Neuroendocrine Integration of Satiety and Food Reward

饱腹感和食物奖励的神经内分泌整合

• 批准号: 10359770
• 负责人: Diana L Williams
• 金额: $ 39.64万
• 依托单位: FLORIDA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2024-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10359770
• 关键词: Affect; Agonist; Anatomy; Area; Behavioral; Biological Factors; Brain; Brain region; Cell Nucleus; Cells; Chronic; Complex; Data; Development; Eating; Electrophysiology (science); Food; Functional disorder; G-Protein-Coupled Receptors; GLP-I receptor; Gastrointestinal tract structure; Hyperphagia; Hypothalamic structure; Individual; Lateral; Location; Maintenance; Malaise; Mediating; Metabolic Diseases; Methods; Motivation; Mus; Neurons; Neuropeptides; Neurosecretory Systems; Nucleus solitarius; Nutrient; Obesity; Organism; Palate; Pathway interactions; Pharmacological Treatment; Pharmacology; Play; Population; Property; Prosencephalon; Research; Rewards; Role; Satiation; Signal Pathway; Signal Transduction; Site; Slice; Source; Stress; Structure of terminal stria nuclei of preoptic region; Synapses; System; Testing; Time; Transgenic Mice; Viral; Work; base; behavior influence; brain circuitry; cell type; experimental study; feeding; gastrointestinal; glucagon-like peptide 1; hindbrain; improved; insight; mind control; mouse model; neural network; neurotransmission; obesity treatment; preproglucagons; receptor function; relating to nervous system; signal processing

Overconsumption of highly palatable calorically dense food is a major contributor to obesity and related metabolic disorders. This proposal investigates one of the neuropeptide systems thought to underlie neural integration of the rewarding value of food with input from gut-derived satiety signals, Glucagon-like peptide 1 (GLP-1). Preproglucagon (PPG, the precursor to GLP-1) neurons project to many brain areas where activation of GLP-1 receptors (GLP-1R) promotes satiety and reduces motivation for food. Most research has focused on one or another individual PPG neuron projection and GLP-1R population at a time, and although this has informed us about brain GLP-1 action, this approach does not provide broad insight into the functional organization of the central GLP-1 network. Here we will take advantage of transgenic mouse models to investigate GLP-1R neuron projections that mediate behavioral effects. We hypothesize that: 1) activation of some, and inhibition of other GLP-1R neuron projections reduce feeding; 2) that GLP-1R neurons in different brain nuclei receive synaptic input from unique brain regions; and 3) that GLP-1R neurons communicate with one another across brain regions. Based on our data implicating GLP-1R neurons of the Lateral Septum (LS) and Bed Nucleus of the Stria Terminalis (BNST) in feeding control, we focus on two exemplar cell populations: the LS GLP-1R neuron projection to Lateral Hypothalamus (LH); and the BNST GLP-1R neuron projection to the LH. Aim 1 focuses on the GLP-1R LS-to-LH pathway, which we hypothesize promotes satiety and suppresses food reward when activated. Aim 2 examines the GLP-1R BNST-to-LH projection, which we hypothesize works in the opposite direction, such that inhibition of these neurons promotes satiety and suppresses food reward. Experiments will test these hypotheses using a combination of cell type-specific chemogenetic and pharmacologic approaches to manipulate the activity of each of these GLP-1R neuron projections to LH. We will conduct detailed behavioral analyses to distinguish effects on satiation, satiety, motivation, and stress or malaise that can alter feeding, and we will use slice electrophysiology to characterize the underlying neuronal signaling pathways. Aim 3 will determine sources of synaptic input to GLP-1R neurons in each location, testing the hypothesis that they receive distinct sources of input from PPG and other neurons, including GLP-1R+ neurons in other nuclei. Studies in this aim will apply a combination of traditional retrograde tracing and cutting edge cell type- and anatomic pathway-specific mono- and transsynaptic viral tracing methods. Together, our results will elucidate new mechanisms for GLP-1's hypophagic effects, identify new cell type-specific neuronal pathways that play a role in brain control of feeding, and provide a more complete picture of how PPG neurons and GLP-1-receptive cells throughout the brain coordinate to influence behavior. We propose that central GLP-1 signaling pathways are not unique in their integrated network organization, and expect that our findings will serve as a template for assessing these same questions for other circuits.

