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Principal Investigator: Serena Sweet
Organization: VANDERBILT UNIVERSITY
Fiscal Year: 2024
Award: $31,694
Funding agency: Eunice Kennedy Shriver National Institute of Child Health and Human Development
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.
Terms: <21+ years old><Acute><Adult><Adult Human><Affect><Age><Anatomic Sites><Anatomic structures><Anatomy><Anorexia><Appetite Stimulants><Appetite-Stimulating Drugs><Architecture><Arcuate Nucleus><Automobile Driving><Autoregulation><BNOS><Behavior><Behavior assessment><Behavioral><Blood><Blood Reticuloendothelial System><Body Weight><Body Weight decreased><Body Weights and Measures><Brain><Brain Nervous System><Cell Communication and Signaling><Cell Signaling><Common Rat Strains><Communication><Confocal Microscopy><Consumption><Cues><DNA Recombination><Dehydration><Dependence><Development><Encephalon><Engineering / Architecture><Environmental Factor><Environmental Risk Factor><Event><Exposure to><Fluid Balance><Fluid Homeostasis><Food><Genetic Recombination><Health><Homeostasis><Hunger><Hypothalamic structure><Hypothalamus><Immunohistochemistry><Immunohistochemistry Cell/Tissue><Immunohistochemistry Staining Method><Impairment><Infundibular Nucleus><Ingestion><Intake><Intermediary Metabolism><Intracellular Communication and Signaling><Label><Leptin><Life><Link><Liquid substance><Malnutrition><Maps><Mediating><Metabolic><Metabolic Diseases><Metabolic Disorder><Metabolic Processes><Metabolism><Mice><Mice Mammals><Milk><Murine><Mus><NC-NOS><NNOS><NOS 1 protein><NOS type I><NOS1 protein><Neonatal><Nerve Cells><Nerve Impulse Transmission><Nerve Transmission><Nerve Unit><Neural Cell><Neural Constitutive Nitric Oxide Synthase><Neural Pathways><Neuranatomies><Neuranatomy><Neuroanatomies><Neuroanatomy><Neurocyte><Neuroendocrine><Neuroendocrine System><Neuronal Transmission><Neurons><Neuropeptides><Neurosecretory Systems><Nipples><Nitric Oxide Synthase Type I><Nutrient><Nutritional><Nutritional Deficiency><Ob Gene Product><Ob Protein><Obese Gene Product><Obese Protein><Obesity><Organism><Osmolalities><Overnutrition><Paraventricular Hypothalamic Nucleus><Peptides><Physiologic><Physiological><Physiological Homeostasis><Physiology><Population><Position><Positioning Attribute><Prevalence><Process><Rat><Rats Mammals><Rattus><Recombination><Regulation><Saline><Saline Solution><Signal Transduction><Signal Transduction Systems><Signaling><Solid><Specific qualifier value><Specified><Structure of nucleus infundibularis hypothalami><Testing><Thesaurismosis><Thirst><Time><Undernutrition><Weight Loss><Weight Reduction><adiposity><adulthood><ages><axon signaling><axon-glial signaling><axonal signaling><behavioral assessment><biological signal transduction><body water dehydration><body weight loss><brain nitric oxide synthase><corpulence><critical developmental period><critical period><developmental><dietary deficiency><drinking><driving><energy balance><environmental risk><experiment><experimental research><experimental study><experiments><feeding><fluid><glia signaling><glial signaling><hypothalamic><ingest><innervation><insight><liquid><living system><malnourished><metabolic phenotype><metabolism disorder><metabotype><milk intake><nNOS enzyme><neonatal mice><neonatal period><nerve signaling><nerve supply><neural><neural circuit><neural circuitry><neural signaling><neurocircuitry><neuronal><neuronal NOS><neuronal form of nitric oxide synthase><neuronal nitric oxide synthase><neuronal signaling><neurotransmission><new drug target><new druggable target><new pharmacotherapy target><new therapeutic target><new therapy target><nitric oxide synthase 1><novel><novel drug target><novel druggable target><novel pharmacotherapy target><novel therapeutic target><novel therapy target><nutrition deficiency><nutrition deficiency disorder><nutritional deficiency disorder><nutritious><offspring><orexigenic><paraventricular nucleus><postnatal><preoptic nucleus><pup><response><synaptic circuit><synaptic circuitry><wt-loss>