Thirst and renal antidiuresis represent the fundamental systems for body water homeostasis. Fetal swallowing occurs early during ontogeny and has important roles in amniotic fluid homeostasis, fetal gastrointestinal development, and perhaps somatic growth. Swallowing of contaminated amniotic fluid has been recognized as a major route for neonatal HIV transmission. Ovine feta osmotic-dipsogenic systems become functional ("switch-on") acutely during the last third of gestation, though the fetus has reduced osmotic sensitivity as compared to the adult. Importantly, our recent studies indicate that the development of osmoregulatory mechanisms is influenced and imprinted during the last third of gestation. AngiotensinII (Angll) neurons are the putative neural pathway for both osmotic and Angll-induced dipsogenesis. Both systemic and central putative dipsogens=action, are mediated at brain circumventricular organs (CVOs) which may respond to blood-borne, cerebrospinal fluid and central neura signals. The proposed studies explore the ontogeny of fetal central Angll-dipsogenic mechanisms to develop an understanding of normal and abnormal fluid homeostatic responses. We hypothesize:(a) dipsogenic responsiveness develops as a result of maturation of neural pathways integrating select nuclei within the CVOs, (b) the development of endocrine modulation of Angll dipsogenic responses coincides with the onset of specific receptor binding in the CVOs, and (c) fetal dipsogenic responses to central Angll may be fundamentally different from the adult, as a result of the developmental pattern of dipsogenic mechanisms. A stepwise series of physiologic, neural and cellular/molecular experiments are proposed to: (1) Determine if central AnglI preferentially stimulates water vs. salt ingestion. (2) Identify CVO nuclei stimulated by central AngIl and the relative sensitivity to Angl, Angll and Ang III. (3) Examine the ontogeny of central Angll-induced physiologic responses and cFos expression among putative dipsogenic CVO nuclei. (4) Determine the essential role of these nuclei via microablation and neural tract tracing, and (5) Correlate the maturation of the modulation of Angll dipsogenic responses with changes in cerebral Ang AT1, AT2 and NMDA receptors, and nNOS enzyme expression. This combination of neural, physiologic and endocrine approaches and the examination of select cerebral nuclei function will provide important new information, in a precocial species, concerning the in utero maturation of central dipsogenic mechanisms essential for extrauterine fluid homeostasis. Furthermore, these studies represent a model to examine the development and function of neuronal pathways and mechanisms regulating fetal physiology.

R01DK043311

1991-08-01

2009-08-31