Fetal swallowing has important roles in fetal gastrointestinal development, and perhaps fetal somatic growth and maturation. Ingestive behavior responses must develop in utero to provide for acquisition of water and food intake during the neonatal period. At birth, the rat, ovine and human fetus have developed mechanisms to acquire food via suckling and swallowing and taste mechanisms are functional. Thus, in sheep and likely human fetuses, dipsogen-mediated swallowing and antidiuretic responses are present during the last third of gestation. We hypothesize that appetite and satiety mechanisms also develop in utero and the related neurotransmitters involved in this process are functional and may influence fetal growth and development. Two potential candidates for ingestive behavior regulation are leptin and neuropeptide-Y (NPY). In adults, leptin is a protein produced in adipocytes with actions in the hypothalamus to decrease food intake. NPY, produced primarily in the hypothalamus, increases food intake. We hypothesize: (1) Central NPY will stimulate swallowing of a macronutrient specific solution while leptin stimulated responses will be independent of solution content (i.e., dipsogen mediated), (2) Lateral ventricular leptin and NPY will stimulate preterm swallowing activity, and (3) Intra-ventricular administration of leptin and NPY will differentially stimulate discrete areas of the fetal brain. The proposed studies will explore the ontogeny and mechanisms of leptin and NPY in the modulation of fetal swallowing, utilizing an integrative approach of physiologic experiments and immunohistochemistry. We will expand upon our preliminary studies to specifically address appetite-mediated ingestive behavior, by providing the fetus the oral-availability (sublingual) of a palatable nutrient solution. Our objective is to determine whether fetal swallowing activity is altered by central leptin and NPY. Moreover, we will examine the ontogenic activity of, and identify central neuronal sites activated upon by central leptin and NPY administration. Chronically prepared, near term ovine fetuses will be administered central (lateral ventricle) recombinant human leptin or ovine NPY in artificial cerebral spinal fluid (aCSF) and fetuses monitored for swallowing activity. At time of sacrifice, fetal brains will be removed, perfusion fixed, sectioned and immunostained for neuronal activity. Neuronal activity, in both appetite and dipsogenic centers, will be examined for activation of the immediate-early gene product Fos. Fos activation and fetal swallowing responses will be correlated. Although neurodevelopment has been investigated during embryologic periods, there has been limited investigation of the near term maturation of ingestive behavior. These studies will provide important new information concerning the in utero maturation of ingestive behavior. In addition, these studies represent a model to examine the development and function of neuronal pathways and mechanisms which regulate fetal physiology.

R03HD039671

2001-05-18

2004-04-30