The neural basis of deficits in acquisition and extinction of fear in schizophren

精神分裂症患者恐惧获得和消除缺陷的神经基础

• 批准号: 8218407
• 负责人: DAPHNE J HOLT
• 金额: $ 59.75万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2016-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8218407
• 关键词: Amygdaloid structure; Antipsychotic Agents; Anxiety; Arousal; Brain region; Characteristics; Code; Conditioned Stimulus; Delusions; Disease; Early Diagnosis; Emotional; Esthesia; Exhibits; Extinction (Psychology); Fright; Functional Magnetic Resonance Imaging; Functional disorder; Galvanic Skin Response; Genetic; Goals; Hippocampus (Brain); Human; Impairment; Knowledge; Lead; Learning; Link; Mammals; Measures; Medial; Mediating; Memory; Methods; Modeling; Molecular; Neurobiology; Neurophysiology - biologic function; Noise; Patients; Persons; Pharmaceutical Preparations; Phenotype; Prefrontal Cortex; Procedures; Process; Protocols documentation; Psychophysiology; Research; Resistance; Rest; Retrieval; Rodent; Schizophrenia; Severities; Stimulus; Symptoms; System; Testing; Therapeutic Agents; Time; Work; base; conditioned fear; experience; improved; learning extinction; memory process; memory recall; memory retrieval; neuromechanism; novel; novel marker; relating to nervous system; response; success

DESCRIPTION (provided by applicant): People who develop schizophrenia show deficits in emotional learning and memory, which have been linked to the symptoms of the disorder. Yet the neurobiological basis of these deficits is unknown. One challenging issue associated with this question is that the medications used to treat schizophrenia also cause some impairment in emotional function, so it has been difficult in previous studies to distinguish effects of the disorder from those of the medications used by the majority of the patients with the illness. One common method used to study emotional learning and memory in mammals, including humans, is called Pavlovian fear conditioning. In Pavlovian fear conditioning procedures, a person is exposed to a neutral stimulus, such as a tone or picture, which is followed by an unpleasant sensation, such as a loud noise or mild electrical stimulus. After a certain number of repetitions of this procedure, the person begins to experience some anticipatory anxiety or fear when exposed to the neutral stimulus by itself. A second type of learning can occur when this neutral stimulus is later presented several times without being followed by the unpleasant stimulus; this is called extinction learning and it requires the formation of a memory trace that is coded separately from the fear memory. These fear and extinction memories can be recalled at a later time, depending on the circumstances (called the "context") during the formation and recall of the memories. We have found evidence suggesting that the learning and later recall of fear and extinction memories is abnormal in schizophrenia. In this project, we will test the hypothesis that these abnormalities in fear and extinction learning and memory in schizophrenia are related to specific changes in the function of the brain regions known to drive these processes, and that these neural changes are linked to specific symptoms of schizophrenia. We will also determine whether any of the abnormalities in this system arise from, are worsened or improved by treatment with antipsychotic medications. This project has implications for understanding the fundamental pathophysiology of schizophrenia and for developing early markers and new treatments for the disorder. ! PUBLIC HEALTH RELEVANCE: The proposed research will test the hypothesis that the symptoms of schizophrenia arise from disruption of basic neural mechanisms governing emotional learning and memory. The findings of this project could lead to the identification of novel treatment targets for therapeutic agents aimed at ameliorating treatment-resistant symptoms of schizophrenia, and a quantitative neural phenotype for genetic and early detection studies of the disorder.

描述（由申请人提供）：精神分裂症患者表现出情感学习和记忆方面的缺陷，这与精神分裂症的症状有关。然而，这些缺陷的神经生物学基础尚不清楚。与这个问题相关的一个具有挑战性的问题是，用于治疗精神分裂症的药物也会导致一些情绪功能的损害，因此，在以前的研究中，很难将这种疾病的影响与大多数患有这种疾病的患者使用的药物的影响区分开来。研究包括人类在内的哺乳动物情感学习和记忆的一种常用方法被称为巴甫洛夫恐惧条件反射。在巴甫洛夫恐惧条件反射过程中，一个人被暴露在一个中性的刺激下，比如一个声音或图片，然后是一个不愉快的感觉，比如大声的噪音或轻微的电刺激。在这个过程重复一定次数之后，当人单独暴露于中性刺激时，他开始体验到一些预期性焦虑或恐惧。第二种类型的学习可以发生在中性刺激出现几次之后，没有不愉快的刺激紧随其后；这被称为消退学习，它需要形成一个与恐惧记忆分开编码的记忆痕迹。这些恐惧和灭绝记忆可以在稍后的时间被回忆起来，这取决于记忆形成和回忆时的环境（称为“上下文”）。我们已经发现证据表明，精神分裂症患者对恐惧和消失记忆的学习和后来的回忆是不正常的。在这个项目中，我们将测试这样一种假设，即精神分裂症患者在恐惧、灭绝、学习和记忆方面的这些异常与驱动这些过程的大脑区域功能的特定变化有关，这些神经变化与精神分裂症的特定症状有关。我们还将确定该系统中的任何异常是否由抗精神病药物治疗引起，恶化或改善。该项目对理解精神分裂症的基本病理生理学以及开发精神分裂症的早期标志物和新的治疗方法具有重要意义。！