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.

项目概要 本行政补充文件的主要目标是确定神经兴奋性和 阿尔茨海默病（AD）期间和衰老过程中哺乳动物听觉脑干内的突触强度 我们将使用成熟的转基因小鼠品系和品系作为实验。 AD 和 ARHL 模型 正如我们在 R01 资助中提出的，我们将研究 AD 和 ARHL 中的两个特殊突触。 听性脑干：梯形体内侧核（MNTB）的 Held 突触大萼和 外侧上橄榄 (LSO) 的小布顿型甘氨酸能和谷氨酸能突触。 对于计算高频声源定位的听觉脑干电路至关重要。 听觉是哺乳动物定位声源的重要机制。 从背景噪声中过滤重要听觉输入的关键手段。 噪音环境中的声源定位或感知语音是听力损失的常见形式，尤其是老年人 听力受损也会导致 ARHL 患者的社会孤立。 长期目标是刺激他们的认知，加重甚至导致痴呆症。 确定动物 MNTB 和 LSO 突触的神经元兴奋性和生物物理特性 体验 AD 和 ARHL 进展的不同阶段我们将进行单细胞膜片钳。 成年小鼠和衰老小鼠不同阶段的小鼠脑干切片的电生理学记录 我们的初步数据表明，控制模型和 AD 模型中的成年期和衰老有几个基本方面。 年轻成年小鼠（三只）的脑干突触和神经兴奋性已经发生显着变化 月龄）之后，在 AD 的严重症状变得明显之前，在成年期和衰老过程中，进一步突触。 观察到兴奋性变化，有时是相反的方向，因此我们建议研究。 AD 和 AD 患者大脑中神经元的突触强度、短期突触可塑性和神经元兴奋性 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着减少，使兴奋性突触后电位变得更难 (EPSP) 达到尖峰阈值的第二个假设是 AD 和衰老中的突触强度。 由于突触小泡释放概率的变化和/或，脑干突触发生显着变化 突触小泡易于释放池大小的变化这些结果将提供揭示的新见解。 导致年轻人和老年人 AD 病理学和听力缺陷的几种潜在机制 因此，拟议的研究将极大地刺激听觉神经元和突触的额外活动。 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。