Functional Role of Neurogenesis in Hippocampal Mossy Fiber Sprouting
神经发生在海马苔藓纤维发芽中的功能作用
基本信息
- 批准号:9324721
- 负责人:
- 金额:$ 3.76万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-09-01 至 2019-08-31
- 项目状态:已结题
- 来源:
- 关键词:AdultAffectAgeAttenuatedAutomobile DrivingAxonBiological Neural NetworksCellsChronicClinical ManagementComplexCoupledDataDevelopmentDisabled PersonsDiseaseElectrophysiology (science)EpilepsyEpileptogenesisEtiologyFeedbackFiberFutureGoalsHippocampal Mossy FibersHippocampus (Brain)HumanInfectionInterneuronsLabelMedicalMethodsModelingMorphologyMusNatureNeurologicNeuronsNewborn InfantPathologicPathologyPatientsPhysiologic pulsePhysiologicalPhysiologyPilocarpinePlayPopulationPresynaptic TerminalsPropertyRecurrenceRoleRunawaySeizuresStaining methodStainsStrokeStructure of molecular layer of cerebellar cortexSymptomsSynapsesTemporal Lobe EpilepsyTestingTransgenic MiceTransgenic OrganismsTraumatic Brain Injuryadult neurogenesisaxonal sproutingcohortdentate gyrusdesigner receptors exclusively activated by designer drugsexperimental studygranule cellinsightmossy fibermouse modelneurogenesisneuronal circuitrynovel strategiesoptogeneticspatch clamppreventreceptor
项目摘要
Project Summary
Epilepsy is a chronic condition that can develop after various neurological insults, including traumatic brain
injury, stroke, and infection. However, despite years of study, the mechanism for the development of epilepsy
from an initial neurological insult has remained elusive. In the hippocampal dentate gyrus, seizures drive
pathologic retrograde sprouting of granule cell mossy fiber axons. Although sprouting may contribute to
epileptogenesis, the physiologic consequences of mossy fiber sprouting are unknown. Additionally, the dentate
gyrus is a locus for adult neurogenesis and adult-born granule cells might directly give rise to sprouted mossy
fibers, though this is widely debated and unresolved. In our hands, preliminary data has indicated that adult-
born granule cells do give rise to sprouted mossy fibers, which form large boutons in the inner molecular layer
of the dentate gyrus. Moreover, whole-cell patch clamp recordings from mature granule cells indicate that
these adult-born neurons functionally contribute to recurrent excitatory circuitry. The goal of this project is to
better understand mechanisms that contribute to hippocampal hyperexcitability and provide a targetable
mechanism for future treatments to prevent epileptogenesis. Our overall hypothesis is that adult-born granule
cells provide the bulk of mossy fiber sprouting and that these aberrant synapses create recurrent microcircuits
that drive runaway excitation within the hippocampus. This hypothesis will be tested using the pilocarpine
model of epilepsy and transgenic labeling of age-defined cohorts of granule cells in mice. Mossy fiber sprouting
will be quantified by immunofluorescent staining of granule cells, and whole-cell electrophysiology will be used
to detect recurrent circuits and interrogate the sprouted synapse using optogenetic stimulation of granule cell
cohorts. The specific aims of this proposal independently examine the contribution of adult-born granule cells
to mossy fiber sprouting and the physiological properties of a sprouted synapse. Furthermore, this proposal
investigates whether silencing of sprouted mossy fibers can attenuate the hippocampal hyperexcitability that is
associated with epilepsy. Taken together, this proposal aims to understand circuit rearrangements functionally
affect the epileptic hippocampus, so that future treatments can target the disease of epilepsy, rather than the
symptoms.
项目概要
癫痫是一种慢性疾病,可能在各种神经损伤(包括脑外伤)后出现
受伤、中风和感染。然而,尽管经过多年的研究,癫痫的发生机制
最初的神经损伤仍然难以捉摸。在海马齿状回,癫痫发作
颗粒细胞苔藓纤维轴突的病理性逆行出芽。尽管发芽可能有助于
癫痫发生过程中,苔藓纤维发芽的生理后果尚不清楚。此外,齿状
脑回是成体神经发生的场所,成体出生的颗粒细胞可能直接产生发芽的苔藓
纤维,尽管这个问题引起了广泛的争论并且尚未解决。我们手中的初步数据表明,成人-
新生的颗粒细胞确实会产生发芽的苔藓纤维,这些纤维在内分子层中形成大的纽扣
齿状回。此外,成熟颗粒细胞的全细胞膜片钳记录表明
这些成年神经元在功能上有助于周期性兴奋回路。该项目的目标是
更好地了解导致海马过度兴奋的机制并提供有针对性的
未来治疗预防癫痫发生的机制。我们的总体假设是,成年颗粒
细胞提供了大量的苔藓纤维发芽,这些异常的突触产生了循环微电路
驱动海马体内失控的兴奋。该假设将使用毛果芸香碱进行检验
癫痫模型和小鼠年龄定义的颗粒细胞群的转基因标记。苔藓纤维发芽
将通过颗粒细胞的免疫荧光染色进行定量,并将使用全细胞电生理学
使用颗粒细胞的光遗传学刺激来检测循环回路并询问萌芽突触
队列。该提案的具体目标是独立检查成年颗粒细胞的贡献
苔藓纤维发芽和发芽突触的生理特性。此外,这项提案
研究发芽苔藓纤维的沉默是否可以减弱海马的过度兴奋性
与癫痫有关。总而言之,该提案旨在从功能上理解电路重排
影响癫痫海马体,以便未来的治疗可以针对癫痫疾病,而不是癫痫病
症状。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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William David Hendricks的其他文献
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{{ truncateString('William David Hendricks', 18)}}的其他基金
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皮质中间神经元在视觉感知中的作用
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$ 3.76万 - 项目类别:
Role of cortical interneurons in visual perception
皮质中间神经元在视觉感知中的作用
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10468259 - 财政年份:2020
- 资助金额:
$ 3.76万 - 项目类别:
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