Sexual differentiation of the gonadotropin surge release mechanism: a new role for the canonical NfκB signaling pathway.

Sex differences in luteinizing hormone (LH) release patterns are controlled by the hypothalamus, established during the perinatal period and required for fertility. Female mammals exhibit a cyclic surge pattern of LH release, while males show a tonic release pattern. In rodents, the LH surge pattern is dictated by the anteroventral periventricular nucleus (AVPV), an estrogen receptor-rich structure that is larger and more cell-dense in females. Sex differences result from mitochondrial cell death triggered in perinatal males by estradiol derived from aromatization of testosterone. Herein we provide an historical perspective and an update describing evidence that molecules important for cell survival and cell death in the immune system also control these processes in the developing AVPV. We conclude with a new model proposing that development of the female AVPV requires constitutive activation of the Tnfα, Tnf receptor 2, NfκB and Bcl2 pathway that is blocked by induction of Tnf receptor-associated factor 2-inhibiting protein (Traip) in the male.

Regional distribution of benzodiazepine binding sites in the human newborn and infant hypothalamus. A quantitative autoradiographic study.

Using in vitro quantitative autoradiography and [3H]flunitrazepam we examined the rostrocaudal distribution of benzodiazepine binding sites in the human neonate/infant hypothalamus. The autoradiographic analysis shows the presence of a heterogeneous distribution throughout the rostrocaudal extent of this brain structure. High [3H]flunitrazepam binding corresponds primarily to the diagonal band of Broca and the preoptic region. The labelling in the preoptic region showed a rostrocaudal increase, contrasting in that with the other hypothalamic structures. Intermediate densities were present in the septohypothalamic, suprachiasmatic, periventricular and paraventricular nuclei as well as in the mammillary complex. Low binding was observed in the other hypothalamic structures. The benzodiazepine binding sites analyzed belong mostly to type II receptors. In an attempt to unravel possible differences related to age, we compared the autoradiographic distribution in three postnatal age ranges. The topographical distribution of these binding sites was almost identical in each period analyzed. We found, however, that benzodiazepine binding is generally low in the neonatal period and a tendency in increasing densities is observed during development. Taken together, these results provide evidence for a large distribution of benzodiazepine binding sites in neonate/infant hypothalamus, suggesting their implication in the development of this brain structure and the maintenance of its various functions.

Retinohypothalamic tract development in the hamster and rat.

The development of the retinohypothalamic tract (RHT) in the albino rat and golden hamster was studied using anterograde transport of cholera toxin conjugated to horseradish peroxidase (CT-HRP). The RHT has three components in the adult: (1) a dense projection to the ventrolateral subdivision of the suprachiasmatic nucleus (SCN) with some fibers extending into the dorsomedial SCN; (2) a projection to adjacent areas, the anterior hypothalamic area (AHA) and retrochiasmatic area (RCA) and in the hamsters, into the preoptic area (POA); (3) a projection to the lateral hypothalamic area (LHA). In the rat, the projection to the SCN and adjacent areas first appears as scattered varicosities at the ventral border of the SCN at postnatal day 1 (P1) and gradually increases until the adult pattern is achieved at approximately P10. The projections to the AHA and RCA are seen first at P2-P3 and gradually increase to the adult appearance by P15. Both the projection to the SCN and adjacent areas and to the LHA, initially are more extensive than in the adult. Many of the axons extend well beyond the zone of the adult pattern but these anomalous fibers are eliminated by P6-P10. The LHA projection first appears at embryonic day 21-22 (E 21-22) and gradually increases in density from P1-P6. In the hamster the projections to the SCN, AHA and LHA appear first on P4 and gradually increase in density to reach the adult pattern by P15. The projections to the RCA and POA are present by P6 and reach the adult pattern by P15. None of the RHT projections in the hamster has the initial extended growth followed by pruning back that characterizes RHT development in the rat. Thus, the development of the RHT in both the rat and the hamster is complex with components of the projection appearing at different times with differing patterns of development that indicate specialized interactions of the developing axons with their target neurons. Synaptogenesis in the hamster hypothalamus was analyzed using an antiserum to synapsin I. Few synapses are present at E16, the last day of gestation, in the LHA, SCN and AHA. From P1-P3, synaptogenesis proceeds rapidly and the adult pattern is achieved in all three areas by P4.

Effects of sex and androgen treatment on dendritic dimensions of neurons in the sexually dimorphic preoptic/anterior hypothalamic area of male and female ferrets.

A sexually dimorphic group of cells at the dorsal border of the preoptic/anterior hypothalamic area (POA/AH) of ferrets has been previously identified in Nissl-stained tissue. In this study, Golgi-stained tissue was examined in order 1) to determine whether sex differences exist in dendritic dimensions of neurons from this region, and 2) to assess the effects of adult androgen treatment on dendritic morphology in ferrets of both sexes. Brains from adult ferrets given daily injections of testosterone propionate (5 mg/kg body weight) or oil vehicle for 5 weeks after gonadectomy were impregnated by Golgi-Cox procedures. After sectioning at 120 microns, 78 multipolar neurons were selected from the sexually dimorphic POA/AH of 12 ferrets and reconstructed in three dimensions with the aid of a computer-assisted neuron tracing system. Large sex differences were observed in somal area and most aspects of dendritic morphology, including total length, number of branches, and total dendritic surface area. Androgen also appeared to accentuate dendritic arborization in both sexes, but this effect was weaker than the sex effect, more apparent in males than females, and restricted to fewer variables. The most statistically significant effects of adult androgen treatment in males were found for total dendritic surface area and percentage of fourth order dendrites, and in females, average dendritic thickness. These data show that strong sex differences exist in dendritic structure of neurons in the POA/AH, and suggest that alterations in levels of gonadal steroids in adulthood may promote synaptic remodeling in a region of the brain involved in the control of sexually dimorphic behaviors.

Differing postnatal development of the somatostatin- and luliberin- systems in the male and female rat.

By means of light-microscopic immunohistochemistry the perikarya of the luliberin-(LRF-) and somatostatin systems of neonate rats were found to be in differing stages of development. At a time point when the LRF-producing neurons had obviously attained their final shape and size, the somatostatin-immunoreactive perikarya were still in a postnatal phase of maturation. Whereas the number of the latter perikarya increases with advancing age, the number of LRF-immunoreactive perikarya decreases significantly from postnatal day 7 onward. Both peptide-hormone systems do not project concomitantly and to the same extent to their principal neurohemal regions in the organum vasculosum laminae terminalis (OVLT) and the median eminence (ME). In all presently studied stages of development, despite considerable individual variations in one age group, among the components of the LRF-system the OVLT displays a more intense immunoreactivity than the ME. The somatostatin system, however, projects to the OVLT with a conspicuous temporal delay compared to the ME, and, furthermore, in the OVLT the pattern of immunoreactivity characteristic of adult rats is not yet attained at postnatal day 21. Evidence for differences in the immunoreactivity between male and female animals was restricted to the LRF-system. Finally, the results obtained on the stria terminalis speak in favour of the fact that the long-range extrahypothalamic projections of the somatostatin system also undergo postnatal maturation. In the stria terminalis, somatostatin-immunoreactive fibers can be demonstrated initially on postnatal day 7. They attain their full immunoreactivity on postnatal day 21. Furthermore, in the bed nucleus of the stria terminalis an intermittent cytoplasmic immunoreactivity is observed, which is limited to the animals of postnatal day 7 and disappears completely during the further course of development.