Fear learning alters primary sensory representations of threat-predictive stimuli

描述（由申请人提供）：恐惧学习允许动物对威胁环境做出适应性反应（Bolles 1970）。然而，大脑恐惧学习系统的失调会导致衰弱性焦虑症（Rosen and Schulkin 1998），包括创伤后应激障碍（PTSD）。在小鼠嗅觉恐惧学习模型的初步实验中，纵向光学成像实验显示，当嗅感觉神经元（OSNs）受到恐惧相关气味（CS+）的刺激时，它们的神经递质释放大量的、关联的、刺激特异性的增加。与对中性气味的反应相比，这种对CS+的神经反应在条件反射后都得到了增强，这表明恐惧条件反射选择性地改变了输入到大脑的CS+的神经表征。在恐惧条件反射之后，这些对足震预测气味的主要感官反应实际上比控制环境下任何浓度的气味所能引起的反应都要大，这可能是一种“警告信号”，以增强对CS+的反应或引起人们的注意。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，焦虑症包括对危险或不愉快刺激的普遍注意偏见。该项目将结合光学神经成像、行为学和药理学技术来研究这种学习诱导的感觉神经可塑性。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环境，以及它与气味和恐惧诱导刺激相关的记忆形成的关系；2)了解这种感觉神经可塑性发生的神经机制，包括关于CS+恐惧关联的信息到达初级感觉神经元的回路；3)在正常情绪学习和创伤后应激障碍啮齿动物模型中，CS+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.