Glucocorticoid-endocannabinoid interactions in the amygdala

杏仁核中糖皮质激素-内源性大麻素的相互作用

• 批准号: 7876055
• 负责人: JEFFREY G TASKER
• 金额: $ 22.35万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-14 至 2012-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7876055
• 关键词: Acute; Address; Adrenal Cortex Hormones; Amygdaloid structure; Anxiety Disorders; Binding; Biological; Biology; Brain; CNR1 gene; Cell Nucleus; Cells; Chemicals; Complex; Cues; Drug abuse; Drug usage; Emotional; Endocannabinoids; Event; Extinction (Psychology); Financial compensation; Fright; Generations; Genetic; Glucocorticoid Receptor; Glucocorticoids; Hormones; Hydrocortisone; Hypothalamic structure; Illicit Drugs; In Vitro; Knock-out; Knockout Mice; Life; Link; Lipids; Measures; Mediating; Membrane; Memory; Mental disorders; Mineralocorticoid Receptor; Mineralocorticoids; Modeling; Mus; Neurons; Nightmare; Outcome Study; Patients; Pharmacological Treatment; Phobic anxiety disorder; Population; Post-Traumatic Stress Disorders; Rattus; Receptor Activation; Recurrence; Research; Retrieval; Rodent; Role; Signal Pathway; Slice; Stress; Structure; Symptoms; Synapses; Testing; Trauma; anandamide; biological adaptation to stress; cannabinoid receptor; conditioned fear; design; experience; gamma-Aminobutyric Acid; genetic manipulation; improved; insight; liquid chromatography mass spectrometry; memory process; novel; patch clamp; positive emotional state; prevent; public health relevance; receptor; response; steroid hormone; stress related disorder; tool

DESCRIPTION (provided by applicant): Post-traumatic stress disorder (PTSD) is triggered by a traumatic life event and is characterized by the recurrent retrieval of the traumatic memory in the form of context-induced flashbacks and recurrent nightmares. The amygdala is a critical brain structure involved in both the formation and the extinction of emotional memories. Glucocorticoids, steroid hormones secreted as part of the general stress response, and endocannabinoids, lipid molecules that bind to CB1 receptors in the brain, have been shown to be important for the consolidation and extinction of fear conditioning. Both glucocorticoids and endocannabinoids enhance fear memory formation and extinction via actions within the basolateral amygdaloid complex (BLA). Patients suffering from PTSD typically show low circulating levels of corticosteroids, particularly at the nadir of the diurnal cortisol secretory rhythm, and corticosteroid treatment causes improvement in subjective measures of PTSD symptoms. A recent study showed that the glucocorticoid facilitation of conditioned fear extinction is dependent on CB1 receptor activation in the BLA, linking the actions of glucocorticoids and endocannabinoids in the BLA in conditioned fear extinction. The current study is designed to determine the cellular mechanisms that link glucocorticoid and endocannabinoid effects on fear conditioning in the BLA. We will test the hypothesis that glucocorticoids trigger endocannabinoid synthesis and retrograde release at GABA synapses in the BLA, leading to the suppression of synaptic inhibitory input to BLA neurons. The specific aims of the proposal are: 1) to test biochemically for a rapid glucocorticoid-induced increase in endocannabinoid synthesis in the BLA and CeA using a liquid chromatography-mass spectrometry approach; and 2) to determine electrophysiologically whether glucocorticoids induce a rapid suppression of GABA synaptic inputs to BLA neurons via activation of a membrane receptor and the retrograde release of endocannabinoids using whole-cell patch clamp recordings in acute in vitro slices of amygdala. Pharmacological and genetic manipulations of glucocorticoid, mineralocorticoid and cannabinoid receptors and intracellular signaling pathways will be employed to characterize the novel molecular interactions between glucocorticoids and endocannabinoids in the BLA. The importance of endocannabinoids and glucocorticoids in the BLA in the consolidation and extinction of fear conditioning, and the relevance of fear conditioning to memory processing in PTSD, suggests that the outcome of this study will provide important insight into, and possible targets for, pharmacological treatment of stress-related disorders such as PTSD. PUBLIC HEALTH RELEVANCE: The proposed research on glucocorticoid-endocannabinoid interactions in the amygdala will provide critical insight into the basic biological mechanisms responsible for emotional memory formation and retention/extinction. The better understanding of emotional memory mechanisms gained from these studies will enhance our ability and improve the tools available to address increasingly prevalent and devastating mental illnesses brought on by stress and trauma, including posttraumatic stress disorder, anxiety disorders and phobias. The link between corticosteroids and endogenous cannabinoids is relevant not only to the basic biology of emotional memory formation, but also to the interaction between illicit drug use and anxiety disorders, as increased drug abuse in certain emotionally disturbed populations may be the result of compensation for a deficit in endogenous psychoactive chemicals involved in the generation of positive emotions.

