Developmental programming of neural circuits integrating drinking and feeding

整合饮水和进食的神经回路的发育编程

• 批准号: 10599934
• 负责人: Serena Sweet
• 金额: $ 3.17万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10599934
• 关键词: Acute; Adult; Affect; Age; Anatomy; Anorexia; Appetite Stimulants; Architecture; Automobile Driving; Behavior; Behavior assessment; Behavioral; Blood; Body Weight; Body Weight decreased; Body Weights and Measures; Brain; Communication; Confocal Microscopy; Consumption; Cues; Dehydration; Dependence; Development; Environmental Risk Factor; Event; Exposure to; Fluid Balance; Food; Genetic Recombination; Health; Homeostasis; Hunger; Hypothalamic structure; Immunohistochemistry; Impairment; Ingestion; Intake; Label; Leptin; Life; Link; Liquid substance; Malnutrition; Maps; Mediating; Metabolic; Metabolic Diseases; Metabolism; Milk; Mus; Neonatal; Neural Pathways; Neuroanatomy; Neurons; Neuropeptides; Neurosecretory Systems; Nipples; Nitric Oxide Synthase Type I; Nutrient; Nutritional; Obesity; Organism; Osmolalities; Overnutrition; Peptides; Physiological; Physiology; Population; Positioning Attribute; Prevalence; Process; Rattus; Regulation; Saline; Signal Transduction; Solid; Specific qualifier value; Structure of nucleus infundibularis hypothalami; Testing; Thirst; Time; critical developmental period; critical period; drinking; energy balance; experimental study; feeding; insight; metabolic phenotype; milk intake; neonatal mice; neonatal period; nerve supply; neural; neural circuit; neurotransmission; new therapeutic target; novel; offspring; paraventricular nucleus; postnatal; preoptic nucleus; pup; response

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.

项目摘要 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越来越高，但我们对代谢紊乱的发育整合的理解， 连接自我平衡的饮水和进食状态的神经回路仍然很不发达。刺鼠相关肽 （AgRP）神经元的理想位置，无论是解剖学和功能，调解直接沟通， 在代谢回路中。重要的是，AgRP神经元对发育线索作出反应，投射到 下丘脑室旁核（PVH）和下丘视前正中核 （MePO）在生命的第二周。PVH整合了多种神经内分泌信号，而MePO 调节液体摄入与神经元型一氧化氮合酶（nNOS）表达神经元激活响应 渴了开车喝酒。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之间的解剖学组织和功能整合尚未被证实。 确定，也没有组织和整合他们的神经投射在发展过程中， 定义了大鼠的证据表明，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，这表明牛奶摄入量是由口渴而不是饥饿的激活控制的。 在早期发育阶段。此外，营养过剩或营养不足对发育线索的破坏 似乎减少了对PVH的AgRP输入。此外，成年人长期脱水会导致 喂养和体重，直到血液渗透压已经恢复，这意味着喂养和 喝酒由于PVH接受来自AgRP和nNOS表达神经元的输入，它可能代表一个核心， 一个神经节点，其功能是整合饮水和进食状态。然而，详细了解 缺乏摄食和饮水的发育整合机制。因为早期的扰动 在发育的关键时期，进食回路的组织，以及进食和饮水， 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调节回路结构的永久性变化， physiology.本申请的总体假设是，在饮酒过程中调节饮酒的神经回路的激活 一个关键的发展时期会对馈电电路的结构产生影响，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，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）定义如何早期 暴露于反复脱水影响AgRP输入PVH的发展，和3）确定 对成人PVH中脱水诱导的厌食反应和神经元信号传导的后续影响。 这些目标的完成将为理解大脑如何整合饮酒建立一个新的框架 以及对影响整个生命代谢表型的发育事件的新见解。