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: 9812489
• 负责人: Shaolin Liu
• 金额: $ 0.44万
• 依托单位: HOWARD UNIVERSITY
• 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 2021-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9812489
• 关键词: Achievement; Afferent Neurons; Amplifiers; Animals; Apical; Axon; Behavioral; Brain; Cells; Characteristics; Cholecystokinin; Data; Dendrites; Dendrodendritic Synapse; Detection; Electron Microscopy; Equilibrium; Feedback; Frequencies; Glutamates; Interneurons; Knowledge; Lead; Light; Mediating; Neurons; Neurosciences; Odorant Receptors; Odors; Olfactory Pathways; Output; Perception; Peripheral; Pharmacogenetics; Physiological; Play; Receptor Gene; Research; Role; Sampling; Sensory; Side; Signal Transduction; Smell Perception; Stimulus; Synapses; System; Testing; Time; Transgenic Mice; designer receptors exclusively activated by designer drugs; granule cell; inhibitory neuron; neural circuit; novel; olfactory bulb; olfactory sensory neurons; operation; optogenetics; prevent; public health relevance; recruit; response; sensory input; sensory stimulus

 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（由申请人提供）：感知依赖于感官刺激的获取和处理。在嗅觉中，嗅觉向嗅觉感觉神经元（OSN）呈现重复的气味样本。表达相同气味受体的 OSN 轴突汇聚到位于每个嗅球 (OB) 相对侧的一对肾小球上。这两个“镜像肾小球”通过球内关联系统（IAS）相互连接，该系统由每个相应肾小球下方外部丛状层中的浅簇状（ST）细胞组成。然而，这种感觉神经元投射和 IAS 的独特排列的生理意义仍然未知。电子显微镜研究显示突触与颗粒细胞的接触导致了普遍的观点，即 IAS 主要是一个抑制回路。相比之下，我们的试点数据表明，IAS 作为一种有效的兴奋性回路，在双重层面发挥作用：（1）通过一个镜像肾小球中顶端树突之间的树突突触向 OB 输出神经元二尖瓣/簇状细胞（MTC）提供兴奋性输入； (2) 通过轴突向 IPL 中的 MTC 提供直接兴奋性输入，该 MTC 源自 OB 另一侧的第二镜像肾小球。这表明 MTC 接收来自 IAS-STC 的双重前馈激励，IAS-STC 与两个独立的镜像肾小球相关，以响应感觉输入。我们假设这两组前馈激励相加并在 MTC 中产生放大的响应，因为镜像肾小球在相对较短的时间窗口内接收相同的气味诱发的感觉输入。这些新发现引出了我们的中心假设：IAS 充当 MTC 感觉输入的放大器并调节动物对气味的敏感性。 IAS-STC 表达谷氨酸和胆囊收缩素 (CCK)，这为 IAS-STC 提供了特定标记，使我们能够利用强大的光遗传学和药物遗传学方法来双向控制 IAS 并测试我们在细胞、电路和行为方面的中心假设 水平。我们的试验数据还表明，虽然 IAS-STC 激活会导致肾小球水平的谷氨酸作用，但 CCK 仅在输入频率增加时释放。这一发现与我们未发表的对仅对 GABA 能肾小球中间神经元的 CCK 作用的观察相结合，得出我们的第二个假设：随着输入频率的增加，IAS 会差异性地参与肾小球抑制。随着输入频率（即嗅探速率）的增加，这种频率依赖性抑制增强可能会抵消双重兴奋作用。三个具体目标是 测试我们的新假设： 目标 1：确定 IAS 是否调节对气味的行为敏感性。目标 2：测试 IAS 作为双前馈兴奋电路来放大 MTC 的感觉输入的假设。目标 3：研究 IAS 是否产生频率依赖性的肾小球抑制募集。这些目标的实现将为嗅觉系统中特征性镜像肾小球排列的生理意义提供重要的线索，并加深我们对 OB 如何编码传递到更高嗅觉网络的感觉信息的理解。