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

摘要进食是维持生命的一项重要活动，其调节与多种大脑机制有关，这些机制共同确保动物适当进食。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学方法来识别有助于控制摄食行为的新电路。确定这个回路最终将使我们能够确定它是如何与我们已经了解的其他喂养回路一起工作的，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，这项工作不仅将增加我们对与大脑如何调节行为相关的基本原理的理解，而且还可能导致对喂养失调以及与之相关的慢性疾病的意想不到的见解，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项目，为本科生提供综合研究经验，特别是那些来自科学和医学领域代表性不足的学生。这些研究经验将为这些学生提供体验式学习机会，为未来在生物医学或基础研究科学方面的成功奠定基础。许多研究一致认为，瘦素通过激活下丘脑瘦素受体（lepr）来控制食物摄入。此外，最近的报告还研究了下丘脑外lepr的参与。在这方面，我们已经在大鼠中缝核中发现了被瘦素激活的神经元。脑内给药瘦素增加pSTAT3在离散的血清素能神经元中的表达并抑制食物摄入。利用光遗传学方法，我们能够在光刺激对瘦素有反应的中缝神经元时抑制摄食行为，并且我们发现中缝内瘦素增加了下丘脑5-HT水平。因此，zpur的总体假设是，除了直接作用于下丘脑外，瘦素还通过激活位于中隔核的lepr来有效调节食物摄入，从而刺激下丘脑核中5-HT的释放，其中5-HT发挥厌食作用。目前的项目将通过研究中脑和下丘脑核之间的功能性解剖5-羟色胺能连接来验证这一假设，测量中脑核瘦素反应神经元在接受5-羟色胺能终端的下丘脑核中的体内5-羟色胺释放；并确定被瘦素刺激的血清素释放激活的下丘脑神经元的表型。瘦素作用于多个靶点，包括脑中的血清素能神经元，这一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，特别是来自弱势群体的学生提供深入的研究机会。

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.