Fear learning alters primary sensory representations of threat-predictive stimuli

描述（由申请人提供）：恐惧学习允许动物适应性地对威胁性环境做出反应（Bolles 1970）。然而，大脑系统对恐惧学习的失调会导致衰弱性焦虑症（罗森和舒尔金1998），包括创伤后应激障碍（PTSD）。在嗅觉恐惧学习的小鼠模型中的初步实验中，纵向光学成像实验揭示了当嗅觉感觉神经元（OSN）在体内被恐惧相关气味（CS+）刺激时，来自OSN的神经递质释放的大的、关联的、刺激特异性的增加。与对中性气味的反应相比，以及与其自身的预调节基线相比，对CS+的神经反应在调节后得到增强，从而表明恐惧调节选择性地改变了CS+在大脑输入处的神经表征。在恐惧条件反射后，这些对预测脚震的气味的初级感觉反应实际上比在控制环境下任何浓度的气味所引起的反应都要大，这可能是一种“警告信号”，以增强对CS+的反应或引起对CS+的注意。这一结果表明，对威胁相关刺激的感觉处理的变化可能在焦虑症中发挥作用，这包括对危险或不愉快刺激的普遍注意偏向。本计画将结合联合收割机、光学神经影像、行为学及药理学等技术来探讨学习诱发的感觉神经可塑性。该项目的具体目标是：1）使用各种恐惧条件反射范式来确定这种感觉神经可塑性发生的情况，以及它如何与气味和恐惧诱导刺激相关的记忆形成有关，2）学习这种感觉神经可塑性发生的神经机制，包括CS+的恐惧关联信息到达初级感觉神经元的回路，以及3）辨别在正常情绪学习之后和在创伤后应激障碍的啮齿动物模型中，CS+的神经表征的变化如何改变大脑对感觉输入的表征。

DESCRIPTION (provided by applicant): Fear learning permits an animal to respond adaptively to threatening circumstances (Bolles 1970). However, dysregulation of the brain's systems for fear learning can lead to debilitating anxiety disorders (Rosen and Schulkin 1998), including post-traumatic stress disorder (PTSD). In preliminary experiments in a mouse model of olfactory fear learning, longitudinal optical imaging experiments revealed large, associative, stimulus- specific increases in neurotransmitter release from olfactory sensory neurons (OSNs) when they are stimulated by fear-associated odors (CS+) in vivo. This neural response to the CS+ is enhanced after conditioning both compared to responses to neutral odors and compared to its own pre-conditioning baseline, thus showing that fear conditioning selectively changes the neural representation of the CS+ at the input to the brain. After fear conditioning, these primary sensory responses to footshock-predictive odors were actually larger than could be evoked by any concentration of that odor under control circumstances, perhaps serving as a "warning signal" to enhance reaction to the CS+ or to draw attention to it. This result suggests that changes in sensory processing of threat-related stimuli could play a role in anxiety disorders, which include a ubiquitous attentional bias toward dangerous or unpleasant stimuli. This project will combine optical neuroimaging, behavioral, and pharmacological techniques to investigate this learning-induced sensory neuroplasticity. The Specific Aims of the project are 1) to use various fear conditioning paradigms to determine the circumstances under which this sensory neuroplasticity occurs and how it relates to the formation of memories relating the odor and fear-inducing stimuli, 2) to learn the neural mechanisms by which this sensory neuroplasticity occurs, including the circuitry by which information about the fearful associations of CS+ reaches the primary sensory neurons, and 3) to discern how the change in the neural representation of the CS+ alters the brain's representation of sensory input both after normal emotional learning and in a rodent model of PTSD.