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

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.

项目概要/摘要 由于活动依赖性可塑性在中枢神经系统中普遍存在，因此大脑刺激可能会对神经系统产生长期影响。 然而，最近这些影响很少受到关注。 对皮质在塑造脊髓通路中的长期作用的认识表明，长期脊髓 事实上，弱电皮层刺激（ECS）的效果可能是显着的。 ECS 结束后三个月，大鼠感觉运动皮层的 GABA 受体对脊髓产生持久的影响。 运动神经元仍然减少，H 反射（类似于脊髓牵张反射）仍然增加。 该提案旨在确定 ECS 如何在大鼠中产生这些脊柱效应，并表征 对生理、解剖和分子水平的影响。 脊髓效应的发生是因为 ECS 刺激了脊髓 GABA 能突触的皮质脊髓束 (CST) 神经元 与比目鱼肌运动神经元突触的中间神经元，这种输入减少了 GABA 代谢受体， 改变运动神经元特性，从而增强 H 反射（并影响其他脊髓回路），并且 特定的基因激活是这些效应的基础。两个特定的目标检验了这一假设。 第一个目标是确定 ECS 参数如何影响其对脊髓的影响并定义 负责的下行通路将由硬膜外电极给出。 示踪剂将根据初步数据和其他研究确定关键通路及其脊柱目标。 CST 是重要的通路，它通过 GABA 能中间神经元连接到脊髓运动神经元。 第二个目标是描述 ECS 对脊髓神经元和回路的短期和长期影响 这些研究将：检查 ECS 对运动神经元的影响。 特性（例如放电阈值）和脊髓反射通路；探讨 ECS 对免疫组织化学的影响； GABA能和其他（例如谷氨酸能）脊髓中间神经元和突触及其在比目鱼肌和 其他脊髓运动神经元；使用下一代测序方法 (RNA-Seq) 来识别 ECS 引起的变化 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 特性、脊髓回路功能和免疫组织化学测量。 总之，该提案使用明确的实验模型来探索皮质对脊柱的影响 通过表征这种刺激产生的脊髓可塑性的性质和机制， 它应该提供关于皮质刺激的更广泛影响的基本新见解，以及如何 皮层在整个生命过程中都会改变脊髓此外，结果应该指导刺激的发展。 进一步探索这些影响的方案，以及可以诱导有益可塑性以增强的刺激方案 中枢神经系统创伤或疾病后的功能恢复。