DEVELOPMENT OF THE HUMAN HYPOTHALAMUS

The hypothalamus has been claimed to be involved in a great number of physiological functions in development, such as sexual differentiation (gender, sexual orientation) and birth, as well as in various develop mental disorders including mental retardation, sudden infant death syn drome (SIDS), Kallman's syndrome and Prader-Willi syndrome. In this re view a number of hypothalamic nuclei have therefore been discussed wit h respect to their development in health and disease. The suprachiasma tic nucleus (SCN) is the clock of the brain and shows circadian and se asonal fluctuations in vasopressin-expressing cell numbers. The SCN al so seems to be involved in reproduction, adding interest to the sex di fferences in shape of the vasopressin-containing SCN subnucleus and in its VIP cell number. In addition, differences in relation to sexual o rientation can be seen in this perspective. The vasopressin and VIP ne urons of the SCN develop mainly postnatally, but as premature children may have circadian temperature rhythms, a different SCN cell type is probably more mature at birth. The sexually dimorphic nucleus (SDN, in termediate nucleus, INAH-I) is twice as large in young male adults as in young females. At the moment of birth only 20% of the SDN cell numb er is present. From birth until two to four years of age cell numbers increase equally rapidly in both sexes. After this age cell numbers st art to decrease in girls, creating the sex difference. The size of the SDN does not show any relationship to sexual orientation in men. The large neurosecretory cells of the supraoptic (SON) and paraventricular nucleus (PVN) project to the neurohypophysis, where they release vaso pressin and oxytocin into the blood circulation. In the fetus these ho rmones play an active role in the birth process. Fetal oxytocin may in itiate or accelerate the course of labor. Fetal vasopressin plays a ro le in the adaptation to stress-caused by the birth process-by redistri bution of the fetal blood flow. Corticotropin-releasing hormone (CRH) neurons of the PVN play a central role in stress response. Thus fetal CRH neurons may play a role in the timing of the moment of birth. Rece ntly, alterations have been described in peptidergic, aminergic and ch olinergic transmitters in;the hypothalamus in SIDS. Future research wi ll have to establish whether these changes are part of the course of S IDS. A large proportion of the SON and PVN neurons also produce tyrosi ne hydroxylase (TH). In neonates the majority of TH-immunoreactive neu rons colocalizes vasopressin, while in the adult the majority of TH-po sitive neurons colocalizes oxytocin. TH-expression might be a sign of hyperactivation, for example from perinatal hypoxia. Oxytocin neurons also project to the brain stem. These neurons have an inhibitory effec t on eating. Interestingly, in the Prader-Willi syndrome, characterize d for example by insatiable hunger, we have found that the number of o xytocin-expressing neurons is about half the normal value. It can be c oncluded that the various hypothalamic nuclei are involved in a great number of functions and show clear and differential changes in develop ment with respect to sexual differentiation, birth and a number of dis eases. I believe that only a small proportion of such changes has at p resent been revealed.