Mechanisms Underlying Maladaptive Organization of Long-range Epileptic Circuits A

描述（由申请人提供）：临床皮层刺激和制图研究表明，发育不良的神经网络是功能整合和非典型组织的。然而，异常神经网络和非典型脑组织的建立机制有待阐明。在皮质畸形患者中，多微回以感觉运动区最为常见，癫痫发作常发生在语言和运动功能皮质区或其附近。由于皮质发育不良的这些常见临床特征，我们修改了新生儿冷冻病变动物模型，以询问正常运动皮层（M1）的输出活动如何与位于同侧畸形感觉皮层（S1）的致痫回路相互作用。在我们的新小鼠模型中，光遗传学方法将与传统的局灶性冻结病变相结合，研究远程运动皮质投射与畸形感觉皮质局部回路之间的相互作用。我们假设1)畸形S1皮质中M1到中间神经元的远程连接严重改变，导致icgenesis和繁殖增强。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神经支配；从而减轻运动皮层引起的S1癫痫发作。这项探索性拨款旨在提供第一个证据，证明远程运动投射在S1中诱导的ictogenesis，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经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，可能用于减轻或根除人类癫痫病理。

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.