Homeostatic Effects of Activity on Neurotransmission

活动对神经传递的稳态影响

• 批准号: 7082968
• 负责人: KRISTA L MOULDER
• 金额: $ 12.93万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-20 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7082968
• 关键词: cell morphology; confocal scanning microscopy; electrical measurement; electrophysiology; glutamates; homeostasis; laboratory rat; neural plasticity; neural transmission; neurons; neurotrophic factors; newborn animals; protein localization; synapses; synaptic vesicles

DESCRIPTION (provided by applicant): Chronic changes in electrical excitability profoundly affect synaptic transmission throughout the lifetime of a neuron. Activity-dependent plasticity can be manifest as the up- or down regulation of subsequent synaptic signaling, and can occur through both presynaptic and postsynaptic targets. The objective of this application is to use sophisticated imaging techniques to examine the neuronal response to increased electrical activity, as mimicked by tonic depolarization, in hippocampal neurons. The rationale is that if we can understand the signaling changes in neurons that accompany tonic depolarization, then we should gain insight into the homeostatic mechanisms that are initiated by drugs of abuse, as well as by neuronal injury and disease. In preliminary patch-clamp electrophysiology studies, tonic depolarization elicited a homeostatic decrease in subsequent glutamate neurotransmission. In the proposed study, it is hypothesized that a presynaptic alteration of the synapic vesicle pool accounts for this decrease. A selective, homeostatic depression of glutamate release from excitatory neurons may be a model for the response of synapses to drugs of abuse, many of which act by altering overall activity levels for prolonged periods. In order to characterize the deficits in glutamate signaling fully, immunohistochemistry, electron microscopy, and vital fluorescent dye (FM1-43) experiments are proposed to supplement the previous electrophysiology data. The combination of imaging and electrophysiological methods will also be used to define the molecular mechanisms responsible for the depression of glutamate transmission after tonic depolarization. Training in these advanced imaging techniques will greatly enhance the career development of the applicant, allowing her to assess synaptic function from many perspectives. Importantly, the scientific and technical expertise gained in the course of these studies will allow the candidate to attain her long-term goal of establishing an independent research career in neuroscience.

描述（由申请人提供）： 电兴奋性的慢性变化在神经元的整个生命周期中深刻地影响突触传递。活动依赖性可塑性可以表现为后续突触信号传导的上调或下调，并且可以通过突触前和突触后靶点发生。本申请的目的是使用复杂的成像技术来检查海马神经元中神经元对增加的电活动的反应，如强直性去极化所模仿的。其基本原理是，如果我们能够理解伴随紧张性去极化的神经元信号变化，那么我们应该深入了解滥用药物以及神经元损伤和疾病引发的稳态机制。在初步的膜片钳电生理学研究中，强直性去极化引起随后谷氨酸神经传递的稳态下降。在拟议的研究中，假设突触囊泡池的突触前改变解释了这种减少。兴奋性神经元谷氨酸释放的选择性稳态抑制可能是突触对滥用药物的反应的模型，其中许多药物通过长时间改变整体活动水平而起作用。为了充分表征谷氨酸信号传导的缺陷，免疫组织化学，电子显微镜，和活体荧光染料（FM 1 -43）实验，建议补充以前的电生理数据。影像学和电生理学方法的结合也将被用来定义负责强直性去极化后谷氨酸传输的抑制的分子机制。这些先进的成像技术的培训将大大提高申请人的职业发展，使她能够从多个角度评估突触功能。重要的是，在这些研究过程中获得的科学和技术专业知识将使候选人能够实现她在神经科学领域建立独立研究生涯的长期目标。