Functional contribution of adult-born neurons to epileptogenesis

成年神经元对癫痫发生的功能贡献

• 批准号: 9210540
• 负责人: Eric Schnell
• 金额: --
• 依托单位: PORTLAND VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9210540
• 关键词: Acute; Adult; Affect; American; Animal Model; Animals; Axon; Birth; Brain; Brain Injuries; Brain region; Cells; Clinical Management; Convulsants; Cytoplasmic Granules; Development; Electroencephalography; Electrophysiology (science); Epilepsy; Epileptogenesis; Equilibrium; Exhibits; Fiber; Frequencies; Generations; Genetic; Goals; Grant; Growth; Head; Hippocampus (Brain); Human; Image; Infection; Injury; Interneurons; Label; Learning; Medical; Memory; Methodology; Methods; Military Personnel; Modeling; Mus; Neonatal; Neurologic; Neurons; Output; Pathogenesis; Pathologic; Pathway interactions; Physiologic pulse; Physiological; Pilocarpine; Play; Post-Traumatic Epilepsy; Process; Property; Recording of previous events; Recovery; Recurrence; Resistance; Role; Seizures; Severities; Slice; Source; Stroke; Synapses; Techniques; Temporal Lobe Epilepsy; Testing; Tissue imaging; Tissues; Traumatic Brain Injury; United States; Veterans; Work; adult neurogenesis; cohort; experimental study; feeding; genetic manipulation; granule cell; in vivo; insight; mossy fiber; mouse model; neurogenesis; neuronal circuitry; novel strategies; optogenetics; postnatal; prevent; public health relevance; response; synaptogenesis; therapeutic target; therapy design; tool

 DESCRIPTION (provided by applicant): Epilepsy is a potentially devastating neurologic condition that affects about 2 million Americans and is often resistant to medical treatment. Animal studies have demonstrated that epilepsy is associated with compensatory changes in the brain, which includes the aberrant growth and rewiring of neuronal circuits. In particular, epilepsy is associated with altered connectivity in te hippocampus, a region of the brain that is frequently the focal point for the initiation of seizure. The hippocampus is also one of few brain regions exhibiting constitutive adult neurogenesis, in which hippocampal granule cells are born in adulthood, and these new neurons play important roles in learning and memory. The generation of these adult-born neurons increases after certain types of injury, including seizures and traumatic brain injury, and might represent a homeostatic response to enhance recovery. One particular hippocampal circuit rearrangement associated with epilepsy involves the growth ("sprouting") of granule cell axons (the mossy fibers) in a retrograde direction. These sprouted fibers could directly cause hippocampal hyperexcitability by forming recurrent excitatory circuits, or alternatively increase the activity f inhibitory circuits and thus prevent seizures. Although experimental evidence exists to support each of these possibilities, direct functional analysis of these fibers has been lacking, due primarily to an inability to selectively isolate these fibers for physiologic characterization. Thu, their role in epileptogenesis is still unclear. Animal studies have suggested that sprouted mossy fibers might selectively, or perhaps exclusively, derive from adult-born cells. If these fibers are involved in generating seizure activity, adult-born neurons might then directly contribute to the development of epileptic circuits. Thus, they would possess a detrimental, rather than salutary, role during epileptogenesis. Furthermore, as granule cells contribute a major excitatory input into hippocampal region CA3, and also drive potent feed-forward inhibition in that region, changes in the development of this projection by adult-born cells could cause an imbalance between excitation and inhibition. Again, the functional role of these adult-born granule cell projections in epilepsy has not been explored, as it has not been possible to selectively analyze these cells and their connections in an efficient manner. In this grant, we propose to study whether adult-born neurons contribute to the formation of hyper- excitable circuits in a mouse model of epilepsy, and whether they directly promote the occurrence of seizures. We have combined various lines of genetically modified mice, which allow us to specifically label and activate these cells in live tissue. We will induce experimental epilepsy using the well-established pilocarpine model of epilepsy, and use electrophysiologic recording techniques to study the functional connectivity of these adult- born cells in the hippocampal circuit. Furthermore, we will use additional genetic manipulations to modify the electrical activity of these cells in epileptic mice in vivo, to determine how this affects seizure frequency. Our work will answer long-standing questions regarding the pathogenesis of several forms of epilepsy, by directly defining the functional role of this aberrant fiber pathway. We will be able to selectivel study sprouted mossy fiber function, regardless of the source of these fibers, as our technique allows for the selective stimulation of granule cell axons from either postnatally derived or adult born granule cells. This will provide an insight into the function of this pathway regardless of it source, but also allow us to determine whether the sprouting is partially, or perhaps predominantly, derived from adult born cells. If adult-born neurons directly contribute to the development of epilepsy, this would provide a specific therapeutic target to potentially prevent the development of epilepsy after injury, by modulating the generation and synaptic integration of these adult- born cells.

