A new model for the HPA axis explains dysregulation of stress hormones on the timescale of weeks.

Stress activates a complex network of hormones known as the hypothalamic-pituitary-adrenal (HPA) axis. The HPA axis is dysregulated in chronic stress and psychiatric disorders, but the origin of this dysregulation is unclear and cannot be explained by current HPA models. To address this, we developed a mathematical model for the HPA axis that incorporates changes in the total functional mass of the HPA hormone-secreting glands. The mass changes are caused by HPA hormones which act as growth factors for the glands in the axis. We find that the HPA axis shows the property of dynamical compensation, where gland masses adjust over weeks to buffer variation in physiological parameters. These mass changes explain the experimental findings on dysregulation of cortisol and ACTH dynamics in alcoholism, anorexia, and postpartum. Dysregulation occurs for a wide range of parameters and is exacerbated by impaired glucocorticoid receptor (GR) feedback, providing an explanation for the implication of GR in mood disorders. These findings suggest that gland-mass dynamics may play an important role in the pathophysiology of stress-related disorders.

Single-Cell Reconstruction of Oxytocinergic Neurons Reveals Separate Hypophysiotropic and Encephalotropic Subtypes in Larval Zebrafish.

Oxytocin regulates a diverse set of processes including stress, analgesia, metabolism, and social behavior. How such diverse functions are mediated by a single hormonal system is not well understood. Different functions of oxytocin could be mediated by distinct cell groups, yet it is currently unknown whether different oxytocinergic cell types exist that specifically mediate peripheral neuroendocrine or various central neuromodulatory processes via dedicated pathways. Using the Brainbow technique to map the morphology and projections of individual oxytocinergic cells in the larval zebrafish brain, we report here the existence of two main types of oxytocinergic cells: those that innervate the pituitary and those that innervate diverse brain regions. Similar to the situation in the adult rat and the adult midshipman, but in contrast to the situation in the adult trout, these two cell types are mutually exclusive and can be distinguished based on morphological and anatomical criteria. Further, our results reveal that complex oxytocinergic innervation patterns are already established in the larval zebrafish brain.

Male Sexual Development and the Androgenic Gland: Novel Insights through the de novo Assembled Transcriptome of the Eastern Spiny Lobster, Sagmariasus verreauxi.

The Eastern spiny lobster, Sagmariasus verreauxi, is commercially important in fisheries, with growing aquaculture potential, driving an interest to better understand male sexual differentiation. Amongst the Decapoda, the androgenic gland (AG) and the insulin-like androgenic gland hormone (IAG) have a well-defined function in male sexual differentiation. However, IAG is not a sex determinant and therefore must be considered as part of a broader, integrated pathway. This work uses a transcriptomic, multi-tissue approach to provide an integrated description of male-biased expression as mediated through the AG. Transcriptomic analyses demonstrate that IAG expression is stage- and eyestalk-regulated (low in immature, high in mature and 6-times higher in hypertrophied glands), with IAG being the predominant AG-specific factor. The low expression of this key factor in immature males suggests the involvement of other tissues in male sexual differentiation. Across tissues, the gonad (87.8%) and antennal gland (73.5%) show the highest male-biased differential expression of transcripts and also express 4 sex-determination regulators, known as Dmrts, with broader expression of Sv-Sxl and Sv-TRA-2. In order to better understand male sexual differentiation, tissues other than the AG must also be considered. This research highlights the gonad and antennal gland as showing significant male-biased expression patterns, including the Sv-Dmrts.

Frailty, sarcopenia, and hormones.

Frailty is now a definable clinical syndrome with a simple screening test. Age-related changes in hormones play a major role in the development of frailty by reducing muscle mass and strength (sarcopenia). Selective Androgen Receptor Molecules and ghrelin agonists are being developed to treat sarcopenia. The role of Activin Type IIB soluble receptors and Follistatin-like 3 mimetics is less certain because of side effects. Exercise (resistance and aerobic), vitamin D and protein supplementation, and reduction of polypharmacy are keys to the treatment of frailty.

