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: 7991934
• 负责人: Jimok Kim
• 金额: $ 19万
• 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/7991934
• 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; 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; deprivation; disturbance in affect; neuroprotection; neurotoxic; neurotoxicity; novel; novel therapeutics; presynaptic; public health relevance; 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（申请人提供）：内源性大麻素是丰富的内源性脂质分子，具有多种神经功能，例如认知改变和神经保护。当 Ca2+ 增加或 G 蛋白激活时，神经元中会迅速产生内源性大麻素。一旦释放到细胞外空间，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递。由于内源性大麻素的快速产生和吸收，它们的作用暂时受到限制。除了内源性大麻素的这种阶段性作用外，神经元还会紧张地释放内源性大麻素。然而，内源性大麻素音调的调节机制在很大程度上尚不清楚。由于紧张性内源性大麻素水平与神经活动的持久状态（例如焦虑和神经变性）有关，因此内源性大麻素的张力可能受到神经元活动的慢性改变的调节。拟议的研究旨在追踪强效内源性大麻素信号传导活动依赖性修饰的细胞和分子靶标。该项目将进一步确定内源性大麻素张力在突触稳态和神经退行性疾病中的功能意义，这两种疾病都涉及神经元活动的慢性变化。持续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，但对两者之间的关系知之甚少，因此建议在此进行研究。如果内源性大麻素的张力降低，例如由于长期不活动，考虑到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，当对内源性大麻素介导的神经保护的需求很高时，内源性大麻素缺乏的有害影响可能会加剧。我建议测试阿尔茨海默病模型中神经元活动减少时内源性大麻素张力减弱的作用。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视角。 公共健康相关性：该项目旨在研究神经系统中组成性发生的一种新型内源性大麻素信号传导。这项研究预计将揭示基础内源性大麻素张力的调节，这可能对于维持神经功能至关重要，并与神经退行性疾病的新治疗途径相关。