Developmental programming of neural circuits integrating drinking and feeding

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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.