Spinal Effects of Cortical Stimulation: Mechanisms and Functional Impact
皮质刺激的脊髓效应:机制和功能影响
基本信息
- 批准号:10470019
- 负责人:
- 金额:$ 74.17万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-09-30 至 2024-07-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAnatomyAreaAttentionBrainCellsCentral Nervous System DiseasesCerebral PalsyChronicContralateralCorticospinal TractsDataDevelopmentDistantElectrodesExperimental ModelsFrequenciesGABA ReceptorGene ActivationGene ExpressionGenetic TranscriptionGlutamatesGoalsH-ReflexHumanImplantInterneuronsIpsilateralLesionLifeLong-Term DepressionLong-Term EffectsLong-Term PotentiationMeasuresMethodsMolecularMolecular BiologyMonitorMotor CortexMotor NeuronsMuscleNatureNeuromuscular DiseasesNeuronsPathway interactionsPatternPersonsPhysiologicalPhysiologyPropertyProtocols documentationRattusRecoveryRecovery of FunctionRoleShapesSoleus MuscleSpinalSpinal CordSpinal Cord PlasticitySpinal cord injuryStrokeStructureSynapsesTestingTraumatic CNS injuryanaloganatomical tracingantagonistbaseexpectationgamma-Aminobutyric Acidinsightnext generation sequencingnovel therapeuticspreventreceptorspinal reflexstretch reflextranscriptome sequencing
项目摘要
Project Summary/Abstract
Because activity-dependent plasticity is ubiquitous in the CNS, brain stimulation may have long-term effects on
areas to which the stimulated area connects. These effects have received little attention. Nevertheless, recent
appreciation of the long-term role of cortex in shaping spinal cord pathways suggests that the long-term spinal
effects of cortical stimulation are likely to be substantial. In fact, weak electrical cortical stimulation (ECS) of
rat sensorimotor cortex has lasting spinal effects. Three months after ECS ends, GABA receptors in spinal
motoneurons remain decreased and the H-reflex (analog of the spinal stretch reflex) remains increased.
This proposal seeks to determine in rats how ECS produces these spinal effects and to characterize the
effects on physiological, anatomical, and molecular levels. Preliminary studies support the hypothesis that the
spinal effects occur because ECS excites corticospinal tract (CST) neurons that synapse on spinal GABAergic
interneurons that synapse on soleus motoneurons, that this input reduces GABA metabotropic receptors and
thereby modifies motoneuron properties so as to increase the H-reflex (and also affect other spinal circuits), and
that specific gene activations underlie these effects. Two specific aims test this hypothesis.
The first aim is to determine how ECS parameters affect its impact on the spinal cord and to define the
responsible descending pathway. ECS will be given by epidural electrodes. Pathway lesions and anatomical
tracers will identify the key pathway and its spinal targets. Based on initial data and other studies, the expectation
is that the CST is the essential pathway and that it connects to spinal motoneurons via GABAergic interneurons.
The second aim is to characterize the short-term and long-term effects of ECS on spinal neurons and circuits
on physiological, anatomical, and transcriptional levels. These studies will: examine ECS impact on motoneuron
properties (e.g., firing threshold) and on spinal reflex pathways; explore immunohistochemically ECS impact on
GABAergic and other (e.g., glutamatergic) spinal interneurons and synapses and their receptors in soleus and
other spinal motoneurons; use next-generation sequencing methods (RNA-Seq) to identify ECS-induced changes
in gene expression in spinal motoneurons that correlate with and are likely to account for the changes in neuronal
properties, spinal circuit function, and immunohistochemical measures.
In summary, this proposal uses a well-defined experimental model to explore the spinal effects of cortical
stimulation. By characterizing the nature and mechanisms of the spinal cord plasticity produced by this stimulation,
it should provide fundamental new insight into the wider effects of cortical stimulation, and also into how the
cortex modifies the spinal cord throughout life. Furthermore, the results should guide development of stimulation
protocols to further explore these effects, and stimulation protocols that can induce beneficial plasticity to enhance
functional recovery after CNS trauma or disease.
项目总结/摘要
由于活动依赖性可塑性在中枢神经系统中普遍存在,因此脑刺激可能对中枢神经系统产生长期影响。
受刺激区域所连接的区域。这些影响很少受到关注。然而,最近
对皮质在塑造脊髓通路中的长期作用的认识表明,
皮层刺激的效果可能是实质性的。事实上,大脑皮层的弱电刺激(ECS)
大鼠感觉运动皮层具有持久的脊髓效应。ECS结束后3个月,脊髓背角GABA受体
运动神经元保持减少,H-reflux(脊髓牵张反射的类似物)保持增加。
该提案旨在确定大鼠ECS如何产生这些脊髓效应,并表征ECS的作用机制。
对生理、解剖和分子水平的影响。初步研究支持了这样的假设,
脊髓效应的发生是因为ECS兴奋皮质脊髓束(CST)神经元,皮质脊髓束(CST)神经元与脊髓GABA能神经元突触
在比目鱼肌运动神经元上突触的中间神经元,这种输入减少GABA代谢型受体,
从而改变运动神经元的特性,以增加H-反射(也影响其他脊髓回路),
特定的基因激活是这些效应的基础。有两个具体的目标来检验这个假设。
第一个目的是确定ECS参数如何影响其对脊髓的影响,并定义
负责任的下行通路。将通过硬膜外电极给予ECS。通路病变和解剖学
示踪剂将识别关键通路及其脊髓靶点。根据初步数据和其他研究,
CST是重要的通路,它通过GABA能中间神经元与脊髓运动神经元相连。
第二个目的是表征ECS对脊髓神经元和回路的短期和长期影响
在生理学解剖学和转录水平上。这些研究将:检查ECS对运动神经元的影响
属性(例如,放电阈值)和脊髓反射通路;探索化学ECS对
GABA能和其他(例如,比目鱼肌内的脊髓中间神经元和突触及其受体,
其他脊髓运动神经元;使用下一代测序方法(RNA-Seq)鉴定ECS诱导的变化
脊髓运动神经元的基因表达与神经元的变化相关并可能解释神经元的变化
特性、脊髓回路功能和免疫组织化学测量。
总之,这项建议使用了一个定义明确的实验模型来探索皮质类固醇对脊髓的影响。
刺激.通过表征由这种刺激产生的脊髓可塑性的性质和机制,
它应该为皮层刺激的更广泛影响提供基本的新见解,也可以了解大脑皮层刺激是如何产生的。
皮质在整个生命过程中都会改变脊髓。此外,研究结果应指导刺激措施的开发
协议,以进一步探索这些影响,和刺激协议,可以诱导贝内的可塑性,以提高
CNS创伤或疾病后的功能恢复。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Jonathan Saul Carp其他文献
Jonathan Saul Carp的其他文献
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{{ truncateString('Jonathan Saul Carp', 18)}}的其他基金
Spinal Effects of Cortical Stimulation: Mechanisms and Functional Impact
皮质刺激的脊髓效应:机制和功能影响
- 批准号:
10666526 - 财政年份:2019
- 资助金额:
$ 74.17万 - 项目类别:
Spinal Effects of Cortical Stimulation: Mechanisms and Functional Impact
皮质刺激的脊髓效应:机制和功能影响
- 批准号:
10237412 - 财政年份:2019
- 资助金额:
$ 74.17万 - 项目类别:
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