Hypothalamic circuits regulating energy balance and obesity: synaptic physiology

调节能量平衡和肥胖的下丘脑回路：突触生理学

• 批准号: 8080502
• 负责人: SHANE T HENTGES
• 金额: $ 28.59万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8080502
• 关键词: Address; Adult; Affect; Attention; Biological Neural Networks; Brain; Caring; Cessation of life; Complex; Coronary heart disease; Data; Development; Diabetes Mellitus; Disease; Eating; Energy Metabolism; Expenditure; FOS gene; Fasting; Food Energy; Glutamates; Goals; Health; Heterogeneity; Homeostasis; Hypothalamic structure; Immunofluorescence Immunologic; Knockout Mice; Label; Leptin; Maintenance; Malignant Neoplasms; Measures; Mus; Neuraxis; Neurons; Neuropeptides; Neurotransmitters; Obesity; Obesity associated disease; Overweight; Peptides; Phenotype; Physiological; Physiological Processes; Physiology; Population; Prevalence; Pro-Opiomelanocortin; Regulation; Risk; Role; Site; Stroke; Structure of nucleus infundibularis hypothalami; Synapses; Testing; Therapeutic; Tracer; Transgenic Mice; United States; Work; design; energy balance; feeding; gamma-Aminobutyric Acid; mouse model; neuronal circuitry; novel strategies; presynaptic; prevent; research study

DESCRIPTION (provided by applicant): Approximately two-thirds of adults in the United States are overweight or obese and therefore at increased risk for developing diabetes, coronary heart disease, stroke, some forms of cancer and other health serious problems. A better understanding of the physiological mechanisms that regulate energy balance is a key step towards developing therapeutic approaches to prevent and treat obesity. Proopiomelanocortin (POMC) neurons in the hypothalamic arcuate nucleus release multiple neuropeptides that are necessary for the maintenance of normal energy balance. POMC neurons also release classical neurotransmitters, however the role of synaptic transmitters in POMC neurons has not been well-studied. The goal of the proposed work is to test the overall hypothesis that subsets of POMC neurons release different classical neurotransmitters and that this heterogeneity among POMC neurons is important in the regulation of energy balance. The following specific hypotheses will be tested: 1) That subpopulations of POMC neurons can be defined by the presence and release of GABA or glutamate. Transgenic mice with co-labeled POMC, GABAergic and glutamatergic neurons will be used to examine the neurotransmitter phenotype of subsets of POMC neurons and the effects that obesity and leptin treatment have on the rapid transmitter phenotype of POMC neurons will be determined. 2) That there is differential regulation of subsets of POMC neurons. The presynaptic regulation and basal activity of subsets of POMC neurons will be studied using electrophysiological recordings and the effects that leptin and fasting have on these parameters in each subpopulation will be studied. 3) That GABAergic and glutamatergic POMC neurons project to distinct target sites. Retrograde labeling experiments will be performed in transgenic mice to identify where specific populations of POMC neurons project. The results of these studies will provide a clearer picture of how POMC neurons function in the CNS circuitry controlling energy balance. 7. PUBLIC HEALTH RELEVANCE: Obesity contributes to about 112,000 deaths per year and is the primary reason for over $75 billion in heath care expenditures in the United States. A better understanding of the physiological mechanisms that regulate energy balance is a key step towards developing therapeutic approaches to prevent and treat obesity. This study will determine how specific neurons in the brain that are critical for the maintenance of normal energy balance are regulated.

描述（由申请人提供）：美国大约三分之二的成年人超重或肥胖，因此患糖尿病、冠心病、中风、某些癌症和其他严重健康问题的风险增加。更好地了解调节能量平衡的生理机制是开发预防和治疗肥胖的治疗方法的关键一步。下丘脑弓状核中的阿黑皮质素原 (POMC) 神经元释放多种神经肽，这些神经肽是维持正常能量平衡所必需的。 POMC 神经元还释放经典神经递质，但突触递质在 POMC 神经元中的作用尚未得到充分研究。这项工作的目标是检验以下总体假设：POMC 神经元子集释放不同的经典神经递质，并且 POMC 神经元之间的这种异质性对于能量平衡的调节很重要。将测试以下具体假设：1）POMC 神经元亚群可以通过 GABA 或谷氨酸的存在和释放来定义。具有共同标记的 POMC、GABA 能和谷氨酸能神经元的转基因小鼠将用于检查 POMC 神经元亚群的神经递质表型，并确定肥胖和瘦素治疗对 POMC 神经元快速递质表型的影响。 2) POMC 神经元亚群存在差异调节。将使用电生理记录来研究 POMC 神经元亚群的突触前调节和基础活动，并将研究瘦素和禁食对每个亚群中这些参数的影响。 3) GABA能和谷氨酸能POMC神经元投射到不同的目标位点。逆行标记实验将在转基因小鼠中进行，以确定 POMC 神经元的特定群体投射的位置。这些研究的结果将提供关于 POMC 神经元如何在 CNS 回路中控制能量平衡的功能的更清晰的图景。 7. 公共卫生相关性：肥胖每年导致约 112,000 人死亡，是美国医疗保健支出超过 750 亿美元的主要原因。更好地了解调节能量平衡的生理机制是开发预防和治疗肥胖的治疗方法的关键一步。这项研究将确定如何调节大脑中对于维持正常能量平衡至关重要的特定神经元。