INVESTIGATING THE GUT-BRAIN SIGNALING DYNAMICS REGULATING FOOD INTAKE

研究调节食物摄入的肠脑信号动力学

• 批准号: 10513159
• 负责人: Amber L Alhadeff
• 金额: $ 3.38万
• 依托单位: MONELL CHEMICAL SENSES CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10513159
• 关键词: ART protein; Affect; American; Animals; Award; Axon; Body Weight; Body Weight decreased; Brain; Brain region; Calcium; Calories; Cell Nucleus; Communication; Cues; Data; Detection; Development; Eating; Fiber; Food; Gastrointestinal tract structure; Grant; Heterogeneity; Hunger; Hypothalamic structure; Image; Imaging Techniques; Individual; Infusion procedures; Intake; Knowledge; Macronutrients Nutrition; Measures; Mediating; Mentors; Mentorship; Monitor; Mus; Neurons; Neurosciences; Nutrient; Obesity; Peripheral; Phase; Photometry; Population; Positioning Attribute; Public Health; Publishing; Regulation; Research; Research Personnel; Role; Satiation; Sensory; Signal Transduction; Smell Perception; Stomach; Structure; Synapses; Technical Expertise; Techniques; Technology; Testing; Time; Training; United States; Vagus nerve structure; Vision; Weight Gain; Work; awake; base; career; career development; cell type; comorbidity; design; detection of nutrient; energy balance; experience; experimental study; feeding; food consumption; gastrointestinal; gut-brain axis; hindbrain; in vivo; in vivo calcium imaging; integration site; microendoscopy; novel; obesity treatment; post-doctoral training; programs; relating to nervous system; response; two photon microscopy; weight loss intervention

PROJECT SUMMARY The recent increase in obesity is a major public health concern. Since energy balance regulation is coordinated by communication between the gastrointestinal (GI) tract and the brain, understanding these gut-brain interactions will enable the development of novel obesity treatments. The hypothalamus and the hindbrain are critical brain regions that integrate information from the gut to control food intake. Here, I will leverage recent technological advances to explore the regulation of both these brain regions in awake, behaving animals. Within the hypothalamus, agouti-related protein (AgRP)-expressing neurons are essential for food intake control. Activity in AgRP neurons is high during hunger and is rapidly inhibited by food. My recent work demonstrates that AgRP neurons are primarily regulated by calorie intake, rather than sensory detection of food, since direct gastric infusion of macronutrients into the stomach rapidly suppresses AgRP neuron activity in vivo. Further, this effect is recapitulated by administration of GI satiation signals normally released following food consumption. However, the mechanisms through which the gut transmits signals to AgRP neurons remain unknown. The mentored phase (Aims I and II) of this grant will build upon my previous work by elucidating the mechanisms through which nutrient detection in the gut leads to AgRP neuron activity reductions. Specifically, these aims will determine whether GI signals are transmitted vagally or through direct action on the brain, and will uncover the AgRP axon projections that transmit nutritive signals throughout the brain. Importantly, the mentored experiments will afford me training in peripheral manipulation of the GI tract, as well as in vivo calcium imaging of individual neurons using microendoscopy and 2-photon microscopy, expanding my technical expertise and enabling the proposed R00 experiments. The hindbrain nucleus tractus solitarius (NTS) is the first central site of integration of GI-derived signals from vagal afferents, and is a key signaling node that transmits signals from the gut to higher-order brain structures such as the hypothalamus. For the independent phase (Aims III and IV) of my grant, I have designed experiments that build upon both my graduate and postdoctoral training to determine how different hindbrain NTS neuron populations receive signals from the GI tract, at unprecedented levels of temporal and cellular detail. These complementary research aims combined with the proposed career development activities will provide me with the training necessary to successfully transition to independence, under the guidance of my mentorship team who have extensive collective experience with neuroscience techniques and mentorship. Overall, this award will facilitate my career as an independent investigator characterizing the role of gut-brain signaling on the in vivo activity dynamics of feeding-relevant neurons.

