Identifying a new circuit that controls feeding behavior: leptin and serotonin interactions.

识别控制进食行为的新回路：瘦素和血清素相互作用。

• 批准号: 1656626
• 负责人: Claudia Grillo
• 金额: $ 90万
• 依托单位: University of South Carolina at Columbia
• 依托单位国家: 美国
• 项目类别: Continuing Grant
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-15 至 2023-04-30
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1656626&HistoricalAwards=false
• 关键词: Identifying; new; circuit; controls; feeding

Non-technical AbstractFeeding is an essential activity for the maintenance of life, and its regulation is associated with multiple brain mechanisms that work together to ensure that animals eat appropriately. The complexity of these interactions has presented challenges to our efforts to fully appreciate the neural basis of food intake. However, before we can understand that complexity we must first identify the individual brain circuits that regulate food intake. The main goal of this project is therefore to use advanced genetic and anatomical approaches to identify a novel circuit that contributes to the control of feeding behavior. Identifying this circuit will ultimately allow us to determine how it works together with other feeding circuits that we already know more about to regulate a complex behavior critical for animal survival. In achieving that goal the work will not only increase our understanding of fundamental principles associated with how the brain regulates behavior, but may also lead to unexpected insights into feeding disorders and the chronic medical conditions associated with them that create considerable economic and social burdens, nationally and globally. In addition, this project includes a Summer Internship Program that will provide an integrated research experience for undergraduate students, particularly students who will be recruited from populations that are under-represented in science and medicine. These research experiences will provide such students with experiential learning opportunities that will create a foundation for future success in biomedical or basic research science.Technical AbstractMany studies agree that leptin controls food intake through activation of hypothalamic leptin receptors (LepRs). In addition, recent reports have examined the participation of extra-hypothalamic LepRs. In this regard, we have identified neurons in the rat raphe nuclei that are activated by leptin. Intra raphe administration of leptin increases pSTAT3 expression in discrete serotonergic neurons and suppresses food intake. Using optogenetic approaches, we were able to inhibit feeding behavior when the raphe neurons responsive to leptin were photo-stimulated, and we showed that intra-raphe leptin increases hypothalamic 5-HT levels.zpur overarching hypothesis is therefore that, in addition to direct hypothalamic actions, leptin powerfully regulates food intake by activating LepRs located in the raphe nuclei, thus stimulating 5-HT release in the hypothalamic nuclei where 5-HT exerts anorectic effect. The current project will test this hypothesis by studying the functional anatomical serotonergic connections between the raphe and the hypothalamic nuclei, measuring in vivo 5-HT release in the hypothalamic nuclei that receive serotonergic terminals following optogenetic stimulation of leptin responsive neurons of the raphe nuclei; and identifying the phenotype of the hypothalamic neurons that are activated by leptin-stimulated serotonin release. The idea that leptin is acting at multiple target sites including serotonergic neurons in the raphe will advance our understanding of the regulation of feeding behavior. This research will also be used to provide in-depth research opportunities for students from a nearby liberal arts college, particularly students from under-represented populations.

