Gene therapy against conditioned fear

对抗条件性恐惧的基因疗法

• 批准号: 6890018
• 负责人: ROBERT M. SAPOLSKY
• 金额: $ 18.91万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-05-01 至 2006-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6890018
• 关键词: Alphaherpesvirinae; amygdala; anxiety disorders; behavior; behavior test; behavioral /social science research tag; chronic disease /disorder; conditioning; corticosteroid receptors; electrophysiology; fear; gene expression; gene therapy; hippocampus; hydroxysteroid dehydrogenases; laboratory rat; learning; neural plasticity; neurophysiology; neuroprotectants; nonhuman therapy evaluation; psychopathology; stress; transfection /expression vector

DESCRIPTION (provided by applicant): It is clear that repeated exposure to stress increases the risk of developing and expressing symptoms of human disorders of fear and anxiety, however little is known about the mechanisms by which this occurs. Numerous studies have shown that the hippocampus is profoundly affected by chronic stress. Accordingly, patients with disorders of fear and anxiety often exhibit reduced hippocampal activity, and impairments in hippocampus-dependent learning and memory. In contrast, such patients are reported to exhibit increases in amygdala activity and enhancement of amygdala-dependent learning and memory. Because the amygdala plays an essential role in both innate and learned fear, this region may be a locus of stress-related changes that underlie fear and anxiety disorders. However, almost no work has examined the impact of chronic stress on the amygdala. In the proposed research, we will characterize stress-related changes in the amygdala in rats, using functional measures (behavior and synaptic plasticity) for which stress-related impairments in hippocampal neurons are well documented. We hypothesize that a regimen of chronic stress that negatively impacts hippocampal function across multiple measures will facilitate amygdala function along those same measures, thereby modeling the relationship between stress and disorders of fear and anxiety in humans. We will then examine the efficacy of two gene therapeutic interventions in reversing stress-related enhancement of fear. We will generate stress-inducible herpes simplex-1 viral amplicons designed to express an activity-dependent potassium channel (Kv1. 1), a calcium-dependent potassium channel (SK), the enzyme 11-beta-hydroxysteroid dehydrogenase-2 (11B), or a transdominant negative glucocorticoid receptor (Td). We will examine the impact of overexpressing these proteins in two amygdaloid regions (the basolateral complex or central nucleus) during stress to determine whether reducing either neuronal excitability (Kv1.1 and SK) or the actions of glucocorticoids (11B or Td) in the amygdala during stress restores normative function across behavioral and electrophysiological measures. These studies will be among the first to probe the feasibility of gene therapy in treating models of psychiatric disorders, and will provide important and novel insights into the mechanisms by which chronic stress impacts amygdala function.

描述（由申请人提供）：很明显，反复暴露在压力下会增加人类恐惧和焦虑障碍的发生和表现症状的风险，但人们对这种情况发生的机制知之甚少。 大量研究表明，海马体深受慢性压力的影响。因此，患有恐惧和焦虑症的患者通常表现出海马活动减少以及海马依赖性学习和记忆障碍。相比之下，据报道，此类患者的杏仁核活动增加，杏仁核依赖性学习和记忆能力增强。由于杏仁核在先天恐惧和后天恐惧中都发挥着重要作用，因此该区域可能是导致恐惧和焦虑症的压力相关变化的场所。然而，几乎没有研究研究慢性压力对杏仁核的影响。 在拟议的研究中，我们将使用功能测量（行为和突触可塑性）来描述大鼠杏仁核中与压力相关的变化，其中海马神经元中与压力相关的损伤已得到充分记录。我们假设，对海马功能产生负面影响的多种措施的慢性压力疗法将促进杏仁核功能沿着相同的措施，从而模拟人类压力与恐惧和焦虑障碍之间的关系。 然后，我们将检查两种基因治疗干预措施在逆转与压力相关的恐惧增强方面的功效。我们将生成应激诱导型单纯疱疹-1 病毒扩增子，旨在表达活性依赖性钾通道 (Kv1.1)、钙依赖性钾通道 (SK)、11-β-羟基类固醇脱氢酶-2 (11B) ，或跨显性阴性糖皮质激素受体（Td）。我们将检查应激期间两个杏仁核区域（基底外侧复合体或中央核）过度表达这些蛋白质的影响，以确定是否会降低杏仁核中的神经元兴奋性（Kv1.1 和 SK）或糖皮质激素（11B 或 Td）的作用在压力期间恢复行为和电生理测量的正常功能。这些研究将是首批探讨基因疗法治疗精神疾病模型可行性的研究之一，并将为慢性压力影响杏仁核功能的机制提供重要而新颖的见解。