Hypothalamic Expression of Neuropeptide Y (NPY) and Pro-OpioMelanoCortin (POMC) in Adult Male Mice Is Affected by Chronic Exposure to Endocrine Disruptors.

In the arcuate nucleus, neuropeptide Y (NPY) neurons, increase food intake and decrease energy expenditure, and control the activity of pro-opiomelanocortin (POMC) neurons, that decrease food intake and increase energy expenditure. Both systems project to other hypothalamic nuclei such as the paraventricular and dorsomedial hypothalamic nuclei. Endocrine disrupting chemicals (EDCs) are environmental contaminants that alter the endocrine system causing adverse health effects in an intact organism or its progeny. We investigated the effects of long-term exposure to some EDCs on the hypothalamic NPY and POMC systems of adult male mice that had been previously demonstrated to be a target of some of these EDCs after short-term exposure. Animals were chronically fed for four months with a phytoestrogen-free diet containing two different concentrations of bisphenol A, diethylstilbestrol, tributyltin, or E2. At the end, brains were processed for NPY and POMC immunohistochemistry and quantitatively analyzed. In the arcuate and dorsomedial nuclei, both NPY and POMC immunoreactivity showed a statistically significant decrease. In the paraventricular nucleus, only the NPY system was affected, while the POMC system was not affected. Finally, in the VMH the NPY system was affected whereas no POMC immunoreactive material was observed. These results indicate that adult exposure to different EDCs may alter the hypothalamic circuits that control food intake and energy metabolism.

Allopregnanolone: state of the art.

Allopregnanolone, a neuroactive steroid derived from progesterone, is synthesized within the nervous tissue, by means of specific enzymes. Contrary to progesterone and its first metabolite dihydroprogesterone, allopregnanolone is able to interact with GABA-A receptor and not with the classical progesterone receptor. This suggests that the effect of progesterone administration may be due to activation of progesterone receptor, or of GABA-A receptor, or both. However, this is rarely considered in the experimental studies. Here we summarize and discuss the hot topics involving the actions of allopregnanolone within the nervous tissue. One major role of this neuroactive steroid is neuroprotection in case of lesion, ischemia or peripheral neuropathies (i.e., diabetes). In addition, allopregnanolone may reduce the symptoms of neurodegenerative diseases (e.g., Alzheimer, Parkinson, Niemann-Pick type C, multiple sclerosis) in animal models and now translational studies are developed for its therapeutic use. Allopregnanolone may exert a beneficial effect also in case of neuropathic pain and it is also a potential candidate for the treatment of mood and anxiety disorders. Finally, this neuroactive steroid seems to have important physiological roles in the early differentiation of some neural circuits (in particular at hippocampal level), and to reduce stress during pregnancy. In conclusion, it appears that allopregnanolone is a key regulator of physiological functions and may have interesting therapeutic perspectives for neurodegenerative and psychiatric disorders.

The Japanese quail: a model for studying reproductive aging of hypothalamic systems.

During aging, the decline of neuroendocrine, endocrine, and behavioral components of reproduction ultimately leads to reproductive failure. These studies considered both neuroendocrine and behavioral aspects of reproductive aging in Japanese quail, using chronological age and reproductive status to separate animals into experimental groups. In Study I, age-related changes in the gonadotropin releasing hormone (GnRH-I) system were investigated and a sharp decrease was observed in GnRH-I concentration in the median eminence of aging animals of both sexes, whereas preoptic-lateral septal region GnRH-I concentrations declined only in aging males. Immunohistochemistry confirmed these findings since aging females retained, whereas males lost GnRH-I cells. Functional changes were assessed by in vitro incubation of parasaggittal hypothalamic slices collected from young and old inactive males and females. Results showed reduced baseline GnRH-I release and diminished response to norepinephrine (NE). Deteriorating fertility also correlated with decreased male sexual behavior and loss of aromatase immunoreactive (AROM-ir) neurons in the medial, but not lateral preoptic nucleus (POA). Sexual behavior and AROM-ir were restored with exogenous testosterone, which was associated with increased cell size in the medial POA. Comparison of cell size and number of AROM-ir cells showed that aged sexually active males had fewer, larger AROM-ir cells when compared to young males, suggesting neuroplasticity of specific neural systems and a critical role of estradiol in maintaining reproductive function.

