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，重复暴露于压力会增加发展和表达人类恐惧和焦虑症症状的风险，但是对这种情况的机制知之甚少。 许多研究表明，海马受到慢性应激的深刻影响。因此，患有恐惧和焦虑症疾病的患者通常表现出降低的海马活动，以及海马依赖性学习和记忆的障碍。相比之下，据报道，此类患者在杏仁核活性中表现出增加，并增强了杏仁核依赖性学习和记忆。由于杏仁核在先天和学习的恐惧中都起着至关重要的作用，因此该地区可能是与压力相关的变化的源头，这是恐惧和焦虑症的基础。但是，几乎没有工作检查慢性应激对杏仁核的影响。 在拟议的研究中，我们将使用功能措施（行为和突触可塑性）来表征大鼠杏仁核与压力相关的变化，以证明海马神经元中与压力相关的损害有充分的文献记录。我们假设一种慢性压力方案对多种措施对海马功能产生负面影响的一种方案将沿着相同的措施促进杏仁核功能，从而对人类的恐惧和恐惧和焦虑症之间的关系进行建模。 然后，我们将研究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。我们将产生旨在表达活性依赖性钾通道（KV1。1）的抗压力诱导疱疹，这是一种依赖性钙依赖性钾通道（SK），酶11-甲基 - 羟基 - 羟基肌动型脱氢酶-2（11b），或透射性负glucorticoticotor（11B）。我们将检查在压力期间两个杏仁核区域（基底外侧复合物或中央核）中过表达这些蛋白的影响，以确定在压力恢复在压力恢复的跨压力恢复的神经元兴奋性（KV1.1和SK）还是糖皮质激素（11B或TD）的作用。这些研究将是最早探究基因治疗在治疗精神疾病模型中的可行性的研究者之一，并将为慢性应激影响杏仁核功能的机制提供重要和新颖的见解。