Feedforward Activation of AgRP Neurons and Hunger

AgRP 神经元的前馈激活和饥饿

基本信息

  • 批准号:
    10732358
  • 负责人:
  • 金额:
    $ 51.91万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-08-04 至 2028-04-30
  • 项目状态:
    未结题

项目摘要

AgRP neurons play a vital role in causing hunger – the desire to find and consume food. Hence, it is important to understand how the activity of AgRP neurons is controlled. The conventional view is that feedback signals, which track changes in energy balance, are the primary regulators of AgRP neurons. For example, the fasting- induced increase in AgRP neuron activity is thought to be caused by falls in leptin and perhaps insulin, and an increase in ghrelin. Conversely, recent studies using real-time in vivo monitoring of neural activity have unexpectedly uncovered novel forms of regulation that are clearly unrelated to feedback from energy stores. For example, detection of sensory cues related to food, and ingestion of food, both rapidly decrease AgRP neuron activity – well before energy stores are affected. While these examples clearly document the existence of rapid, “feedforward” inhibition of AgRP neurons, to date there have been no examples of the converse – i.e. rapid, feedforward activation of AgRP neurons. By performing long-term in vivo recordings of AgRP neuron activity, we have recently discovered that denial of access to food rapidly, within 30-60 minutes, activates AgRP neurons. Importantly, this rapid activation is to a high level that does not increase further as fasting progresses. This relatively rapid, “square wave” pattern of activation strongly indicates that it must be caused by novel mechanisms which, importantly, are unrelated to changes in feedback signals. This discovery, which could lead to a revision in models of AgRP neuron regulation, indicates that fasting-related activation, like feeding-related inhibition, utilizes feedforward mechanisms. Given that AgRP neuron activity is vital for appetite, and given that feedforward activation is not part of present models of AgRP neuron regulation, we believe that uncovering the neural basis for this, and establishing its function, as we recently did for sensory food cue inhibition of AgRP neurons, will provide important, previously unknown insights into the biology of hunger. In preliminary studies, we have identified the source of this rapid feedforward activation. Remarkably, the excitatory circuit carrying this activation to AgRP neurons shows a large degree of activity-dependent synaptogenesis plasticity – which we believe functions to amplify and sustain feedforward activation of AgRP neurons. Thus, the overall goal of this grant is to discover the basis for and understand the purpose of rapid, feedforward activation of AgRP neurons. In Aim 1 we will use our single neuron transcriptomic dataset and marker gene recombinase driver mice to establish the neural afferent basis for this regulation. In Aim 2 we will determine the behavioral scenarios that trigger feedforward activation – we hypothesize a key role for awareness that food is unavailable. In Aim 3 we will establish its function – this will be done by blocking the responsible afferents and then examining consequences. Finally, in Aim 4, we will identify the molecular mediators of and role for activity-dependent synaptogenesis / plasticity in this excitatory afferent à AgRP neuron circuit – we hypothesize important roles for presynaptic release of Cbln2 and Bdnf.
AgRP神经元在引起饥饿--寻找和消耗食物的欲望--中起着至关重要的作用。因此, 了解AgRP神经元的活动是如何控制的。传统观点认为反馈信号, 追踪能量平衡的变化,是AgRP神经元的主要调节器。例如,禁食- AgRP神经元活性的诱导增加被认为是由瘦素和可能的胰岛素的福尔斯下降引起的, Ghrelin增加。相反,最近的研究使用实时体内监测神经活动, 出人意料地发现了与能量存储反馈明显无关的新监管形式。 例如,检测到与食物相关的感觉线索,以及摄入食物,都迅速降低AgRP 神经元活动--在能量储存受到影响之前。虽然这些例子清楚地证明了 快速,“前馈”抑制AgRP神经元,迄今为止还没有匡威的例子-即。 快速前馈激活AgRP神经元。通过对AgRP神经元进行长期的体内记录, 活动,我们最近发现,拒绝获得食物迅速,在30-60分钟内,激活 AgRP神经元。重要的是,这种快速激活达到了一个高水平,不会随着禁食而进一步增加 进步。这种相对快速的“方波”激活模式强烈表明, 通过新的机制,重要的是,与反馈信号的变化无关。这一发现, 可能导致AgRP神经元调节模型的修订,表明禁食相关的激活,如 摄食相关抑制,利用前馈机制。考虑到AgRP神经元活动对于 食欲,并鉴于前馈激活不是目前AgRP神经元调节模型的一部分,我们 我相信,揭开这一点的神经基础,并建立其功能,就像我们最近为感觉神经所做的那样, 食物线索抑制AgRP神经元,将提供重要的,以前未知的见解生物学 饥饿在初步研究中,我们已经确定了这种快速前馈激活的来源。值得注意的是, 将这种激活传递到AgRP神经元的兴奋回路显示出很大程度的活动依赖性 突触发生可塑性-我们认为其功能是放大和维持AgRP的前馈激活 神经元因此,这项赠款的总体目标是发现基础和了解快速, 前馈激活AgRP神经元。在目标1中,我们将使用我们的单神经元转录组数据集, 标记基因重组酶驱动小鼠建立这种调节的神经传入基础。在目标2中, 确定触发前馈激活的行为场景-我们假设 意识到食物是不可用的。在目标3中,我们将建立其功能-这将通过阻止 负责任的传入,然后检查后果。最后,在目标4中,我们将确定 在这种兴奋性传入中激活依赖性突触发生/可塑性的介质和作用 神经元电路-我们假设Cbln 2和BDNF的突触前释放的重要作用。

