Fear learning-induced transformations of olfactory bulb odor representations and behavioral generalization

项目摘要/摘要 联想恐惧学习，创伤后应激障碍(PTSD)等障碍的根本原因， 包括将刺激与令人厌恶的结果配对。这种配对产生了强大的恐惧反应 条件性刺激。气味记忆，比如那些在嗅觉恐惧学习过程中形成的记忆，获得得很快， 是持久的，早在构成第一个部位的嗅球(OB)肾小球就很明显 中枢神经系统嗅觉的感觉处理。这使得OB成为一个理想的调查地点 感觉加工和可塑性的潜在机制，因为它们与恐惧学习有关。在此，我们向大家介绍 飞行员数据证实，气味呈现与脚部电击相匹配会引发行为恐惧，并增强 清醒行为转基因小鼠对条件刺激(CS)的肾小球反应 荧光钙指示剂。同样，气味-足部电击体验会引起恐惧，并增强肾小球 对中性的、无条件的气味刺激的反应，这一过程被称为刺激泛化，其中恐惧 从CS转移到中性的、无条件的刺激。此外，CS和CS的感觉表征 中性气味经历了转化，增加了表征的相似性，可能导致 行为泛化。然而，感觉加工中学习诱导转换的时间进程 而普遍行为和肾小球改变背后的神经网络仍然未知。通过 结合行为方法和清醒行为的广域钙成像，我们将阐明何时 联合嗅觉恐惧学习调节肾小球层感觉信息的处理 嗅球和负责编码刺激-恐惧联系的神经网络的作用 这些变化，以及这与嗅觉恐惧在行为层面上的泛化有何关系。我们 将检验这样一种假设，即肾小球对CS的增强是在获取期间开始的，尽管是泛化的 在固结过程中，与激波不成对的气味会得到增强，而在基底侧面的活动 杏仁核(BLA)是恐惧学习的假定中心，负责概括。来刻画时间 学习后的感觉变化过程，小鼠将在嗅觉过程中接受成像试验 将对CS和中性气味诱发的肾小球反应进行恐惧条件反射和比较 在训练前和训练后的不同时间点。然后，另一组小鼠将接受恐惧条件反射 虽然血乳酸被灭活，恐惧的行为表达和训练诱导的肾小球反应 变化将被量化，以评估血乳酸活动对行为和生理的影响 泛化。总之，这些实验将描述OB的生物行为适应 在获得和巩固联想恐惧学习的过程中。此外，这些实验将 提供对行为恐惧泛化的潜在机制的见解，具有潜在的临床意义 在创伤后应激障碍以及其他感觉处理机制中。

Project Summary/Abstract Associative fear learning, the underlying cause of disorders such as Post-Traumatic Stress Disorder (PTSD), involves the pairing of a stimulus with an aversive outcome. This pairing produces robust fear responses to the conditioned stimulus. Odor memories, such as those formed during olfactory fear learning are acquired quickly, are long lasting, and are apparent as early as the olfactory bulb (OB) glomeruli, which constitutes the first site of central nervous system olfactory sensory processing. This makes the OB an ideal place to investigate mechanisms underlying sensory processing and plasticity as they relate to fear learning. Herein, we present pilot data establishing that pairing odor presentations with foot shock induces behavioral fear and enhances glomerular responses to the conditioned stimulus (CS) in awake, behaving transgenic mice expressing a fluorescent calcium indicator. Similarly, odor-foot shock experience induces fear and enhances glomerular responses to neutral, unconditioned odor stimuli, a process known as stimulus generalization in which fear is transferred from the CS to neutral, unconditioned stimuli. Furthermore, sensory representations of the CS and neutral odors undergo transformations increasing the representational similarities, possibly leading to behavioral generalization. However, the time course of learning-induced transformations in sensory processing and the neural networks underlying generalized behavior and glomerular alterations is still unknown. By combining behavioral methods with awake, behaving wide-field calcium imaging, we will elucidate when associative olfactory fear learning modulates the processing of sensory information at the glomerular layer of the olfactory bulb and the role of the neural networks responsible for encoding the stimulus-fear association in these transformations, as well as how this relates to generalization of olfactory fear at the behavioral level. We will test the hypothesis that glomerular enhancement to the CS begins during acquisition, while generalized enhancements to odors not paired with shock occur during consolidation, and that activity in the basolateral amygdala (BLA), the putative center of fear learning, is responsible for generalization. To characterize the time course of sensory transformations following learning, mice will be subjected to imaging trials during olfactory fear conditioning and comparisons of the CS and neutral odor-evoked glomerular responses will be made before and at different time points after training. Then a separate cohort of mice will undergo fear conditioning while the BLA is inactivated and both behavioral expressions of fear and training-induced glomerular response alterations will be quantified to assess the impact of BLA activity on behavioral and physiological generalization. Together, these experiments will characterize the biobehavioral adaptations of the OB throughout acquisition and consolidation of associative fear learning. Furthermore, these experiments will provide insights into underlying mechanism of behavioral fear generalization with potential clinical implications in PTSD as well as other sensory processing mechanisms.