Developmental programming of neural circuits integrating drinking and feeding

项目概要 调节代谢状态的神经回路的发育编程对于维持体内平衡至关重要。 尽管代谢紊乱的患病率不断增加，但我们对发育整合的理解 连接稳态饮酒和进食状态的神经回路仍然很初级。刺豚鼠相关肽 (AgRP) 神经元在解剖学和功能上都处于理想的位置，可以介导直接交流 在代谢循环内。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 (PVH) 和下丘脑正中视前核 （MePO）在生命的第二周。 PVH 整合了多种神经内分泌信号，MePO 通过表达神经元一氧化氮合酶 (nNOS) 的神经元来调节液体摄入量 渴则驱饮。最近的证据表明 MePO 和 PVH 通过不同的神经连接联系在一起。 然而，MePO 和 PVH 之间的解剖组织和功能整合尚未得到证实。 其神经投射在发育过程中的组织和整合也尚未确定。 定义的。大鼠身上的证据表明，在 AgRP 预测之前，控制生命早期饮水功能的回路 达到下丘脑目标，表明牛奶摄入量是通过口渴而不是饥饿的激活来控制的 在发育早期。此外，营养过剩或营养不足会扰乱发育线索 似乎减少了 AgRP 对 PVH 的输入。此外，成人长期脱水会导致 喂养和体重，直到血液渗透压恢复，这意味着喂养和体重的密切结合 喝酒。由于 PVH 接收来自 AgRP 和 nNOS 表达神经元的输入，因此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，详细了解 缺乏摄食和饮水的发育整合机制。因为早期扰动指定 在发育的关键时期喂养电路的组织以及喂养和饮水 成人的综合反应，在这些时期接触高渗盐水可能会导致 PVH 中 AgRP 调节电路的结构发生永久性变化，从而导致代谢 生理学。该申请的总体假设是，在饮酒过程中调节饮酒的神经回路的激活 发展的关键时期会影响馈电回路的架构，并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，我们将追求以下具体目标：1) 定义新生小鼠控制口渴的神经回路的发育时间过程； 2) 定义提前多久 反复脱水会影响 PVH 中 AgRP 输入的发展，并且 3) 确定 对脱水引起的厌食反应和成人 PVH 神经元信号传导的后续影响。 完成这些目标将为理解大脑如何整合饮酒建立一个新颖的框架 并对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.