Fear Modulation of IL excitability

IL 兴奋性的恐惧调节

• 批准号: 8574536
• 负责人: James T. Porter
• 金额: $ 47.76万
• 依托单位: PONCE SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8574536
• 关键词: Affect; Agonist; Animals; Auditory; Bilateral; Brain; Cells; Depressed mood; Development; Dopamine; Dopamine Receptor; Extinction (Psychology); Fright; Functional Imaging; Glucocorticoid Receptor; Goals; Hippocampus (Brain); Infusion procedures; Ion Channel; Lead; Measurement; Measures; Medial; Mediating; Memory; Mental Depression; Muscimol; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; Neurons; Patients; Phobic anxiety disorder; Post-Traumatic Stress Disorders; Prefrontal Cortex; Rattus; Research; Role; Slice; Structure; Testing; Voltage-Gated Potassium Channel; base; conditioned fear; conditioning; improved; inhibitor/antagonist; neuronal excitability; novel; patch clamp; prevent; public health relevance; receptor; research study; response; voltage

DESCRIPTION (provided by applicant): Functional imaging studies in PTSD patients suggest that reduced activation of the medial prefrontal cortex (mPFC) contributes to the excessive fear response seen in these patients. To understand why the mPFC is less activated in PTSD patients, we need to understand the mechanisms by which fear conditioning and extinction alter mPFC excitability. Patch-clamp recordings of infralimbic (IL) neurons in the mPFC revealed that the intrinsic excitability of IL neurons was depressed by fear conditioning in rats. The depressed IL excitability could reduce IL activation and enhance conditioned fear responses. Consistent with this, reducing IL intrinsic excitability enhances conditioned fear response. These findings imply that intrinsic plasticity in IL contributes to the consolidation of the conditioned fear memory. The goal of this proposal is to extend these results by examining the mechanisms and circuits involved in this fear conditioning-induced depression of IL intrinsic excitability. In Aim1, the role of NMDA receptors, D2-like dopamine receptors, and glucocorticoid receptors in the fear conditioning-induced depression of IL intrinsic excitability will be examined. In Aim 2, the role of hippocampal inputs in the fear conditioning-induced depression of IL excitability will be evaluated. In Aim 3, we will evaluate whether sustained voltage-gated K+ channels contribute to the fear conditioning-induced depression of IL excitability. A better understanding of the mechanisms leading to intrinsic plasticity in this brain structure may provide direction for the development of novel treatments for PTSD.

描述（由申请人提供）：PTSD患者的功能成像研究表明，内侧前额叶皮层（mPFC）的激活减少导致这些患者出现过度恐惧反应。为了理解为什么mPFC在PTSD患者中激活较少，我们需要了解恐惧条件反射和消退改变mPFC兴奋性的机制。膜片钳记录显示，大鼠mPFC的边缘下（IL）神经元的内在兴奋性被恐惧条件反射抑制。抑制IL的兴奋性可降低IL的激活，增强条件性恐惧反应。与此一致，降低IL内在兴奋性增强条件性恐惧反应。这些结果表明，IL的内在可塑性有助于巩固的条件性恐惧记忆。这项建议的目标是通过研究这种恐惧条件反射诱导的IL内在兴奋性抑制的机制和电路来扩展这些结果。在Aim 1中，将检查NMDA受体、D2样多巴胺受体和糖皮质激素受体在恐惧条件反射诱导的IL内在兴奋性抑制中的作用。在目的2中，将评估海马输入在恐惧条件化诱导的IL兴奋性抑制中的作用。在目标3中，我们将评估持续的电压门控K+通道是否有助于恐惧条件反射诱导的IL兴奋性抑制。更好地理解导致这种大脑结构内在可塑性的机制可能为开发PTSD的新治疗方法提供方向。