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
• 负责人: Jonathan Saul Carp
• 金额: $ 74.77万
• 依托单位: ALBANY RESEARCH INSTITUTE, INC.
• 依托单位国家: 美国
• 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: https://reporter.nih.gov/project-details/10237412
• 关键词: Affect; Anatomy; Area; Attention; Brain; Cells; Central Nervous System Diseases; Cerebral Palsy; Chronic; Contralateral; Corticospinal Tracts; Data; Development; Distant; Electrodes; Experimental Models; Frequencies; GABA Receptor; Gene Activation; Gene Expression; Genetic Transcription; Glutamates; Goals; H-Reflex; Human; Implant; Interneurons; Ipsilateral; Lesion; Life; Long-Term Depression; Long-Term Effects; Long-Term Potentiation; Measures; Methods; Molecular; Molecular Biology; Monitor; Motor Cortex; Motor Neurons; Muscle; Nature; Neuromuscular Diseases; Neurons; Pathway interactions; Pattern; Physiological; Physiology; Property; Protocols documentation; Rattus; Recovery; Recovery of Function; Role; Shapes; Soleus Muscle; Spinal; Spinal Cord; Spinal Cord Plasticity; Spinal cord injury; Stroke; Structure; Synapses; Testing; Traumatic CNS injury; analog; anatomical tracing; base; expectation; gamma-Aminobutyric Acid; insight; next generation sequencing; novel therapeutics; prevent; receptor; spinal reflex; stretch reflex; transcriptome sequencing; Affect; Anatomy; Area; Attention; Brain; Cells; Central Nervous System Diseases; Cerebral Palsy; Chronic; Contralateral; Corticospinal Tracts; Data; Development; Distant; Electrodes; Experimental Models; Frequencies; GABA Receptor; Gene Activation; Gene Expression; Genetic Transcription; Glutamates; Goals; H-Reflex; Human; Implant; Interneurons; Ipsilateral; Lesion; Life; Long-Term Depression; Long-Term Effects; Long-Term Potentiation; Measures; Methods; Molecular; Molecular Biology; Monitor; Motor Cortex; Motor Neurons; Muscle; Nature; Neuromuscular Diseases; Neurons; Pathway interactions; Pattern; Physiological; Physiology; Property; Protocols documentation; Rattus; Recovery; Recovery of Function; Role; Shapes; Soleus Muscle; Spinal; Spinal Cord; Spinal Cord Plasticity; Spinal cord injury; Stroke; Structure; Synapses; Testing; Traumatic CNS injury; analog; anatomical tracing; base; expectation; gamma-Aminobutyric Acid; insight; next generation sequencing; novel therapeutics; prevent; receptor; spinal reflex; stretch reflex; transcriptome sequencing

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.

项目摘要/摘要 由于与活动相关的可塑性在中枢神经系统中无处不在，因此大脑刺激可能会对 刺激区域连接的区域。这些影响很少受到关注。然而，最近 对皮层在塑造脊髓途径中的长期作用的欣赏表明长期脊柱 皮质刺激的影响可能很大。实际上，弱的皮质刺激（EC） 大鼠感觉运动皮层具有持久的脊柱作用。 EC结束三个月后，脊柱中的GABA受体 运动神经元保持改善，H-RE-REFEX（脊柱拉伸的类似物）保持增加。 该建议旨在确定大鼠ECS如何产生这些脊柱作用并表征 对物理，解剖和分子水平的影响。初步研究支持以下假设 发生脊柱效应是因为EC激发皮质脊髓束（CST）神经元在脊柱Gabaergic上突触 在比目鱼节神经元上突触的中间神经元，该输入降低了GABA代谢受体和 从而修饰运动神经元的特性，以增加h-re ex（也影响其他脊柱电路），并且 该特定基因激活是这些作用的基础。两个具体的目的检验了这一假设。 第一个目的是确定EC参数如何影响其对脊髓的影响并定义 负责的下降途径。 EC将由硬膜外电极给出。途径病变和解剖学 示踪剂将确定关键途径及其脊柱靶标。根据初始数据和其他研究，期望 是CST是必不可少的途径，它通过GABA能中间神经元连接到脊髓运动神经元。 第二个目的是表征EC对脊柱神经元和电路的短期和长期影响 在物理，解剖和转录水平上。这些研究将：检查EC对运动神经元的影响 性质（例如，插阈值）和脊柱频道；探索免疫组织化学的ECS对 gabaergic和其他（例如谷氨酸能）脊柱中间神经元和突触及其受体在比目鱼和受体中 其他脊柱运动神经元；使用下一代测序方法（RNA-Seq）识别EC诱导的变化 在脊柱运动神经元中的基因表达中，与神经元的变化相关并可能解释 性质，脊柱电路功能和免疫组织化学测量。 总而言之，该提案使用一个精确的实验模型来探索皮质的脊柱效应 刺激。通过表征该刺激产生的脊髓可塑性的性质和机制， 它应该为皮质刺激的更广泛影响以及如何提供基本的新见解，也应该对 皮层整个生命都会修饰脊髓。此外，结果应指导刺激的发展 进一步探索这些效果的协议，以及可以引起利益可塑性以增强的刺激协议 中枢神经系统创伤或疾病后的功能恢复。