Injury and adaptation in the developing rat corticospinal and rubrospinal tracts

发育中的大鼠皮质脊髓和红核脊髓束的损伤和适应

• 批准号: 8900364
• 负责人: Jason Brant Carmel
• 金额: $ 18.46万
• 依托单位: WINIFRED MASTERSON BURKE MED RES INST
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8900364
• 关键词: Adult; Affect; Area; Axon; Birth; Brain; Brain Injuries; Bypass; Cerebral Palsy; Child; Chronic; Corticospinal Tracts; Electric Stimulation; Figs - dietary; Financial compensation; Food; Goals; Hand; Human; Hyperreflexia; Implanted Electrodes; Infant; Injury; Ipsilateral; Learning; Limb structure; Logic; Measures; Mediating; Methods; Modeling; Motor; Motor Cortex; Motor Pathways; Motor Skills; Movement; Neonatal; Paralysed; Pathway interactions; Pattern; Perinatal Brain Injury; Physical therapy; Plastics; Posture; Rattus; Recovery; Red nucleus structure; Reflex action; Relative (related person); Side; Spinal; Spinal Cord; Structure of rubrospinal tract; Suid Herpesvirus 1; System; Techniques; Testing; Time; Viral; Walking; base; density; disability; feeding; functional restoration; grasp; improved; inhibitor/antagonist; injured; juvenile animal; mature animal; motor control; motor function recovery; motor recovery; neural circuit; novel; relating to nervous system; repaired; response; response to injury; skills; visual motor

DESCRIPTION (provided by applicant): Summary: Most injuries to the brain or spinal cord spare some connections between the areas of brain that initiate movement and the areas of spinal cord that produce movement. A pivotal question for recovery of movement is the degree to which spared connections can compensate for injured ones. We will study the adaptation of spared motor pathways to injury of the corticospinal tract (CST), the principal pathway for voluntary movement in humans. The CST, which connects the motor cortex to the spinal cord, controls fine hand movements and modulates spinal cord reflexes. We will cut the CST emanating from one hemisphere and test the ability of spared circuits to take over the lost function. Specifically, we will examine two circuits: 1) the uninjured half of the CST through its sparse ipsilateral projections, and 2) a bypass circuit on the injured side from cortex to red nucleus to spinal cord. We will injure rats soon after birth, a time when these connections are plastic and the opportunity for compensation is highest. We then measure the response of these spared systems using two novel techniques-retrograde transsynaptic tracing using pseudorabies virus, and stereological quantification of axonal connections. Thus, we will determine which spared system sprouts greater connections in response to injury. In adult rats with neonatal injury to one half of the CST, we will test the functional limits of pathway compensation. We will use both novel and proven tests of functions that depend critically on the CST: reaching to grasp, walking over a ladder, food manipulation, and control of a spinal cord reflex. We predict that there will be incomplete recovery of the specialized motor skills. For functions that do recover, we will temporarily inactivate each of the two spared pathways, by infusing an inhibitor of neural activity, to test their contribution to recovery. We expect that the recovered functions will be lost transiently in the pathway that shows the greatest amount of injury-induced plasticity. Finally, we will selectively activate the most adaptive circuit to try to improve upon endogenous recovery. Using chronic stimulation through an implanted electrode, we intend to harness activity-dependent plasticity to strengthen motor connections. We predict that these targeted manipulations will create a more adaptive pattern of brain- spinal cord connections, as measured by tracing and stimulation techniques, and help to restore function, based on the aforementioned motor tasks. Many human infants, especially those born prematurely, sustain injury to the CST. This often results in paralysis and spasticity on one side of the body. Activity, in the form of physical therapy and non-invasive brain stimulation can be used to alter connections in humans. These studies will help to determine where activity should be applied in order to strengthen the circuits that mediate spontaneous recovery. Thus, we use anatomically precise injury, tracing, inactivation, and stimulation to determine the circuit-level logic for repair of the motor systems. This could improve our ability to restore function in people with early brain injury.

