Role of Thalamus in Post-stroke epileptogenesis

大脑皮层中风是老年人残疾的主要来源和癫痫的常见原因 在儿童身上也是如此。卒中后倾向于补偿丧失的功能的神经可塑性涉及重组 幸存的神经回路。然而，重组的某些方面可能是不适应的， 随着时间的推移会导致癫痫的发生。 丘脑皮质回路调节与癫痫相关的神经网络振荡。虽然有一个很大的 支持丘脑参与全身性特发性癫痫的证据很少 已知丘脑在损伤后癫痫发生中的作用。皮质梗塞导致细胞退行性变 兴奋性但不是抑制性丘脑细胞的一部分死亡。 我的初步数据显示，在局灶性皮质梗塞后的几周后，分离的丘脑切片 (不包含大脑皮层的)自发地产生癫痫样网络振荡。这是平行的 通过丘脑内兴奋性连接的增加和丘脑内抑制的减少。令人惊讶的是， 尽管皮层的兴奋性传入大量丢失，但突触兴奋在 丘脑皮质细胞位于与局灶性皮质卒中区域功能相关的胶质质区。 总而言之，这些结果表明，皮质梗塞导致丘脑内强健的回路重新连接。 这一重组的某些方面可以支持功能恢复。例如，减少了对 中继核可以增加TC细胞的输出，增强丘脑皮质的兴奋，这可能是 促进丘脑和大脑皮层感觉回路的恢复。然而，癫痫样网络的存在 受损丘脑的振荡提示，丘脑重组的某些方面可能是 适应不良，参与外伤性癫痫。这项研究提案的两个主要目标是 如下：(1)确定异常网络兴奋性的潜在机制和 丘脑的突触兴奋；(2)确定这种增强的活动是否在受伤的人中 丘脑可能增强皮质丘脑网络的兴奋性，参与癫痫的发生。 这些问题对于我们理解卒中后丘脑皮质损伤的机制至关重要。 重组导致癫痫。我设计了几个实验来回答这些目标。其中几个 他们依赖于使用体内光遗传方法的光学电极、谷氨酸成像、激光技术 光刺激/谷氨酸去除，自由活动动物的脑电记录，我将从我的 在计划书的指导阶段同意对我进行培训的导师和顾问。我的龙- 学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疾病相关的独立 学术背景。

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.