Brain-wide functional mapping of circuits controlling hedonic feeding in obesity

控制肥胖享乐喂养的回路的全脑功能图谱

基本信息

批准号：
10434601
负责人：
Li Ye
金额：
$ 7.52万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-07-01 至 2022-12-31
项目状态：
已结题

项目摘要

Project Summary: The proposal describes a five-year plan with a one-year extension for training Dr. Li Ye to achieve his goal to become an independent investigator in the central regulation of metabolism. The training plan includes a compelling research project, training in laboratory techniques, didactic scientific and career development courses. The applicant has more than a decade of experiences working in both metabolism and systems neurosciences. Dr. Ye’s previous findings in metabolic research have been published in many high- impact journals and have been then cited near 6,000 times by his peers. During the proposed training, Dr. Karl Deisseroth and Dr. Hollies Cline, leading experts in neurosciences will mentor the applicant’s scientific and career development. A committee with expertise in hypothalamic research (Dr. Luis de Lecea and Dr. Brad Lowell) will provide further scientific and career guidance. The goal of the project is to study neural mechanisms coordinating food intake and metabolic demands. Obesity is a result of energy imbalance, in which energy consumption exceeds the expenditure. Food intake can be driven by metabolic need or the hedonic value of palatable food. The former is mainly regulated by the hypothalamic structures that are responsive to hormonal signals. The latter is largely controlled by the mesolimbic reward systems. Preliminary studies suggested these systems converge in the lateral hypothalamus area (LH). Dissecting the circuit, cellular and molecular bases separating these two systems is key to understanding the central control of energy balance and its dysfunction during obesity, however, differentiating intermingled neural ensembles has been difficult. The candidate has developed a series of CLARITY and optogenetics-based technologies with sufficient throughput to map brain-wide connectivity and with the ability to retain molecular information to distinguish intermingled neuronal populations. The candidate has successfully dissected two anatomically intermingled but functionally distinct ensembles representing opposite valences in the prefrontal cortex. Thus, these systems provide us a unique opportunity to dissect the LH ensembles recruited by hedonic vs. metabolic feeding. The central hypothesis is that hedonic and metabolic feeding recruit distinct LH ensembles. Specifically, these ensembles quantitatively differ in: (1) the inputs they receive from upstream regions, (2) activity during different types of feeding, and (3) causal impact on feeding. The adaptation of these ensembles to diet is key to the development of hyperphagia. The approach is to use neuroscience tools to monitor and manipulate neural activity in animals (Aim 1&2). The circuit adaption will be measured using ribosome-profiling and imaging approaches (Aim3). Together, this study will elucidate neural mechanisms underlying the HFD-induced hyperphagia and provide the candidate with the training to start an independent research program focusing on the central regulation of energy homeostasis.

项目概要：该提案描述了一个五年计划，并延长一年，旨在培训李野博士实现了成为代谢中枢调节领域的独立研究者的目标。计划包括引人注目的研究项目、实验室技术培训、教学科学和职业申请人在新陈代谢和开发课程方面拥有十多年的工作经验。叶博士之前在代谢研究方面的研究成果已发表在许多高级别期刊上。 Karl 博士在拟议的培训期间被同行引用了近 6,000 次。神经科学领域的顶尖专家 Deisseroth 和 Hollies Cline 博士将指导申请人的科学和具有下丘脑研究专业知识的委员会（Luis de Lecea 博士和 Brad 博士）洛厄尔）将提供进一步的科学和职业指导。该项目的目标是研究协调食物摄入和代谢需求的神经机制。是能量不平衡的结果，其中能量消耗超过了食物摄入量。前者主要受代谢需求或可口食物的享乐价值驱动。对激素信号敏感的下丘脑结构主要由激素信号控制。初步研究表明这些系统集中在下丘脑外侧。剖析分隔这两个系统的电路、细胞和分子基础是关键。了解肥胖期间能量平衡的中央控制及其功能障碍，但是，区分候选人已经开发出一系列清晰和混合的神经元集合。基于光遗传学的技术，具有足够的吞吐量来绘制全脑连接图，并具有保留分子信息以区分混合的神经群体。成功地解剖了两个解剖学上混合但功能上不同的整体，代表相反的因此，这些系统为我们提供了解剖 LH 的独特机会。通过享乐与代谢喂养招募的群体中心假设是享乐和代谢。具体来说，这些集合在数量上有所不同：（1）它们的输入。从上游地区接收的信息，(2) 不同类型摄食期间的活动，以及 (3) 对摄食的因果影响。这些组合对饮食的适应是饮食过量发展的关键。监测和操纵动物神经活动的神经科学工具（目标 1 和 2）。这项研究将使用核糖体分析和成像方法进行测量（目标3）。 HFD 引起的食欲亢进的潜在机制，并为候选人提供培训以开始专注于能量稳态中央调节的独立研究计划。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Pathways to clinical CLARITY: volumetric analysis of irregular, soft, and heterogeneous tissues in development and disease.

通往临床清晰度的途径：对发育和疾病中的不规则、软和异质组织进行体积分析。

DOI：
发表时间：
2017-07-19
期刊：
影响因子：
4.6
作者：
Hsueh, Brian;Burns, Vanessa M;Pauerstein, Philip;Holzem, Katherine;Ye, Li;Engberg, Kristin;Wang, Ai;Gu, Xueying;Chakravarthy, Harini;Arda, H Efsun;Charville, Gregory;Vogel, Hannes;Efimov, Igor R;Kim, Seung;Deisseroth, Karl
通讯作者：
Deisseroth, Karl

Xiphoid nucleus of the midline thalamus controls cold-induced food seeking.

中线丘脑的剑突核控制寒冷引起的食物寻找。

DOI：
发表时间：
2023-03-18
期刊：
影响因子：
0
作者：
Lal, Neeraj K;Le, Phuong;Aggarwal, Samarth;Zhang, Alan;Wang, Kristina;Qi, Tianbo;Pang, Zhengyuan;Yang, Dong;Nudell, Victoria;Yeo, Gene W;Banks, Alexander S;Ye, Li
通讯作者：
Ye, Li

Somatosensory innervation of adipose tissues.

脂肪组织的体感神经支配。

DOI：
发表时间：
2023-06-01
期刊：
影响因子：
2.9
作者：
Wang, Yu;Ye, Li
通讯作者：
Ye, Li

Xiphoid nucleus of the midline thalamus controls cold-induced food seeking.

中线丘脑的剑突核控制寒冷引起的食物寻找。

DOI：
发表时间：
2023-09
期刊：
影响因子：
64.8
作者：
Lal, Neeraj K;Le, Phuong;Aggarwal, Samarth;Zhang, Alan;Wang, Kristina;Qi, Tianbo;Pang, Zhengyuan;Yang, Dong;Nudell, Victoria;Yeo, Gene W;Banks, Alexander S;Ye, Li
通讯作者：
Ye, Li

Cortical Representations of Conspecific Sex Shape Social Behavior.

同种性别的皮质表征塑造社会行为。