Fear learning alters primary sensory representations of threat-predictive stimuli

恐惧学习改变了威胁预测刺激的主要感官表征

• 批准号: 8848430
• 负责人: John P McGann
• 金额: $ 38.75万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8848430
• 关键词: Adult; Afferent Neurons; American; Amygdaloid structure; Animals; Anxiety; Anxiety Disorders; Attention; Behavior; Behavioral; Biological Models; Brain; Brain region; Calcium; Cell Nucleus; Data; Development; Disease; Disease model; Emotional; Environment; Extinction (Psychology); Feedback; Fright; Image; Lateral; Lead; Learning; Measures; Mediating; Memory; Mus; Neuronal Plasticity; Odors; Olfactory tract; Optics; Output; Patients; Phase; Play; Post-Traumatic Stress Disorders; Presynaptic Terminals; Process; Reaction; Rodent; Rodent Model; Role; Sensory; Sensory Process; Shapes; Shock; Signal Transduction; Stimulus; Stress; Synapses; System; Techniques; Testing; Time; Training; Trauma; attentional bias; base; behavioral response; classical conditioning; conditioned fear; conditioning; effective therapy; experience; in vivo; memory retrieval; mouse model; neurobiological mechanism; neuroimaging; neuromechanism; neurotransmitter release; olfactory bulb; olfactory sensory neurons; optical imaging; presynaptic; prevent; public health relevance; receptor; relating to nervous system; research study; response; sensory input; sensory stimulus; sensory system; temporal measurement

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.

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可能导致令人衰弱的焦虑症（Rosen 和 Schulkin 1998），包括创伤后应激障碍（PTSD）。在嗅觉恐惧学习小鼠模型的初步实验中，纵向光学成像实验表明，当嗅觉感觉神经元（OSN）在体内受到与恐惧相关的气味（CS+）刺激时，它们释放的神经递质会出现大量的、关联的、刺激特异性的增加。与对中性气味的反应相比，以及与其自身的预处理基线相比，这种对 CS+ 的神经反应在条件反射后均得到增强，从而表明恐惧条件反射选择性地改变了 CS+ 在大脑输入端的神经表征。经过恐惧调节后，这些对足部震动预测气味的初级感官反应实际上比在控制环境下任何浓度的气味所能引起的反应都要大，这可能作为一个“警告信号”来增强对 CS+ 的反应或引起人们的注意。这一结果表明，与威胁相关的刺激的感觉处理的变化可能在焦虑症中发挥作用，其中包括对危险或不愉快的刺激普遍存在的注意力偏差。该项目将结合光学神经影像、行为和药理学技术来研究这种学习引起的感觉神经可塑性。该项目的具体目标是 1) 使用各种恐惧调节范式来确定这种感觉神经可塑性发生的情况以及它与气味和恐惧诱发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，包括有关 CS+ 的恐惧关联的信息到达初级感觉神经元的电路，以及 3) 辨别在正常情绪学习后和 PTSD 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。