Energy metabolism in the newborn farm animal with emphasis on the calf: endocrine changes and responses to milk-born and systemic hormones.

Neonatal mammals need adaption to changes in nutrient supply because energy intake shifts from continuous parenteral supply of nutrients (mainly glucose, lactate, and amino acids) via the placenta to discontinuous colostrum and milk intake with lactose and fat as main energy sources. Besides ingested lactose, endogenous glucose production is essential in the neonate to assure sufficient glucose availability. Fetal endogenous glucose production is low, but endocrine changes (especially the prenatal rise of glucocorticoid production) promote maturation of metabolic pathways that enable marked glycogen synthesis before and enhanced gluconeogenesis after birth to establish an adequate glucose status during postnatal maturation. In preterm born farm animals gluconeogenic activity is low, mainly because of a low glucocorticoid and thyroid status. In full-term neonates, endogenous glucose production increases with age. Colostral bioactive components (such as growth factors, hormones, bioactive peptides, and cytokines) do not have a direct effect on endogenous glucose production. However, colostrum feeding stimulates intestinal growth and development, an effect at least in part mediated by bioactive substances. Increased nutrient and glucose absorption thus allows increased glucose supply and hepatic glycogen storage, which improves the glucose status. The improved energetic status of colostrum-fed neonates is reflected by an accelerated maturation of the somatotropic axis, leading especially to enhanced production of IGF-I in the neonate. Secretion and production of hormones involved in the regulation of glucose and fat metabolism in neonates depend on the developmental stage and the response to feeding. In addition, many such hormones have actions in the neonate that differ from adult animals. Endocrine action to support endogenous energy supply in neonates is probably not fully established, and therefore, needs postnatal maturation. Therefore, our knowledge on energy metabolism in the neonate needs to be extended to better understand the function and the failure and to assess endocrine responses during the neonatal period.

Elevated androgens during puberty in female rhesus monkeys lead to increased neuronal drive to the reproductive axis: a possible component of polycystic ovary syndrome.

BACKGROUND: Hyperandrogenemia is associated with several clinical disorders in which both reproductive dysfunction and metabolic changes may coexist [i.e. polycystic ovary syndrome (PCOS), obesity and congenital adrenal hyperplasia]. Moreover, there is growing evidence that the elevated levels of circulating androgens in obese girls may lead to an increased neuroendocrine drive to the reproductive axis, similar to that associated with PCOS. METHODS: To test whether androgen exposure in the childhood and adolescent period could lead to pubertal alterations in LH secretory patterns, female rhesus monkeys received subcutaneous testosterone implants prepubertally beginning at 1 year of age, maintaining a 3.7-fold increase (P = 0.001) in circulating testosterone levels over cholesterol-implant controls (n = 6/group) into the post-pubertal period. In early adulthood, pulsatile secretion of LH was measured over 12 h during the early follicular phase of a menstrual cycle, and responsiveness of the pituitary to gonadotrophin-releasing hormone was determined. In addition, ultrasounds were performed to assess ovarian morphology and glucose tolerance testing was performed to assess insulin sensitivity. RESULTS: The timing of menarche was similar between groups. Testosterone-treated animals had a significantly greater LH pulse frequency during the early follicular phase compared with controls (P = 0.039) when measured at 5 years of age. There was a larger LH response to GnRH when testosterone-treated animals were 4 years of age (P = 0.042), but not when the animals were 5 years old (P = 0.57). No differences were seen in insulin sensitivity or ovarian morphology, and the groups showed similar rates of ovulation in early adulthood. CONCLUSIONS: Exposure to increased levels of androgens over the course of pubertal development appears to trigger physiological changes in the neural drive to the reproductive axis that resemble those of obese hyperandrogenemic girls in early adulthood and are characteristic of PCOS.

Hedgehog signaling: endocrine gland development and function.

