Olfactory Glomeruli: Cellular and Network Mechanisms

描述(申请人提供)：肾小球回路很重要。它们将感觉输入转换为输出信号，从而影响所有下游嗅觉网络。抑制是这些转变的关键。肾小球内抑制在突触前调节感觉突触，并提供反馈和前馈抑制，从而形成M/TC对感觉信号反应的强度和时间结构。对肾小球间抑制知之甚少。令人兴奋的新数据显示，构成肾小球间回路的短轴突细胞共同释放GABA和DA。这些共递质在外部丛生细胞中触发时间上的双相抑制-兴奋反应，这些细胞是肾小球回路功能的关键神经元。它们还产生强烈的、时间上不对称的对M/TCS的直接抑制，使得早期激活的肾小球抑制其 后来激活了邻居，导致了“早起的鸟儿有虫吃”假说。这些发现是通过光遗传学结合识别出的基因靶向细胞类型特定神经元的记录来完成的。人们对多巴胺的释放及其在球茎中的新陈代谢知之甚少。快速扫描循环伏安法将被用来确定DA在体外和体内的释放动力学。新的数据表明，FDA批准的COMT抑制剂可能会增强球部DA功能；这可能会使帕金森患者受益。我们将检验这一假设。肾小球间和肾小球内神经元之间的抑制-抑制相互作用尚未被探索。使用光遗传学的试点数据结合已识别的细胞记录表明，相互作用很强。我们将定义抑制-抑制相互作用，它们的突触动力学，以及它们如何塑造肾小球内和肾小球间的信号。

DESCRIPTION (provided by applicant): Glomerular circuits are important. They transform sensory input into output signals that impact all downstream olfactory networks. Inhibition is key to these transforms. Intraglomerular inhibition presynaptically regulates sensory synapses and provides feedback and feed forward inhibition that shapes the strength and temporal structure of M/TC responses to sensory signals. Less is known about interglomerular inhibition. Exciting new data show that short axon cells, which form the interglomerular circuit, co-release GABA and DA. These co-transmitters trigger a temporally biphasic inhibitory-excitatory response in external tufted cells, neurons critical to glomerular circuit function. They also generate strong, temporally asymmetric, direct inhibition of M/TCs such that early-activated glomeruli inhibit their later activated neighbors, leading to "The early bird gets the worm" hypothesis. These discoveries were made using optogenetics combined with recordings from identified gene-targeted cell-type specific neurons. Little is known about DA release or it's metabolism in the bulb. Fast Scan Cyclic Voltammetry will be used to define the kinetics of DA release in vitro and in vivo. New data suggest that FDA-approved COMT inhibitors may enhance bulb DA function; this could benefit Parkinson's patients. We will test this hypothesis. Inhibitory-inhibitory interactions among inter- and intraglomerular neurons have not been explored. Pilot data using optogenetics combined with identified cell recordings indicate robust interactions. We will define inhibitory-inhibitory interactions, their synaptic dynamics and how they shape intra- and interglomerular signaling.