BDNF up-regulates pre-pro-TRH mRNA expression in the fetal/neonatal paraventricular nucleus of the hypothalamus. Properties of the transduction pathway.

Brain derived neurotrophic factor (BDNF) increases the levels of pre-pro-thyrotropin releasing hormone (TRH) mRNA in fetal rodent hypothalamic neurons that express TrkB receptors. The present studies aimed at better understanding the role of BDNF in establishing and maintaining the TRH phenotype in hypothalamic neurons during early development. To determine where BDNF regulates the expression of pre-pro-TRH mRNA in vivo, we compared the hypothalamic distribution of pre-pro-TRH mRNA to that of TrkB mRNA. Full-length TrkB (FL-TrkB) mRNA was detected earlier in development than pre-pro-TRH mRNA in the region that gives rise to the paraventricular nucleus of the hypothalamus (PVN). We also evaluated the effects of BDNF on the expression of pre-pro-TRH mRNA in vitro. BDNF up-regulated the levels of pre-pro-TRH mRNA in primary cell cultures obtained from the hypothalamus or the PVN of 17 days old fetuses or newborn rats. This effect was abolished by PD98059, an inhibitor of the mitogen-activated protein kinase kinase (MEK) 1/2 or 5. The effect of BDNF on pre-pro-TRH mRNA levels was reversible. The continuous application of BDNF led to a desensitization of the response at day 10 in vitro, an effect that correlated with a drop in the levels of FL-TrkB protein. In conclusion, BDNF enhances the expression of pre-pro-TRH mRNA in PVN neurons. This effect is reversible, decreases with time, and requires an active MEK. BDNF may contribute to the enhancement of pre-pro-TRH mRNA expression in the hypothalamic PVN during development.

Neuropeptide cells and fibers in the hypothalamus and pituitary of the fetal sheep: comparison of oxytocin and arginine vasopressin.

Both oxytocin (OXY) and arginine vasopressin (AVP) enhance the effects of corticotropin-releasing factor on ACTH release by the pituitary. One of these, AVP, plays a role in the control of fluid balance and responses to hypoxemic stress in the fetal sheep. To determine the possibility that OXY also participates in fetal neuroendocrine events, OXY-containing neuronal structures must first be demonstrated within the fetal endocrine hypothalamus. OXY-immunoreactive elements were examined in fetal sheep hypothalami late in gestation and compared to AVP-containing structures using immunocytochemical procedures. Six fetal sheep ranging from 126 to 144 days gestational age were delivered via cesarian section from timed pregnant Rambouillet-Columbia ewes and killed by an overdose of anesthesia. The fetal head was perfused via bilateral carotid catheters and processed for immunocytochemical localization of OXY or AVP using the avidin-biotin complex procedure. At all fetal ages examined, OXY- and AVP-containing neurons were found within the paraventricular nuclei (PVN), supraoptic nuclei (SON) and accessory magnocellular hypothalamic nuclei. OXY-containing neurons were found principally in the SON and PVN. They were generally less numerous and less intensely stained than the AVP neurons. In the SON, they concentrated along the dorsal borders of the nucleus above the AVP neurons. In PVN, clusters of OXY cells were located along the dorsal and lateral borders of the nucleus surrounding the AVP neurons; in the periventricular division, they were intermingled with the AVP neurons. Small numbers of OXY axons were located in the external zone of the median eminence; whereas most OXY axons extended into the hypothalamo-neurohypophyseal tract and posterior lobe of the pituitary. A few of the OXY axons in the pituitary stalk were diverted to the pars intermedia. Likewise, some of the OXY fibers from the external zone of the median eminence entered the pars tuberalis but were rarely found in the distal lobe of the pituitary. In contrast, AVP axons richly innervated the external zone of the median eminence, and neural lobe. Like OXY, AVP axons from the median eminence and the pituitary stalk sent projections to the adenohypophysis. AVP fibers in the pars distalis frequently contacted corticotropes and were more numerous than OXY fibers in this region. These data provide anatomical evidence that OXY and AVP may directly regulate the fetal adenohypophysis. Of these two neuropeptides, AVP predominates anatomically.