The role of hedgehog signaling is analyzed in relation to the developing endocrine glands: pituitary, ovary, testis, adrenal cortex, pancreas, prostate, and epiphyseal growth. Experimental and pathological correlates of these organs are also discussed. The second section addresses a number of topics. First, the pituitary gland, no matter how hypoplastic, is present in most cases of human holoprosencephaly, unlike animals in which it is always said to be absent. The difference appears to be that animal mutations and teratogenic models involve both copies of the gene in question, whereas in humans the condition is most commonly heterozygous. Second, tests of endocrine function are not reported with great frequency, and an early demise in severe cases of holoprosencephaly accounts for this trend. Reported tests of endocrine function are reviewed. Third, diabetes insipidus has been recorded in a number of cases of holoprosencephaly. Its frequency is unknown because it could be masked by adrenal insufficiency in some cases and may not be recognized in others. Because of the abnormal hypothalamic-infundibular region in holoprosencephaly, diabetes insipidus could be caused by a defect in the supra-optic or paraventricular hypothalamic nuclei or in release of ADH via the infundibulum and posterior pituitary.

Endocrine signatures underlying plasticity in postembryonic development of a lower termite, Cryptotermes secundus (Kalotermitidae).

Wood-dwelling termites are characterized by an extremely high and unique developmental flexibility that allows workers, which are immatures, to explore all caste options. The endocrine signatures underlying this flexibility are only vaguely understood. We determined juvenile hormone (JH) and ecdysteroid hemolymph titers during postembryonic development and in terminal instars of the drywood termite Cryptotermes secundus using field and laboratory colonies. Postembryonic development is characterized by a drop in JH titers at the transition from larval (individuals without wing buds) to nymphal (individuals with wing buds) instars. JH titers were low in winged sexuals and reproducing primary reproductives (<200 pg/microl) but were by an order of magnitude higher in neotenic replacement reproductives. The unique regressive molts of termites seem to be characterized by elevated JH titers, compared with progressive or stationary molts. Ecdysteroid titers were generally low in nymphal instars and in primary reproductives (<50 pg/microl). It was only during the third and fourth nymphal instars and in winged sexuals where some individuals showed elevated ecdysteroid titers. These results are the most comprehensive endocrinological data set available for any lower termite, with the potential to serve as baseline for understanding the extreme developmental flexibility underlying the evolution of social life in termites.

Insulin stimulates ecdysteroidogenesis by prothoracic glands in the silkworm, Bombyx mori.

It is generally accepted that the prothoracicotropic hormone (PTTH) is the stimulator of ecdysteroidogenesis by prothoracic glands in larval insects. In the present study, we investigated activation of ecdysteroidogenesis by bovine insulin in prothoracic glands of the silkworm, Bombyx mori. The results showed that the insulin stimulated ecdysteroidogenesis during a long-term incubation period and in a dose-dependent manner. In addition, insulin also stimulated both DNA synthesis and viability of prothoracic glands. Insulin-stimulated ecdysteroidogenesis was blocked by either LY294002 or wortmannin, indicating involvement of the phosphatidylinositol 3-kinase (PI3K) signaling pathway. Activation of ecdysteroidogenesis by insulin appeared to be developmentally regulated. Moreover, in vitro activation of ecdysteroidogenesis of prothoracic glands by insulin was also verified by in vivo experiments: injection of insulin into day 6 last instar larvae greatly increased both hemolymph ecdysteroid levels and ecdysteroidogenesis 24 h after the injection, indicating its possible in vivo function. Phosphorylation of Akt and the insulin receptor was stimulated by insulin, and stimulation of Akt phosphorylation appeared to be PI3K-dependent and developmentally regulated. Insulin did not stimulate extracellular signal-regulated kinase (ERK) signaling of the prothoracic glands. These results suggest that in silkworm prothoracic glands, in addition to the PTTH and an autocrine factor, ecdysteroidogenesis is also stimulated by insulin during development.

D-aspartate: an atypical amino acid with neuromodulatory activity in mammals.

