Synaptic zinc release in the dorsal cochlear nucleus: implications for tinnitus

耳蜗背核中突触锌的释放：对耳鸣的影响

• 批准号: 8713064
• 负责人: CHARLES ANDERSON
• 金额: $ 5.33万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8713064
• 关键词: Accounting; Acoustic Trauma; Acute; Address; Affect; American; Auditory; Behavioral; Brain; Brain Stem; Brain region; Cell Nucleus; Chelating Agents; Chronic; Consensus; Custom; Data; Disease; Ear; Electrophysiology (science); Equilibrium; Extracellular Space; Glutamates; Hearing; Hyperactive behavior; Interneurons; Light; Long-Term Depression; Long-Term Potentiation; Measurement; Measures; Mediating; Metals; Mus; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neurologic; Neuromodulator; Pathology; Pathway interactions; Perception; Play; Positioning Attribute; Property; Role; Shapes; Signal Transduction; Slice; Structure; Synapses; Synaptic Transmission; Synaptic plasticity; Therapeutic Intervention; Tinnitus; Zinc; design; dorsal cochlear nucleus; excitatory neuron; extracellular; insight; neurophysiology; novel; public health relevance; ratiometric; research study; response; sensor; sound; tool; transmission process

DESCRIPTION (provided by applicant): Tinnitus - the perception of phantom sounds -is frequently caused by acoustic trauma. This widespread neurological condition affects approximately 40 million people in the U.S. Recent evidence suggests that the auditory brainstem, and in particular, the dorsal cochlear nucleus (DCN), plays a crucial role in the induction of tinnitus. The DCN displays hyperexcitability in tinnitus, hypothesized to result from endogenous compensatory mechanisms in response to acoustic trauma, termed maladaptive plasticity. Multiple mechanisms have been proposed to account for changes to the DCN in tinnitus, but to date, there has been no consensus as to how this brainstem nucleus transitions into a pathological state during this disorder. The DCN has a well-defined synaptic organization and contains multiple inhibitory and excitatory pathways that shape the response properties of this structure to sound. There are a rich variety of synaptic plasticity mechanisms present in the DCN, so factors that influence synaptic plasticity are potential substrates for the chronic hyperexcitability observed in the DCN during tinnitus. The DCN is unique among the auditory brainstem nuclei because it contains high levels of synaptic zinc - a strong regulator of long-term plasticity. Zinc is released from glutamatergic terminals during synaptic transmission, and because it potently inhibits NMDA receptors, it is poised to have a dramatic effect on synaptic signaling. My preliminary data indicate that mice with behavioral evidence of tinnitus have a dramatic reduction of synaptic zinc released from the DCN. This is a novel neurophysiological correlate of tinnitus. I hypothesize that synaptic zinc is critical for the normal functioning of the DCN and tht the loss of zinc is crucial feature of the pathology of the DCN during tinnitus. My preliminary data suggest that reduced synaptic zinc release leads to reduced inhibitory drive in the DCN. This has the potential to change to the balance of excitation and inhibition in the DCN, and be a contributing factor to the hyperexcitability of this structure in tinnitus. I will use newly developed ratiometric fluorescent zinc sensors and chelators in combination with brain slice electrophysiology to examine the role of synaptic zinc in the DCN in normal hearing and in tinnitus. My results will shed new light onto the mechanisms by which the DCN transitions into a state of pathological hyperactivity and potentially offer new strategies for therapeutic interventions for tinnitus.

描述(申请人提供)：耳鸣--幻听的感觉--通常是由听觉创伤引起的。这种广泛的神经系统疾病影响着美国大约4000万人。最近的证据表明，听性脑干，特别是耳蜗背核(DCN)，在耳鸣的诱发中起着至关重要的作用。DCN在耳鸣中表现出高度兴奋性，被认为是内源性代偿机制对声音创伤反应的结果，称为适应不良可塑性。人们提出了多种机制来解释耳鸣时DCN的变化，但到目前为止，对于这种脑干核团在耳鸣期间如何转变为病理状态还没有达成共识。 DCN有一个明确的突触组织，并包含多个抑制和兴奋通路，这些通路塑造了该结构对声音的反应特性。DCN中存在多种突触可塑性机制，因此影响突触可塑性的因素是耳鸣期间DCN中观察到的慢性高兴奋性的潜在底物。DCN在听觉脑干核团中是独一无二的，因为它含有高水平的突触锌--一种强大的长期可塑性调节器。锌在突触传递过程中从谷氨酸能终末释放出来，由于它能有效地抑制NMDA受体，它可能会对突触信号产生戏剧性的影响。 我的初步数据表明，有耳鸣行为证据的小鼠从DCN释放的突触锌显著减少。这是耳鸣的一种新的神经生理学关联。我推测突触锌对DCN的正常功能至关重要，而锌的丢失是DCN在耳鸣期间的重要病理特征。我的初步数据表明，突触锌释放减少会导致DCN中抑制驱动的减少。这有可能改变DCN中兴奋和抑制的平衡，并成为耳鸣这一结构过度兴奋的一个促成因素。 我将使用新开发的比率荧光锌传感器和螯合剂，结合脑片电生理学，研究突触锌在正常听力和耳鸣中的DCN中的作用。我的结果将为DCN转变为病理性多动状态的机制提供新的线索，并可能为耳鸣的治疗干预提供新的策略。