Developmental Programming of Hypothalamic Neural Circuits Integrating Fluid and Energy Homeostasis
Abstract
Drinking and feeding are coordinated homeostatic events, but our understanding of the development of their converging hypothalamic neural circuits remains rudimentary. Many environmental factors developmentally program neural circuits during critical periods in early postnatal life. Agouti-related peptide (AgRP) neurons are substrates of developmental programming, responding to nutritional cues during a critical period to reach downstream targets. The paraventricular nucleus of the hypothalamus (PVH) receives inputs from both AgRP neurons and the median preoptic nucleus (MEPO) to regulate energy and fluid homeostasis, representing a possible node of integration. We used TRAP2;Ai14 double transgenic mice to show a population of active neurons responding to water deprivation (Thirst-TRAP) overlaps with fast-refeed Fos induction (Hunger-Fos) in the PVH. To determine the age at which MEPO projections reach the PVH, we used DiI axonal labeling as well as Fos-labeling in response to hypertonic saline (HS). Our results indicate neurons in the MEPO project to the PVH and respond to HS by the end of the first week of life, and densities of Fos-labeled nuclei in the PVH do not peak until the second postnatal week, preceding innervation of the PVH by AgRP neurons. Based on these observations, we hypothesized perturbations to fluid homeostasis in neonatal mice may impact the formation of AgRP circuitry with sustained changes in ingestive behavior. Adult male mice exposed to HS treatment daily from postnatal day (P) 5 to P15 (HSPN) displayed significantly increased densities of AgRP axons in the MEPO and PVH, while female HSPN mice experienced a decrease in the MEPO. Short-term high fat diet (HFD) exposure leads to greater water intake in adult HSPN male mice, while long-term HFD leads to a significantly lower body weight gain in HSPN females. Moreover, a dehydration-anorexia challenge results in a sustained anorexic response HSPN males after rehydration, while a fast-refeed challenge results in a sustained decrease in water intake in HSPN males after refeeding. Together, these results suggest a sexually dimorphic effect of early perturbations to fluid homeostasis on the development of feeding circuits, with context-specific consequences for ingestive behavior.
Description
Keywords
agouti-related peptide, critical period, development, energy homeostasis, fluid homeostasis, ingestive behavior, median preoptic nucleus, paraventricular nucleus, TRAP2