Functional mechanisms underlying the intrabulbar associational circuit in the olfactory system

嗅觉系统球内关联回路的功能机制

• 批准号: 10829500
• 负责人: Shaolin Liu
• 金额: $ 23.18万
• 依托单位: UNIVERSITY OF GEORGIA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-02-09 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10829500
• 关键词: Functional; mechanisms; underlying; intrabulbar; associational

 DESCRIPTION (provided by applicant): Perception relies on the acquisition and processing of sensory stimuli. In olfaction, sniffing presents repetitive odor samples to the olfactory sensory neurons (OSNs). Axons of OSNs expressing the same odorant receptor converge upon a pair of glomeruli located on opposite sides of each olfactory bulb (OB). These two "mirror glomeruli" are interconnected by the intra-bulbar association system (IAS) composed of superficial tufted (ST) cells in the external plexiform layer beneath each corresponding glomerulus. However, the physiological significance of this unique arrangement of sensory neuron projection and the IAS remains unknown. Electron microscopy studies showing synaptic contacts with granule cells lead to the prevailing idea that the IAS is primarily an inhibitory circuit. By contrast, our pilotdata show that IAS functions as a potent excitatory circuit acting at dual levels: (1) providing excitatory input to the OB output neurons mitral/tufted cells (MTCs) via dendrodendritic synapses between their apical dendrites in one mirror glomerulus; (2) providing direct excitatory input via their axons to MTCs in the IPL arising from the second mirror glomerulus on the opposite side of the OB. This suggests that MTCs receive dual feedforward excitation from IAS-STCs affiliating with the two separate mirror glomeruli in response to sensory input. We hypothesize that these two sets of feedforward excitation summate and produce an amplified response in MTCs since mirror glomeruli receive the same odorant-evoked sensory input in a relatively short time window. These novel findings lead to our central hypothesis that the IAS functions as an amplifier of sensory input to MTCs and modulates animal sensitivity to odors. IAS-STCs express glutamate and cholecystokinin (CCK), which provides a specific marker for IAS-STCs and enables us to exploit the powerful opto- and pharmacogenetic approaches to bidirectionally control the IAS and test our central hypothesis at cellular, circuit and behavioral levels. Our pilot data also show that while IAS-STC activation leads to glutamate action at the glomerular level, CCK is released only as input frequency increases. This finding combined with our unpublished observation of CCK action on only GABAergic glomerular interneurons leads to our secondary hypothesis is that the IAS differentially engages glomerular inhibition as input frequency increases. This frequency dependent enhancement of inhibition may counteract the dual excitatory role as input frequency (i.e. sniffing rate) increases. Three specific aims are for testing our novel hypotheses: Aim 1: Determine if the IAS regulates behavioral sensitivity to odors. Aim 2: Test the hypothesis that the IAS functions as a dual feedforward excitatory circuit to amplify sensory input to MTCs. Aim 3: Investigate whether the IAS generates frequency- dependent recruitment of glomerular inhibition. Achievement of these aims will shed crucial light on the physiological significance of the characteristic mirror glomeruli arrangement in the olfactory system and advance our understanding how the OB encodes sensory information conveyed to higher olfactory networks.

 描述（由适用提供）：感知取决于感觉刺激的获取和处理。在嗅觉中，嗅探向嗅觉感觉神经元（OSN）提供了重复的气味样本。表达相同气味受体的OSN的轴突会在一个位于每个嗅球的相对侧（OB）的一对肾小球上收敛。这两个“镜面glomerulli”与裂缝内关联系统（IAS）互连，该系统由每个相应的肾小球下方的外部丛状层中的浅表簇（ST）细胞组成。但是，这种感觉神经元投影和IAS的独特布置的物理意义仍然未知。电子显微镜研究表明，与颗粒细胞的突触接触导致普遍的想法，即IAS是主要的抑制作用。相比之下，我们的试验表明，IAS起作用的潜在兴奋回路，该电路在双重级别上作用：（1）通过在一个Mirror Mirror glomerulus中，通过树突根突触在其顶端树突之间向OB输出神经元二尖瓣/簇细胞（MTC）提供兴奋的输入； （2）通过其轴突在IPL中通过其轴突提供直接的兴奋输入，该IPL是由OB另一侧的第二个镜子肾小球引起的。这表明MTC从与感觉输入的两个单独的镜像glomerulli相关的IAS-STC中获得双馈激发。我们假设这两组馈电兴奋总结并在MTC中产生放大器响应，因为Mirror Glomerulli在相对较短的时间窗口中接收了相同的气味诱发的感觉输入。这些新颖的发现导致了我们的中心假设，即IAS充当了对MTC的感觉输入的放大器，并调节动物对气味的敏感性。 IAS-STCS表达谷氨酸和胆囊化素（CCK），它为IAS-STC提供了特定标记，使我们能够探索双向控制IAS并在细胞，电路和行为上测试我们的中心假设的强大选择和药物遗传学方法 水平。我们的试点数据还表明，尽管IAS-STC激活导致肾小球水平的谷氨酸作用，但CCK仅随着输入频率的增加而释放。这一发现与我们对CCK对CCK作用仅对GABA能肾小球中间神经元的观察结果结合起来，导致我们的次要假设是，随着输入频率的增加，IAS会差异地接合肾小球抑制。这种频率依赖性抑制作用可能会抵消双重兴奋性作用，因为输入频率（即嗅探速率）增加。三个特定目标是 测试我们的新假设：目标1：确定IAS是否调节行为对气味的敏感性。 AIM 2：检验IAS充当双馈兴奋回路以扩大感觉输入到MTC的双馈电路的假设。目标3：研究IAS是否会产生肾小球抑制的频率依赖性募集。这些目标的实现将使嗅觉系统中特征镜glomerulli布置的物理意义提出至关重要的阐明，并促进了我们的理解，OB如何编码传达给更高嗅觉网络的感官信息。

项目成果

CCKergic Tufted Cells Differentially Drive Two Anatomically Segregated Inhibitory Circuits in the Mouse Olfactory Bulb.

CCKergic 簇绒细胞差异驱动小鼠嗅球中两个解剖学上分离的抑制电路。

• DOI: 10.1523/jneurosci.0769-20.2020
• 发表时间: 2020
• 期刊: The Journal of neuroscience : the official journal of the Society for Neuroscience
• 作者: Sun,Xicui;Liu,Xiang;Starr,EricR;Liu,Shaolin
• 通讯作者: Liu,Shaolin

Cholecystokinin selectively activates short axon cells to enhance inhibition of olfactory bulb output neurons.

缩胆囊素选择性激活短轴突细胞，增强对嗅球输出神经元的抑制。

• DOI: 10.1113/jp275511
• 发表时间: 2018
• 期刊: The Journal of physiology
• 作者: Liu,Xiang;Liu,Shaolin
• 通讯作者: Liu,Shaolin