Developmental programming of neural circuits integrating drinking and feeding

项目总结 调节代谢状态的神经回路的发育编程对维持体内平衡至关重要。 尽管代谢紊乱的发病率越来越高，但我们对儿童发育整合的理解 连接体内平衡、饮酒和进食状态的神经回路仍然很初级。刺鼠相关肽 (AgRP)神经元在解剖学上和功能上都处于理想的位置，可以调节直接的交流。 在新陈代谢回路中。重要的是，AgRP神经元对发育线索做出反应，投射到 下丘脑室旁核和下丘脑视前正中核 (MePO)在生命的第二周。PVH整合了多种神经内分泌信号，而MePO 通过激活神经元型一氧化氮合酶(NNOS)表达的神经元来调节液体摄入 酒后驾车口渴。最近的证据表明，MePO和PVH通过不同的神经联系联系在一起。 然而，MePO和PVH之间的解剖组织和功能整合尚未得到 他们在发育过程中神经投射的组织和整合也没有被确定 已定义。在老鼠身上的证据表明，在AgRP投射之前，在生命早期控制饮酒功能的回路 达到下丘脑的目标，表明牛奶的摄入量是由口渴而不是饥饿来控制的 在发育的早期阶段。此外，营养过剩或营养不足对发育线索的干扰 似乎减少了对PVH的AgRP输入。此外，成年人长时间脱水会导致 摄食和体重，直到血液渗透压已恢复，这意味着摄食和 喝酒。因为PVH接受来自AgRP和nNOS表达神经元的输入，所以它可能代表一个核心 负责整合饮水和进食状态的神经节点。然而，如果详细了解 缺乏进食和饮水发育一体化的机制。因为早期的扰动规定 在发育的关键时期的摄食回路的组织，以及摄食和饮水 在成人的综合反应中，在这些时期暴露于高渗盐水可能会导致 PVH中AgRP调节电路结构的永久性变化，从而导致代谢 生理学。这一应用的总体假设是，在饮酒过程中，调节饮酒的神经回路被激活 发展的关键时期影响馈电电路的体系结构，对能源产生持久的影响 平衡调节。作为检验这一假设的第一步，将追求以下具体目标：1) 确定新生小鼠控制口渴的神经回路的发育时间进程；2)确定多早 反复脱水影响PVH的AgRP输入的发育，以及3)决定 对成人PVH中脱水诱导的厌食反应和神经元信号转导的后续影响。 这些目标的完成将为理解大脑如何结合饮酒建立一个新的框架 并为影响一生代谢表型的发育事件提供新的见解。

PROJECT SUMMARY Developmental programming of neural circuits modulating metabolic state is critical to maintain homeostasis. Despite an increasing prevalence of metabolic disorders, our understanding of the developmental integration of neural circuitry linking homeostatic drinking and feeding states remains rudimentary. Agouti-related peptide (AgRP) neurons are ideally positioned, both anatomically and functionally, to mediate direct communication within metabolic circuits. Importantly, AgRP neurons respond to developmental cues to project to the paraventricular nucleus of the hypothalamus (PVH) and the median preoptic nucleus of the hypothalamus (MePO) during the second week of life. The PVH integrates a variety of neuroendocrine signals, and the MePO modulates fluid intake with neuronal nitric oxide synthase (nNOS)-expressing neurons activated in response to thirst to drive drinking. Recent evidence suggests the MePO and PVH are linked by distinct neural connections. However, the anatomical organization and functional integration between the MePO and PVH has not been determined, nor has the organization and integration of their neural projections during development been defined. Evidence in rats suggests circuits controlling drinking function early in life, prior to AgRP projections reaching hypothalamic targets, suggesting milk intake is controlled by activation of thirst rather than hunger during the early developmental period. Further, disruptions to developmental cues by over- or undernutrition appears to decrease AgRP inputs to the PVH. Moreover, prolonged dehydration in adults results in decreased feeding and body weight until blood osmolality has been restored, implicating close integration of feeding and drinking. Because the PVH receives inputs from AgRP and nNOS-expressing neurons, it may represent a core neural node that functions to integrate drinking and feeding states. However, a detailed understanding of the mechanisms of developmental integration of feeding and drinking is lacking. Because early perturbations specify the organization of feeding circuitry during critical periods of development, and feeding and drinking have integrated responses in adults, it is possible that exposure to hypertonic saline during these periods may cause permanent changes in the architecture of AgRP-regulated circuits in the PVH, and consequently, metabolic physiology. The overall hypothesis of this application is that activation of neural circuits regulating drinking during a critical period of development impacts the architecture of feeding circuits with lasting consequences for energy balance regulation. As a first step toward testing this hypothesis, the following specific aims will be pursued: 1) Define the developmental time course of neural circuits controlling thirst in neonatal mice; 2) Define how early exposure to repeated dehydration impacts the development of AgRP inputs to the PVH, and 3) Determine the subsequent effects on the dehydration-induced anorexia response and neuronal signaling in the PVH in adults. Completion of these aims will establish a novel framework for understanding how the brain integrates drinking and feeding with new insight into the developmental events that impact metabolic phenotypes throughout life.