Mechanisms of inhibitory processing in the olfactory bulb and its contribution to olfactory discrimination behavior

抑制回路是小鼠早期嗅觉加工和气味辨别行为的关键机制。我们最近的工作已经建立了一个直接的联系之间的抑制性相互作用的颗粒细胞和僧帽/簇状细胞的嗅球和气味辨别行为。在确定抑制定义生理相关的行为特征后，该资助的重点是阐明嗅球抑制回路的机械性质：抑制如何塑造气味表征？这将通过时空靶向分子扰动、行为测试、气味诱发反应的体内分析和新颖的光遗传学工具来解决。首先，通过特异性地删除颗粒细胞中除GluA 2之外的所有离子型谷氨酸受体亚基，颗粒细胞和二尖瓣/簇状细胞之间的谷氨酸能突触传递将被阻断。将在细胞、体内网络和行为水平上评估这种扰动的后果。利用我们以前的努力，后者将以完全自动化的方法进行，确保最小的可变性和大量行为参数的采集。然后，在改变相位抑制之前和之后观察二尖瓣/簇状细胞中的气味诱发反应。将采用包括颗粒细胞和肾小球周围细胞的中间神经元群体的剂量药理学以及光遗传学沉默来测量不同组的中间神经元对抑制性处理的不同贡献。最后，这些数据将被纳入我们现有的数学模型的嗅球功能。

Inhibitory circuits emerge as a key mechanism in early olfactory processing and odor discrimination behavior in mice. Our recent work has established a direct link between inhibitory interactions of granule cells and mitral/tufted cells in the olfactory bulb and odor discrimination behavior. After establishing that inhibition defines physiologically relevant behavioral features, a focus of this grant is the elucidation of the mechanistic nature of olfactory bulb inhibitory circuits: How does inhibition shape odor representations? This will be addressed by spatio-temporally targeted molecular perturbations, behavioral testing, in vivo analysis of odor-evoked responses and novel optogenetic tools. Firstly, glutamatergic synaptic transmission between granule cells and mitral/tufted cells will be blocked by specifically deleting all ionotropic glutamate receptor subunits but GluA2 in granule cells. The consequences of this perturbation will be assessed on the cellular, in vivo network and behavioral levels. Taking advantage of our previous efforts, the latter will be carried out in an entirely automated approach, ensuring minimal variability and acquisition of a larger number of behavioral parameters. Then, odor-evoked responses in mitral/tufted cells will be observed before and after altering phasic inhibition. Dosed pharmacological as well as optogenetic silencing of interneuron populations including granule cells and periglomerular cells will be employed to gauge the distinct contribution of different sets of interneurons to inhibitory processing. Finally, these data will be incorporated into our existing mathematical model of olfactory bulb function.