Olfactory Bulb Local Circuits

项目摘要-摘要 当气味配体结合在嗅觉上皮细胞上时，气味的感知开始于嗅觉上皮细胞。 感觉神经元，其中每一个仅表达约1200个候选受体中的一个。轴突来自 表达相同气味受体的神经元仅会聚到2/3的肾小球/嗅球中， 它们与投射神经元形成突触，每个投射神经元支配单个肾小球。深至 在肾小球外丛状层（EPL）内，气味编码由局部突触回路调节。 破译与EPL的连接是理解中枢神经系统机制的第一步。 气味处理已经提出了几种EPL中的局部加工假设， 突触组织通常被认为是典型的。然而，我们缺乏对 中间神经元、颗粒细胞（GC）、结构、分子和地形的多样性 组织影响EPL局部电路，这是解释功能研究的障碍。这里我们 就可能影响组织的因素提出一系列可检验的假设和实验 和它们的局部突触回路。这些研究建立在我们先前的发展和 超微结构工作以及对当前文献的系统综述，并认识到， EPL组织和连通性的基本特征已经被假定，但不是经验性的 测试.首先，我们提出的假设，即克隆的历史，时间和顺序的GC 神经发生是它们在嗅球中的组织/分布的决定因素。使用多个 追踪神经发生、细胞谱系/命运的策略，我们将评估GC的多刺树突状乔木 从胚胎开始，以固定的间隔持续到200天的年龄。在 此外，而不是在以前的研究中，我们建议仔细评估GC基底的组织， 树突是传入离心调制的主要接受者（Rothermei和 Wachowiak，2014; Kapoor等人，2016; de Almeida等人，2015）。第二，我们建议测试 EPL中树-树突触的突触学和分子特征不同的假说 as a function函数of age年龄.目前，很少有人知道的结构特点，调节树突状细胞 突触或二尖瓣与GC的分子特性以及GC与二尖瓣细胞的相互作用 突触可能不同。这些分析将解决这一根本问题，并提供一个健全的 气味处理功能分析的解释基础。此外，我们将解决 突触并置沿着2 o树突的空间分布以及突触并置的特征 突触特化随年龄变化。因为我们要解决的问题是 重要的是在整个神经系统，我们预计，结果将有广泛的影响， 了解整个大脑神经元的靶向、层状特异性和突触连接。

Project Summary – Abstract The perception of odors begins in the olfactory epithelium when odorant ligands bind on olfactory sensory neurons, each of which expresses only 1 of ~1200 candidate receptors. Axons coming from neurons expressing the same odorant receptor converge into only 2/3 glomeruli/olfactory bulb where they synapse onto projection neurons, each of which innervates a single glomerulus. Deep to the glomeruli, within the external plexiform layer (EPL), odor coding is tuned by local synaptic circuits. Deciphering connectivity with the EPL is the first step toward understanding the mechanisms of central odor processing. Several hypotheses of local processing within the EPL have been proposed and its synaptic organization is often presented as canonical. However, we lack a fundamental understanding of the how the diversity in interneuron, granule cell (GC), structural, molecular, and topographical organization affects EPL local circuits, which is an impediment to interpreting functional studies. Here we propose a series of testable hypotheses and experiments on factors that may influence the organization of GCs and their local synaptic circuits. These studies build on our prior developmental and ultrastructural work as well as a systematic review of the current literature and the recognition that fundamental features of EPL organization and connectivity have been presumed, but not empirically tested. First, we propose to address the hypotheses that the clonal history, timing and order of GC neurogenesis are determinants of their organization/distribution in the olfactory bulb. Using multiple strategies to track neurogenesis, cell lineage/fate we will assess the spiny dendritic arbors of GCs beginning in the embryo and continuing at regular intervals to those generated up 200 days of age. In addition, and not among prior studies, we propose to carefully assess the organization of the GC basal dendrites which are the primary recipients of incoming centrifugal modulation (Rothermei and Wachowiak, 2014; Kapoor et al., 2016; de Almeida et al., 2015). Second, we propose to test the hypothesis that the synaptology and molecular features of the dendrodendritic synapses in the EPL vary as a function of age. Presently, little is known of the structural features that regulate dendrodendritic synapses or how the molecular properties of the mitral to GC and the reciprocal GC to mitral cell synapses may differ. The analyses will address that fundamental problem and provide a sound foundation for the interpretation of functional analyses of odor processing. In addition, we will address the spatial distribution of synaptic appositions along 2o dendrites and the degree to which the features of the synaptic specialization change with age. Because the questions we propose to address are important throughout the nervous system, we anticipate that the results will have broad implications for understanding targeting, laminar specificity, and synaptic connectivity of neurons throughout the brain.