Modulation of intrinsic excitability in mPFC neurons

mPFC 神经元内在兴奋性的调节

• 批准号: 6999021
• 负责人: DARAH Esther FONTANEZ
• 金额: $ 2.67万
• 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: 2005-11-16 至 2009-11-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6999021
• 关键词: action potentials; amygdala; behavioral /social science research tag; behavioral extinction; charge coupled device camera; conditioning; fear; glutamate receptor; laboratory rat; microcapsule; neural plasticity; neurons; neuropsychology; predoctoral investigator; prefrontal lobe /cortex; psychopharmacology; receptor expression; stereotaxic techniques; voltage /patch clamp

DESCRIPTION (provided by applicant): This proposal addresses a fundamental question in emotion research; can fear extinction be pharmacologically enhanced? Fear extinction is the decrease in fear responses that normally occurs when a conditioned stimulus like a tone is repeatedly presented in the absence of the unconditioned stimulus such as a shock. Our overall goal is to understand the neural mechanisms by which fear extinction can be enhanced. Although behavioral and in vivo electrophysiological studies implicate an increase in medial prefrontal cortex (mPFC) activity in fear extinction, nothing is known about the cellular mechanisms involved. Our current working hypothesis is that pharmacological enhancement of the intrinsic excitability of mPFC neurons projecting to the amygdala will lead to an increase in the recall of extinction. Because the mPFC projection to the amygdala is central to our model of extinction expression, we will concentrate our efforts on mPFC neurons which are known to project to the amygdala. Aim 1 will examine the mechanisms by which the intrinsic excitability of mPFC neurons projecting to the amygdala can be enhanced in vitro through the stimulation of glutamate receptors. Aim 2 will determine whether intrinsic excitability of mPFC neurons is enhanced by synaptic stimulation. Aim 3 will determine whether receptor agonists which enhance the intrinsic excitability of mPFC neurons in vitro enhance extinction learning. Because extinction-based exposure therapies are the main treatment for post-traumatic stress disorder (PTSD) and phobias, there is considerable interest in facilitating extinction with pharmacological agents.

描述（由申请人提供）：该提案解决了情绪研究中的一个基本问题；恐惧会在药理学上增强吗？恐惧灭绝是恐惧反应的减少，通常会在没有无条件的刺激（例如震动）的情况下反复出现诸如音调的条件刺激。我们的总体目标是了解可以增强恐惧灭绝的神经机制。尽管行为和体内电生理研究表明，恐惧消灭中内侧前额叶皮层（MPFC）活性的增加，但对所涉及的细胞机制一无所知。我们目前的工作假设是，投射到杏仁核的MPFC神经元的内在兴奋性的药理增强将导致灭绝召回的召回。由于对杏仁核的MPFC投影对于我们的灭绝表达模型至关重要，因此我们将精力集中在已知会投射到杏仁核的MPFC神经元上。 AIM 1将检查投射到杏仁核的MPFC神经元的内在兴奋性可以通过刺激谷氨酸受体增强的机制。 AIM 2将确定MPFC神经元的内在兴奋性是否通过突触刺激增强。 AIM 3将确定在体外增强灭绝学习中增强MPFC神经元内在兴奋性的受体激动剂。由于基于灭绝的暴露疗法是创伤后应激障碍（PTSD）和恐惧症的主要治疗方法，因此人们对促进药理学剂的灭绝引起了极大的兴趣。