Regulation of Basal Endocannabinoid Tone in the Hippocampus

海马基础内源性大麻素张力的调节

• 批准号: 8318727
• 负责人: Jimok Kim
• 金额: $ 18.38万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8318727
• 关键词: 2-arachidonylglycerol; Alzheimer' s Disease; Alzheimer' s disease model; Anxiety; Area; Behavioral; Binding; Biochemical; Brain; Chronic; Cognitive; Data; Desire for food; Disease model; Dopamine; Endocannabinoids; Extracellular Space; GTP-Binding Proteins; Goals; Health; Hippocampus (Brain); Homeostasis; Hydrolysis; Learning; Link; Lipids; Maintenance; Mediating; Metabolism; Metabotropic Glutamate Receptors; Modeling; Modification; Molecular Target; Muscarinic Acetylcholine Receptor; Nerve Block; Nerve Degeneration; Nervous System Physiology; Nervous system structure; Neurodegenerative Disorders; Neurons; Neurophysiology - biologic function; Normal Range; Outcome; Outcome Study; Pain; Pathway interactions; Physiological; Play; Production; Regulation; Role; Signal Transduction; Slice; Synapses; Synaptic Transmission; Testing; Tetrodotoxin; anandamide; cannabinoid receptor; cellular targeting; deprivation; disturbance in affect; neuroprotection; neurotoxic; neurotoxicity; novel; novel therapeutics; presynaptic; relating to nervous system; research study; simulation; uptake

DESCRIPTION (provided by applicant): Endocannabinoids, abundant endogenous lipid molecules, have various neurological functions such as cognitive alteration and neuroprotection. The production of endocannabinoids occurs rapidly in neurons upon a rise in Ca2+ or an activation of G proteins. Once released into extracellular space, endocannabinoids bind to presynaptic cannabinoid receptors and suppress synaptic transmission. Due to rapid production and uptake of endocannabinoids, their action is temporally limited. In addition to this phasic action of endocannabinoid, neurons tonically release endocannabinoid. However, regulatory mechanisms for endocannabinoid tone are largely unknown. Since tonic endocannabinoid level has been implicated in lasting state of neural activity such as anxiety and neurodegeneration, it is possible that the endocannabinoid tone may be regulated by chronic alterations of neuronal activity. The proposed studies aim to track down the cellular and molecular targets of the activity-dependent modification of tonic endocannabinoid signaling. This project will further determine functional significance of endocannabinoid tone in synaptic homeostasis and neurodegenerative disease, both of which involve chronic shift in neuronal activity. Persistent inactivity may induce both synaptic homeostasis and a change in basal endocannabinoid level, but the relationship between the two is poorly understood and therefore is proposed to be investigated here. If endocannabinoid tone is reduced, e.g., by chronic inactivity, the outcome may not be always advantageous, given the various beneficial functions of endocannabinoids. For example, detrimental effects of endocannabinoid deficiency could be accentuated when neuroprotection mediated by endocannabinoids is on high demand. I propose to test for roles of diminished endocannabinoid tone when neuronal activity is reduced in Alzheimer's disease models. The outcome of these studies will provide new perspectives on the regulation of endocannabinoid tone and its roles in physiological and pathological settings. PUBLIC HEALTH RELEVANCE: This project aims to study a novel form of endocannabinoid signaling that occurs constitutively in the nervous system. The regulation of basal endocannabinoid tone, which is expected to be uncovered by this study, may be critical for maintenance of neural functions and relevant to a new therapeutic pathway for neurodegenerative diseases.

描述（由申请人提供）：内源性大麻素，丰富的内源性脂质分子具有各种神经功能，例如认知改变和神经保护。内源性大麻素的产生在Ca2+升高或G蛋白激活后迅速发生在神经元中。一旦释放到细胞外空间中，内源性大麻素就会与突触前大麻素受体结合并抑制突触传播。由于迅速产生和内源性大麻素的吸收，它们的作用在时间上受到限制。除了内源性大麻素的这种阶段作用外，神经元还可以释放内源性大麻素。但是，内源性大麻素张力的调节机制在很大程度上未知。由于补品内源性大麻素水平已与神经活动（例如焦虑和神经变性）的持久状态有关，因此内源性大麻素张力可能受神经元活性的慢性改变来调节。拟议的研究旨在追踪强大性大麻素信号转导活性依赖性修饰的细胞和分子靶标。该项目将进一步确定突触稳态和神经退行性疾病中内源性大麻素张力的功能显着性，这两者都涉及神经元活性的慢性变化。持续的不活动可能会引起突触稳态和基础内源性大麻素水平的变化，但是两者之间的关系知之甚少，因此建议在此处研究。如果降低内源性大麻素的张力，例如，通过慢性无效，鉴于内源性大麻素的各种有益功能，结果可能并不总是有利的。例如，当由内源性大麻素介导的神经保护症的需求量很高时，内源性大麻素缺乏症的有害作用可能会突出。我建议在阿尔茨海默氏病模型中降低神经元活性时测试内源性大麻素张力降低的作用。这些研究的结果将为内源性大麻素张力的调节及其在生理和病理环境中的作用提供新的观点。 公共卫生相关性：该项目旨在研究一种新型的内源性大麻素信号传导，该信号在神经系统中构成发生。预计这项研究会发现基础内源性大麻素张力的调节对于维持神经功能可能至关重要，并且与神经退行性疾病的新治疗途径有关。