Regulation of Energy Homeostasis by BDNF

BDNF 对能量稳态的调节

基本信息

批准号：
8663890
负责人：
RICHARD B SIMERLY
金额：
$ 53.32万
依托单位：
SCRIPPS FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-06-15 至 2016-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8663890
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

项目摘要

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有关能量稳态的分子和神经机制。脑衍生的神经营养因子（BDNF）在能量平衡中起着至关重要的作用，因为BDNF基因的突变及其受体TRKB导致小鼠和人类的肥胖症。但是，BDNF在体重调节中的确切作用仍然未知。下丘脑神经回路的组织和活动在控制能量平衡和BDNF中起着至关重要的作用，是神经元发育和突触可塑性的有效调节剂。该应用建议通过调节劣质下丘脑中的神经回路的形成来测试BDNF控制体重的假设，该假设已知可以控制能量平衡。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展，这反过来会损害反映营养状态和脂肪储存状态的信号的下丘脑整合。 AIM 1将确定弧形核（ARC）中表达TRKB的神经元是否响应喂食状态的变化，并研究BDNF是否使用体内和体外方法调节BDNF是否调节这些神经元的轴突生长。 AIM 2将调查BDNF是否在弧形神经元中差异调节兴奋性和抑制性突触的形成，从而使用两种免疫组织化学对突触前标记物和全球贴片贴片录制的均采用了神经肽Y或proOpiomelananocortin的形成。 AIM 3将确定控制能量平衡的控制下丘脑（DMH）中的TRKB是否需要在缺乏局部BDNF合成局部BDNF合成并发展出严重肥胖的突变小鼠中改变了表达TRKB DMH神经元的树突状刺的数量和形状。该拟议项目的发现将提供有关BDNF调节能量平衡以及下丘脑神经回路中结构变化在肥胖发展中的作用的机制的见解。