Role of Thalamus in Post-stroke epileptogenesis

丘脑在中风后癫痫发生中的作用

• 批准号: 8846361
• 负责人: Jeanne T Paz
• 金额: $ 24.9万
• 依托单位: J. DAVID GLADSTONE INSTITUTES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8846361
• 关键词: Animals; Area; Axon; Behavioral; Biological Neural Networks; Cell Death; Cell Nucleus; Cells; Cerebral cortex; Child; Data; Development; Elderly; Electrodes; Electroencephalography; Electrophysiology (science); Epilepsy; Epileptogenesis; Equilibrium; Evolution; Frequencies; Generalized Epilepsy; Glutamates; Goals; Hyperactive behavior; Image; Impaired health; In Vitro; Infarction; Injury; Lasers; Lead; Learning; Maps; Mediating; Mentors; Methodology; Neuronal Plasticity; Neurons; Outcome; Output; Parkinson Disease; Partial Epilepsies; Phase; Probability; Rattus; Recovery; Recovery of Function; Research Proposals; Role; Seizures; Sensory; Slice; Somatosensory Cortex; Source; Stroke; Synapses; Techniques; Technology; Thalamic Nuclei; Thalamic structure; Therapeutic; Time; Training; base; complement C2a; design; disability; extracellular; in vivo; inhibitory neuron; injured; insight; nervous system disorder; neural circuit; optogenetics; patch clamp; post stroke; presynaptic; prevent; research study

Stroke in the cerebral cortex is a major source of disability and a common cause of epilepsy in the elderly and in children. Neural plasticity after stroke that tends to compensate lost functions involves reorganization of the surviving neural circuits. However, some aspects of the reorganization might be maladaptive and lead to epileptogenesis over time. Thalamocortical circuits mediate neural network oscillations associated with epilepsy. While there is a large body of evidence supporting thalamic involvement in the generalized idiopathic epilepsies, very little is known about the role of thalamus in post-injury epileptogenesis. Cortical infarcts lead to retrograde cell death of a subset of excitatory  but not inhibitory  thalamic cells. My preliminary data indicate that after several weeks following focal cortical infarcts, isolated thalamic slices (that do not contain the cortex) spontaneously generate epileptiform network oscillations. This is paralleled by increases in intra-thalamic excitatory connectivity and decreases in intra-thalamic inhibition. Surprisingly, despite a major loss of excitatory afferents from the cortex, synaptic excitation is enhanced in thalamocortical cells located in the gliotic area functionally related to the region of focal cortical stroke. Altogether, these results suggest that cortical infarcts lead to robust circuit rewiring within the thalamus. Some aspects of this reorganization could support functional recovery. For example, reduced inhibition of relay nuclei could increase the output of TC cells and enhance thalamocortical excitation, which may facilitate recovery of thalamic and cortical sensory circuits. However, the presence of epileptiform network oscillations in the injured thalamus suggests that some aspects of the thalamic reorganization could be maladaptive, participating in injury-induced epilepsy. The two main goals of this research proposal are as follows: (1) To determine the mechanisms underlying the aberrant network excitability and synaptic excitation in the thalamus; (2) To determine whether this enhanced activity in the injured thalamus might amplify corticothalamic network excitability and contribute to epileptogenesis. These questions are crucial to our understanding of the mechanisms of post-stroke thalamocortical reorganization leading to epilepsy. I have designed several experiments to answer these goals. Several of them rely on techniques  optrodes using optogenetic approaches in vivo , glutamate imaging, laser photostimulation/ glutamate uncaging, EEG recordings in freely moving animals  that I will learn from my mentor and consultants who have agreed to train me during the mentored phase of the proposal. My long- term goal is to continue studying the mechanisms generating abnormal neural network oscillations associated with neurological disorders such as epilepsy or Parkinson's disease in an independent academic setting.

大脑皮层中风是导致残疾的主要原因，也是老年人癫痫的常见原因 和儿童。中风后的神经可塑性往往会补偿失去的功能，包括重组 幸存的神经回路然而，重组的某些方面可能不适应， 随着时间的推移导致癫痫发生。 丘脑皮层回路介导与癫痫相关的神经网络振荡。虽然有一个大的 尽管有大量证据支持丘脑参与全身性特发性癫痫，但很少有证据支持丘脑参与全身性特发性癫痫。 已知丘脑在损伤后癫痫发生中的作用。皮质梗死导致细胞逆行 兴奋性神经元亚群死亡  但不抑制  丘脑细胞 我的初步数据表明，在局灶性皮质梗死后几周， (that不包含皮层）自发地产生癫痫样网络振荡。这是一个 通过增加丘脑内兴奋性连接和减少丘脑内抑制。令人惊奇的是， 尽管来自皮层的兴奋性传入纤维大量丢失， 位于神经胶质区的丘脑皮质细胞，功能上与局灶性皮质卒中区域相关。 总之，这些结果表明，皮质梗死导致丘脑内强大的电路重新布线。 这种重组的某些方面可以支持功能恢复。例如，降低对 中继核可增加TC细胞的输出，增强丘脑皮质兴奋，这可能与 促进丘脑和皮层感觉回路的恢复。然而，癫痫网络的存在 受损丘脑的振荡表明，丘脑重组的某些方面可能是 适应不良，参与损伤诱发的癫痫。本研究提案的两个主要目标是 （1）研究异常网络兴奋性的机制， 丘脑中的突触兴奋;（2）为了确定这种增强的活动是否在受伤的 丘脑可能放大皮质丘脑网络的兴奋性，并参与癫痫的发生。 这些问题对于我们理解脑卒中后丘脑皮质的机制至关重要， 重组导致癫痫。我设计了几个实验来回答这些目标。几 他们依靠技术  体内使用光遗传学方法的光极，谷氨酸成像，激光 光刺激/谷氨酸释放，自由活动动物的EEG记录  我会从我的 导师和顾问，他们同意在建议书的指导阶段对我进行培训。我的长- 长期目标是继续研究产生异常神经网络振荡的机制 与癫痫或帕金森病等神经系统疾病相关的独立研究中， 学术设置。