Anatomical relationships between aromatase-immunoreactive neurons and nitric oxide synthase as evidenced by NOS immunohistochemistry or NADPH diaphorase histochemistry in the quail forebrain.

In Japanese quail (Coturnix japonica), previous studies indicated that the distribution of reduced nicotinamide dinucleotide phosphate (NADPH) diaphorase overlaps with steroid-sensitive areas that contain dense populations of aromatase-immunoreactive (ARO-ir) cells. We investigated here the anatomical relationships between aromatase (ARO) and nitric oxide synthase (NOS)-containing cells that were visualized both by NOS-immunohistochemistry and NADPH-histochemistry. The distribution of ARO-ir and of NADPH-positive cells in the forebrain observed here matched exactly the distribution previously reported. The distribution of NOS-immunoreactive material in the vicinity of ARO-ir cell groups appeared similar to the distribution of NADPH-positive structures previously identified by histochemistry. The number of NOS-immunoreactive cells was similar to the number of NADPH-positive cells and they were found in the same brain regions. In contrast, few NOS-immunoreactive fibers were observed whereas numerous NADPH-positive fibers and punctuate structures were present in many areas. Major groups of NOS-immunoreactive/NADPH-positive neurons were adjacent to the main ARO-ir cell groups, such as the medial preoptic nucleus, the bed nucleus of the stria terminalis and the nucleus ventromedialis hypothalamic. However, examination of adjacent sections indicated that there is very little overlap between the NOS-immunoreactive and ARO-ir cell populations. This notion got further support by double-labeled sections where no double-labeled cells could be identified. In sections stained simultaneously by histochemistry for NADPH and immunohistochemistry for ARO, many NADPH-positive fibers and punctate structures were closely associated with ARO-ir perikarya. Taken together, the present data indicate that NOS is not or very rarely colocalized with ARO but that NOS inputs are closely associated with ARO-ir cells. Based on previous work in a variety of model systems, it can be hypothesized that these inputs modulate the expression or activity of ARO in the quail brain.

The parvocellular vasotocin system of Japanese quail: a developmental and adult model for the study of influences of gonadal hormones on sexually differentiated and behaviorally relevant neural circuits.

Vasotocin (VT; the antidiuretic hormone of birds) is synthesized by diencephalic magnocellular neurons projecting to the neurohypophysis. A sexually dimorphic system of VT-immunoreactive (ir) parvocellular elements has been described within the male medial preoptic nucleus (POM) and the nucleus of the stria terminalis, pars medialis (BSTm). VT-ir fibers are present in many diencephalic and extradiencephalic locations, and quantitative morphometric analyses demonstrated their sexually dimorphic distribution in regions involved in the control of different aspects of reproduction. Moreover, systemic or intracerebroventricular injections of VT markedly inhibit the expression of some aspects of male sexual behavior. In adult animals, circulating levels of testosterone (T) have a profound influence on the VT immunoreactivity within BSTm, POM, and lateral septum. Castration markedly decreases the immunoreaction, whereas T-replacement therapy restores a situation similar to the intact birds. We observed no changes in gonadectomized females treated with T. These changes parallel similar changes in male copulatory behavior (not present in castrated male quail, fully expressed in castrated, T-treated males). The restoration by T of the VT immunoreactivity in castrated male quail could be fully mimicked by a treatment with estradiol (E(2)), suggesting that the aromatization of T into E(2) may play a key limiting role in both the activation of male sexual behavior and the induction of VT synthesis. This dimorphism has an organizational nature: administration of E(2) to quail embryos (a treatment that abolishes male sexual behavior) results in a dramatic decrease of the VT immunoreactivity in sexually dimorphic regions. Conversely, the inhibition of E(2) synthesis during embryonic life (a treatment that stimulates the expression of male copulatory behavior in treated females exposed in adulthood to T) results in a malelike distribution of VT immunoreactivity. The VT parvocellular system of the Japanese quail can therefore be considered an accurate marker of the sexual differentiation of brain circuits mediating copulatory behavior and could be a very sensitive indicator of the activity of estrogenlike substances on neural circuits.