Amygdala and Pain-Associated Mood Disorders

杏仁核和疼痛相关的情绪障碍

• 批准号: 8802508
• 负责人: Eugene Dimitrov
• 金额: $ 39万
• 依托单位: ROSALIND FRANKLIN UNIV OF MEDICINE & SCI
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-01 至 2019-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8802508
• 关键词: Address; Affect; Amygdaloid structure; Animals; Anxiety; Basic Science; Behavior; Behavioral; Brain; Brain region; Cell Nucleus; Clinical; Clinical Research; Comorbidity; Data; Databases; Depressed mood; Development; Dissociation; Drug Design; Economic Burden; Emotional; Engineering; Equipment; Foundations; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; Genetic; Goals; Health system; Hippocampus (Brain); Impaired cognition; Incidence; Individual; Injury; Interneurons; Knowledge; Laboratories; Learning; Link; Major Depressive Disorder; Memory; Memory impairment; Mental Depression; Mental disorders; Mission; Modeling; Mood Disorders; Moods; Mus; Neurons; Neuropathy; Neuropeptides; Neurotransmitters; Nociception; Output; Pain; Peripheral; Persistent pain; Pharmaceutical Preparations; Pharmacologic Substance; Phenotype; Population; Precipitating Factors; Process; Public Health; Reagent; Relative (related person); Research; Research Proposals; Resolution; Role; Sensory; Short-Term Memory; Signal Transduction; Societies; Spinal Cord; Stimulus; Stress; Syndrome; Techniques; Technology; Testing; Therapeutic; Work; anxiety-like behavior; base; behavioral impairment; biological adaptation to stress; burden of illness; chronic pain; depressive symptoms; design; disability; effective therapy; emotion regulation; emotional distress; gamma-Aminobutyric Acid; genetic approach; hypothalamic-pituitary-adrenal axis; in vivo; information processing; innovation; learned behavior; monoamine; neurogenesis; neuronal circuitry; novel; public health relevance; receptor; response; spatial memory; transmission process

DESCRIPTION (provided by applicant): Chronic pain often leads to pathological mood changes and associated cognitive impairment. There is a fundamental need for development of better therapeutic approaches for both the pain and the comorbid mood disorders. Specific and detailed information about mechanisms causing mood changes in chronic pain is required for treatment advances. The central nucleus of the amygdala (CE) mainly consists of inhibitory GABAergic neurons. They coexpress several neuropeptides that may serve as co-transmitters and modulate aspects of pain and mood. Therefore, the CE inhibitory GABAergic neurons are likely to be a critical link between pain and mood. The long-term goal of my research is to establish new strategies for pharmaceutical development of psychotropic medications for treatment of mood disorders associated with chronic pain. The study objective in this proposal is to determine the mechanism by which GABA signaling in the amygdala modulates manifestations of anxiety, depression and memory impairment that develop during chronic pain, and to identify the specific brain targets of the CE GABA neurons. My central hypothesis is that the over-activity of specific CE GABAergic neuronal subpopulations, brought on by the increased nociceptive input during chronic pain, negatively affects emotional processing and induces depressive mood in susceptible individuals. The rationale for the proposed studies is that description of a new mechanism underlying development of mood disorders will provide opportunities for the development of new pharmacological strategies based on highly selective (potentially GABAergic) drugs, for both mood and pain. Three specific aims will be used to prove my hypothesis: 1) determine the relative contributions of amygdalar inhibitory subpopulations to the development of behavioral changes associated with pain; 2) assess the sequelae of increased amygdalar GABA activity on learning and memory during pain and 3) evaluate the long-term consequences of pain, after the pain is resolved, on pain associated behavior. I will use a pharmacological-genetic approach that allows spatial and temporal control of G-protein coupled receptor signaling in vivo to address the first two aims and I will use a newly developed technique for reversal of neuropathic injury to accomplish the last aim. Two collaborators will provide their expertise. The laboratory has the equipment and facilities required for this project. This contribution will be significant because it will aid the identifiction of specific, functionally distinct, neuronal groups in the amygdala and their role in the development of anxiety and depressed mood triggered by persistent pain. The proposed research is innovative because it has been designed specifically to evaluate the contribution of specific CE populations, as defined by their neurotransmitter expression, to pain generated anxiety and depressive mood.

描述（由申请人提供）：慢性疼痛常常导致病理性情绪变化和相关的认知障碍。根本需要开发针对疼痛和共存情绪障碍的更好的治疗方法。治疗进展需要有关导致慢性疼痛情绪变化的机制的具体而详细的信息。杏仁核中央核 (CE) 主要由抑制性 GABA 能神经元组成。它们共同表达几种神经肽，这些神经肽可以作为共同递质并调节疼痛和情绪的各个方面。因此，CE 抑制性 GABA 能神经元可能是疼痛和情绪之间的关键联系。我研究的长期目标是建立精神药物的药物开发新策略，用于治疗与慢性疼痛相关的情绪障碍。本提案的研究目的是确定杏仁核中 GABA 信号传导调节慢性疼痛期间出现的焦虑、抑郁和记忆障碍表现的机制，并确定 CE GABA 神经元的特定大脑目标。我的中心假设是，慢性疼痛期间伤害性输入增加导致特定 CE GABA 能神经元亚群过度活跃，对情绪处理产生负面影响，并诱发易感个体的抑郁情绪。拟议研究的基本原理是，对情绪障碍发展的新机制的描述将为开发基于高选择性（潜在 GABA 能）药物的新药理学策略提供机会，用于情绪和疼痛。 将使用三个具体目标来证明我的假设：1）确定杏仁核抑制亚群对与疼痛相关的行为变化的发展的相对贡献； 2) 评估疼痛期间杏仁核 GABA 活性增加对学习和记忆的后遗症，以及 3) 评估疼痛缓解后疼痛对疼痛相关行为的长期影响。我将使用一种药理学遗传学方法，允许体内 G 蛋白偶联受体信号传导的空间和时间控制，以实现前两个目标，并且我将使用一种新开发的技术来逆转神经性损伤，以实现最后一个目标。两名合作者将提供他们的专业知识。实验室具备本项目所需的设备和设施。 这一贡献将具有重要意义，因为它将有助于识别杏仁核中特定的、功能独特的神经元群，以及它们在持续疼痛引发的焦虑和抑郁情绪发展中的作用。拟议的研究具有创新性，因为它是专门为评估特定 CE 人群（根据其神经递质表达而定义）对疼痛产生的焦虑和抑郁情绪的贡献而设计的。