Arcuate Nucleus Glutamatergic Neurons Modulate Energy Homeostasis

弓状核谷氨酸神经元调节能量稳态

基本信息

  • 批准号:
    8423379
  • 负责人:
  • 金额:
    $ 33.16万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2010
  • 资助国家:
    美国
  • 起止时间:
    2010-04-10 至 2015-02-28
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): The underlying health problem that this application addresses is the growing epidemic of obesity that now affects 30% of the adult population, and the resultant increase in heart disease, hypertension, diabetes, joint dysfunction, stroke, cancer, and early death that is estimated to cost upwards of 75 billion dollars per year. Many factors contribute to the obesity problem today. The hypothalamic arcuate nucleus in the brain acts like the information hub of energy balance, receiving information both from peripheral organs involved in energy storage or release, and receiving axonal information from other regions of the brain that also play important roles in CNS regulation of energy homeostasis, and sending out efferent information that regulates food intake and utilization. A focus for many years in this field has been the neuropeptides involved in energy regulation, and the hypothalamic neurons that secrete them. Most of the critical peptides involved in the regulation of energy homeostasis have been colocalized with the inhibitory transmitter GABA in the arcuate nucleus. This application focuses on what appears to be a new cellular player in the CNS regulation of energy balance that we have identified, the arcuate glutamatergic neuron, a cell that has the profile of one that reduces food intake. In most other regions of the brain glutamate is recognized as a major neurotransmitter. But in the hypothalamus, relatively little attention has been given to glutamate neurons, despite the fact that in the presence of glutamate receptor antagonists there is virtually no excitatory synaptic activity in the arcuate nucleus, or elsewhere in the hypothalamus. Prior to submitting this application, we have solved a central problem, that of recognizing these glutamate cells that exhibit no morphological difference from other hypothalamic cells, by generating a transgenic mouse that expresses the reporter GFP under the control of the vesicular glutamate transporter 2 (vGluT2) selectively in glutamate neurons. Our experiments utilize a combination of whole cell patch clamp electrophysiology, tract tracing with fluorogold and pseudorabies virus, ultrastructural immunocytochemistry, and altered gene expression in the context of challenges to whole animal energy balance. The first set of experiments address the hypothesis that the glutamate neurons show the same efferent axonal projections as the inhibitory neurons of the arcuate nucleus. This will be tested with fluorogold and recombinant pseudorabies virus microinjections into putative target regions. To test the hypothesis that arcuate glutamate cells regulate the activity of anorexigenic proopiomelanocortin (POMC) neurons, we will record from POMC neurons while stimulating local glutamate cells with the excitatory microdrop method to activate cell bodies but not axons of passage. Parallel experiments address the question of whether glutamate cells innervate each other, thereby increasing the timing and power of their output. Ultrastructural dual label immunocytochemistry will be used to test the hypothesis that local orexigenic neuropeptide Y (NPY) immunoreactive axons make synaptic contact with the glutamate cells, similar to the NPY axons that synapse with the anorexigenic POMC neurons. A second set of experiments, using whole cell patch clamp recording in hypothalamic slices, addresses the question of "What active or passive membrane characteristics make the glutamate neurons unique", compared with the GABAergic neurons of the arcuate nucleus that have received substantial attention. A third set of electrophysiological experiments tests the hypothesis that neuropeptides released from other arcuate nucleus neurons involved in the regulation of energy homeostasis modulate the activity of the arcuate glutamate neurons. In the fourth set of experiments, we ask whether arcuate glutamate neurons respond to long distance cues relating to energy homeostasis, particularly glucose and leptin. Together, these experiments will reveal the organization and cellular actions and responses of a unique and previously uncharacterized excitatory neuron in the arcuate nucleus. Understanding these glutamatergic cells should give us a better appreciation of the cellular mechanisms underlying energy homeostasis and body weight regulation, and should give us new insight into the potential treatment of obesity through those neurons that control food intake and expenditure. Many neurons in the arcuate nucleus have multiple roles; it is possible that the glutamate cell is no exception, and may play a role in other functions that this small but critical part of the brain controls, including regulation of the pituitary and other endocrine organs, reproduction and lactation, growth, metabolism, and response to stress.
描述(申请人提供):这项申请解决的潜在健康问题是肥胖的日益流行,目前影响着30%的成年人口,以及由此导致的心脏病、高血压、糖尿病、关节功能障碍、中风、癌症和过早死亡的增加,据估计,这些疾病每年造成超过750亿美元的损失。导致当今肥胖问题的因素很多。大脑中的下丘脑弓状核起着能量平衡信息中枢的作用,既接受来自参与能量储存或释放的外周器官的信息,也接受来自大脑其他区域的轴突信息,这些区域也在中枢神经系统调节能量稳态方面发挥重要作用,并发出调节食物摄入和利用的传出信息。多年来,该领域的一个焦点一直是参与能量调节的神经肽,以及分泌它们的下丘脑神经元。大多数参与能量平衡调节的关键多肽都与抑制性递质GABA共同定位于弓状核。这项应用关注于我们已经确定的中枢神经系统能量平衡调节中的一个新的细胞参与者,弓状谷氨酸能神经元,一个具有减少食物摄入量的细胞的轮廓。在大脑的大多数其他区域,谷氨酸被认为是一种主要的神经递质。但在下丘脑,人们对谷氨酸神经元的关注相对较少,尽管在谷氨酸受体拮抗剂存在的情况下,弓状核或下丘脑其他部位几乎没有兴奋性突触活动。在提交本申请之前,我们已经解决了一个中心问题,即识别这些与其他下丘脑细胞没有形态差异的谷氨酸细胞,方法是通过产生一只在谷氨酸神经元中选择性地表达报告GFP的转基因小鼠,该转基因小鼠在谷氨酸神经元中选择性地表达囊泡谷氨酸转运体2(VGluT2)。我们的实验结合了全细胞膜片钳电生理学、荧光金和伪狂犬病病毒的轨迹追踪、超微结构免疫细胞化学以及在整个动物能量平衡面临挑战的背景下基因表达的改变。第一组实验解决了这样的假设,即谷氨酸神经元显示出与弓状核抑制性神经元相同的传出轴突投射。这将通过将荧光金和重组伪狂犬病病毒显微注射到假定的靶区来进行测试。为了验证弓状谷氨酸细胞调节厌食性阿片黑质原皮质素(POMC)神经元活动的假设,我们将记录POMC神经元,同时用兴奋性微滴方法刺激局部谷氨酸细胞激活细胞体,但不激活传代轴突。平行实验解决了谷氨酸细胞是否相互作用的问题,从而增加了它们输出的时间和功率。我们将用超微结构双重标记免疫细胞化学方法来验证这样一种假说,即局部的厌食性神经肽Y(NPY)免疫反应轴突与谷氨酸细胞发生突触接触,类似于NPY轴突与厌食性POMC神经元的突触。第二组实验使用下丘脑脑片的全细胞膜片钳记录,与受到大量关注的弓状核的GABA能神经元相比,解决了这样的问题:“是什么主动或被动的膜特性使谷氨酸神经元独一无二”。第三组电生理实验测试了一种假设,即参与能量稳态调节的其他弓状核神经元释放的神经肽调节弓状谷氨酸神经元的活动。在第四组实验中,我们询问弓状谷氨酸神经元是否对与能量稳态有关的远距离信号做出反应,特别是葡萄糖和瘦素。综上所述,这些实验将揭示弓状核中一种独特的、以前未描述过的兴奋性神经元的组织、细胞行为和反应。了解这些谷氨酸能细胞可以让我们更好地理解能量平衡和体重调节的细胞机制,并让我们对通过控制食物摄入和支出的神经元治疗肥胖症的潜在方法有新的见解。弓状核中的许多神经元具有多重作用;谷氨酸细胞可能也不例外,它可能在大脑这一小但关键的部分控制的其他功能中发挥作用,包括调节垂体和其他内分泌器官、生殖和哺乳、生长、新陈代谢和对应激的反应。

