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Journal: Journal of neuroendocrinology

28

The production of bioactive peptides from biologically inactive precursors involves extensive post-translational processing, including enzymatic cleavage by proteolytic peptidases. Endoproteolytic prohormone-convertases initially cleave the precursors of many neuropeptides at specific amino acid sequences to generate intermediates with basic amino acid extensions on their C-termini. Subsequently, the related exopeptidases, carboxypeptidases D and E (CPD and CPE), are responsible for removing these amino acids before the peptides achieve biological activity. We investigated the effect of photoperiod on the processing of the neuropeptide precursor pro-opiomelanocortin (POMC) and its derived neuropeptides, α- melanocyte-stimulating hormone (MSH) and β-endorphin (END), within the hypothalamus of the seasonal Siberian hamster (Phodopus sungorus). We thus compared hypothalamic distribution of CPD, CPE, α-MSH and β-END using immunohistochemistry and measured the enzyme activity of CPE and concentrations of C-terminally cleaved α-MSH in short-day (SD; 8 : 16 h light/dark) and long-day (LD; 16 : 8 h light/dark) acclimatised hamsters. Increased immunoreactivity (-IR) of CPE, as well as higher CPE activity, was observed in SD. This increase was accompanied by more β-END-IR cells and substantially higher levels of C- terminally cleaved α-MSH, as determined by radioimmunoassay. Our results suggest that exoproteolytic cleavage of POMC-derived neuropeptides is tightly regulated by photoperiod in the Siberian hamster. Higher levels of biological active α-MSH- and β-END in SD are consistent with the hypothesis that post-translational processing is a key event in the regulation of seasonal energy balance.

Concepts: Protein, Amino acid, Acid, Metabolism, Hamster, Hamsters, Phodopus, Winter White Russian Dwarf Hamster

27

Tonic gonadotrophin secretion throughout the menstrual cycle is regulated by the negative feedback actions of ovarian oestradiol (E(2) ) and progesterone (P). While kisspeptin neurones in the arcuate nucleus (ARC) of the hypothalamus appear to play a major role in mediating these feedback actions of the steroids in non-primate species, this issue has been less well studied in the monkey. Here, we used immunohistochemistry (IHC) and in situ hybridization (ISH) to examine kisspeptin and KISS1 expression, respectively, in the mediobasal hypothalamus (MBH) of adult ovariectomised (OVX) rhesus monkeys. We also examined kisspeptin expression in the MBH of ovarian intact females, and the effect of E(2) , P and E(2) +P replacement on KISS1 expression in OVX animals. Kisspeptin or KISS1 expressing neurons and pronounced kisspeptin fibres were readily identified throughout the ARC of ovariectomised monkeys, but in intact animals on the other hand kisspeptin cell bodies were small in size and number and only fine fibers were observed. Replacement of OVX monkeys with physiologic levels of E(2) , either alone or with luteal phase levels of P, abolished KISS1 expression in the ARC. Interestingly, P replacement alone for 14 days also resulted in a significant downregulation of KISS1 expression. These findings support the view that, in primates, as in rodents and sheep, kisspeptin signaling in ARC neurones appears to play an important role in mediating the negative feedback action of E(2) on gonadotrophin secretion, and indicate a need to further study their regulation by P. © 2013 British Society for Neuroendocrinology.

Concepts: Hypothalamus, Macaque, Menstrual cycle, Primate, Corpus luteum, Rhesus Macaque, Puberty, Monkeys in space