描述（由申请人提供）：总结：大多数脑或脊髓损伤都会使启动运动的脑区和产生运动的脊髓区之间的一些连接中断。运动恢复的一个关键问题是备用连接可以补偿受损连接的程度。我们将研究备用运动通路对皮质脊髓束（CST）损伤的适应性，皮质脊髓束是人类自主运动的主要通路。CST连接运动皮层和脊髓，控制精细的手部运动和调节脊髓反射。我们将切断从一个半球发出的CST，并测试备用电路接管失去功能的能力。具体来说，我们将检查两个回路：1）通过其稀疏的同侧投射的CST的未受伤的一半，以及2）从皮层到红核到脊髓的受伤侧的旁路回路。我们会在出生后不久伤害老鼠，那时这些连接是可塑的，补偿的机会最高。然后，我们测量这些备用系统的反应，使用两种新的技术-逆行跨突触追踪伪狂犬病病毒，轴突连接的体视学定量。因此，我们将确定哪一个备用系统在受伤时会产生更大的连接。在新生儿损伤一半的CST的成年大鼠中，我们将测试通路补偿的功能限制。我们将使用新的和经过验证的功能测试，这些功能严重依赖于CST：伸手去抓，在梯子上行走，食物操作和脊髓反射的控制。我们预测，将有专门的运动技能的不完全恢复。对于恢复的功能，我们将通过注入神经活动抑制剂来暂时阻断两个备用通路中的每一个，以测试它们对恢复的贡献。我们预计，恢复的功能将在显示最大量的损伤诱导的可塑性的通路中暂时丧失。最后，我们将选择性地激活最具适应性的回路，以尝试改善内源性恢复。通过植入电极的慢性刺激，我们打算利用活动依赖的可塑性来加强运动连接。我们预测，这些有针对性的操作将创造一个更适应的模式，大脑-脊髓连接，通过跟踪和刺激技术测量，并有助于恢复功能，基于上述运动任务。许多人类婴儿，特别是早产儿，都会对CST造成损伤。这通常会导致身体一侧的瘫痪和痉挛。活动，以物理治疗和非侵入性脑刺激的形式，可以用来改变人类的连接。这些研究将有助于确定应该在哪里进行活动，以加强介导自发恢复的回路。因此，我们使用解剖学上精确的损伤、追踪、失活和刺激来确定用于修复运动系统的电路级逻辑。这可以提高我们恢复早期脑损伤患者功能的能力。

项目成果

Clinically Relevant Levels of 4-Aminopyridine Strengthen Physiological Responses in Intact Motor Circuits in Rats, Especially After Pyramidal Tract Injury.

临床相关水平的 4-氨基吡啶可增强大鼠完整运动回路的生理反应，特别是在锥体束损伤后。

• DOI: 10.1177/1545968316688800
• 发表时间: 2017
• 期刊: Neurorehabilitation and neural repair
• 影响因子: 4.2
• 作者: Sindhurakar,Anil;Mishra,AshtM;Gupta,Disha;Iaci,JenniferF;Parry,TomJ;Carmel,JasonB
• 通讯作者: Carmel,JasonB

Paired Stimulation to Promote Lasting Augmentation of Corticospinal Circuits.

• DOI: 10.1155/2016/7043767
• 发表时间: 2016
• 期刊: Neural plasticity
• 影响因子: 3.1
• 作者: Harel NY;Carmel JB
• 通讯作者: Carmel JB

Feasibility of caregiver-directed home-based hand-arm bimanual intensive training: a brief report.

• DOI: 10.3109/17518423.2014.948641
• 发表时间: 2015-02
• 期刊: Developmental neurorehabilitation
• 影响因子: 1.3
• 作者: Ferre CL;Brandão MB;Hung YC;Carmel JB;Gordon AM
• 通讯作者: Gordon AM

Neural Circuits Catch Fire.

神经回路着火。

• DOI: 10.1007/s13311-016-0428-4
• 发表时间: 2016
• 期刊: Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics
• 作者: Carmel,JasonB;Willis,DiannaE
• 通讯作者: Willis,DiannaE

Flipping the transcriptional switch from myelin inhibition to axon growth in the CNS.

• DOI: 10.3389/fnmol.2015.00034
• 发表时间: 2015
• 期刊: Frontiers in molecular neuroscience
• 影响因子: 4.8
• 作者: Carmel JB;Young W;Hart RP
• 通讯作者: Hart RP