Showing papers in "Journal of Neuroendocrinology in 2010"
TL;DR: The data obtained in the present study indicate that prenatal social stress differentially programmes anxiety behaviour and HPA axis responses to stress in male and female offspring.
Abstract: Stress exposure during pregnancy can 'programme' adult behaviour and hypothalamic-pituitary-adrenal (HPA) axis stress responsiveness. In the present study, we utilised an ethologically relevant social stressor to model the type of stress that pregnant women may experience. We investigated the effects of social defeat by a resident lactating rat over 5 days during the last week of pregnancy on the pregnant intruder rat HPA axis, and on HPA responsivity to stress and anxiety-related behaviour in the adult offspring of the socially-defeated intruder rats. HPA axis responses after social defeat were attenuated in the pregnant rats compared to virgin females. In the adult offspring, systemic interleukin (IL)-1beta or restraint increased adrenocorticotrophic hormone and corticosterone secretion in male and female control rats; however, in prenatally stressed (PNS) offspring, HPA responses were greatly enhanced and peak hormone responses to IL-1beta were greater in females versus males. Male PNS rats displayed increased anxiety behaviour on the elevated plus maze; however, despite marked changes in anxiety behaviour across the oestrous cycle, there were no differences between female control and PNS rats. Investigation of possible mechanisms showed mineralocorticoid mRNA levels were reduced in the hippocampus of male and female PNS offspring, whereas glucocorticoid receptor mRNA expression was modestly reduced in the CA2 hippocampal subfield in female PNS rats only. Corticotropin-releasing hormone mRNA and glucocorticoid receptor mRNA expression in the central amygdala was greater in PNS males and females compared to controls. The data obtained in the present study indicate that prenatal social stress differentially programmes anxiety behaviour and HPA axis responses to stress in male and female offspring. Attenuated glucocorticoid feedback mechanisms in the limbic system may underlie HPA axis hyper-reactivity to stress in PNS offspring.
251 citations
TL;DR: The KiSS‐1 gene is also highly conserved and has been identified in mammals, amphibians and fish, but not birds, rodents or primates.
Abstract: Gonadotrophin-releasing hormone (GnRH) is the primary hypothalamic factor responsible for the control of gonadotrophin secretion in vertebrates. However, within the last decade, two other hypothalamic neuropeptides have been found to play key roles in the control of reproductive functions: gonadotrophin-inhibitory hormone (GnIH) and kisspeptin. In 2000, we discovered GnIH in the quail hypothalamus. GnIH inhibits gonadotrophin synthesis and release in birds through actions on GnRH neurones and gonadotrophs, mediated via GPR147. Subsequently, GnIH orthologues were identified in other vertebrate species from fish to humans. As in birds, mammalian and fish GnIH orthologues inhibit gonadotrophin release, indicating a conserved role for this neuropeptide in the control of the hypothalamic-pituitary-gonadal axis across species. Subsequent to the discovery of GnIH, kisspeptin, encoded by the KiSS-1 gene, was discovered in mammals. By contrast to GnIH, kisspeptin has a direct stimulatory effect on GnRH neurones via GPR54. GPR54 is also expressed in pituitary cells, but whether gonadotrophs are targets for kisspeptin remains unresolved. The KiSS-1 gene is also highly conserved and has been identified in mammals, amphibians and fish. We have recently found a second isoform of KiSS-1, designated KiSS-2, in several vertebrates, but not birds, rodents or primates. In this review, we highlight the discovery, mechanisms of action, and functional significance of these two chief regulators of the reproductive axis.
188 citations
TL;DR: Novel tools were introduced that are capable of disrupting the central NAergic system more selectively and/or thoroughly than the neurotoxins employed in previous studies: the anti‐dopamine‐β hydroxylase (DBH)‐saporin is an immunotoxin that is taken up from nerve endings and disrupt the NAergic neurones in a retrograde manner.