Within the pool of endogenous amino acids, serine and aspartate are the only two residues occurring at significant concentrations in free D-form in mammalian tissues. D-Serine (D-Ser) is mainly localized in the forebrain structures of the CNS throughout embryonic development and postnatal phase. Compelling evidence demonstrates that D-Ser has a functional role as an endogenous co-agonist at N-methyl-D-aspartate receptors (NMDARs) and shows its beneficial involvement in psychiatric disorders including schizophrenia. On the other hand, knowledge concerning the role of free D-Asp in mammals has so far been less extensive. D-Asp occurs in the brain as well as in peripheral tissues including the endocrine glands. In endocrine glands, D-Asp levels increase during the postnatal period in concomitance with their functional maturation. The involvement of D-Asp in the regulation of the synthesis and/or release of different hormones has been clearly demonstrated. However, its biological significance in the brain is still obscure. D-Asp appears with a peculiar temporal pattern of localization, being abundant during embryonic development and strongly decreasing after birth. This phenomenon is the result of the postnatal onset of D-Asp oxidase (DDO) expression, the only known enzyme that strictly controls the endogenous levels of D-Asp. The pharmacological affinity of D-Asp for the glutamate site of NMDARs has raised the intriguing question whether this D-amino acid may have some in vivo influence on responses mediated by this subclass of glutamate receptors. In order to unveil the physiological function of D-Asp and of its metabolizing enzyme, genetic and pharmacological approaches have been recently developed. It has now become possible to generate animal models with abnormally elevated levels of D-Asp in adulthood based on the targeted deletion of the Ddo gene and on the oral administration of D-Asp. These animal models have thus highlighted that D-Asp has a neuromodulatory role at NMDARs in brain areas where they regulate crucial nervous functions. Indeed, abnormally high D-Asp levels in the hippocampus are able to strongly enhance NMDAR-dependent LTP and, in turn, to facilitate spatial memory of mice. Moreover, in both mutant and treated animals, this deregulated D-Asp content completely suppresses striatal LTD, most likely via overactivation of NMDARs. The later synaptic plasticity alteration resembles that produced by chronic administration of haloperidol and is probably the neurobiological substrate responsible for the attenuation of prepulse inhibition deficits induced by amphetamine and MK-801 in Ddo knockout and D-Asp-treated mice. These in vitro and in vivo findings, together with others reported in this review, support a neuromodulatory action for D-Asp at glutamatergic synapses. In addition, they suggest that this D-amino acid may play a potential beneficial role in conditions related to a pathological hypofunctioning of NMDARs in the mammalian brain.

Effect of experimental litter reduction in female rats on parameters of brain and endocrine gland development in the progeny.

We studied the relationship between parameters of brain development, elevated plus-maze behavior, and the status of the endocrine glands in the progeny of 4.5-5- and 8-9-month-old females after litter reduction by removal of one uterine tube. The progeny of young experimental females differed from the progeny of control animals by brain weight (at the age of 1 day), morphometrical characteristics of the cortex and its neurons, activity of 3beta-hydroxysteroid dehydrogenase in the adrenal cortex (at the age of 1 and 40 days), and behavioral reactions in the elevated plus-maze (at the age of 30 days). The differences in these parameters between the progeny from old females with experimentally reduced litter size and control females were significantly less pronounced.

Recent patents of TGF-beta family and VEGF associated with ovarian follicular development in mammals.

In mammalian ovary, follicular development in mammals is regulated by the complex process including endocrine, paracrine and autocrine. During the last decade, the role of growth factors in ovarian folliculogenesis has been extensively studied in mammals. In particular, a growing body of evidence indicates that the vascular endothelial growth factor (VEGF) system plays a key role in follicular development and atresia in the woman, rodents and domestic animal species. More recently, the bone morphogenetic protein (BMP) and growth differentiation factor (GDF) that belong to TGF-beta family have been shown to be involved in the regulation of follicle growth. In this paper, we will essentially consider the role of these growth factor systems in mammalian ovary. Moreover, we will review recent patents associated with ovarian follicular development in mammals.

