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

项目概要/摘要 联想性恐惧学习是创伤后应激障碍（PTSD）等疾病的根本原因， 涉及刺激与厌恶结果的配对。这种配对产生了强烈的恐惧反应， 条件刺激气味记忆，如在嗅觉恐惧学习过程中形成的记忆， 持续时间长，并且早在构成第一个部位的嗅球（OB）肾小球中就很明显 中枢神经系统的嗅觉感觉处理。这使得OB成为理想的调查场所 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，我们提出 试验数据表明，将气味呈现与足部电击配对会诱导行为恐惧， 肾小球反应条件刺激（CS）在清醒，行为转基因小鼠表达， 荧光钙指示剂同样，气味足休克的经验，诱导恐惧和增强肾小球 反应中性，无条件气味刺激，一个过程被称为刺激泛化，其中恐惧是 从CS转移到中性的无条件刺激。此外，CS的感觉表征和 中性气味经历转变，增加了代表性的相似性，可能导致 行为泛化然而，学习引起的感觉加工转变的时间过程 神经网络的基础广泛的行为和肾小球的变化仍然是未知的。通过 结合行为方法与清醒，行为宽场钙成像，我们将阐明当 联想嗅觉恐惧学习调节感觉信息在肾小球层的处理， 嗅球和负责编码刺激-恐惧关联的神经网络的作用 这些转变，以及这与行为层面嗅觉恐惧的普遍化有何关系。我们 将检验这一假设，即肾小球增强到CS开始在收购，而广义 强化气味不配对休克发生在巩固，并在基底外侧的活动， 杏仁核（BLA），假定的恐惧学习中心，负责概括。来描述时间 在学习后的感觉转变过程中，小鼠将在嗅觉过程中进行成像试验。 将进行恐惧条件反射和比较CS和中性气味诱发的肾小球反应 在训练前和训练后的不同时间点。然后另一组老鼠将接受恐惧条件反射 而BLA失活，恐惧和训练诱导的肾小球反应的行为表达 将对改变进行量化，以评估BLA活性对行为和生理的影响。 一般化总之，这些实验将表征OB的生物行为适应性 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 创伤后应激障碍以及其他感觉处理机制。

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.