27

SH2-containing inositol 5'-phosphatase 2 (SHIP2) is a lipid phosphatase which negatively regulates insulin’s metabolic signalling in peripheral tissues; however, the expression of SHIP2 in the hypothalamus and its functional roles are largely unknown. In the present study, immunohistochemical analysis demonstrated that SHIP2 protein exists in neuronal cells expressing neuropeptide Y and pro-opiomelanocortin in the arcuate nucleus of the hypothalamus in C57BL/6J mice. Interestingly, the expression levels of SHIP2 in the hypothalamus were elevated in aged C57BL/6J mice and diabetic db/db mice. To clarify the significance of the increased expression of SHIP2 in the hypothalamus, we examined the central effects of insulin and leptin in transgenic mice overexpressing SHIP2 (SHIP2-Tg). Accumulation of phosphatidylinositol (3,4,5)-trisphosphate and phosphorylation of Akt in the hypothalamus, induced by intracerebroventricular (i.c.v.) injection of insulin, were attenuated in SHIP2-Tg compared to wild-type mice, whereas leptin-induced phosphorylation of Stat3 in the hypothalamus was comparable between them. The suppression of food intake after i.c.v. administration of insulin, but not leptin, was attenuated consistently in SHIP2-Tg. In addition, SHIP2-Tg showed increased food consumption after starvation and become heavier with visceral fat accumulation than wild-type mice, despite normal levels of oxygen consumption and spontaneous movement. These results suggest that SHIP2 contributes to the regulation of food intake mainly via attenuation of insulin signalling in the hypothalamus of mice. © 2013 British Society for Neuroendocrinology.

Concepts: Hypothalamus, Gene expression, Nutrition, Neuroendocrinology, Appetite, Leptin, Neuropeptide Y, Arcuate nucleus

23

Increased attention has been paid in recent years to the ways in which estrogens and estrogen receptors rapidly affect learning and memory. These rapid effects occur within a timeframe too narrow for the classical genomic mode of estrogen action, thus suggesting non-classical effects as underlying mechanisms. The present review examines recent developments in the study of the rapid effects of 17β-estradiol and estrogen receptor (ER) agonists on learning and memory tasks in female rodents, including social recognition, object recognition, object placement (spatial memory), and social learning. By comparing studies utilizing systemic or intracranial treatments, as well as pre- and post-acquisition administration of estradiol or ER agonists, the respective contributions of individual ERs within specific brain regions to various forms of learning and memory can be elucidated. The first part of this review explores the effects of systemic administration of 17β-estradiol and ER agonists on memory when administered either pre- or post-acquisition. The second part focuses on the effects of pre- and post-acquisition infusions of 17β-estradiol or ER agonists into the dorsal hippocampus on memory, but also discusses the contributions of other brain regions including the medial amygdala, medial prefrontal cortex, and paraventricular nucleus of the hypothalamus. The cellular mechanisms mediating the rapid effects of 17β-estradiol on memory, including activation of intracellular signaling cascades and epigenetic processes, are discussed. Finally, the review concludes by comparing pre- and post-acquisition findings and effects of 17β-estradiol and ER agonists in different brain regions. This article is protected by copyright. All rights reserved.

Concepts: Amygdala, Hypothalamus, Brain, Estrogen, Estrogen receptor, Cerebrum, Hippocampus, Limbic system

10

The neurohormone oxytocin (OT) has been one the most studied peptides in behavioral sciences over the past two decades. Primarily known for its crucial role in labor and lactation, a rapidly growing literature suggests that intranasal OT (IN-OT) may also play a role in humans' emotional and social lives. However, the lack of a convincing theoretical framework explaining IN-OT’s effects that would also allow to predict which moderators exert their effects and when, has raised healthy skepticism regarding the robustness of human behavioral IN-OT research. The poor knowledge of OT’s exact pharmacokinetic properties, crucial statistical and methodological issues and the absence of direct replication efforts may have lead to a publication bias in IN-OT literature with many unpublished studies with null results lying in laboratories' drawers. Is there a file drawer problem in IN-OT research? If this is the case, it may also be the case in our laboratory. This paper aims to answer that question, document the extent of the problem and discuss its implications for OT research. Through eight studies (including 13 dependent variables overall, assessed through 25 different paradigms) performed in our lab between 2009 and 2014 on 453 subjects, results were too often not those expected. Only five publications emerged from our studies and only one of these reported a null-finding. After realizing that our publication portfolio has become less and less representative of our actual findings and because the non-publication of our data might contribute to generating a publication bias in IN-OT research, we decided to get these studies out of our drawer and encourage other laboratories to do the same. This article is protected by copyright. All rights reserved.

