Biophysical mechanisms that contribute to multiple output channels in the olfactory bulb

项目摘要 气味分子与鼻上皮中的嗅觉感觉神经元(OSNs)结合，从而突触地兴奋两个 嗅球的兴奋性输出细胞、簇状细胞(TCS)和二尖瓣细胞(MC)。在体内，TCS和 MCS对气味刺激的反应不同：TCS具有更宽的调谐范围、更快的响应时间，并且 比MC对低气味浓度更敏感。这实际上创建了来自 嗅球，它将不同的气味信息传递到大脑皮层。这项提案旨在确定 TC和MC对OSN激活反应不同的机制。一个中心焦点将是一个 连接蛋白-36(Cx36)介导的缝隙连接的潜在分流功能 在MC中比在TC中表达得更高，但该提案还将审查一些其他潜在的贡献 枝晶中的抑制和活性电导等因素。提案的目标1和目标2将测试 用嗅球切片的实验预测不同的机制。其中包括两国关系 外加OSN刺激(光生或电刺激)的强度与电流和电压之间 MCs和TCS的反应(目标1)，以及刺激-反应关系对 调节每种机制的操作(目标2)。AIM 2中使用的操作将包括Cx36 KO小鼠和GABAA受体和电压门控性钠通道的药理阻断。AIM 3将使用 计算机建模，以探索目标1和目标2中确定的机制是否足以 解释TC和MC响应之间的差异。AIM 3还将测试替代机制，这些机制 难以实验操作，例如细胞形态的贡献。 培训和环境：为了达到项目的目标，申请者将发展感官方面的专业知识 系统神经科学，通过与她的赞助人Nathan Schoppa博士(嗅觉专家)的定期会议 和共同赞助人Joel Zylberberg博士(一位在视觉系统方面有专长的计算神经学家)。Dr。 除了嗅觉之外，Zylberberg在感官系统方面的专业知识将帮助申请者保持对如何 建议中研究的具体电路机制可以推广到其他感觉系统。这个 申请者还将在脑片和脑片中培养膜片钳电生理学方面的技术专长 计算建模，通过她的导师的经验和指导。研究培训将会进行 在科罗拉多大学安舒茨医学院(UCAMC)的协作环境中提供 多学科培训，涵盖神经生物学的广度。与该提案相关的是，UCAMC有一个 尤其是在化学意义上的研究计划很强。

Project Summary Odor molecules bind to olfactory sensory neurons (OSNs) in the nasal epithelium, which synaptically excite two classes of excitatory output cells in the olfactory bulb, tufted cells (TCs) and mitral cells (MCs). In vivo, TCs and MCs respond differently to odorant stimulation: TCs have broader tuning profiles, faster response times, and are more sensitive to low odor concentrations than MCs. This effectively creates two output channels from the olfactory bulb, that carry different information about the odor to the cortex. This proposal seeks to identify mechanisms that underlie the difference in TC and MC responses to OSN activation. A central focus will be on a potential shunting function of connexin-36 (Cx36)-mediated gap junctions, which appear to be much more highly expressed in MCs than TCs, but the proposal will also examine a number of other potential contributing factors such as inhibition and active conductances in dendrites. Aims 1 and 2 of the proposal will test the predictions of different mechanisms with experiments in olfactory bulb slices. These include the relationship between the intensity of an applied OSN stimulus (optogenetic or electrical) and the current and voltage responses of MCs and TCs (Aim 1), and also the sensitivity of the stimulus-response relationships to manipulations that modulate each mechanism (Aim 2). The manipulations employed in Aim 2 will include Cx36 KO mice and pharmacological blockade of GABAA receptors and voltage-gated sodium channels. Aim 3 will use computational modeling to explore whether the identified mechanisms from Aims 1 and 2 are sufficient to explain the difference between TC and MC responses. Aim 3 will also test alternative mechanisms that are difficult to manipulate experimentally, for example the contribution of cellular morphology. TRAINING AND ENVIRONMENT: To achieve the project’s goal, the applicant will develop expertise in sensory systems neuroscience, through regular meetings with her sponsor Dr. Nathan Schoppa (an expert in olfaction) and co-sponsor Dr. Joel Zylberberg (a computational neuroscientist with expertise in the visual system). Dr. Zylberberg’s expertise in a sensory system besides olfaction will help the applicant maintain perspective on how the specific circuit mechanisms studied within the proposal can generalize to other sensory systems. The applicant will also develop technical expertise in patch-clamp electrophysiology in brain slices and computational modeling, through experience and guidance of her mentors. The research training will take place at University of Colorado, Anschutz Medical Campus (UCAMC) in a collaborative environment that provides multidisciplinary training, covering the breadth of neurobiology. Relevant to the proposal, UCAMC has an especially strong research program in the chemical senses.