Abstract: The locus coeruleus (LC) is regarded as a part of the central ‘stress circuitry’ because robust activation of the LC has been reported after stressful stimuli in experimental animals. A considerable amount of clinical evidence also suggests the relationship between the central noradrenergic (NAergic) system and fear/anxiety states or depression. However, previous animal studies have not been able to demonstrate unequivocally the involvement of the NAergic system in mediating fear or anxiety. The forebrain structures, including the hypothalamus, receive massive inputs from the medullary NAergic nuclei via the ventral NAergic bundle (VNAB). The VNAB has been implicated in the neuroendocrine stress axis mainly through its action on the corticotrophin-releasing factor neurones in the paraventricular nucleus of the hypothalamus. Novel tools were introduced that are capable of disrupting the NAergic system more selectively and/or thoroughly than the neurotoxins employed in previous studies: the anti-dopamine-β hydroxylase (DBH)-saporin is an immunotoxin that is taken up from nerve endings and disrupt the NAergic neurones in a retrograde manner. The genetically DBH-depleted mice were also introduced, which lack endogenous noradrenaline. Owing to the rapid development of functional imaging technique, visualisation of the emotional phenomena has become possible in human subjects. Along with the advent of these technologies, endeavors have been continued to unravel the functional relevance of the central NAergic system to stress, anxiety and depression.
180 citations
TL;DR: The migration of GnRH‐1 cells is the best characterised example of neurophilic/axophilic migration, with the cells using a subset of olfactory‐derived vomeronasal axons as their pathway and numerous molecules to guide their movement into the forebrain.
Abstract: Gonadotrophin-releasing hormone-1 (GnRH-1) is essential for mammalian reproduction, controlling release of gonadotrophins from the anterior pituitary. GnRH-1 neurones migrate from the nasal placode into the forebrain during development. Although first located within the nasal placode, the embryonic origin/lineage of GnRH-1 neurones is still unclear. The migration of GnRH-1 cells is the best characterised example of neurophilic/axophilic migration, with the cells using a subset of olfactory-derived vomeronasal axons as their pathway and numerous molecules to guide their movement into the forebrain. Exciting work in this area is beginning to identify intersecting pathways that orchestrate the movement of these critical neuroendocrine cells into the central nervous system, both spatially and temporally, through a diverse and changing terrain. Once within the forebrain, little is known about how the axons target the median eminence and ultimately secrete GnRH-1 in a pulsatile fashion.
175 citations
TL;DR: NK3R is distributed in areas of the sheep POA and hypothalamus known to be involved in the control of reproductive neuroendocrine function and the lack of NK3R in GnRH neurones suggests that the actions of NKB on GnRH neurosecretory activity in the ewe are mediated indirectly via other neurones and/or neuropeptides.
Abstract: Recent evidence has implicated neurokinin B (NKB) in the complex neuronal network mediating the effects of gonadal steroids on the regulation of gonadotrophin-releasing hormone (GnRH) secretion. Because the neurokinin 3 receptor (NK3R) is considered to mediate the effects of NKB at the cellular level, we determined the distribution of immunoreactive NK3R in the septal region, preoptic area (POA) and hypothalamus of the ewe. NK3R cells and/or fibres were found in areas including the bed nucleus of the stria terminalis, POA, anterior hypothalamic and perifornical areas, dopaminergic A15 region, dorsomedial and lateral hypothalamus, arcuate nucleus (ARC) and the ventral premammillary nucleus. We also used dual-label immunocytochemistry to determine whether a neuroanatomical basis for direct modulation of GnRH neurones by NKB was evident. No GnRH neurones at any rostral-caudal level were observed to contain NK3R immunoreactivity, although GnRH neurones and fibres were in proximity to NK3R-containing fibres. Because NKB fibres formed close contacts with NKB neurones in the ARC, we determined whether these NKB neurones also contained immunoreactive NK3R. In luteal-phase ewes, 64% +/- 11 of NKB neurones colocalised NK3R. In summary, NK3R is distributed in areas of the sheep POA and hypothalamus known to be involved in the control of reproductive neuroendocrine function. Colocalisation of NK3R in NKB neurones of the ARC suggests a potential mechanism for the autoregulation of this subpopulation; however, the lack of NK3R in GnRH neurones suggests that the actions of NKB on GnRH neurosecretory activity in the ewe are mediated indirectly via other neurones and/or neuropeptides.