过度食用高可口的高热量食物是肥胖和相关疾病的主要原因。 代谢紊乱这项提议研究了一种神经肽系统，这种神经肽系统被认为是神经系统的基础。 整合食物的奖励价值与来自肠道来源的饱腹感信号的输入，胰高血糖素样肽1 （GLP-1）。前胰高血糖素原（PPG，GLP-1的前体）神经元投射到许多脑区，在这些脑区激活 GLP-1受体（GLP-1 R）的释放促进饱腹感，减少进食的动力。大多数研究都集中在 一次一个或另一个单独的PPG神经元投射和GLP-1 R群体，尽管这有 尽管这种方法告诉我们脑GLP-1的作用，但它并没有提供对脑GLP-1功能的广泛了解。 中心GLP-1网络的组织。在这里，我们将利用转基因小鼠模型， 研究介导行为效应的GLP-1 R神经元投射。我们假设：1）激活 一些GLP-1 R神经元投射和抑制其他GLP-1 R神经元投射减少进食; 2）不同GLP-1 R神经元中的GLP-1 R神经元 脑核从独特的脑区域接收突触输入;和3）GLP-1 R神经元与 在大脑的各个区域相互传递。基于我们涉及外侧隔（LS）GLP-1 R神经元的数据 和终纹床核（BNST）在摄食控制中的作用，我们关注两个示例性细胞群： LS GLP-1 R神经元投射到外侧下丘脑（LH）; BNST GLP-1 R神经元投射到 的LH。目的1关注GLP-1 R LS-to-LH通路，我们假设该通路促进饱腹感， 当激活时抑制食物奖励。目的2检查GLP-1 R BNST至LH的投射， 假设在相反的方向工作，这样，这些神经元的抑制促进饱腹感， 抑制食物奖励。实验将使用细胞类型特异性 化学发生学和药理学方法来操纵这些GLP-1 R神经元中的每一个的活性 预测LH。我们将进行详细的行为分析，以区分对饱腹感，饱腹感， 动机，压力或不适，可以改变喂养，我们将使用切片电生理学来表征 潜在的神经信号通路。目的3将确定GLP-1 R神经元的突触输入来源 在每个位置，测试它们从PPG和其他神经元接收不同输入源的假设， 包括其他核团中的GLP-1 R+神经元。在这方面的研究将采用传统的逆行结合 追踪和切割边缘细胞类型和解剖学途径特异性单突触和跨突触病毒追踪 方法.总之，我们的研究结果将阐明GLP-1的低吞噬作用的新机制， 细胞类型特异性神经元通路在大脑控制进食中发挥作用，并提供更完整的 这张图片展示了整个大脑中的PPG神经元和GLP-1受体细胞如何协调影响行为。 我们认为，中枢GLP-1信号通路在其整合的网络组织中并不是唯一的， 我希望我们的发现可以作为一个模板，用于评估其他电路的同样问题。

项目成果

Ventral tegmental area orexin 1 receptors promote palatable food intake and oppose postingestive negative feedback.

• DOI: 10.1152/ajpregu.00097.2016
• 发表时间: 2016-09
• 期刊: American journal of physiology. Regulatory, integrative and comparative physiology
• 作者: S. J. Terrill;Kellie M. Hyde;Kristen E Kay;H. Greene;Calyn B Maske;Amanda E Knierim;Jon F. Davis;Diana L. Williams

Role of lateral septum glucagon-like peptide 1 receptors in food intake.

• DOI: 10.1152/ajpregu.00460.2015
• 发表时间: 2016-07
• 期刊: American journal of physiology. Regulatory, integrative and comparative physiology
• 作者: S. J. Terrill;Christine M. Jackson;H. Greene;N. Lilly;Calyn B Maske;S. Vallejo;Diana L. Williams

Preproglucagon Neurons in the Nucleus of the Solitary Tract Are the Main Source of Brain GLP-1, Mediate Stress-Induced Hypophagia, and Limit Unusually Large Intakes of Food.

• DOI: 10.2337/db18-0729
• 发表时间: 2019-01
• 期刊: Diabetes
• 影响因子: 7.7
• 作者: Holt MK;Richards JE;Cook DR;Brierley DI;Williams DL;Reimann F;Gribble FM;Trapp S
• 通讯作者: Trapp S

GLP-1 action in the mouse bed nucleus of the stria terminalis.

• DOI: 10.1016/j.neuropharm.2017.12.007
• 发表时间: 2018-03-15
• 期刊: Neuropharmacology
• 影响因子: 4.7
• 作者: Williams DL;Lilly NA;Edwards IJ;Yao P;Richards JE;Trapp S
• 通讯作者: Trapp S

Endogenous GLP-1 in lateral septum contributes to stress-induced hypophagia.

• DOI: 10.1016/j.physbeh.2018.03.001
• 发表时间: 2018-08-01
• 期刊: Physiology & behavior
• 影响因子: 2.9
• 作者: Terrill SJ;Maske CB;Williams DL
• 通讯作者: Williams DL