NMDA Mediated Processes in Extinction of Conditioned Fear

NMDA 介导的消除条件性恐惧的过程

• 批准号: 6918423
• 负责人: Gregory J Quirk
• 金额: $ 9.14万
• 依托单位: PONCE SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-06-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6918423
• 关键词: NMDA receptors; amygdala; behavioral /social science research tag; behavioral extinction; conditioning; excitatory aminoacid; fear; gene expression; genetic transcription; inhibitor /antagonist; laboratory rat; learning; memory; neural plasticity; neuropharmacology; neurophysiology; neuropsychological tests; neuropsychology; polymerase chain reaction; prefrontal lobe /cortex; stimulant /agonist; western blottings

This proposal addresses a fundamental issue in neuroscience, namely, how do sensory stimuli acquire emotional significance? More specifically, how are fearful responses to stimuli extinguished once the stimuli no longer predict danger? The acquisition of fear associations to aversive stimuli occurs through a form of classical conditioning known as fear conditioning. In auditory fear conditioning, a tone conditioned stimulus (CS) is paired with a footshock unconditioned stimulus (US), resulting in the acquisition of fear responses to the tone such as freezing and response suppression. Fear conditioning depends critically on the amygdala, but less is known about the neural mechanisms of extinction, where unreinforced tones cause fear responses to decrease. Converging data suggests that the ventral medial prefrontal cortex (vmPFC), which projects to the amygdala, is necessary for consolidation of extinction learning. Blockade of NMDA glutamate receptors, which are involved in synaptic plasticity, prevents consolidation of extinction. The central hypothesis of this proposal is that extinction learning requires NMDA-mediated plasticity in prefrontal-amygdala circuits. Using rats, we propose three Aims to test this hypothesis: 1) We will determine the time course of NMDA receptor involvement in consolidation of fear extinction (Hypothesis: Post-training infusion of NMDA antagonists or agonists into the mPFC will impair or facilitate, respectively, extinction memory and neuronal plasticity vmPFC). 2) We will determine the time course of extinction-induced gene expression in mPFC (Hypothesis: Extinction upregulates c-Fos and CREB in the mPFC in an NMDA-deperdent manner), 3) We will determine if strengthening extinction memory with vmPFC stimulation depends on NMDA receptors (Hypothesis: stimulation-induced strengthening of extinction memory will be impaired or enhanced by NMDA antagonists or antagonists, respectively). This proposal combines pharmacological, physiological and molecular approaches to probe the neural mechanisms of fear extinction. Deficits m extinction learning are thought to underlie anxiety disorders such as post-traumatic stress disorder and specific phobia. This research is likely to lead to new methods to strengthen extinction, which could augment extinction-based exposure therapies for these disorders.

该提案解决了神经科学中的一个基本问题，即感觉刺激如何获得情感意义？更具体地说，一旦刺激不再预测危险，对刺激的恐惧反应将如何消失？通过一种称为恐惧调节的经典条件形式发生了与厌恶刺激的恐惧关联的获取。在听觉恐惧条件中，音调条件刺激（CS）与脚震无条件刺激（US）配对，从而获得了对诸如冻结和响应抑制之类的音调的恐惧反应。恐惧条件严重取决于杏仁核，但 对灭绝的神经机制知之甚少，在这种神经机制中，未增强的音调会导致恐惧反应减少。融合数据表明，向杏仁核投射的腹侧内侧前额叶皮层（VMPFC）对于灭绝学习的整合是必不可少的。与突触可塑性有关的NMDA谷氨酸受体的阻断可防止灭绝的巩固。该提议的中心假设是，灭绝学习需要前额叶 - 杏仁核电路中NMDA介导的可塑性。使用大鼠，我们提出了三个旨在检验这一假设的目的：1）我们将确定NMDA受体参与恐惧灭绝的时间过程（假设：NMDA拮抗剂或激动剂的训练后输注MPFC将损害或促进，分别损害或促进灭绝的记忆和神经启动记忆， 可塑性VMPFC）。 2）我们将在MPFC中确定灭绝诱导的基因表达的时间过程（假设：灭绝以NMDA-抑制方式上调MPFC的C-FOS和CREB，3）我们将确定是否可以增强用VMPFC刺激来增强内存的灭绝（VMPFC刺激的强制性强度）：刺激的强制性强度或刺激的强制性强度，以下方面的强制性强度或NMDA拮抗剂或拮抗剂）。该建议结合了药理，生理和分子方法，以探测恐惧灭绝的神经机制。缺陷灭绝学习被认为是焦虑症的基础，例如创伤后应激障碍和特定恐惧症。这项研究可能会导致加强灭绝的新方法，从而增加基于这些疾病的基于灭绝的暴露疗法。