IN VIVO IMAGING OF SEIZURE-INDUCED ASTROCYTIC INJURY

 描述（由申请人提供）：癫痫通常与致残性合并症相关，包括认知障碍、精神和行为障碍以及其他神经功能缺损。癫痫发作本身可能会导致脑损伤，这可能在一定程度上导致这些共病状况，以及促进癫痫发生的渐进过程，导致癫痫发作恶化。虽然神经元仍然是介导癫痫及其合并症的主要细胞，但胶质细胞在调节癫痫发生和相关脑损伤中的作用已越来越被认识。体内成像的最新进展表明，星形胶质细胞在各种生理和病理条件下经历快速，动态的结构变化，包括神经元活性依赖性调节。然而，关于癫痫状态下星形胶质细胞的快速动态变化的信息很少。这项研究建议的主要假设是癫痫发作引起星形胶质细胞的急性动态结构变化，这与邻近树突的损伤有关。在这项研究中，我们将利用体内多光子成像来评估红藻氨酸诱导的癫痫发作对小鼠皮质星形胶质细胞的急性和慢性影响。该提案在应用尖端的体内成像方法研究脑损伤方面具有创新性。这项工作也具有很强的临床意义，因为它将为解剖癫痫诱导的胶质细胞损伤的潜在机制基础和测试针对星形胶质细胞的癫痫的合理治疗干预奠定基础。

 DESCRIPTION (provided by applicant): Epilepsy is often associated with disabling comorbidities, including cognitive impairment, psychiatric and behavioral disorders, and other neurological deficits. Seizures themselves may cause brain injury, which might, in part, contribute to these comorbid conditions, as well as promote a progressive process of epileptogenesis leading to worsening seizures. Although neurons remain the principal cells mediating epilepsy and its comorbidities, the role of glia in regulating epileptogenesis and associated brain injury has become increasingly recognized. Recent advances with in vivo imaging demonstrate that astrocytes undergo rapid, dynamic structural changes under a variety of physiological and pathological conditions, including neuronal activity-dependent modulation. However, minimal information is available on rapid, dynamic changes in astrocytes occurring in epileptic states. The primary hypothesis of this research proposal is that seizures cause acute, dynamic structural changes in astrocytes, which correlate with injury to neighboring dendrites. In this grant, we will utilize in vivo multiphoton imaging to assess both the acute and evolving chronic effects of kainate-induced seizures on cortical astrocytes in mice. This proposal is innovative in applying cutting-edge in vivo imaging methods for studying seizure-induced brain injury. This work also has strong clinical significance, as it will lay the foundation for dissectig the underlying mechanistic basis of seizure-induced glial injury and testing rational therapeutic interventions for epilepsy targeting astrocytes.