DEVELOPMENT OF NEURONAL CIRCUITS IN THE AUDITORY SYSTEM

描述(改编自申请人摘要)：长期目标 这项研究是为了了解神经细胞通过 活动在形成、重组和稳定方面发挥作用。 精确组织的神经元连接。拟议项目的目的是 为了阐明在音调组织的发展中的这些机制， 大鼠听性脑干兴奋性和抑制性联系的汇聚 哺乳动物。焦点将集中在外侧上橄榄核(LSO)，即 双耳核团参与声音定位，其中强直性 有组织的同侧和对侧甘氨酸能输入汇聚在单个 细胞。此前的研究表明，甘氨酸和GABA具有抑制作用 在发育中的LSO中，成体系统中的神经递质正在去极化 当抑制连接被提炼的时候。申请者将测试 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，用于依赖于活动的精细化 发展抑制性突触。 他们将使用从出生前和出生后制备的体外脑干切片 测定1)去极化神经递质甘氨酸和 GABA增加发育中LSO神经元细胞内钙离子浓度，2) 去极化抑制性突触是否像兴奋性突触，3) LSO中抑制连接的精化是否涉及 功能突触的消除，以及4)去极化抑制 LSO中的连接可以表达突触的活动依赖性变化 LTP和Ltd.等实力。为了实现这些具体目标，全细胞和 穿孔膜片钳记录将与单细胞示踪相结合， 钙成像与神经递质的快速、局部光解裂解 (光刺激)。 这些实验将对了解神经元活动如何 参与形成和重组所涉及的听觉回路 在声音定位方面。这项拟议的研究可能会为 人类交流障碍，如言语感知、特定语言 由于听觉处理受损而导致的功能障碍和阅读障碍 可能有发育成分。了解基本的细胞 支配抑制回路发育和可塑性的机制是 这是理解许多病理性大脑状态的原因的基础， 包括癫痫，这是由于抑制的异常组织造成的 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.