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）：发展精神分裂症的人在情绪学习和记忆中表现出与疾病症状有关的缺陷。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引起情绪功能的损害，因此在先前的研究中很难将疾病的作用与大多数患有该疾病患者使用的药物的作用区分开。一种用于研究包括人类在内的哺乳动物的情绪学习和记忆的常见方法称为帕夫洛夫恐惧调节。在帕夫洛维亚的恐惧调节程序中，一个人暴露于中性刺激（例如音调或图片），然后是不愉快的感觉，例如响亮的噪音或轻度的电刺激。经过一定数量的重复，该人本身就开始经历一些预期的焦虑或恐惧。当这种中性刺激后来几次出现而不受不愉快的刺激后，可能会发生第二种学习。这称为灭绝学习，它需要形成与恐惧记忆分开编码的内存跟踪。这些恐惧和灭绝记忆可以在以后的时间召回，具体取决于记忆的形成和回忆期间的情况（称为“上下文”）。我们发现了证据表明，在精神分裂症中，学习和后来回忆的恐惧和灭绝记忆是异常的。在这个项目中，我们将检验以下假设：精神分裂症中的这些异常和灭绝的学习和记忆中的这些异常与已知驱动这些过程的大脑区域功能的特定变化有关，并且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通过用抗精神病药治疗而导致或改善的。该项目对理解精神分裂症的基本病理生理学以及为该疾病开发新的标记和新疗法具有影响。呢 公共卫生相关性：拟议的研究将检验以下假设：精神分裂症的症状是由控制情绪学习和记忆的基本神经机制的中断引起的。该项目的发现可能导致鉴定用于改善精神分裂症治疗耐药症状的治疗剂的新型治疗靶标，以及用于疾病遗传和早期检测研究的定量神经表型。