项目概要 最近肥胖人数的增加是一个主要的公共卫生问题。由于能量平衡调节是协调的 通过胃肠道 (GI) 和大脑之间的沟通，了解这些肠脑 相互作用将有助于开发新型肥胖疗法。下丘脑和后脑是 整合来自肠道的信息以控制食物摄入的关键大脑区域。在这里，我将利用最近 探索清醒、行为动物这两个大脑区域的调节的技术进步。 在下丘脑内，表达刺鼠相关蛋白 (AgRP) 的神经元对于食物摄入至关重要 控制。 AgRP 神经元的活性在饥饿期间很高，并且会被食物迅速抑制。我最近的工作 表明 AgRP 神经元主要受卡路里摄入的调节，而不是感觉检测 食物，因为直接向胃中注入常量营养素会迅速抑制 AgRP 神经元活性 体内。此外，通过给予胃肠道饱足感信号来概括这种效果，通常在 食品消费。然而，肠道向 AgRP 神经元传递信号的机制仍然存在 未知。这笔赠款的指导阶段（目标 I 和 II）将建立在我之前的工作基础上，阐明 肠道中营养物质检测导致 AgRP 神经元活性降低的机制。具体来说， 这些目标将决定胃肠道信号是通过迷走神经传递还是通过直接作用于大脑来传递，以及 将揭示在整个大脑中传递营养信号的 AgRP 轴突投射。重要的是， 指导实验将为我提供胃肠道外周操作以及体内操作的培训 使用显微内窥镜和双光子显微镜对单个神经元进行钙成像，扩大了我的研究范围 技术专业知识并支持拟议的 R00 实验。后脑孤束核 (NTS) 是整合来自迷走神经传入的胃肠道衍生信号的第一个中心位点，并且是关键的信号传导节点 将信号从肠道传输到下丘脑等高级大脑结构。对于独立人士 在我的资助的阶段（目标 III 和 IV），我设计了基于我的研究生和 博士后培训以确定不同的后脑 NTS 神经元群体如何接收来自胃肠道的信号 道，以前所未有的时间和细胞细节水平。这些互补的研究目标结合在一起 拟议的职业发展活动将为我提供成功所需的培训 在我的导师团队的指导下过渡到独立，他们拥有广泛的集体经验 具有神经科学技术和指导的经验。总的来说，这个奖项将促进我作为一名 独立研究者描述肠脑信号传导对体内活动动态的作用 喂养相关神经元。

项目成果

Hypothalamic detection of macronutrients via multiple gut-brain pathways.

• DOI: 10.1016/j.cmet.2020.12.018
• 发表时间: 2021-03-02
• 期刊: Cell metabolism
• 影响因子: 29
• 作者: Goldstein N;McKnight AD;Carty JRE;Arnold M;Betley JN;Alhadeff AL
• 通讯作者: Alhadeff AL

Monitoring In Vivo Neural Activity to Understand Gut-Brain Signaling.

• DOI: 10.1210/endocr/bqab029
• 发表时间: 2021-05-01
• 期刊: Endocrinology
• 影响因子: 4.8
• 作者: Alhadeff AL

Inhibition of Itch by Hunger and AgRP Neuron Activity.

• DOI: 10.1016/j.neuroscience.2020.06.005
• 发表时间: 2020-12-01
• 期刊: Neuroscience
• 影响因子: 3.3
• 作者: Alhadeff AL;Park O;Hernandez E;Betley JN
• 通讯作者: Betley JN

Growth differentiation factor 15 (GDF15) and semaglutide inhibit food intake and body weight through largely distinct, additive mechanisms.

• DOI: 10.1111/dom.14663
• 发表时间: 2022-06
• 期刊: DIABETES OBESITY & METABOLISM
• 影响因子: 5.8
• 作者: Ghidewon, M.;Wald, H. S.;McKnight, A. D.;De Jonghe, B. C.;Breen, D. M.;Alhadeff, A. L.;Borner, T.;Grill, H. J.
• 通讯作者: Grill, H. J.