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: 10396872
• 负责人: Amber L Alhadeff
• 金额: $ 8.75万
• 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 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10396872
• 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.

项目摘要 最近的肥胖症增加是一个主要的公共卫生问题。由于能源平衡法规是协调的 通过胃肠道（GI）和大脑之间的交流，了解这些肠道 相互作用将使新型肥胖治疗的发展。下丘脑和后脑是 关键的大脑区域将肠道的信息整合到控制食物摄入量。在这里，我将利用最近的 技术进步，探索在醒着的动物中对这两个大脑区域的调节。 在下丘脑内，表达与Agouti相关的蛋白（AGRP）神经元对于食物摄入至关重要 控制。饥饿期间AGRP神经元的活性很高，食物迅速抑制。我最近的工作 证明AGRP神经元主要由卡路里摄入调节，而不是对 食物，因为将大量营养素直接胃输注到胃中会迅速抑制AGRP神经元活性 体内。此外，通过通常释放的GI饱满信号来概括此效果 食物消费。但是，肠道传播信号到AGRP神经元的机制仍然存在 未知。这笔赠款的指导阶段（目标I和II）将通过阐明我以前的工作为基础 肠道中营养检测导致AGRP神经元活性降低的机制。具体来说， 这些目的将确定GI信号是通过对大脑的直接行动进行传播，以及 将发现在整个大脑中传递营养信号的AGRP轴突投影。重要的是， 指导的实验将使我能够培训胃肠道的外围操作以及体内 使用微观镜检查和2光子显微镜对单个神经元的钙成像，扩展了我 技术专长并启用拟议的R00实验。后脑核小核索他叶（NTS） 是从迷走神经传入的GI衍生信号集成的第一个中心地点，并且是一个关键信号节点 将信号从肠道传输到下丘脑等高阶脑结构。对于独立 我的赠款的阶段（AIM III和IV），我设计了基于我的毕业生和 博士后训练以确定不同的后脑NTS神经元种群如何从GI中获得信号 在空前的时间和细胞细节水平上。这些互补的研究目的结合了 随着拟议的职业发展活动，我将为我提供成功的培训 在我的指导团队的指导下过渡到独立 具有神经科学技术和指导的经验。总体而言，该奖项将有助于我作为一个职业 独立研究者表征了肠道信号传导在体内活性动力学动力学方面的作用 与喂养相关的神经元。