Concepts: Scientific method, Psychology, Epistemology, Oxytocin, Academic publishing, Laboratory, All rights reserved, Copyright

4

Visceral pain describes pain originating from the internal organs of the body and is a common feature of many disorders including irritable bowel syndrome (IBS). Stress is implicated in the development and exacerbation of many visceral pain disorders. Recent evidence suggests that stress and the gut microbiota can interact through complementary or opposing factors to influence visceral nociceptive behaviors. The presentation at this Young Investigator Forum at the International Society of Psychoneuroendocrinology (ISPNE) annual meeting described the experimental evidence by which the gut microbiota can affect the stress response to affect visceral pain. Building upon human imaging data showing abnormalities in that central processing of visceral stimuli in patients with IBS with the knowledge that the amygdala plays a pivotal role in facilitating the stress axis, we reviewed our latest experimental evidence supporting amygdala-mediated mechanisms in stress-induced visceral pain. The final part of the session at ISPNE reviewed experimental evidence that visceral pain in IBS may be due, at least in part, to afferent nerve sensitization following increases in epithelial permeability and mucosal immune activation. This article is protected by copyright. All rights reserved.

Concepts: Immune system, Gut flora, Constipation, Pain, Irritable bowel syndrome, Flatulence, All rights reserved, Copyright

1

Folate receptor α (FRα) autoantibodies (FRAAs) are prevalent in Autism Spectrum Disorder (ASD). FRAAs disrupt folate transport across the blood-brain barrier by binding to the FRα. Thyroid dysfunction is frequently found in children with ASD. We measured blocking and binding FRAAs and thyroid stimulating hormone (TSH), free T4 (FT4), total T3 (TT3), reverse T3 (rT3), thyroid releasing hormone (TRH) and other metabolites in 87 children with ASD, 84 of whom also underwent behavior and cognition testing and in 42 of whom FRAAs, TSH and FT4 were measured at two time points. To better understand the significance of the FRα in relation to thyroid development, we examined FRα expression on prenatal and postnatal thyroid. TSH, TT3 and rT3 were above the normal range in 7%, 33% and 51% of the participants and TRH was below the normal range in 13% of the participants. FT4 was rarely outside the normal range. TSH concentration was positively and the FT4/TSH, TT3/TSH and rT3/TSH ratios were inversely related to blocking FRAA titers. On repeated measurements, change in TSH and FT4/TSH ratio were found to correspond to change in blocking FRAA titers. TSH and the FT4/TSH, TT3/TSH and rT3/TSH ratios were related to irritability on the Aberrant Behavior Checklist and several scales of the Social Responsiveness Scale (SRS), while TT3 was associated with SRS subscales and TRH were related to Vineland Adaptive Behavior Scale subscales. The thyroid showed significant FRα expression during the early prenatal period but expression decreased significantly in later gestation and postnatal thyroid tissue. This study suggests that thyroid dysfunction in ASD may be related to the blocking FRAA. The high expression of FRα in the early fetal thyroid suggests that fetal and neonatal exposure to maternal FRAAs could affect the development of the thyroid and may contribute to the pathology in ASD. This article is protected by copyright. All rights reserved.

Concepts: Pregnancy, Childbirth, Infant, Embryo, Thyroid-stimulating hormone, Autism, Autism spectrum, Thyrotropin-releasing hormone

1

Central oxytocin suppresses appetite. It has been shown that oxytocin neuronal activity and release coincide with satiation as well as with adverse events, such as hyperosmolality, toxicity or excessive stomach distension, that necessitate an immediate termination of eating behavior. Oxytocin also decreases consumption driven by reward, especially derived from ingesting carbohydrates and sweet tastants. This review summarizes the current knowledge of the role of oxytocin in food intake regulation and points to a growing body of evidence that oxytocin is a conditional anorexigen, i.e., its effects on appetite differ significantly in certain contexts of (patho)physiological, behavioral and social nature. This article is protected by copyright. All rights reserved.

