Effects of fear learning on early olfactory processing

恐惧学习对早期嗅觉处理的影响

• 批准号: 8649439
• 负责人: MARLEY D KASS
• 金额: $ 3.41万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8649439
• 关键词: Affect; Affective; Afferent Neurons; Animal Model; Animals; Anxiety; Anxiety Disorders; Attention; Aversive Stimulus; Behavior; Bilateral; Brain; Brain region; Calcium; Cephalic; Complex; Data; Detection; Development; Dorsal; Dyes; Electric Stimulation; Elements; Emotional; Exhibits; Exocytosis; Extinction (Psychology); Feedback; Fluorescent Dyes; Freezing; Fright; Gene Targeting; Hallucinations; Image; Imaging Techniques; Implant; Individual; Interneurons; Learning; Mediating; Methods; Microscopy; Modeling; Mood Disorders; Mus; Nature; Nerve; Neurobiology; Neuronal Plasticity; Odorant Receptors; Odors; Olfactory Epithelium; Olfactory Nerve; Output; Pathology; Pattern; Photons; Physiological; Physiology; Post-Traumatic Stress Disorders; Presynaptic Terminals; Process; Research; Resolution; Role; Sensory; Sensory Process; Shock; Signal Transduction; Stimulus; Symptoms; Synapses; System; Techniques; Testing; Time; Training; base; classical conditioning; conditioned fear; conditioning; deprivation; design; experience; in vivo; learning extinction; nerve supply; neurophysiology; neurotransmitter release; olfactory bulb; olfactory stimulus; optical imaging; optogenetics; presynaptic; programs; public health relevance; relating to nervous system; research study; response; sensory stimulus; sensory system; two-photon

DESCRIPTION (provided by applicant): Sensory system physiology in both higher order (Li et al. 2008; Edeline & Weinberger 1991; Gdalyahu et al. 2012) and early (Fletcher 2012) processing centers can be modified by emotional learning. Sensory pathologies are in fact a common element of many affective disorders, ranging from outright hallucinations in post traumatic stress disorder (Mueser & Butler 1987; Freeman & Fowler 2009) to more subtle changes in attentional processing (Desseilles et al. 2009; Adenauer et al. 2010) which may bias incoming sensory information to threat-predictive stimuli in anxiety disorders (Beck & Clark 1997; Buckley 2000). Anxiety disorders are routinely studied in animal models using associative fear conditioning paradigms, in which an animal learns that a neutral sensory stimulus, such as an odor (the CS+), predicts the occurrence of an aversive stimulus, such as a footshock. Such models provide a unique opportunity to investigate the role of sensory processing in emotional learning, and in preliminary studies we found that discriminative olfactory fear conditioning causes a surprising enhancement of CS+-evoked neurotransmitter release from olfactory sensory neurons (OSNs), the primary (first) sensory inputs to the brain. This enhancement may be beneficial in facilitating later detection of the CS+ or focusing attention towards similar sensory stimuli, or alternatively, may be maladaptive and contribute to anxiety. To further investigate the associations between early sensory processing and anxiety-like states, this study will perform longitudinal in vivo physiological and morphometric optical imaging procedures in mice that undergo discriminative olfactory fear conditioning. Odorant-evoked OSN synaptic output to olfactory bulb glomeruli will be visualized through a bilateral cranial window implanted above the dorsal olfactory bulbs at baseline, after fear learning, and again after extinction learning in individual mice expressing the synaptopHluorin (spH) exocytosis indicator in all mature OSN axon terminals (Bozza et al. 2004). Presynaptic sniff-locked Ca2+ signals in mice whose OSN axon terminals have been loaded with calcium-sensitive dye will be visualized before and after fear conditioning to assess how odorant-evoked response dynamics of CS+-responsive OSNs are modified by emotional learning. In vivo two-photon-based morphometric analyses will be performed on glomeruli identified during physiological imaging experiments to assess potential structural plasticity in OSN glomerular innervation (Jones et al. 2008). Our preliminary data suggest that the enhanced representation of the CS+ is mediated by changes in the olfactory bulb circuitry that gates incoming sensory information (i.e., emotional learning may cause the gate to open). To test this in vivo in mice that undergo fear conditioning, we will pharmacologically manipulate the intraglomerular circuit that presynaptically modulates OSN activity, electrically stimulate the olfactory nerve, and directly visualize odor- evoked activity n GABAergic interneurons that presynaptically inhibit neurotransmitter release from OSN axon terminals (in mice expressing the genetically-encoded Ca2+ indicator GCamP3 in GAD65-ergic interneurons).

描述（由申请人提供）：高级（Li et al. 2008; Edeline & Weinberger 1991; Gdalyn et al. 2012）和早期（弗莱彻2012）处理中心的感觉系统生理学都可以通过情绪学习来改变。感觉病理事实上是许多情感障碍的共同因素，从创伤后应激障碍中的完全幻觉（Mueser & Butler 1987; Freeman & Fowler 2009）注意力处理的更微妙变化（Desseilles等人，2009年; Adenauer et al. 2010），这可能会使传入的感官信息偏向焦虑症中的威胁预测刺激（Beck & Clark 1997; Buckley 2000）。焦虑症通常在动物模型中使用联想恐惧条件反射范式进行研究，其中动物学习到中性感觉刺激，如气味（CS+），预测厌恶刺激的发生，如电击脚。这种模型提供了一个独特的机会来研究感觉处理在情绪学习中的作用，在初步研究中，我们发现，辨别性嗅觉恐惧条件反射会导致CS+诱发的神经递质从嗅觉感觉神经元（OSN）释放的惊人增强，嗅觉感觉神经元是大脑的主要（第一）感觉输入。这种增强可能有利于促进CS+的稍后检测或将注意力集中到类似的感官刺激，或者可替代地，可能是适应不良的并导致焦虑。为了进一步研究早期感觉处理和焦虑样状态之间的关联，本研究将在经历辨别性嗅觉恐惧条件反射的小鼠中进行纵向体内生理和形态光学成像程序。在所有成熟OSN轴突终末中表达突触荧光蛋白（spH）胞吐指示物的个体小鼠中，在基线、恐惧学习后和消退学习后，通过植入背侧嗅球上方的双侧颅骨窗观察气味诱发的OSN突触向嗅球肾小球的输出（Bozza et al.2004）。将在恐惧条件反射之前和之后可视化其OSN轴突末端已经加载有钙敏感染料的小鼠中的突触前嗅探锁定的Ca 2+信号，以评估CS+响应OSN的气味诱发的响应动力学如何通过情绪学习来修改。将对生理成像实验期间鉴定的肾小球进行基于体内双光子的形态测定分析，以评估OSN肾小球神经支配的潜在结构可塑性（Jones等人，2008）。我们的初步数据表明，CS+的增强表现是由控制传入感觉信息的嗅球回路的变化介导的（即，情绪学习可能会导致大门打开）。为了在经历恐惧条件反射的小鼠中体内测试这一点，我们将间接操纵突触前调节OSN活性的肾小球内回路，电刺激嗅觉神经，并直接可视化GABA能中间神经元中的气味诱发的活性，所述GABA能中间神经元突触前抑制神经递质从OSN轴突终末释放（在GAD 65能中间神经元中表达遗传编码的Ca 2+指示剂GCamP 3的小鼠中）。