Role of Thalamus in Post-stroke epileptogenesis

描述（由申请人提供）：大脑皮层卒中是残疾的主要来源，也是老年人和儿童癫痫的常见原因。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是适应不良的，并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。虽然有大量的证据支持丘脑参与全身性特发性癫痫，但对丘脑在损伤后癫痫发生中的作用知之甚少。皮质梗死导致一部分兴奋性丘脑细胞逆行性死亡，但不导致抑制性丘脑细胞逆行性死亡。我的初步数据显示， 局灶性皮质梗塞后数周，分离的丘脑切片（不含皮质）自发地产生癫痫样网络振荡。这是由丘脑内兴奋性连接的增加和丘脑内抑制的减少引起的。令人惊讶的是， 尽管来自皮质的兴奋性传入的主要损失，但是在位于功能上与局灶性皮质中风区域相关的胶质化区域中的丘脑皮质细胞中，突触兴奋增强。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，减少对中继核的抑制可以增加TC细胞的输出并增强丘脑皮质兴奋，这可能有助于丘脑和皮质感觉回路的恢复。然而，在受损的丘脑中存在癫痫样网络振荡表明丘脑重组的某些方面可能是适应不良的，参与了损伤诱导的癫痫。本研究的两个主要目的是：（1）确定丘脑异常网络兴奋性和突触兴奋的机制;（2）确定受损丘脑中这种增强的活动是否可能放大皮质丘脑网络兴奋性并有助于癫痫发生。这些问题对于我们理解脑卒中后丘脑皮质重组导致癫痫的机制至关重要。我设计了几个实验来回答这些目标。其中一些依赖于技术-使用体内光遗传学方法的光极，谷氨酸成像，激光光刺激/谷氨酸释放，自由运动动物的EEG记录-我将从我的导师和顾问那里学习，他们同意在建议的指导阶段培训我。我的长期目标是在独立的学术环境中继续研究与癫痫或帕金森病等神经系统疾病相关的异常神经网络振荡的产生机制。 公共卫生相关性：大脑皮层卒中是残疾的主要原因，也是癫痫的常见原因。中风后功能的恢复不仅涉及神经回路的存活，还涉及新神经回路的建立。该提案旨在了解中风后神经回路如何重组，以及这种重组的哪些方面可能导致癫痫。这可能会导致对治疗方法的新见解，促进功能恢复，同时限制其损害健康的结果和预防癫痫。

DESCRIPTION (provided by applicant): 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 cortial 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. PUBLIC HEALTH RELEVANCE: Stroke in the cerebral cortex is a major source of disability and a common cause of epilepsy. Recovery of function after stroke involves not only surviving neural circuits but also the establishment of new neural circuits. This proposal aims to understand how neural circuits reorganize after stroke and what aspects of this reorganization can lead to epilepsy. This may lead into new insights on therapeutic approaches that promote functional recovery while limiting its health-impairing outcomes and preventing epilepsy.