The Glycine Receptor in a Rat Tinnitus Model: A Possible Therapeutic Target

大鼠耳鸣模型中的甘氨酸受体：可能的治疗靶点

• 批准号: 7371960
• 负责人: Donald M. Caspary
• 金额: $ 30.31万
• 依托单位: SOUTHERN ILLINOIS UNIVERSITY SCH OF MED
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7371960
• 关键词: Affinity; Age; Aging; Animal Model; Animals; Appearance; Auditory; Auditory system; Autoradiography; Behavioral; Binding; Brain-Derived Neurotrophic Factor; Cell surface; Chronic; Cochlea; Condition; Deafferentation procedure; Detection; Development; Dose; Elderly; Electrodes; Esthesia; Event; Frequencies; Functional disorder; Fusiform Cell; Generations; Glycine; Glycine Receptor Binding; Glycine Receptors; Hyperactive behavior; In Situ Hybridization; Incidence; Label; Laboratories; Lead; Link; Longevity; Measures; Modeling; Molecular; Nerve Growth Factor Receptors; Neurons; Neurotrophic Tyrosine Kinase Receptor Type 2; Noise; Numbers; Output; Pattern; Peripheral; Pharmaceutical Preparations; Pharmacology; Plastics; Population; Property; Protein Subunits; Proteins; Quality of life; Radiolabeled; Range; Rate; Rattus; Research Personnel; Role; Scaffolding Protein; Series; Structure; Strychnine; Surgical Disarticulation; Testing; Therapeutic; Thinking; Tinnitus; Trauma; Western Blotting; Work; age related; aged; dorsal cochlear nucleus; experience; gephyrin; immunocytochemistry; insight; juvenile animal; neurochemistry; neurotransmission; neurotrophic factor; novel; programs; radiotracer; receptor; receptor binding; receptor sensitivity; relating to nervous system; response; sensory system; sound; therapeutic target; young adult

DESCRIPTION (provided by applicant): Chronic tinnitus is a phantom auditory sensation experienced by up to 15% of the population. Between 2 and 10% of the tinnitus population typically experience a continuous high frequency ringing or hiss sufficiently loud to impact severely on their quality of life (Cooper, 1994). Tinnitus has been found to increase with aging. Thus, the incidence of tinnitus is likely to increase due to increased longevity and recreational noise exposure. Much of the present thinking regarding the generation of tinnitus revolves around the appearance of spontaneous activity and neural hyperactivity in certain central auditory structures. A working hypothesis which parallels findings in other sensory systems suggests that partial deafferentation leads to central changes, generally involving altered inhibitory neurotransmission. Partial peripheral auditory deafferentation may produce tinnitus, coincident with a selective loss of inhibitory glycinergic function in the dorsal cochlear nucleus (DCN). Proposed studies will examine the functional and molecular neurochemical impact of aging in rats with behavioral evidence of tinnitus. Preliminary results find age and noise-exposure related changes in glycine receptor and neurotrophic factor neurochemistry in DCN of rats with behavioral evidence of tinnitus. Proposed studies will compare functional and molecular neurochemical changes between young and aged controls, and young and aged sound-exposed rats with behavioral evidence of tinnitus. Specifically: 1) quantitative measures of message and protein will be used to examine changes in the subunit make up of the glycine receptor, the scaffolding protein, gephyrin, and the protective neurotrophin BDNF; 2) recordings from DCN fusiform cells will parallel behavioral studies/gap detection and examine inhibitory response properties and glycine receptor sensitivity and 3) quantitative receptor binding will be used to examine changes in glycine and neurotrophin receptor pharmacology. Findings from these studies will provide new information regarding tinnitus-related changes in glycine neurotransmission and possible neurotrophin protection in an animal model of tinnitus. Understanding the impact of aging on tinnitus-related changes in neurochemistry related to glycine and the BDNF receptor (TrkB) function might help define unique targets for the development and testing of novel selective drugs for the treatment of tinnitus.

描述（由申请人提供）：慢性耳鸣是多达15％人群的幻像听觉感觉。耳鸣种群中有2％至10％的人通常会经历连续的高频响声或嘶嘶声足够大声以严重影响其生活质量（Cooper，1994）。已经发现耳鸣随着衰老而增加。因此，由于寿命增加和休闲噪声暴露，耳鸣的发生率可能会增加。目前关于耳鸣产生的许多思维围绕某些中央听觉结构中自发活动和神经多动症的出现。在其他感觉系统中相似的发现的工作假设表明，部分脱落会导致中心变化，通常涉及抑制性神经传递的改变。部分外围听觉脱落可能会产生耳鸣，同时与背侧耳蜗核（DCN）中抑制性糖激素功能的选择性丧失。拟议的研究将检查大鼠衰老的功能和分子神经化学影响，具有耳鸣的行为证据。初步结果发现，具有耳鸣的行为证据的DCN中甘氨酸受体和神经营养因子神经化学的年龄和噪声相关的变化。拟议的研究将比较年轻对照和老年对照组之间的功能和分子神经化学变化，以及年轻的和年龄的声音暴露大鼠和耳鸣的行为证据。具体：1）信息和蛋白质的定量测量方法将用于检查甘氨酸受体，脚手架蛋白，gephyrin和保护性神经营养蛋白BDNF的亚基的变化； 2）DCN梭形细胞的记录将平行行为研究/GAP检测并检查抑制性反应特性，甘氨酸受体敏感性和3）定量受体结合将用于检查甘霉素和神经营养蛋白受体药理学的变化。这些研究的发现将提供有关甘氨酸神经传递与耳鸣的变化以及在耳鸣模型中可能的神经营养蛋白保护的新信息。了解衰老对与甘氨酸和BDNF受体（TRKB）功能相关的神经化学变化的影响可能有助于定义独特的靶标，以开发和测试新型选择性药物以治疗耳鸣。