT3 transduced samples. However, no recovery was observed as animals transduced with viral constitutively active Akt3 displayed an epileptic phenotype. Further, epileptic animals with constitutively active Akt3 were found to have significant cortical neuron cell hypertrophy, activatived astrogliosis, increased dendritic arbors and hemimegencephalitis (HME). These results indicate a new model for examining mechanisms of HME and mTOR hyperactivity-induced epilepsy in adult rodents.
机译：人类所有脊髓损伤（SCI）的50％以上发生在颈椎水平，四肢瘫痪患者的最大愿望是手和手指功能的恢复。脊髓损伤后数周，发生了多余的内源性途径的重新组织和重塑，并且认为脊髓上和神经内神经网络的可塑性都介导了功能恢复。脊髓原神经元（PNs）是完全在脊髓中发现的神经元，轴突伸向不同的脊髓节段。 PNs通过调节运动，整合脊髓上运动路径和周围感觉传入来发挥功能。最近的研究推测，如果在SCI后保留了PN，这些神经元可以通过在运动神经元上建立突触连接来促进功能恢复。然而，尚不清楚宫颈PNs在多大程度上参与行为的恢复。在我们的第一个研究中，我们生成了慢病毒载体，该载体可在突触末端摄取后允许高效逆行转运（HiRet），以绘制脊髓上和神经元间的图谱。在支配肢体的前肢运动神经元（MNs）附近终止的种群。有了这个载体，我们发现在C3-C4脊髓和红色核中有标记的神经元，这两个主要的种群已知能调节前肢的到达行为。我们还着手使用一种新颖的两病毒载体方法，用四环素诱导性GFP特异性标记同侧C3-C4 PN。组织学分析显示了豆浆，树突以及轴突末端的详细标记。根据这些数据，我们继续确定C3-C4 PNs和红松神经元在颈脊髓脊髓损伤之前和之后对前肢到达和抓握的贡献。成年大鼠的神经元（RSN）。给成年大鼠显微注射表达四环素诱导型抑制性DREADDs的慢病毒载体至C6-T1脊髓水平。将与GIRK2混合的表达TetON的腺相关病毒载体（AAV2）分别注射到红色核和C3-C4脊髓水平。在强力霉素和氯氮平-正氧化物（CNO）施用后，对大鼠的行为障碍进行了测试。受伤前未观察到行为缺陷。然后，大鼠接受C5脊髓损伤以切断前肢运动神经元的皮质输入，并允许其自发恢复4周。重新施用CNO激活抑制性DREADDs后，前肢伸肌出现缺陷。对C3-C4脊髓和红色核的组织学分析表明，在PN和RSN的茎突和树突中共表达GIRK2的DREADD +神经元。在C6-T1运动神经元附近和脑干中观察到表达DREADD的PN末端。对照动物在使用CNO时没有显示出明显的缺陷。这些结果表明，红宝石和脊髓脊柱通路都是恢复前肢到达所必需的。在另一项研究中，我们试图确定促进切断的CST发芽延髓到C3-C4 PNs附近的C5病变是否可以改善SCI后的行为恢复。过去的研究已经通过PI3K / Akt / mTOR级联反应关键成分的病毒上调检查了宫颈脊髓损伤后皮质脊髓束（CST）纤维的萌发和再生。我们检查了CST纤维的再生生长潜力，这些纤维被表达了组成性活性Akt3或STAT3的AAV2分别和组合（Akt3 + STAT3）转导。我们已经观察到，在Akt3和Akt3 + STAT3转导的样品中，CST轴突发芽和再生显着增加。但是，由于用病毒组成性活性Akt3转导的动物表现出癫痫表型，因此未观察到恢复。此外，发现具有组成性活性Akt3的癫痫动物具有明显的皮质神经元细胞肥大，活化的星形胶质细胞增生，树突状树突增加和血脑炎（HME）。这些结果表明了一种新的模型，用于检查成年啮齿动物中HME和mTOR多动症诱发癫痫的机制。

著录项

  • 作者

    Sheikh, Imran S.;

  • 作者单位

    Temple University.;

  • 授予单位 Temple University.;
  • 学科 Neurosciences.
  • 学位 Ph.D.
  • 年度 2018
  • 页码 179 p.
  • 总页数 179
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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