Amygdala and Pain-Associated Mood Disorders

杏仁核和疼痛相关的情绪障碍

• 批准号: 9178671
• 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/9178671
• 关键词: Address; 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; Etiology; Foundations; G Protein-Coupled Receptor Signaling; G-Protein-Coupled Receptors; Genetic; Goals; Health system; Hippocampus (Brain); Impaired cognition; Impairment; Incidence; Individual; Injury; Interneurons; Knowledge; Laboratories; Learning; Link; Major Depressive Disorder; Memory; Memory impairment; Mental Depression; Mental disorders; Mission; Modeling; Mood Disorders; Moods; Mus; National Institute of Mental Health; Neurons; Neuropathy; Neuropeptides; Neurotransmitters; Nociception; Output; Pain; Pain management; Pathologic; Peripheral; Persistent pain; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacology; Phenotype; Population; Precipitating Factors; Public Health; Reagent; Research; Research Proposals; Resolution; Role; Sensory; Short-Term Memory; Signal Transduction; Societies; Spinal Cord; Stimulus; Stress; Syndrome; Techniques; Technology; Testing; Therapeutic; United States National Institutes of Health; anxiety-like behavior; base; biological adaptation to stress; brain dysfunction; burden of illness; chronic pain; depressive symptoms; design; designer receptors exclusively activated by designer drugs; disability; effective therapy; emotion regulation; emotional distress; gamma-Aminobutyric Acid; genetic approach; hypothalamic-pituitary-adrenal axis; in vivo; information processing; innovation; monoamine; negative affect; 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）：慢性疼痛常导致病理性情绪改变和相关的认知障碍。对于疼痛和共病性情绪障碍，迫切需要开发更好的治疗方法。治疗进展需要关于慢性疼痛中引起情绪变化的机制的具体和详细的信息。杏仁核中央核主要由抑制性gaba能神经元组成。它们共同表达几种神经肽，这些神经肽可能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为治疗慢性疼痛相关情绪障碍的精神药物的药物开发建立新的策略。本研究的目的是确定杏仁核中GABA信号调节慢性疼痛中出现的焦虑、抑郁和记忆障碍的机制，并确定CE GABA神经元的特异性脑靶点。我的主要假设是，慢性疼痛期间伤害性输入的增加导致特定CE - gaba能神经元亚群的过度活动，对易感个体的情绪加工产生负面影响，并诱发抑郁情绪。提出这些研究的基本原理是，对情绪障碍发展的新机制的描述将为基于高选择性（潜在的gaba能）药物的新药理学策略的发展提供机会，用于治疗情绪和疼痛。三个具体目标将用于证明我的假设：1)确定杏仁核抑制亚群对与疼痛相关的行为变化发展的相对贡献；2)评估杏仁核GABA活性增加对疼痛期间学习和记忆的后遗症；3)评估疼痛消退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，允许在体内对g蛋白偶联受体信号进行时空控制，以解决前两个目标，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。两位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。这一贡献意义重大，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。拟议的研究是创新的，因为它是专门设计来评估特定CE人群的贡献，根据他们的神经递质表达来定义，疼痛产生的焦虑和抑郁情绪。