Mechanisms Underlying Maladaptive Organization of Long-range Epileptic Circuits A

长程癫痫回路 A 适应不良组织的潜在机制

基本信息

批准号：
8724573
负责人：
Qian-Quan Sun
金额：
$ 17.51万
依托单位：
UNIVERSITY OF WYOMING
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-01 至 2015-08-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Clinical cortical stimulation and mapping studies led to the idea that the dysplastic neural networks are functionally integrated and atypically organized. However, the mechanisms for the establishment of aberrant neural networks and atypical brain organization await elucidation. In patient with cortical malformation, sensorimotor region are most frequent in finding polymicrogyri, and seizure onset commonly occurs with or near cortical areas for language and motor function. Motivated by these common clinical features of cortical dysplasia, we modified a neonatal freeze lesion animal model to interrogate how efferent activities in the normal motor cortex (M1), interacts with epileptogenic circuits located within ipsilateral malformed sensory cortex (S1). In our new mice model, optogenetic approaches will be combined with traditional focal freeze lesion, to study interactions between long-range motor cortical projections and local circuits within malformed sensory cortex. We hypothesize that 1) long-range connections from M1 onto interneurons are severely altered in malformed S1 cortex, leading to heightened ictogenesis and propagation. 2) Sensorimotor experiences during critical periods may selectively promote glutamatergic innervation of interneurons; thereby mitigate motor cortex induced seizure in S1. This exploratory grant is directed to provide the first proof of the involvement of long-range motor projection induced ictogenesis in S1, as well as its modulation by innate animal behavior. Understanding how glutamatergic synapses and epileptic activities are modulated by innate sensorimotor experiences during critical period will help development of stimulation-based physical therapy strategies might be used to mitigate or eradicate epilepsy pathology in humans.

描述（由申请人提供）：临床皮质刺激和绘图研究得出这样的观点：发育不良的神经网络在功能上是整合的并且是非典型组织的。然而，异常神经网络和非典型大脑组织的建立机制仍有待阐明。在皮质畸形患者中，感觉运动区最常发现多小脑回，癫痫发作通常发生在语言和运动功能皮质区或其附近。受皮质发育不良这些常见临床特征的启发，我们修改了新生儿冷冻损伤动物模型，以探究正常运动皮层 (M1) 中的传出活动如何与同侧畸形感觉皮层 (S1) 内的致癫痫回路相互作用。在我们的新小鼠模型中，光遗传学方法将与传统的局灶性冷冻损伤相结合，以研究长程运动皮层投射与畸形感觉皮层内的局部电路之间的相互作用。我们假设 1) 在畸形的 S1 皮层中，从 M1 到中间神经元的长距离连接发生了严重改变，导致了严重的组织生成和传播。 2）关键时期的感觉运动体验可能选择性地促进中间神经元的谷氨酸能神经支配；从而减轻运动皮层诱发的 S1 癫痫发作。这项探索性资助旨在提供第一个证据，证明 S1 中远程运动投射诱导的 ictogenesis 的参与，以及先天动物行为对其的调节。了解关键时期先天感觉运动体验如何调节谷氨酸突触和癫痫活动将有助于开发基于刺激的物理治疗策略，可用于减轻或根除人类癫痫病理。