Understanding the roles of cortico-bulbar feedback in odor identification

 描述(申请人提供)：感觉电路整合了来自环境的输入，以及来自大脑高级区域的反馈信号。前馈和反馈信号的相互作用被认为是在学习和记忆回忆过程中处理与期望、奖励、注意和行动有关的行为相关信息的基础。虽然丰富的谷氨酸皮质反馈投射支配所有嗅球层的抑制性中间神经元，但迄今为止，它们的具体动力学和对嗅觉处理的贡献仍然很大程度上是未知的。通过对清醒的头部固定小鼠的GCaMP5信号进行多光子成像，Albeanu研究小组最近证实，对不同的气味和不同浓度的气味做出反应时，皮质球反馈是稀疏的、气味选择性的、持续时间长的刺激后偏移、空间多样性，并由两种基本上独立的外周/纤维类型携带。在这里，PI，Albeanu，将测试中心假设，在清醒的小鼠中，皮质反馈上下文调制嗅球中的抑制性微电路，以增强对行为相关气味的辨别能力。从机制上讲，Albeanu博士的团队提出，皮质球投射通过增加抑制性中间神经元的气味响应性，以及使二尖瓣/簇状细胞对不同气味的反应去关联来对刺激身份和浓度做出特殊反应，这些反馈效应是通过气味学习来调节的。目的1：药物或光遗传学抑制嗅皮层活动的同时，监测其对球内两类中间神经元--颗粒细胞和深短轴突--在二尖瓣细胞上的动力学的影响，并通过多光子成像技术进行输出。为了获得进一步的特异性，在监测其在灯泡中的靶点的同时，在灯泡中局部抑制皮质反馈。目的2：探讨大脑皮层反馈在嗅觉辨别任务和多感觉反转学习范式习得前后的变化。对头部固定小鼠进行简单嗅觉、不嗅觉和两种强迫选择任务的训练，监测大脑皮层反馈，比较训练前后习得性气味和陌生性气味的相关性，以及不同偶然性条件下对相同感觉刺激的反应。目的：通过监测GCaMP6信号，评估皮层反馈抑制对嗅觉辨别和反向学习任务中行为表现的影响，以及对颗粒细胞、深短轴突细胞和二尖瓣细胞反应的影响。将检验以下假设：(1)皮质反馈将梨状皮质最近的活动模式绑定到嗅球中正在进行的感觉输入，并调节二尖瓣细胞的表征，以便于识别行为相关的气味，以及(2)皮质反馈广播由嗅球输出使用的上下文信号，以帮助识别奖励刺激。

 DESCRIPTION (provided by applicant): Sensory circuits integrate inputs from the environment, as well as feedback signals from higher brain regions. The interplay of feed-forward and feedback signals is proposed to be fundamental for processing behaviorally relevant information related to expectation, reward, attention and action, during learning and memory recall. Though rich glutamatergic cortical feedback projections innervate inhibitory interneurons in all olfactory bulb layers, to date their specific dynamics and contribution to olfactory processing remains largely unknown. Using multiphoton imaging of GCaMP5 signals in awake head-fixed mice, the Albeanu group recently established that, in response to a diverse panel of odors and across concentrations, corticalbulbar feedback is sparse, odor selective, long-lasting post stimulus offset, spatially diverse and carried by two largely independent bouton/fiber types. Here, the PI, Albeanu, will test the central hypothesis that, in awake mice, cortical feedback contextually modulates inhibitory micro-circuits in the olfactory bulb to enhance discriminability of behaviorally relevant odors. Mechanistically, Dr. Albeanu's group proposes that cortico-bulbar projections respond specifically to stimulus identity and concentration by increasing the odor responsiveness of inhibitory interneurons and de-correlating the responses of mitral/tufted cells to different odors, and that these feedback effect are tuned by odor learning. Aim 1: Suppress olfactory cortex activity pharmacologically or optogenetically, while monitoring its effects on the dynamics of two classes of interneurons in the bulb - the granule cells, and the deep short axon - on the mitral cells, the bulb outputs via multiphoton imaging. To achieve further specificity, suppress cortical feedback boutons locally in the bulb while monitoring their targets in the bulb. Aim 2: Investigate how cortical feedback changes pre- versus post-acquisition of olfactory discrimination tasks and multisensory reversal learning paradigms. Train head-fixed mice in simple olfactory go-no go and two forced choice tasks, monitor the cortical feedback, and compare the correlations between learned and unfamiliar odors before and after training, as well as responses to the same sensory stimuli under different contingencies. Aim 3: Assess the effects of cortical feedback suppression on behavioral performance in olfactory sensory discrimination and reverse learning tasks, and on the responses of granule cells, deep short axon cells and mitral cells via monitoring GCaMP6 signals. The following hypotheses will be tested: (1) cortical feedback binds recent activity patterns in the piriform cortex to ongoing sensory inputs in the olfactory bulb and modulates mitral cell representations to facilitate the identification of behaviorally relevant odors, and (2 cortical feedback broadcasts contextual signals that are used by the olfactory bulb output to help identify rewarded stimuli.