Concepts: Nutrition, Eating, Ingestion, Food, Appetite, All rights reserved, Copyright, Anorectic

0

Mammalian reproductive function is controlled by the hypothalamus-pituitary-gonadal (HPG) axis, which is suppressed under infectious stress conditions. We have previously demonstrated, by analyzing the pulsatility of luteinizing hormone (LH), that prostaglandins (PGs) in the central nervous system (CNS) mediate infectious stress to suppress the activity of the HPG axis. The aim of the present study is to characterize the types of PGs responsible for suppression of the HPG axis. We focused on 3 major types of PGs, i.e., PGE2 , PGD2 , and PGF2α . We used female rats overiectomized bilaterally 1 week before the experiments. Lipopolysaccharide (LPS, 100 μg/kg) suppressed LH pulses while enhancing the concentration of all 3 PGs in the CSF, which was restored by indomethacin (10 mg/kg). Subsequently, we observed LH pulsatility after a single injection of each PG and after co-injection of PGE2 with PGF2α into the third cerebral ventricle. A single injection of PGE2 dose-dependently induced a transient increase in mean LH concentration and LH pulse amplitude, and PGD2 significantly increased the amplitude of LH pulses, while PGF2α did not affect LH pulsatility. On the other hand, co-injection of PGE2 and PGF2α induced significant suppression of both frequency and amplitude of LH pulses. These results suggest that PGE2 and PGF2α can be one of the mediators that suppress the HPG axis in situations of infectious stress. Moreover, they imply that there are 2 contradictory effects of PGE2 on LH pulsatility: enhancive when working alone while suppressive when working together with PGF2α . (244/250) This article is protected by copyright. All rights reserved.

Concepts: Central nervous system, Nervous system, Brain, Hormone, Luteinizing hormone, Wavelength, Suppression, Suppression of dissent

0

Damage observed in the hippocampus of the adult spontaneously hypertensive rat (SHR) resembles the neuropathology of mineralocorticoid-induced hypertension, supporting a similar endocrine dysfunction in both entities. In this study we have tested the hypothesis that increased expression of the hippocampal mineralocorticoid receptor (MR) in SHR animals is associated with a prevalent expression of pro-inflammatory over anti-inflammatory factors. For this purpose we measured in hippocampus mRNA expression and immunoreactivity of the MR and the glucocorticoid receptor (GR) using qPCR and histochemistry. We also measured the serum-glucocorticoid-activated kinase 1 (Sgk1 mRNA), the number and phenotype of Iba1+ microglia, mRNA expression levels of the proinflammatory factors cyclooxygenase 2 (Cox2), Nlrp3 inflammasome and tumor necrosis factor alpha (Tnfα). The expression of anti-inflammatory Tgfβ mRNA and the NADPH-diaphorase activity of nitric oxide synthase (NOS) was also determined. The results showed that in the hippocampus of SHR rats the expression of MR and the number of immunoreactive MR / GR co-expressing cells is increased as compared to the Wistar Kyoto control animals. The expression of Sgk1, Cox2, Nlrp3 and the number of ramified glia cells positive for Iba1+ is increased, while Tgfβ mRNA expression and the NADPH-diaphorase activity of NOS are decreased. We propose that in the SHR hippocampus increased MR expression causes a bias towards a pro-inflammatory phenotype characteristic for hypertensive encephalopathy. This article is protected by copyright. All rights reserved.

Concepts: Inflammation, Gene expression, Hypertension, Cortisol, Nitric oxide, Tumor necrosis factor-alpha, Mineralocorticoid, Copyright