Modulation of Exocytosis and Excitability in Mature Auditory Brainstem Neurons

成熟听觉脑干神经元胞吐作用和兴奋性的调节

• 批准号: 10510150
• 负责人: HENRIQUE Prado VON GERSDORFF
• 金额: $ 37.59万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-12-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10510150
• 关键词: 1 year old; Action Potentials; Administrative Supplement; Adult; Age; Aging; Alzheimer' s Disease; Alzheimer' s disease brain; Alzheimer' s disease model; Alzheimer' s disease pathology; American; Amyloid; Amyloid beta-Protein; Amyloid beta-Protein Precursor; Amyloidosis; Animals; Auditory; Auditory system; Award; Biophysics; Brain; Brain Stem; CBA/CaJ Mouse; Cell Nucleus; Cells; Cochlear nucleus; Cognitive; Data; Dementia; Deposition; Elderly; Electrophysiology (science); Engineering; Environment; Episodic memory; Excitatory Postsynaptic Potentials; Excitatory Synapse; Exocytosis; Experimental Models; Fiber; Financial compensation; Florida; Frequencies; Glutamates; Goals; Grant; Hearing; Hippocampus (Brain); Human; Impaired cognition; Incidence; Individual; Inhibitory Synapse; Lead; Location; London; Medial; Membrane; Memory impairment; Modeling; Mus; Mutation; Neurons; Noise; Parents; Pathology; Phase; Physiology; Presbycusis; Probability; Process; Property; Publishing; Resistance; Risk; Rodent; Slice; Social isolation; Sound Localization; Source; Speech; Spike Potential; Symptoms; Synapses; Synaptic Vesicles; Synaptic plasticity; Testing; Transgenic Mice; Work; aged; aging brain; aging population; amyloid pathology; binaural hearing; biophysical properties; experience; familial Alzheimer disease; hearing impairment; insight; lateral superior olive; mouse model; nervous system disorder; neuron loss; neuronal excitability; normal aging; novel; overexpression; patch clamp; presenilin-1; sound; sound frequency; source localization; synaptic function; trapezoid body; vesicular release; young adult

PROJECT SUMMARY The major goal of this Administrative Supplement is to determine the changes in neuronal excitability and synaptic strength within the mammalian auditory brainstem during Alzheimer’s disease (AD) and during age related hearing loss (ARHL). We will use well established transgenic mouse lines and strains as experimental models for AD and ARHL. As proposed in our parent R01 grant, we will study two specialized synapses in the auditory brainstem: the large calyx of Held synapse in the medial nucleus of the trapezoid body (MNTB) and the small bouton-type glycinergic and glutamatergic synapses of the lateral superior olive (LSO). These synapses are pivotal for the auditory brainstem circuits that compute high frequency sound source localization. Binaural hearing constitutes an important mechanism for localizing sound sources in mammalian species. It also provides a critical means for filtering important auditory inputs from background noise. The inability to distinguish sound source location or perceive speech in noisy environments are common forms of hearing loss, especially in elderly individuals. Impaired hearing also contributes for social isolation of individulas who suffer from ARHL, which reduces their cognitive stimulation, aggravating or even leading to instances of dementia. The long-term goal is to determine the neuronal excitability and biophysical properties of the MNTB and LSO synapses as animals experience different stages of AD and ARHL progression. We will perform single cell patch clamp electrophysiology recordings in mouse brainstem slices from adult and aging mice at different stages of adulthood and aging in both control and AD models. Our preliminary data show that several fundamental aspects of brainstem synapses and neuronal excitability are significantly changed already in young adult mice (three month old) before severe symptoms of AD become clearly manifest. During adulthood and aging, further synaptic and excitability changes are observed, sometimes in the opposite direction. We thus propose to study the synaptic strength, short-term synaptic plasticity and neuronal excitability of neurons from the brains of AD and ARHL mouse models. The first hypothesis is that the intrinsic excitability of LSO and MNTB neurons is significantly reduced in AD and aging mice models making it harder for excitatory postsynaptic potentials (EPSPs) to reach spike threshold. The second hypothesis is that the synaptic strength in AD and aging brainstem synapses changes significantly because of changes in synaptic vesicle release probability and/or changes in the readily releasable pool size of synaptic vesicles. The results will provide novel insights that reveal several underlying mechanisms responsible for AD pathology and hearing deficits in young adults and aging auditory neurons and synapses. The proposed studies will thus greatly stimulate additional activity leading to significant progress on the fundamental causes of AD dementia and hearing loss in the mammalian brain.

项目摘要 本行政补充的主要目标是确定神经元兴奋性的变化， 阿尔茨海默病（AD）和老年哺乳动物听觉脑干内突触强度 相关性听力损失（ARHL）我们将使用成熟的转基因小鼠品系和品系作为实验动物。 AD和ARHL的模型。正如我们的父母R 01补助金中所提出的，我们将研究两个专门的突触， 听觉脑干：斜方体内侧核（MNTB）中Held突触的大萼和 外侧上上级橄榄（LSO）的小的钮扣型甘氨酸能和谷氨酸能突触。这些突触 是计算高频声源定位的听觉脑干回路的关键。双耳 听觉是哺乳动物定位声源的重要机制。它还提供 一种从背景噪声中过滤重要听觉输入的关键手段。无法辨别声音 噪声环境中声源定位或感知语音是听力损失的常见形式，尤其是在老年人中 个体听力受损也会导致患有ARHL的人与社会隔离， 减少他们的认知刺激，加重甚至导致痴呆症。长期目标是 以确定动物MNTB和LSO突触的神经元兴奋性和生物物理特性， 经历AD和ARHL进展的不同阶段。我们将进行单细胞膜片钳 成年和衰老小鼠脑干切片在不同阶段的电生理记录 在对照和AD模型中的成年和衰老。我们的初步数据显示， 脑干突触和神经元兴奋性的显著变化已经在年轻的成年小鼠（3 一个月前，他的症状就变得明显了。在成年和衰老期间，进一步的突触 观察到兴奋性变化，有时是相反的方向。因此，我们建议研究 突触强度，短期突触可塑性和神经元兴奋性的神经元从AD和 ARHL小鼠模型。第一个假设是LSO和MNTB神经元的内在兴奋性是 在AD和衰老小鼠模型中显著降低，使得兴奋性突触后电位更难 （EPSP）达到峰值阈值。第二个假设是，AD和衰老中的突触强度 脑干突触由于突触囊泡释放概率的变化而显著变化，和/或 突触囊泡的易释放池大小的变化。这些结果将提供新的见解，揭示 在年轻人和老年人中，导致AD病理学和听力缺陷的几种潜在机制 听觉神经元和突触。因此，拟议的研究将极大地促进更多的活动， 在哺乳动物大脑中AD痴呆和听力损失的根本原因方面取得了重大进展。