描述（由申请人提供）：创伤后应激障碍（PTSD）是由创伤性生活事件引发的，其特征是以情境诱发的闪回和反复噩梦的形式反复检索创伤性记忆。杏仁核是一个关键的大脑结构，参与情绪记忆的形成和消失。糖皮质激素（作为一般应激反应的一部分而分泌的类固醇激素）和内源性大麻素（与大脑中 CB1 受体结合的脂质分子）已被证明对于巩固和消除恐惧条件反射很重要。糖皮质激素和内源性大麻素都通过基底外侧杏仁复合物（BLA）内的作用增强恐惧记忆的形成和消除。患有 PTSD 的患者通常表现出较低的皮质类固醇循环水平，特别是在昼夜皮质醇分泌节律的最低点，皮质类固醇治疗可改善 PTSD 症状的主观测量。最近的一项研究表明，糖皮质激素对条件性恐惧消退的促进依赖于 BLA 中 CB1 受体的激活，将 BLA 中糖皮质激素和内源性大麻素在条件性恐惧消退中的作用联系起来。目前的研究旨在确定糖皮质激素和内源性大麻素对 BLA 恐惧条件作用的细胞机制。我们将检验以下假设：糖皮质激素会触发 BLA 中 GABA 突触的内源性大麻素合成和逆行释放，从而抑制 BLA 神经元的突触抑制输入。该提案的具体目标是：1) 使用液相色谱-质谱法对 BLA 和 CeA 中糖皮质激素诱导的内源性大麻素合成快速增加进行生化测试； 2) 使用全细胞膜片钳记录急性体外杏仁核切片，从电生理学角度确定糖皮质激素是否通过膜受体的激活和内源性大麻素的逆行释放，诱导对 BLA 神经元的 GABA 突触输入的快速抑制。糖皮质激素、盐皮质激素和大麻素受体的药理学和基因操作以及细胞内信号传导途径将用于表征 BLA 中糖皮质激素和内源性大麻素之间的新型分子相互作用。 BLA 中内源性大麻素和糖皮质激素在巩固和消除恐惧条件反射中的重要性，以及恐惧条件反射与 PTSD 记忆加工的相关性，表明本研究的结果将为药物治疗提供重要的见解和可能的目标与压力相关的疾病，如创伤后应激障碍（PTSD）。 公共健康相关性：拟议的关于杏仁核中糖皮质激素-内源性大麻素相互作用的研究将为情绪记忆形成和保留/消退的基本生物学机制提供重要的见解。从这些研究中更好地理解情绪记忆机制将增强我们的能力并改进可用于解决由压力和创伤引起的日益普遍和毁灭性的精神疾病的工具，包括创伤后应激障碍、焦虑症和恐惧症。皮质类固醇和内源性大麻素之间的联系不仅与情绪记忆形成的基本生物学有关，而且还与非法药物使用和焦虑症之间的相互作用有关，因为某些情绪困扰人群中药物滥用的增加可能是对情绪记忆的补偿的结果。参与积极情绪产生的内源性精神活性化学物质的缺乏。