非技术摘要进食是维持生命的一项基本活动，其调节与多种大脑机制有关，这些机制共同作用以确保动物适当进食。这些相互作用的复杂性对我们充分理解食物摄入的神经基础的努力提出了挑战。然而，在我们理解这种复杂性之前，我们必须首先确定调节食物摄入的单个大脑回路。因此，该项目的主要目标是使用先进的遗传和解剖方法来确定一种有助于控制进食行为的新回路。识别这个回路最终将使我们能够确定它如何与其他我们已经知道的喂养回路一起工作，以调节对动物生存至关重要的复杂行为。在实现这一目标的过程中，这项工作不仅会增加我们对与大脑如何调节行为相关的基本原则的理解，而且还可能导致对喂养障碍以及与之相关的慢性疾病的意外见解，这些疾病在国家和全球范围内造成了相当大的经济和社会负担。此外，该项目还包括一个暑期实习计划，该计划将为本科生提供综合研究经验，特别是那些将从科学和医学领域代表性不足的人群中招募的学生。这些研究经验将为这些学生提供体验式学习的机会，这将为未来在生物医学或基础研究science.Technical AbstractMany研究认为，瘦素控制食物摄入通过激活下丘脑瘦素受体（LepRs）的成功奠定基础。此外，最近的报告已经检查了下丘脑外LepRs的参与。在这方面，我们已经确定了瘦素激活的大鼠中缝核神经元。中缝核内给予瘦素可增加离散多巴胺能神经元中pSTAT 3的表达并抑制食物摄入。使用光遗传学方法，当对瘦素有反应的中缝核神经元受到光刺激时，我们能够抑制进食行为，并且我们表明中缝核内瘦素增加下丘脑5-HT水平。因此，zpur总体假设是，除了直接的下丘脑作用外，瘦素通过激活位于中缝核中的LepRs而有力地调节食物摄入，从而刺激下丘脑核中的5-HT释放，其中5-HT发挥厌食作用。目前的项目将通过研究中缝核和下丘脑核之间的功能解剖学多巴胺能连接来测试这一假设，测量在中缝核的瘦素反应神经元的光遗传学刺激后下丘脑核中接收多巴胺能末梢的体内5-HT释放;并鉴定由瘦素刺激的5-羟色胺释放激活的下丘脑神经元的表型。瘦素作用于包括中缝核中的多巴胺能神经元在内的多个靶点的观点将促进我们对摄食行为调节的理解。这项研究还将用于为附近文理学院的学生提供深入研究的机会，特别是来自代表性不足人口的学生。

项目成果

From Flatland to Jupiter: Searching for Rules of Interaction Across Biological Scales

从平地到木星：寻找跨生物尺度的相互作用规则

• DOI: 10.1093/icb/icab159
• 发表时间: 2021
• 期刊: Integrative and Comparative Biology
• 影响因子: 2.6
• 作者: Grillo, Claudia A;Holford, Mandë;Walter, Nils G
• 通讯作者: Walter, Nils G

Serotonin as a Regulator of Leptin-Mediated Food Intake Control Within a Novel Neuronal Circuit Between the Hypothalamus and Raphe Nuclei

• DOI: 10.1210/jendso/bvab048.112
• 发表时间: 2021-05-03
• 期刊: Journal of the Endocrine Society
• 影响因子: 4.1
• 作者: Sadek AT;Cowan HB;Jimenez KM;Crawford JN;Maxwell ND;Fadel JR;Reagan LP;Grillo CA
• 通讯作者: Grillo CA

Pathophysiology in a model of Gulf War Illness: Contributions of pyridostigmine bromide and stress

• DOI: 10.1016/j.psyneuen.2018.07.015
• 发表时间: 2018-10-01
• 期刊: PSYCHONEUROENDOCRINOLOGY
• 影响因子: 3.7
• 作者: Macht, V. A.;Woodruff, J. L.;Reagan, L. P.
• 通讯作者: Reagan, L. P.

Interactions between pyridostigmine bromide and stress on glutamatergic neurochemistry: Insights from a rat model of Gulf War Illness

• DOI: 10.1016/j.ynstr.2019.100210
• 发表时间: 2020-05-01
• 期刊: NEUROBIOLOGY OF STRESS
• 影响因子: 5
• 作者: Macht, V. A.;Woodruff, J. L.;Fadel, J. R.
• 通讯作者: Fadel, J. R.

Delayed cognitive impairments in a rat model of Gulf War Illness are stimulus-dependent

海湾战争病大鼠模型中的迟发性认知障碍是刺激依赖性的

• DOI: 10.1016/j.bbi.2023.07.003
• 发表时间: 2023
• 期刊: and Immunity
• 作者: Burzynski, H.E.;Ayala, K.E.;Frick, M.A.;Dufala, H.A.;Woodruff, J.L.;Macht, V.A.;Eberl, B.R.;Hollis, F.;McQuail, J.A.;Grillo, C.A.
• 通讯作者: Grillo, C.A.