 描述（由申请人提供）： 癫痫是一种潜在的破坏性神经系统疾病，影响约200万美国人，通常对药物治疗有抵抗力。动物研究表明，癫痫与大脑的代偿性变化有关，包括神经元回路的异常生长和重新布线。特别是，癫痫与海马体的连接性改变有关，海马体是大脑的一个区域，经常是癫痫发作的起始点。海马也是少数几个表现出组成性成年神经发生的脑区之一，其中海马颗粒细胞在成年期出生，这些新的神经元在学习和记忆中起重要作用。这些成人出生的神经元的产生在某些类型的损伤后增加，包括癫痫发作和创伤性脑损伤，并且可能代表了促进恢复的稳态反应。 与癫痫相关的一种特定海马回路重排涉及颗粒细胞轴突（苔藓纤维）逆行方向的生长（“发芽”）。这些出芽的神经纤维可能通过形成反复出现的兴奋性回路直接引起海马的过度兴奋，或者增加抑制性回路的活性，从而防止癫痫发作。虽然存在实验证据来支持这些可能性中的每一个，但这些纤维的直接功能分析一直缺乏，主要是由于无法选择性地分离这些纤维用于生理表征。因此，它们在癫痫发生中的作用仍不清楚。 动物研究表明，发芽的苔藓纤维可能选择性地，或者可能完全来自成人出生的细胞。如果这些纤维 成年人出生的神经元参与产生癫痫活动，然后可能直接有助于癫痫回路的发展。因此，它们在癫痫发生过程中具有有害而非有益的作用。此外，由于颗粒细胞为海马CA3区提供了主要的兴奋性输入，并且还驱动该区域的有效前馈抑制，因此成年细胞的这种投射发展的变化可能导致兴奋和抑制之间的不平衡。同样，这些成人出生的颗粒细胞投射在癫痫中的功能作用尚未被探索，因为不可能以有效的方式选择性地分析这些细胞及其连接。 在这项资助中，我们建议研究成年出生的神经元是否有助于癫痫小鼠模型中超兴奋回路的形成，以及它们是否直接促进癫痫发作的发生。我们结合了各种转基因小鼠，使我们能够在活组织中特异性标记和激活这些细胞。我们将使用成熟的癫痫匹罗卡品模型诱导实验性癫痫，并使用电生理记录技术来研究海马回路中这些成年出生的细胞的功能连接。此外，我们将使用额外的遗传操作来修改癫痫小鼠体内这些细胞的电活动，以确定这如何影响癫痫发作频率。 我们的工作将通过直接定义这种异常纤维通路的功能作用来回答关于几种形式癫痫发病机制的长期存在的问题。我们将能够选择性地研究发芽苔藓纤维的功能，而不管这些纤维的来源，因为我们的技术允许选择性刺激来自出生后衍生或成人的颗粒细胞轴突。 出生颗粒细胞。这将提供对该途径的功能的深入了解，无论其来源如何，但也使我们能够确定发芽是否部分或主要来源于成体细胞。如果成人出生的神经元直接促成癫痫的发展，则这将提供特异性治疗靶标，以通过调节这些成人出生的细胞的产生和突触整合来潜在地预防损伤后癫痫的发展。