Hypothalamic circuits regulating energy balance and obesity: synaptic physiology

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、某些形式的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。下丘脑弓状核中的原皮质素（POMC）神经元释放多种维持正常能量平衡所必需的神经肽。POMC神经元也释放经典神经递质，但突触递质在POMC神经元中的作用尚未得到充分研究。本研究的目的是验证POMC神经元亚群释放不同经典神经递质的总体假设，以及POMC神经元之间的这种异质性在能量平衡调节中很重要。以下具体假设将被测试：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。我们将利用同时标记POMC、gaba能和谷氨酸能神经元的转基因小鼠来检测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控。将使用电生理记录研究POMC神经元亚群的突触前调节和基础活动，并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靶点。将在转基因小鼠中进行逆行标记实验，以确定POMC神经元的特定种群。这些研究的结果将为POMC神经元如何在控制能量平衡的中枢神经系统回路中发挥作用提供更清晰的画面。7. 公共卫生相关性：肥胖每年造成约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。这项研究将确定大脑中对维持正常能量平衡至关重要的特定神经元是如何被调节的。

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.