Neuronal ensembles during development of tonotopic maps in the auditory systems

描述(申请人提供)：项目摘要：斜方体内侧核(MNTB)通过向哺乳动物脑干中的听神经元提供快速而准确的突触抑制，在声音定位中发挥关键作用。以前的研究表明，在早期发育过程中，活动依赖机制参与了这一听觉通路的完善。然而，一个仍然令人费解的根本问题是活动的性质，因为完善工作在听证开始之前就开始了。我们已经确认自发爆发式放电是听力发作前自发电活动的主要形式。这项建议的主要目的是利用创新的电生理学和成像技术来确定MNTB在活体中活动依赖的发育的细胞和突触机制。在第一个目标中，我们将研究爆发活动背后的机制。利用电生理学技术，我们将测试不同类型的突触在突触活动中的作用。例如，我们预测突触传递的拮抗剂将阻止出生后早期发育中的爆发活动。在另外的电生理和免疫染色实验中，我们将研究电压激活电导Ih的发育特性和作用，这可能涉及微调MNTB细胞的电特性及其对突触刺激的反应。在第二个目标中，我们将使用双光子钙成像来测量听力前大鼠MNTB中细胞团的活性。我们将通过电生理学实验来验证这一方法，并将描述自发集合活动的空间和时间特性，以及这些模式在出生后发育过程中如何变化。最后，在第三个目标中，我们将与佩卡、切尔尼科夫斯基和斯莫斯曼博士合作，使用第一个和第二个目标中描述的类似方法，结合声音刺激来确定MNTB乐团对简单和复杂声音的反应。通过操纵声音刺激的频谱内容，我们将研究哺乳动物脑干的短期适应能力和局限性。 与公共卫生相关：叙述性耳鸣项目，一种普遍且鲜为人知的疾病，在没有听觉刺激的情况下感知声音，影响到约20%的美国人，并对多达200万公民造成衰弱影响。我们的实验将直接确定部分听觉系统在没有声音的情况下是如何激活的，并可能有助于解释为什么有些人在不应该听到声音的时候听到了声音。

DESCRIPTION (provided by applicant): PROJECT SUMMARY The medial nucleus of the trapezoid body (MNTB) plays a key role in sound localization by delivering fast and precise synaptic inhibition to auditory neurons in the mammalian brainstem. Previous studies indicate that activity-dependent mechanisms are involved in the refinement of this auditory pathway during early development. However, a fundamental issue that remains puzzling concerns the nature of the activity, since the refinement begins before the onset of hearing. We have identified spontaneous burst firing as the major form of spontaneous electrical activity before hearing onset. The major goal of this proposal is to use innovative electrophysiological and imaging techniques to determine the cellular and synaptic mechanisms of activity-dependent development in the MNTB in vivo. In the first aim, we will study the mechanisms that underlie bursting activity. Using electrophysiological techniques we will test the role of different types of synapses in bursting activity. For example, we predict that antagonists of synaptic transmission will block bursting activity during early postnatal development. In additional electrophysiological and immunostaining experiments we will study the developmental properties and roles of the voltage-activated conductance Ih, which could be involved in the fine tuning of electrical properties of MNTB cells and their responses to synaptic stimulation. In the second aim we will use two-photon calcium imaging to measure the activity of cellular ensembles in the MNTB of prehearing rats. We will validate this approach with electrophysiology experiments and will describe the spatial and temporal properties of the spontaneous ensemble activity, and how these patterns change during postnatal development. Finally, in the third aim, and in collaboration with Drs. Peqa, Tchernikovsky and Smotherman we will use similar methods described in the first and second aims in combination with sound stimulation to determine the responses of MNTB ensembles to simple and complex sounds. By manipulating the spectral content of sound stimuli we will study the capacity and limitations for short-term adaptation in the mammalian brainstem. PUBLIC HEALTH RELEVANCE: PROJECT NARRATIVE Tinnitus, a prevalent and poorly understood condition where sounds are perceived in the absence of auditory stimulation affects ~20% of Americans, and has debilitating effects in as many as 2 million citizens. Our experiments will directly determine how parts of the auditory system activate in the absence of sound, and could help explain why some people hear sounds when they shouldn't.