项目成果

期刊论文数量(1)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Hypothalamic arcuate nucleus tyrosine hydroxylase neurons play orexigenic role in energy homeostasis.
  • DOI:
    10.1038/nn.4372
  • 发表时间:
    2016-10
  • 期刊:
  • 影响因子:
    25
  • 作者:
    Zhang X;van den Pol AN
  • 通讯作者:
    van den Pol AN
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ANTHONY N VAN DEN POL其他文献

ANTHONY N VAN DEN POL的其他文献

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{{ truncateString('ANTHONY N VAN DEN POL', 18)}}的其他基金

Zona incerta GABA neurons modulate energy homeostasis
未定带 GABA 神经元调节能量稳态
  • 批准号:
    9564671
  • 财政年份:
    2017
  • 资助金额:
    $ 33.16万
  • 项目类别:
Zona incerta GABA neurons modulate energy homeostasis
未定带 GABA 神经元调节能量稳态
  • 批准号:
    9426268
  • 财政年份:
    2017
  • 资助金额:
    $ 33.16万
  • 项目类别:
Dopamine Excites Orexigenic AgRP/NPY Neurons, but Inhibits Anorexic POMC Neurons
多巴胺兴奋促食欲 AgRP/NPY 神经元,但抑制厌食 POMC 神经元
  • 批准号:
    8888338
  • 财政年份:
    2015
  • 资助金额:
    $ 33.16万
  • 项目类别:
Lassa-VSV targets and kills glioma, and is not neurotoxic
Lassa-VSV 靶向并杀死神经胶质瘤,并且不具有神经毒性
  • 批准号:
    8888841
  • 财政年份:
    2015
  • 资助金额:
    $ 33.16万
  • 项目类别:
Dopamine Excites Orexigenic AgRP/NPY Neurons, but Inhibits Anorexic POMC Neurons
多巴胺兴奋促食欲 AgRP/NPY 神经元,但抑制厌食 POMC 神经元
  • 批准号:
    9015803
  • 财政年份:
    2015
  • 资助金额:
    $ 33.16万
  • 项目类别:
Lassa-VSV targets and kills glioma, and is not neurotoxic
Lassa-VSV 靶向并杀死神经胶质瘤,并且不具有神经毒性
  • 批准号:
    9043833
  • 财政年份:
    2015
  • 资助金额:
    $ 33.16万
  • 项目类别:
Dopamine Excites Orexigenic AgRP/NPY Neurons, but Inhibits Anorexic POMC Neurons
多巴胺兴奋促食欲 AgRP/NPY 神经元,但抑制厌食 POMC 神经元
  • 批准号:
    9213370
  • 财政年份:
    2015
  • 资助金额:
    $ 33.16万
  • 项目类别:
LuIII parvovirus targets glioma
LuIII细小病毒靶向神经胶质瘤
  • 批准号:
    8482343
  • 财政年份:
    2013
  • 资助金额:
    $ 33.16万
  • 项目类别:
LuIII parvovirus targets glioma
LuIII细小病毒靶向神经胶质瘤
  • 批准号:
    8643779
  • 财政年份:
    2013
  • 资助金额:
    $ 33.16万
  • 项目类别:
Vesicular stomatitis VSVrp30 selectively destroys human metastatic melanoma
水疱性口炎VSVrp30选择性破坏人类转移性黑色素瘤
  • 批准号:
    8826056
  • 财政年份:
    2012
  • 资助金额:
    $ 33.16万
  • 项目类别:

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