Investigating the Role of Metabolic Stress in Major Depressive Disorder

调查代谢应激在重度抑郁症中的作用

• 批准号: 9327294
• 负责人: Brendan Murrihy O'Flaherty
• 金额: $ 4.4万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-13 至 2020-04-12
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9327294
• 关键词: 5' -AMP-activated protein kinase; Acute; Adverse effects; Affect; Affective; Amygdaloid structure; Animals; Antidepressive Agents; Area; Behavior; Behavioral; Brain; Brain region; Cells; Chronic; Cognitive; Control Animal; Data; Development; Diet; Disease; Disorder of neurometabolic regulation; Dominant-Negative Mutation; Down-Regulation; Electrophysiology (science); Energy Metabolism; Etiology; Feedback; Fructose; Future; Glucose; Health; Hyperglycemia; Hypoglycemia; Hypothalamic structure; Infusion procedures; Injectable; Injection of therapeutic agent; Lead; Limbic System; Link; Major Depressive Disorder; Measures; Mediating; Membrane; Mental Depression; Metabolic; Metabolic stress; Metabolism; Modeling; Molecular; Moods; Motor; Neurons; Non-Insulin-Dependent Diabetes Mellitus; Pathway interactions; Patients; Peripheral; Pharmacology; Pharmacotherapy; Phenotype; Play; Population; Positron-Emission Tomography; Prevalence; Process; Property; Protein Kinase; Protein Kinase Inhibitors; Rattus; Regulation; Resistance; Role; Selective Serotonin Reuptake Inhibitor; Signal Transduction; Site; Slice; Swimming; Synaptic plasticity; System; Techniques; Testing; United States; Viral; Virus; Western Blotting; Work; anxious; base; behavior test; brain metabolism; cell type; clinical investigation; clinically significant; cohort; cost; depressive symptoms; experimental study; extracellular; lifetime risk; metabolic abnormality assessment; mood regulation; neuronal excitability; novel; object recognition; overexpression; patch clamp; patient population; protein kinase inhibitor; socioeconomics; stressor; treatment-resistant depression

Project Summary The prevalence of major depressive disorder (MDD), one of the most common disorders in the United States, is doubled in patients with type 2 diabetes mellitus (T2DM). Traditionally thought of as two interacting, though fundamentally independent disorders, emerging evidence suggests that MDD and T2DM may share a common etiology: dysregulated metabolism. Dysregulated metabolism could disrupt neuronal activity in key limbic areas, contributing to MDD. However, little is known about how metabolic processes affect neuronal activity in key limbic areas such as the basolateral amygdala (BLA) in control states, or how these processes become dysregulated under metabolically stressful conditions. The central hypothesis of this study is that AMPK plays an important regulatory role in BLA excitability and affective behavior that becomes dysregulated under metabolically stressful conditions. This project will first elucidate how AMPK activity regulates affective behavior in rats. Using site-specific injection of an AMPK inactivator into the BLA, affective behavior will be tested using the elevated plus maze and forced swim task paradigms. Motor and cognitive behavior will also be tested using the open field maze and novel object recognition task. In addition to pharmacological AMPK inactivation, AAV viruses will be injected into the BLA to express a dominant-negative form of the AMPK 2 subunit specifically in BLA principal neurons, testing the effect of cell-type specific AMPK inactivation on affective behavior. Secondly, this project will characterize how AMPK activity modulates BLA principal neuron excitability. Using whole-cell patch clamp slice electrophysiology, the effect of intra- and extracellular administration of an AMPK inactivator on membrane resistance, spike threshold, and LTP threshold of BLA principal neurons will be tested. The effects of dominant negative AMPK 2 subunit expression on these electrophysiological properties will also be measured. Thirdly, the above experiments will be repeated using rats fed a high-fructose diet, a well- characterized model of metabolic stress. We will thus test the effects of the high fructose diet on AMPK activity, affective behavior, and BLA electrophysiology. We will also test if the effects of a high-fructose diet can be rescued through administration of a pharmacological AMPK activator, or cell type specific overexpression of wild-type AMPK 2. The combination of molecular, electrophysiological, and behavioral techniques will help us understand the link between metabolic state and mood regulation in both normal and dysfunctional states. Elucidating the role of the AMPK signaling cascade in the BLA could contribute to our understanding of MDD etiology and lead to novel antidepressant development.

项目摘要 主要抑郁症患病率（MDD）是美国最常见的疾病之一，是 2型糖尿病（T2DM）的患者增加了一倍。传统上认为是两个互动 从根本上是独立的疾病，新兴的证据表明，MDD和T2DM可能共同 病因：代谢失调。代谢失调可能会破坏关键边缘地区的神经元活动， 为MDD做出贡献。但是，关于代谢过程如何影响钥匙中的神经元活动知之甚少 边缘区域，例如对照状态中的副杏仁核（BLA），或这些过程如何变为 在代谢压力条件下失调。这项研究的中心假设是AMPK播放 在BLA令人兴奋和情感行为中的重要调节作用，在 代谢压力条件。该项目将首先阐明AMPK活动如何调节情感行为 在老鼠中。使用特定于位置的AMPK灭活剂到BLA中，将使用情感行为进行测试 高架的迷宫和强迫游泳任务范例。运动和认知行为也将使用 开放式迷宫和新颖的对象识别任务。除了药物AMPK灭活外，AAV 病毒将被注入BLA，以表达AMPK2亚基的主要阴性形式 BLA主神经元，测试细胞类型特异性AMPK失活对情感行为的影响。第二， 该项目将表征AMPK活动如何调节BLA主神经元令人兴奋。使用全细胞 斑块夹切片电生理学，AMPK灭活剂的细胞内和细胞外施用的作用 在膜电阻上，将测试BLA主神经元的尖峰阈值和LTP阈值。效果 这些电生理特性上的主要负AMPK2亚基表达也将是 测量。第三，上述实验将使用喂养高果糖饮食的大鼠重复（一种很好的） 代谢应激的特征模型。因此，我们将测试高果糖饮食对AMPK活性的影响， 情感行为和BLA电生理学。我们还将测试高果糖饮食的影响 通过给予药物AMPK激活剂或细胞类型特异性过表达来救出 野生型AMPK2。分子，电生理和行为技术的结合将有助于我们 了解正常状态和功能障碍状态下的代谢状态与情绪调节之间的联系。 阐明AMPK信号级联在BLA中的作用可能有助于我们对MDD的理解 病因并导致新型的抗抑郁药发育。