DEVELOPMENT OF NEURONAL CIRCUITS IN THE AUDITORY SYSTEM

描述（改编自申请人的摘要）： 这项研究是为了了解神经元的细胞机制， 活动对形成、重组和稳定产生影响 精确组织的神经元连接。拟议项目的目的是 为了阐明这些机制的发展，音调组织， 听觉脑干的兴奋性和抑制性连接 哺乳动物重点将放在外侧上级橄榄核（LSO）上， 双耳核参与声音定位，其中音调定位 有组织的同侧和对侧甘氨酸能输入会聚在单个 细胞以前的研究表明，甘氨酸和GABA，抑制 成年系统中的神经递质，在发育中的LSO去极化 当抑制性连接被完善的时候。申请人将测试 假设这些抑制性神经递质的去极化作用 代表了一种新的细胞机制， 形成抑制性突触 他们将使用一个体外脑干切片制备从产前和产后 大鼠以确定1）去极化神经递质甘氨酸和 GABA增加发育中LSO神经元的细胞内钙浓度，2） 去极化暂时性突触是否像兴奋性突触一样起作用，3） LSO中抑制性连接的细化是否涉及 消除功能性突触，以及4）是否去极化抑制性突触 LSO中的连接可以表达突触的活动依赖性变化， 为了实现这些特定的目标，全细胞和 穿孔膜片钳记录将与单细胞示踪相结合， 钙成像和神经递质的快速、局部光解裂解 （光刺激）。 这些实验对于理解神经元活动 参与听觉回路的形成和重组 声音定位。拟议的研究可能会提供新的见解， 人类交流障碍，如言语感知、特定语言 听觉处理受损导致的损伤和阅读障碍， 可能有发育成分了解基本的细胞 控制抑制回路的发展和可塑性的机制是 这是理解许多病理性大脑状态的基础， 包括癫痫，由抑制性组织异常引起， 电路.

DESCRIPTION (Adapted From The Applicant's Abstract): The long-term objective of this research is to understand the cellular mechanisms by which neuronal activity exerts its effects on the formation, reorganization, and stabilization of precisely organized neuronal connections. The aim of the proposed project is to elucidate these mechanisms in the development of tonotopically organized, converging excitatory and inhibitory connections in the auditory brainstem of mammals. Focus will be on the lateral superior olivary nucleus (LSO), a binaural nucleus involved in sound localization, in which tonotopically organized ipsilateral and contralateral glycinergic inputs converge on single cells. Previous studies have shown that glycine and GABA, the inhibitory neurotransmitter in the adult system, are depolarizing in the developing LSO when inhibitory connections are being refined. The applicant will test the hypothesis that the depolarizing action of these inhibitory neurotransmitters represents a novel cellular mechanism for activity-dependent refinement of developing inhibitory synapses. They will use an in vitro brainstem slice preparations from pre- and postnatal rats to determine 1) whether the depolarizing neurotransmitters glycine and GABA increase intracellular calcium concentration in developing LSO neurons, 2) whether depolarizing inhiitory synapses act like excitatory synapses, 3) whether refinement of inhibitory connections in the LSO involves the elimination of functional synapses, and 4) whether depolarizing inhibitory connections in the LSO can express activity-dependent changes in synaptic strength such as LTP and LTD. To achieve these specific aims whole-cell and perforated patch clamp recordings will be combined with single cell tracing, calcium imaging and fast, localized photolytic cleavage of neurotransmitters (photostimulation). The experiments will be important for understanding how neuronal activity participates in the formation and reorganization of auditory circuits involved in sound localization. The proposed research may provide new insights into human communication disorders such as speech perception, specific language impairment and dyslexia that result from impaired auditory processing and that likely have developmental components. Understanding the basic cellular mechanisms that rule the development and plasticity of inhibitory circuits is fundamental for understanding the cause of numerous pathological brain states, including epilepsy, that result from an abnormal organization of inhibitory circuits.