Dysregulation of developing neural circuits during epileptogenesis

癫痫发生过程中神经回路发育失调

• 批准号: 10701429
• 负责人: CARLOS D AIZENMAN
• 金额: $ 39.88万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-22 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10701429
• 关键词: Affect; Basic Science; Behavior; Biological; Biological Models; Biology; Brain; Brain Injuries; Cell Proliferation; Chemicals; Development; Electrophysiology (science); Ensure; Epilepsy; Epileptogenesis; Equilibrium; Experimental Models; Exposure to; Functional Imaging; Functional disorder; Generations; Genes; Genetic; Goals; Hypersensitivity; Image; Impairment; Individual; Intellectual functioning disability; Knowledge; Label; Lead; Life; Measures; Methods; Modeling; Molecular; Neurodevelopmental Disorder; Neurons; Parents; Pathway interactions; Physiology; Pilot Projects; Population; Predisposition; Preparation; Process; Property; Recurrence; Research; Role; Seizures; Sensory; Series; Shapes; Structure; Study models; Synapses; Tadpoles; Techniques; Tectum Mesencephali; Testing; Time; Traumatic Brain Injury; Xenopus; Xenopus laevis; brain cell; confocal imaging; early experience; experience; experimental study; improved; in vivo; innovation; neural circuit; neurogenesis; neuron development; newborn neuron; novel; prevent; public health relevance; sensory processing disorder; single-cell RNA sequencing; spreading depression; therapeutic target; voltage

New neurons are born throughout life: their generation, integration and function are tightly regulated. Impairment of this process is associated with brain circuit dysfunction and the development of epileptiform activity and sensory hypersensitivity, associated with neurodevelopmental disorders. In several models of epileptogenesis, prior and repeated seizure activity (e.g. from traumatic brain injury) results in increased seizure susceptibility and eventually epilepsy. Neurogenesis is known to be disrupted following repeated seizure activity, which can alter cell proliferation, survival, differentiation and functional maturation of new neurons as they incorporate into existing neural circuits. Since altered neurogenesis has been shown to be a causative factor in both spreading depression and seizure generation, both pathophysiological hallmarks of epilepsy, it is important to understand whether abnormal circuit activity and perturbed neurogenesis cause newborn neurons to improperly integrate and function within existing brain circuits, disturbing activity and leading to epilepsy. This proposal tests the hypothesis that seizure activity and network hyperexcitability perturb development and function of new neurons, resulting in highly excitable neurons that potentiate network hyperexcitability and lead to epilepsy and sensory hypersensitivity. We will a reduced preparation, the Xenopus laevis tadpole tectum—an established model for studying generation of new neurons and the biological basis for epilepsy. It is a highly recurrent structure with ongoing integration of new neurons, and thus ideally placed for understanding the fundamental biological underpinnings of developmental epilepsy. We will use genetic methods to tag later-born neurons and follow them in vivo as they integrate into existing brain circuits following developmental seizure exposure. We will measure the structure and physiology of these neurons as they mature. We will then test whether we can manipulate the electrical activity of these miswired neurons and test whether we can ameliorate seizure activity. Finally, we will examine genes that are expressed incorrectly in later born neurons following a seizure to test whether these genetic pathways can be responsible for the abnormal development of these neurons and miswiring of the brain following a seizure. Improving our understanding of how exposure to prior seizures affects the maturation of neural circuits, and how this in turn leads to epilepsy will not only help illustrate the basic biology underlying epileptogenesis, but will result in potential therapeutic targets that could prevent formation of epilepsy following a series of seizures, such as those experienced after brain injury.

新的神经元在整个生命过程中诞生：它们的生成，整合和功能与神经元的生长密切相关。 监管.这一过程的损害与脑回路功能障碍有关， 癫痫样活动和感觉超敏反应的发展， 神经发育障碍在几种癫痫发生模型中，先前和反复发作 活动（例如创伤性脑损伤）导致癫痫发作易感性增加， 最后是癫痫已知神经发生在反复发作活动后被破坏， 它可以改变细胞增殖、存活、分化和新的细胞的功能成熟， 神经元融入现有的神经回路。自从改变神经发生以来， 在扩散性抑郁症和癫痫发作中， 癫痫的病理生理特征，重要的是要了解是否异常电路 活动和扰乱的神经发生导致新生神经元不适当地整合， 在现有的大脑回路中发挥作用，干扰活动并导致癫痫。 该提议检验了癫痫发作活动和网络过度兴奋扰乱 新神经元的发育和功能，导致高度兴奋的神经元， 网络兴奋过度，导致癫痫和感觉过敏。 我们将减少准备，非洲爪蟾蝌蚪tadpole tectum-一个建立的模型， 研究新神经元的产生和癫痫的生物学基础。这是一个高度重复的 新神经元持续整合的结构，因此非常适合理解 发展性癫痫的基本生物学基础。我们将使用基因 标记后来出生的神经元并在体内跟踪它们整合到现有大脑中的方法 发育性癫痫暴露后的神经回路我们将测量结构， 这些神经元成熟时的生理学。然后我们将测试我们是否可以操纵 这些神经元的电活动，测试我们是否可以改善癫痫发作， 活动最后，我们将检查在后来出生的神经元中错误表达的基因 在癫痫发作后，测试这些基因通路是否可以导致异常的 这些神经元的发展和癫痫发作后大脑的错误布线。改善我们 了解癫痫发作前的暴露如何影响神经回路的成熟， 这又是如何导致癫痫的，这不仅有助于阐明 癫痫发生，但将导致潜在的治疗目标，可以防止形成 一系列癫痫发作后的癫痫，如脑损伤后的癫痫。