Olfactory Glomeruli: Cellular and Network Mechanisms

描述（由申请人提供）：肾小球回路很重要。它们将感官输入转化为影响所有下游嗅觉网络的输出信号。抑制是这些转变的关键。肾小球内抑制突触前调节感觉突触，并提供反馈和前馈抑制，形成对感觉信号的M/TC反应的强度和时间结构。对肾小球间抑制的了解较少。令人兴奋的新数据表明，短轴突细胞，形成肾小球间的电路，共同释放GABA和DA。这些共同的递质触发一个时间双相性兴奋反应的外部簇状细胞，神经元的关键肾小球电路功能。它们还产生对M/TC的强的、时间不对称的直接抑制，使得早期活化的肾小球抑制它们的增殖。 后来激活了邻居，导致了“早起的鸟儿有虫吃”的假设。这些发现是使用光遗传学结合来自鉴定的基因靶向细胞类型特异性神经元的记录进行的。关于DA的释放或它在鳞茎中的代谢知之甚少。将使用快速扫描循环伏安法确定体外和体内DA释放的动力学。新的数据表明，FDA批准的COMT抑制剂可能会增强球状DA功能;这可能会使帕金森病患者受益。我们将测试这个假设。尚未探讨肾小球内和肾小球间神经元之间的抑制-抑制相互作用。使用光遗传学结合识别的细胞记录的试验数据表明了强大的相互作用。我们将定义突触-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传导。

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.