项目成果

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BRADFORD B LOWELL其他文献

BRADFORD B LOWELL的其他文献

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{{ truncateString('BRADFORD B LOWELL', 18)}}的其他基金

Glutamatergic Neurons in the Arcuate Nucleus (ARC) and Regulation of Satiety
弓状核 (ARC) 中的谷氨酸能神经元与饱腹感的调节
  • 批准号:
    9353418
  • 财政年份:
    2016
  • 资助金额:
    $ 51.91万
  • 项目类别:
AGRP NEURONS. NMDARs, Spines, Source of Excitatory Input and Downstream Effectors
AGRP 神经元。
  • 批准号:
    8479355
  • 财政年份:
    2012
  • 资助金额:
    $ 51.91万
  • 项目类别:
AGRP NEURONS. NMDARs, Spines, Source of Excitatory Input and Downstream Effectors
AGRP 神经元。
  • 批准号:
    8668942
  • 财政年份:
    2012
  • 资助金额:
    $ 51.91万
  • 项目类别:
AgRP neurons: circadian control and interactions with the HPA axis
AgRP 神经元:昼夜节律控制以及与 HPA 轴的相互作用
  • 批准号:
    10262957
  • 财政年份:
    2012
  • 资助金额:
    $ 51.91万
  • 项目类别:
AgRP neurons: circadian control and interactions with the HPA axis
AgRP 神经元:昼夜节律控制以及与 HPA 轴的相互作用
  • 批准号:
    10116601
  • 财政年份:
    2012
  • 资助金额:
    $ 51.91万
  • 项目类别:
AgRP Neuron Activity – Plasticity, Gene Expression and Excitatory Afferent Control
AgRP 神经元活性 — 可塑性、基因表达和兴奋性传入控制
  • 批准号:
    9098186
  • 财政年份:
    2012
  • 资助金额:
    $ 51.91万
  • 项目类别:
AgRP neurons: circadian control and interactions with the HPA axis
AgRP 神经元:昼夜节律控制以及与 HPA 轴的相互作用
  • 批准号:
    10668332
  • 财政年份:
    2012
  • 资助金额:
    $ 51.91万
  • 项目类别:
AGRP NEURONS. NMDARs, Spines, Source of Excitatory Input and Downstream Effectors
AGRP 神经元。
  • 批准号:
    8848372
  • 财政年份:
    2012
  • 资助金额:
    $ 51.91万
  • 项目类别:
AgRP neurons: circadian control and interactions with the HPA axis
AgRP 神经元:昼夜节律控制以及与 HPA 轴的相互作用
  • 批准号:
    10461101
  • 财政年份:
    2012
  • 资助金额:
    $ 51.91万
  • 项目类别:
AGRP NEURONS. NMDARs, Spines, Source of Excitatory Input and Downstream Effectors
AGRP 神经元。
  • 批准号:
    8341276
  • 财政年份:
    2012
  • 资助金额:
    $ 51.91万
  • 项目类别:

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脊髓传入神经元如何控制食欲和口渴
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