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Cellular mechanisms mediating extinction of conditioned fear

介导条件性恐惧消失的细胞机制

基本信息

批准号：
7612632
负责人：
VADIM BOLSHAKOV
金额：
$ 20.13万
依托单位：
MCLEAN HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-11 至 2011-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7612632
关键词：
Acoustic Stimulation Address Amygdaloid structure Animals Anxiety Anxiety Disorders Basal Ganglia Behavior Behavioral Brain Cell Nucleus Cells Clinical Complex Conditioned Stimulus Conscious Development Emotional Etiology Event Experimental Models Extinction (Psychology)Fright Individual Interneurons Knowledge Label Laboratories Lateral Learning Link Long-Term Potentiation Mediating Memory Mental disorders Modification Molecular Nature Neuronal Plasticity Neurons Obsessive-Compulsive Disorder Panic Phobic anxiety disorder Plastics Post-Traumatic Stress Disorders Preparation Procedures Process Rattus Resistance Retrieval Role Slice Source Stimulus System Time Training Translating Unconscious State Whole-Cell Recordings classical conditioning conditioned fear improved innovation neural circuit neuronal circuitry neuronal excitability neurotransmission novel therapeutics patch clamp prevent public health relevance relating to nervous system research study response sound therapy resistant

项目摘要

DESCRIPTION (provided by applicant): Anxiety disorders, which include panic, phobias, post-traumatic stress disorder, obsessive-compulsive disorder, and generalized anxiety, are among the most common forms of mental illness. It was suggested that at least some anxiety disorders involve the fear system of the brain. An individual can have very poor conscious memory of a certain traumatic event, but at the same time very strong unconscious emotional memories could be formed through fear conditioning mechanisms. These very resistant to extinction fears can become a source of intense anxiety. A complete understanding of etiology of such pathological conditions requires detailed information about the neuronal mechanisms of fear-related behaviors and, specifically, about the nature of plastic modifications that provide the neural substrate of fear extinction. This could be translated eventually to the clinical setting for the treatment of anxiety and therapy-resistant phobias. Fear conditioning training paradigm is well suited for the cellular and molecular studies of fear learning and fear extinction. Our studies, as well as previous findings from other laboratories, indicate that neuronal plasticity underlying learning can be directly determined in the slice preparation and then correlated to the behavioral status of the experimental animal. Here we propose a combined behavioral and electrophysiological study to address specific questions concerning the nature of plastic modifications in the neural circuitry underlying extinction of conditioned fear. In Aim 1, we will explore the changes in intrinsic excitability of neurons in the infralimbic division of the mPFC projecting to the lateral, basal and central nuclei of the amygdala associated with extinction of conditioned fear. Our approach will be to obtain whole-cell patch clamp recordings from retrogradely labeled neurons in the infralimbic division of the mPFC in brain slices at different time points after extinction training. In Aim 2, we will analyze the effects of fear extinction on GABAeric inhibitory neurotransmission and intrinsic excitability of interneurons in the lateral and basal nuclei of the amygdala in slices from fear conditioned and fear-extinguished rats. These experiments will elucidate the nature of plastic modifications which may provide a neural substrate of fear extinction. A better understanding of the cellular mechanisms of fear extinction will permit the rational development of novel therapeutic treatments for generalized anxiety and posttraumatic stress disorder (PTSD) or other illnesses implicating the fear system of the brain. PUBLIC HEALTH RELEVANCE : The proposed studies will improve our understanding of the cellular mechanisms underlying extinction of fear memory. A better knowledge of the cellular mechanisms of fear-related behavior will permit the rational development of novel therapeutic treatments for posttraumatic stress disorder (PTSD) and generalized anxiety.

描述（由申请人提供）：焦虑症，包括恐慌症、恐惧症、创伤后应激障碍、强迫症和广泛性焦虑症，是最常见的精神疾病。有人认为，至少有一些焦虑症与大脑的恐惧系统有关。一个人对某种创伤性事件的有意识记忆可能很差，但同时，通过恐惧制约机制可以形成非常强烈的无意识情感记忆。这些对灭绝非常抗拒的恐惧可能成为强烈焦虑的来源。要全面了解这种病理状况的病因，需要详细了解恐惧相关行为的神经元机制，特别是提供恐惧消退神经基质的可塑性修饰的性质。这可能最终转化为临床设置治疗焦虑和治疗抵抗性恐惧症。恐惧条件反射训练范式非常适合于恐惧学习和恐惧消退的细胞和分子研究。我们的研究以及其他实验室之前的研究结果表明，学习基础的神经元可塑性可以在切片准备过程中直接确定，然后与实验动物的行为状态相关联。在这里，我们提出了一项结合行为学和电生理学的研究，以解决有关条件恐惧消失的神经回路中可塑性修饰的性质的具体问题。在目的1中，我们将探索与条条性恐惧消退相关的mPFC边缘下区神经元内在兴奋性的变化，这些神经元投射到杏仁核的外侧核、基底核和中央核。我们的方法将是获得全细胞膜片钳记录，从逆行标记的神经元在脑切片的mPFC边缘下分裂在不同的时间点后消失训练。在第二部分中，我们将分析恐惧消退对恐惧条件和恐惧消退大鼠扁桃体侧核和基底核中间神经元gabaic抑制性神经传递和内在兴奋性的影响。这些实验将阐明塑料修饰的本质，这可能提供恐惧消除的神经基础。更好地理解恐惧消退的细胞机制将允许合理地开发新的治疗方法来治疗广泛性焦虑和创伤后应激障碍（PTSD）或其他与大脑恐惧系统有关的疾病。公共卫生相关性：拟议的研究将提高我们对恐惧记忆消失的细胞机制的理解。更好地了解恐惧相关行为的细胞机制将允许合理地开发创伤后应激障碍（PTSD）和广泛性焦虑的新治疗方法。