Regulation of Energy Homeostasis by BDNF

BDNF 对能量稳态的调节

• 批准号: 8280427
• 负责人: RICHARD B SIMERLY
• 金额: $ 47.19万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-15 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8280427
• 关键词: Action Potentials; Address; Adenoviruses; Adult; Affect; Age; Animals; Axon; Body Weight; Brain; Brain-Derived Neurotrophic Factor; Cell Nucleus; Cells; Computer Assisted; Country; Data; Defect; Dendrites; Dendritic Spines; Dependovirus; Development; Disease; Equilibrium; Excitatory Synapse; Exhibits; FOS gene; Fasting; Feeding behaviors; Galactosidase; Genes; Goals; Growth; Head; Health; High Prevalence; Hippocampus (Brain); Homeostasis; Human; Hypothalamic structure; Image Analysis; Immunohistochemistry; In Vitro; Inhibitory Synapse; Label; Lead; Leptin; Measures; Messenger RNA; Metabolic; Methods; Molecular; Morbid Obesity; Morphology; Mus; Mutant Strains Mice; Mutation; Neurites; Neurons; Neurotrophic Tyrosine Kinase Receptor Type 2; Obesity; Phenotype; Physiological; Physiological Processes; Play; Pro-Opiomelanocortin; Property; Regulation; Research; Research Project Grants; Role; Shapes; Signal Transduction; Site; Structure of nucleus infundibularis hypothalami; Synapses; Synaptic plasticity; Testing; Tetrodotoxin; Translations; Vertebral column; Weight Gain; axon growth; base; density; economic cost; effective therapy; energy balance; fat nutrition study; feeding; in vivo; insight; mouse model; mutant; neural circuit; neuromechanism; neuron development; neuropeptide Y; patch clamp; postnatal; postsynaptic; presynaptic; response; synaptogenesis

DESCRIPTION (provided by applicant): The long-term goal of this research project is to understand the molecular and neural mechanisms governing energy homeostasis. Brain-derived neurotrophic factor (BDNF) plays crucial roles in energy balance, as mutations in the genes for BDNF and its receptor TrkB lead to obesity in both mice and humans; however, the precise role of BDNF in the regulation of body weight remains unknown. The organization and activity of hypothalamic neural circuits plays a critical role in the control of energy balance and BDNF is a potent regulator of neuronal development and synaptic plasticity. This application proposes to test the hypothesis that BDNF controls body weight by regulating the formation of neural circuits in the mediobasal hypothalamus that are known to control energy balance. Defects in axonal growth, synaptogenesis, and spine development will alter the development of hypothalamic circuits, which will in turn impair hypothalamic integration of signals reflecting states of nutrition and fat stores. Aim 1 will determine if TrkB-expressing neurons in the arcuate nucleus (ARC) respond to changes in feeding status and investigate if BDNF regulates axonal growth of these neurons using both in vivo and in vitro approaches. Aim 2 will investigate if BDNF differentially regulates the formation of excitatory and inhibitory synapses in ARC neurons expresing either neuropeptide Y or proopiomelanocortin using both immunohistochemistry against presynaptic markers and whole-cell patch-clamp recordings. Aim 3 will determine if TrkB in the dorsomedial hypothalamus (DMH) is required for the control of energy balance and if the number and shape of dendritic spines on TrkB-expressing DMH neurons are altered in mutant mice that lack local BDNF synthesis and develop severe obesity. Findings from this proposed project would provide insights into the mechanism by which BDNF regulates energy balance as well as the role of structural changes in hypothalamic neural circuits in the development of obesity.

描述（由申请人提供）：该研究项目的长期目标是了解控制能量稳态的分子和神经机制。脑源性神经营养因子 (BDNF) 在能量平衡中发挥着至关重要的作用，因为 BDNF 及其受体 TrkB 基因突变会导致小鼠和人类肥胖；然而，BDNF 在体重调节中的确切作用仍不清楚。下丘脑神经回路的组织和活动在能量平衡的控制中起着至关重要的作用，BDNF 是神经元发育和突触可塑性的有效调节剂。本申请旨在测试 BDNF 通过调节下丘脑内侧神经回路的形成来控制体重的假设，这些神经回路已知可控制能量平衡。轴突生长、突触发生和脊柱发育的缺陷将改变下丘脑回路的发育，进而损害下丘脑反映营养和脂肪储存状态的信号整合。目标 1 将确定弓状核 (ARC) 中表达 TrkB 的神经元是否对进食状态的变化做出反应，并使用体内和体外方法研究 BDNF 是否调节这些神经元的轴突生长。目标 2 将使用针对突触前标记物的免疫组织化学和全细胞膜片钳记录来研究 BDNF 是否差异调节表达神经肽 Y 或阿片黑皮素原的 ARC 神经元中兴奋性和抑制性突触的形成。目标 3 将确定下丘脑背内侧 (DMH) 中的 TrkB 是否是控制能量平衡所必需的，以及在缺乏局部 BDNF 合成并发展为严重肥胖的突变小鼠中，表达 TrkB 的 DMH 神经元上的树突棘的数量和形状是否发生改变。该项目的研究结果将深入了解 BDNF 调节能量平衡的机制以及下丘脑神经回路结构变化在肥胖发展中的作用。