166 citations
TL;DR: The remarkable correlation between a diminished presence of vasopressin in the SCN and a deterioration of sleep‐wake rhythms during ageing and depression make it likely that, also in humans, the vasopressingin neurones contribute considerably to the rhythmic output of theSCN.
Abstract: The physiological effects of vasopressin as a peripheral hormone were first reported more than 100 years ago. However, it was not until the first immunocytochemical studies were carried out in the early 1970s, using vasopressin antibodies, and the discovery of an extensive distribution of vasopressin-containing fibres outside the hypothalamus, that a neurotransmitter role for vasopressin could be hypothesised. These studies revealed four additional vasopressin systems next to the classical magnocellular vasopressin system in the paraventricular and supraoptic nuclei: a sexually dimorphic system originating from the bed nucleus of the stria terminalis and the medial amygdala, an autonomic and endocrine system originating from the medial part of the paraventricular nucleus, and the circadian system originating from the hypothalamic suprachiasmatic nuclei (SCN). At about the same time as the discovery of the neurotransmitter function of vasopressin, it also became clear that the SCN contain the main component of the mammalian biological clock system (i.e. the endogenous pacemaker). This review will concentrate on the significance of the vasopressin neurones in the SCN for the functional output of the biological clock that is contained within it. The vasopressin-containing subpopulation is a characteristic feature of the SCN in many species, including humans. The activity of the vasopressin neurones in the SCN shows a pronounced daily variation in its activity that has also been demonstrated in human post-mortem brains. Animal experiments show an important role for SCN-derived vasopressin in the control of neuroendocrine day/night rhythms such as that of the hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonadal axes. The remarkable correlation between a diminished presence of vasopressin in the SCN and a deterioration of sleep-wake rhythms during ageing and depression make it likely that, also in humans, the vasopressin neurones contribute considerably to the rhythmic output of the SCN.
158 citations
TL;DR: The results are consistent with the hypothesis that KP neurones located in the mouse AVPV/PeN receive circadian information from the SCN via a vasopressinergic monosynaptic pathway, which is enhanced by oestrogen.
Abstract: In rodents, a circadian signal from the suprachiasmatic nucleus (SCN) is essential for the pro-oestrous surge of gonadotrophin-releasing hormone (GnRH), which, in turn, induces luteinising hormone (LH) surge and ovulation. We hypothesised that kisspeptin (KP) neurones in the anteroventral periventricular and periventricular preoptic nuclei (AVPV/PeN) form part of the communication pathway between the SCN and GnRH neurones. In anterograde track tracing studies, we first identified vasopressin (VP)-containing axons of SCN origin in apposition to KP-immunoreactive (IR) neurones. Studies to quantify this input relied on the observation that VP-synthesising neurones in the SCN differ from other VP systems in their lack of galanin expression. In ovariectomised mice, 30.79 +/- 1.63% of KP-IR perikarya and proximal dendrites within the AVPV/PeN received galanin-negative VP-IR varicosities. Oestrogen-treatment significantly increased the number of KP-IR neurones, with their percentage apposed by galanin-negative VP-IR varicosities (46.95 +/- 1.88%) and the number of VP-IR appositions on individual KP-IR neurones. At the ultrastructural level, the VP-IR terminals formed symmetric synapses with KP-IR neurones, which was in accordance with the morphology of inhibitory synapses established by SCN neurones. By contrast to VP, vasoactive intestinal polypeptide (VIP), which is synthesised by a distinct subset of SCN neurones, occurred only rarely in axons apposed to KP-IR neurones. Altogether, our results are consistent with the hypothesis that KP neurones located in the mouse AVPV/PeN receive circadian information from the SCN via a vasopressinergic monosynaptic pathway, which is enhanced by oestrogen.
147 citations
TL;DR: Data suggest that placental lactogen secretion may mediate the hormone‐induced loss of response to leptin during pregnancy, and appears to be mediated downstream of the primary leptin‐responsive neurones in the mediobasal hypothalamus, possibly in the paraventricular nucleus.
