Dissecting the Nutritional Regulation of Feeding Circuits

项目总结/摘要 研究策略：肠道和大脑之间的交流对能量稳态至关重要， 但这种交流如何在下丘脑进食回路的动力学中表现尚不清楚。早期 肠-脑轴的研究依赖于间接测量营养调节的影响， 馈电电路上的外围信号。这些研究导致了一个模型，其中关键的下丘脑活动 饥饿神经元- AgRP神经元-随着动物营养状态的变化而逐渐波动。与 开发技术来记录清醒动物中遗传定义的神经元群体的活动， 最近首次在体内观察到AgRP神经元的动力学。这些研究显示， 与流行的模型相反，当动物看到或闻到食物时，AgRP神经元被迅速抑制， 在它咬一口之前;然而，需要食物摄入来维持这种抑制。我们有 开发了一种结合体内AgRP神经元动力学监测和胃内营养输注的工具， 首次表明，在没有通常与之相关的感官刺激的情况下， 在进食的情况下，足以在几分钟的时间尺度内抑制AgRP神经元。这种抑制作用不依赖于 食物的常量营养素组成，但取决于摄入的卡路里数量。这个目标 建议是确定每种常量营养素抑制的分子和电路机制。 AgRP神经元。这将通过三个目标来实现：确定负责的激素介质， 确定所涉及的营养传感器，并剖析这些信号到达AgRP神经元的途径。 候选人/环境：丽莎Beutler博士是加州大学旧金山分校内分泌科的高级研究员。 她最近完成了加州大学旧金山分校的内科住院医师和华盛顿大学的医学博士/博士学位， 她在理查德·帕尔米特博士的实验室里获得了博士学位。她正在完成她的奖学金研究， 是加州大学旧金山分校扎卡里·奈特博士实验室发表在《神经元》杂志上的第一作者论文的主题。 在获得了体内神经记录和先进啮齿动物手术的专业知识后，她现在寻求扩大 她在实验室的专业知识，包括光学电路解剖，单细胞分辨率钙成像，和数据 分析和编程技能之前获得一个独立的立场作为一个学术物理学家，科学家。 职业发展：该奖项将确保Beutler博士能够作为一名 一个独立的调查员，配备了实验工具的组合， 她的领域的边缘（钙基成像技术，光遗传学），并设置她除了在该领域的其他人 （先进的啮齿动物外科技术）。结合她在内分泌学的临床训练，这将使她 独特的准备解决问题，需要详细的知识，神经回路和周边 新陈代谢.该奖项还将促进Beutler博士获得其他专业技能， 独立性，包括科学写作，领导和管理方面的正式培训。

PROJECT SUMMARY/ABSTRACT RESEARCH STRATEGY: Communication between the gut and the brain is essential for energy homeostasis, but how this communication is represented in the dynamics of hypothalamic feeding circuitry is unknown. Early studies of the gut-brain axis relied upon indirect measurements of the effects of nutritionally regulated peripheral signals on feeding circuitry. These studies led to a model in which the activity of key hypothalamic hunger neurons – AgRP neurons – fluctuates gradually as the animal's nutritional state changes. With the development of techniques to record the activity of genetically-defined neuronal populations in awake animals, the dynamics of AgRP neurons were recently observed in vivo for the first time. These studies revealed, contrary to the prevailing model, that AgRP neurons are inhibited rapidly when an animal sees or smells food, before it takes a single bite; however, food ingestion is required for maintenance of this inhibition. We have developed a tool combining in vivo monitoring of AgRP neuron dynamics with intragastric nutrient infusion to show for the first time that nutrient delivery to the gut, in the absence of the sensory stimuli normally associated with eating, is sufficient to inhibit AgRP neurons over a time-scale of minutes. This inhibition is independent of the macronutrient composition of the food but depends upon the number of calories ingested. The goal of this proposal is to determine the molecular and circuit-based mechanisms by which each macronutrient inhibits AgRP neurons. This will be accomplished across three aims: to identify the hormonal mediators responsible, to identify the nutrient sensors involved, and to dissect the pathway by which these signals reach AgRP neurons. CANDIDATE/ENVIRONMENT: Dr. Lisa Beutler is a senior fellow in the Division of Endocrinology at UCSF. She recently completed internal medicine residency at UCSF and an MD/PhD at the University of Washington, where she earned her PhD in Dr. Richard Palmiter's laboratory. She is finishing her fellowship research, which is the subject of a first-author publication in the journal Neuron, in Dr. Zachary Knight's laboratory at UCSF. Having gained expertise in in vivo neural recording and advanced rodent surgery, she now seeks to expand her expertise in the lab to include optical circuit dissection, single-cell resolution calcium imaging, and data analysis and programming skills prior to obtaining an independent position as an academic physician-scientist. CAREER DEVELOPMENT: This award will ensure that Dr. Beutler is able to launch her career as an independent investigator armed with a combination of experimental tools that both position her at the cutting edge of her field (calcium-based imaging techniques, optogenetics) and set her apart from others in the field (advanced rodent surgical techniques). Combined with her clinical training in endocrinology, this will make her uniquely poised to address questions that require detailed knowledge of both neural circuitry and peripheral metabolism. This award will also facilitate Dr. Beutler's acquisition of other professional skills required for independence including formal training in scientific writing, leadership, and management.