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

描述(申请人提供)：精神分裂症患者在情绪学习和记忆方面表现出缺陷，这与该疾病的症状有关。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障碍，因此在之前的研究中，很难区分这种障碍的影响与大多数患者使用的药物的影响。一种用于研究哺乳动物(包括人类)情绪学习和记忆的常用方法被称为巴甫洛夫恐惧条件反射。在巴甫洛夫式的恐惧条件作用过程中，一个人暴露在中性刺激下，如音调或图片，紧随其后的是不愉快的感觉，如巨大的噪音或轻微的电刺激。经过一定次数的重复这一过程后，人开始体验到一些预期的焦虑或恐惧，当暴露在中性刺激中时。第二种类型的学习可能会发生，当这种中性刺激随后出现几次而不是令人不快的刺激时；这被称为消退学习，它需要形成一种与恐惧记忆分开编码的记忆痕迹。这些恐惧和消亡的记忆可以在以后的时间被回忆起来，这取决于记忆形成和回忆过程中的环境(称为“背景”)。我们发现有证据表明，精神分裂症患者对恐惧和消亡记忆的学习和后来的回忆是不正常的。在这个项目中，我们将测试一种假设，即精神分裂症患者在恐惧和消退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，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否由抗精神病药物治疗引起、恶化或改善。该项目对了解精神分裂症的基本病理生理学，以及开发该疾病的早期标志物和新的治疗方法具有重要意义。好了！ 与公共健康相关：这项拟议的研究将检验一种假设，即精神分裂症的症状是由于控制情绪学习和记忆的基本神经机制被破坏而产生的。该项目的发现可能导致为旨在改善精神分裂症治疗抵抗症状的治疗剂确定新的治疗靶点，并为该疾病的遗传学和早期发现研究提供一种定量的神经表型。

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.