Fear learning alters primary sensory representations of threat-predictive stimuli

描述(由申请者提供)：恐惧学习允许动物对威胁环境做出适应性反应(Bolles 1970)。然而，由于恐惧学习而导致的大脑系统调节失调可能会导致衰弱的焦虑症(Rosen和Schulkin 1998)，包括创伤后应激障碍(PTSD)。在嗅觉恐惧学习的小鼠模型的初步实验中，纵向光学成像实验显示，当嗅觉感觉神经元(OSN)受到体内恐惧相关气味(CS+)刺激时，它们释放的神经递质大幅增加。无论是与中性气味的反应相比，还是与其自身的预适应基线相比，条件反射后对CS+的神经反应都得到了增强，从而表明恐惧条件作用选择性地改变了CS+在大脑输入端的神经表征。在恐惧条件作用后，这些对足部电击预测气味的初级感觉反应实际上大于在控制环境下任何浓度的这种气味所能唤起的，可能是增强对CS+的反应或引起人们注意的“警告信号”。这一结果表明，与威胁相关的刺激的感觉加工的变化可能在焦虑症中发挥作用，焦虑症包括普遍存在的对危险或令人不快的刺激的注意力偏向。这个项目将结合光学神经成像、行为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+恐惧联系的信息到达初级感觉神经元的回路，以及3)辨别CS+神经表征的变化如何改变大脑在正常情绪学习后和PTSD啮齿动物模型中对感觉输入的表征。

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.