Mechanisms Underlying Maladaptive Organization of Long-range Epileptic Circuits A

描述(由申请人提供)：临床皮质刺激和标测研究导致了发育障碍神经网络在功能上是集成的和非典型组织的想法。然而，异常神经网络和非典型脑组织的建立机制仍有待阐明。在皮质畸形患者中，感觉运动区是发现多微回最常见的区域，癫痫发作通常发生在语言和运动功能的皮质区域或其附近。受皮质发育不良的这些常见临床特征的启发，我们修改了一个新生儿冷冻损伤动物模型，以询问正常运动皮质(M1)的传出活动如何与同侧畸形感觉皮质(S1)内的致痫回路相互作用。在我们的新的小鼠模型中，光遗传学方法将与传统的局灶性冷冻损伤相结合，以研究远程运动皮质投射与畸形感觉皮质内局部回路之间的相互作用。我们假设：1)在畸形的S1皮层中，从M1到中间神经元的远程连接被严重改变，导致细胞分裂和繁殖加速。2)关键期感觉运动经验可能选择性地促进中间神经元的谷氨酸能神经支配，从而减轻运动皮质诱发的S1癫痫发作。这项探索性拨款旨在提供第一个证据，证明S1参与了远程运动投射诱导的细胞分裂，以及动物先天行为对其调控。了解谷氨酸能突触和癫痫活动是如何在关键时期被固有的感觉运动经验调节的，将有助于开发基于刺激的物理治疗策略，可能被用来减轻或根除人类的癫痫病理。

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.