Ontogeny of synapses in a sexually dimorphic part of the preoptic area in the rat

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  1. The brain is a target for sex steroid hormones. As a result of sex hormone actions on the brain various behavioral changes are observed in animal and man. This paper gives a brief overview over the multiple central nervous functions that are under modulatory control of sexual hormones and describes the complex sex steroid actions on the brain by giving an example for “activating” and “organizing” effects of estrogens on noradrenergic neurons in the brain of rats.

• 2.

  2. Estradiol-17β induced sex specific alterations in the turnover of noradrenaline in the preoptic area and mediobasal hypothalamus showing “female” or “male” responses.

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  3. Neonatal manipulations of female rat pups by testosterone, estradiol-17β or 4-hydroxyestradiol-17β defeminized the “female” response of the noradrenaline turnover in the preoptic area.

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  4. Defeminization was not observed when neonatal females received the non aromatizable sex steroid dihydrotestosterone.

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  5. Activating and organizing effects of sex steroids on animal brain as shown here for noradrenergic neurons are discussed in relation to the regulation of behavior in man. Special regard is given to psychic disorders that might be associated with abnormalities in the production or metabolism of or the response to gonadal hormones.

Stereological electron miscroscopic analysis of the rat hypothalamic ventromedial nucleus (VMN) throughout postnatal development revealed that synaptogenesis takes place up to day 45. Our results disclosed a sexual dimorphism in the synaptic organization of the neuropil of the ventrolateral (VL) subdivision of the VMN. The numerical densities of spine and shaft synapses in the adult male were higher than in the female. A dimorphic pattern in the numerical density of spine synapses occurred as early as day 5, and was present throughout postnatal life, even though in the adult rats both spine and shaft synapses were sexually dimorphic. Neonatal treatment of female rats with testosterone increased the numerical density of axodendritic synapses, inducing a pattern similar to the adult male. On the other hand, administration of tamoxifen to newborn male rats significantly reduced the numerical density of spine synapses to levels comparable to normal female rats.

Sex steroids exert potent influences on modulating neural development and neural circuit formation in both developing and adult sex steroid-sensitive neuroendocrine brain. During development, estrogen or aromatizable androgen can act as a neurotropic factor on neural tissues, stimulating axonal and dendritic growth and synapse formation. The development of sexual dimorphic synaptic organization may reflect sex steroid-modulating synaptogenesis in the hypothalamus and limbic system during the perinatal period. The onset of puberty also may be due, at least in part, to stimulation of synapse formation by estrogen in the hypothalamus. In adulthood, estrogen has a facilitatory effect on synapse formation in neural structures such as septum, hypothalamus and midbrain with or without brain lesions, and androgen plays a significant role in regulating synaptic remodeling in the androgen-sensitive spinal motoneuron pools. Thus, sex steroids seems to be critical from the developmental period to adulthood for organizing and reorganizing the neuronal circuitry driving neuroendocrine and behavioral functions.

A striking sexual dimorphism exists in the distribution of Met-enkephalin (m-ENK) immunoreactive fibers in the preoptic area of the rat brain. A dense plexus of m-ENK fibers, approximately 100 μm wide, is present in the periventricular part of the preoptic area (pePOA) in adult females, but not in males. In the present study, we have examined the time of first expression of this female-typical system during the course of normal brain development. The female-typical plexus of m-ENK fibers in the pePOA is not expressed prepubertally, but first becomes evident during the late peri-pubertal period (usually by 40 days of age). In adult females, the maintenance of immunohistochemically detectable levels of m-ENK in this fiber system is dependent upon the presence of gonadal steroids, especially estradiol⁶⁶. Therefore, we examined whether exposure of pre-pubertal females to estradiol would result in precocious expression of the m-ENK fiber plexus. The results of this experiment demonstrate that exposure to estradiol for 7 days induces the full expression of the m-ENK fiber system in the pePOA of prepubertal females, such that it was indistinguishable from that seen in mature animals. These results demonstrate that while the sexually dimorphic m-ENK system of the pePOA is not normally expressed prepubertally, the neural substrate is nevertheless in place and capable of being activated by exposure to exogenous estradiol.

The ventromedial nuclei of the hypothalamus (VMN) were examined ultrastructurally in both male and female rats at 5, 20, 45 and 100 days of age. Synaptic number in the VMN was increased to 70 80% of that at 45 days of age during the first 20 days. At 5 days of age, sexual difference in the numerical density of dendritic shaft and spine synapses was not detected. Synaptic sexual difference developed by 20 days of age in the ventrolateral VMN where receptors for sex steroid were abundant. This tendency persisted until adulthood. However, no sexual difference in synaptic pattern was recognized in the dorsomedial VMN. From these results, it is suggested that sexual dimorphism in synaptic organization in the VMN develops from the early prepubertal period.