Ltrk is differentially expressed in developing and adult neurons of the Lymnaea central nervous system.

The Trk receptor family plays diverse roles in both development and plasticity of the vertebrate nervous system. Ltrk is a related receptor that is expressed in the CNS of the mollusk Lymnaea, although little is known of its cellular distribution. This study provides three independent lines of evidence (based on RT-PCR, in situ hybridization, and immunohistochemistry) that Ltrk is universally expressed by neurons and dorsal body cells of both the juvenile and the adult Lymnaea CNS. The highest level of expression by neuronal somata occurs in the late juvenile stage, whereas axon collaterals express high levels throughout the animal's life span. Our data support multifunctional roles for Ltrk that parallel those of its mammalian counterparts.

Diverse developmental toxicity of di-n-butyl phthalate in both sexes of rat offspring after maternal exposure during the period from late gestation through lactation.

To evaluate developmental toxicity of di-n-butyl phthalate (DBP) with exposure during the period from late gestation to following lactation, maternal rats were given DBP at dietary concentrations of 0, 20, 200, 2000 and 10,000 ppm from gestational day 15 to postnatal day (PND) 21. At 10,000 ppm, male offspring showed a decreased neonatal anogenital distance and retention of nipples (PND 14), while females showed a slight non-significant delay in the onset of puberty. At PND 21, reduction of testicular spermatocyte development was evident from 20 ppm, as well as mammary gland changes at low incidence in both sexes. At this time point, population changes of pituitary hormone-immunoreactive cells were observed at 10,000 ppm with a similar pattern of increase in the percentages of luteinizing hormone (LH)-positive and decrease in follicle-stimulating hormone (FSH) and prolactin producing cells in both sexes, effects also being evident on FSH from 200 ppm and LH from 2000 ppm in females. During postnatal week (PNW) 8-11, marginal increase of the number of cases with extended diestrus was found at 10,000 ppm. At adult stage necropsy, testicular lesions appeared to be very faint in most cases, but degeneration and atrophy of mammary gland alveoli were observed in males from 20 ppm. Although without clear monotonic dose-dependence, relative pituitary weights were increased with the intermediate doses in males at PNW 11. In females, relative pituitary weights were decreased after 10,000 ppm at PNW 11, and from 200 ppm at PNW 20. The proportion of FSH-positive cells in the pituitaries at PNW 11 was increased in both sexes at 10,000 ppm. Thus, developmental exposure to DBP affected female sexual development involving pituitary function, while in males testicular toxicity was mostly reversible but mammary gland toxicity was persistent at a dose level as low as 20 ppm.

Cell-autonomous roles of the ecdysoneless gene in Drosophila development and oogenesis.

Steroid signaling underlies developmental processes in animals. Mutations that impair steroidogenesis in the fruit fly Drosophila melanogaster provide tools to dissect steroid hormone action genetically. The widely used temperature-sensitive mutation ecdysoneless(1) (ecd(1)) disrupts production of the steroid hormone ecdysone, and causes developmental and reproductive defects. These defects cannot be satisfactorily interpreted without analysis of the ecd gene. Here, we show that ecd encodes an as yet functionally undescribed protein that is conserved throughout eukaryotes. The ecd(1) conditional allele contains an amino acid substitution, whereas three non-conditional larval lethal mutations result in truncated Ecd proteins. Consistent with its role in steroid synthesis, Ecd is expressed in the ecdysone-producing larval ring gland. However, development of ecd-null early larval lethal mutants cannot be advanced by Ecd expression targeted to the ring gland or by hormone feeding. Cell-autonomous ecd function, suggested by these experiments, is evidenced by the inability of ecd(-) clones to survive within developing imaginal discs. Ecd is also expressed in the ovary, and is required in both the follicle cells and the germline for oocyte development. These defects, induced by the loss of ecd, provide the first direct evidence for a cell-autonomous function of this evolutionarily conserved protein.