Abstract: Appetite and food intake are increased during pregnancy, comprising an adaptive response that facilitates energy storage in preparation for the high metabolic demands of pregnancy and subsequent lactation. To maintain the increased energy intake in the face of increased adiposity and rising leptin levels, pregnant females become resistant to the central anorectic actions of leptin. In rats, pregnancy-induced leptin resistance is characterised by elevated neuropeptide Y and reduced pro-opiomelanocortin expression in the arcuate nucleus, reduced leptin receptor mRNA levels and suppression of leptin-induced phosphorylated signal transducer and activator of transcription-3 protein in the ventromedial hypothalamic nucleus, as well as a loss of anorectic responses to both leptin and alpha-melantocyte-stimulating hormone. Our recent data suggest that this leptin-resistance may also cause central insulin resistance and an altered peripheral glucose homeostasis. The specific hormone changes during pregnancy that might mediate these effects on leptin signalling are a current focus of investigation. In pseudopregnant rats, chronic i.c.v. infusion of ovine prolactin to mimic patterns of placental lactogen secretion that occur during pregnancy completely blocked the ability of leptin to suppress food intake. These data suggest that placental lactogen secretion may mediate the hormone-induced loss of response to leptin during pregnancy. This action of prolactin/placental lactogen appears to be mediated downstream of the primary leptin-responsive neurones in the mediobasal hypothalamus, possibly in the paraventricular nucleus. Our studies show complex hormone-induced adaptations in the normal hypothalamic pathways regulating body weight homeostasis during pregnancy.
136 citations
TL;DR: The hypothesis that GR brain targets are responsive to ultradian GC rhythmicity is tested, finding that any perturbation to the pulse frequency or duration would have rapid quantitative effects on the levels of Per1, which could affect hippocampal function, especially circadian related memory and learning processes.
Abstract: In vivo glucocorticoid (GC) secretion exhibits a distinctive ultradian rhythmicity. The lipophilic hormone can rapidly diffuse into cells, although only the pulse peak is of sufficient amplitude to activate the low affinity glucocorticoid receptor (GR). Discrete pulses readily access brain regions such as the hippocampus where GR expression is enriched and known to regulate neuronal function, including memory and learning processes. In the present study, we have tested the hypothesis that GR brain targets are responsive to ultradian GC rhythmicity. We have used adrenalectomised rats replaced with pulses of corticosterone to determine the transcriptional effects of ultradian pulses in the hippocampus. Confocal microscopy confirmed that each GC pulse results in transient GR nuclear localisation in hippocampal CA1 neurones. Concomitant GR activation and DNA binding was demonstrated by synthetic glucocorticoid response element oligonucleotide binding, and verified for the Clock gene Period 1 promoter region by chromatin immunoprecipitation assays. Strikingly each GC pulse induced a 'burst' of transcription of Period 1 measured by heterogeneous nuclear RNA quantitative polymerase chain reaction. The net effect of pulsatile GC exposure on accumulation of the mature transcript was also assessed, revealing a plateau of mRNA levels throughout the time course of pulsatile exposure, indicating the pulse timing works optimally for steady state Per1 expression. The plateau dropped to baseline within 120 min of the final pulse, indicating a relatively short half-life for hippocampal Per1. The significance of this strict temporal control is that any perturbation to the pulse frequency or duration would have rapid quantitative effects on the levels of Per1. This in turn could affect hippocampal function, especially circadian related memory and learning processes.
131 citations
TL;DR: This review highlights the findings obtained with respect to differential cell death and synaptogenesis with an emphasis on region‐specific mechanisms that involve diverse signalling molecules including tumour necrosis factor‐α, BAX, GABA, glutamate, prostaglandin E2, FAK and paxillin.
Abstract: Gonadal steroid hormones exert permanent organisational effects on the developing brain and thereby direct adult hormonal responsiveness to dictate sex-specific behaviour and physiology. Considerable progress has been made in elucidating the cellular mechanism of action of androgens and oestrogens during the perinatal sensitive period during which organisation occurs. This review highlights the findings obtained with respect to differential cell death and synaptogenesis with an emphasis on region-specific mechanisms that involve diverse signalling molecules including tumour necrosis factor-α, BAX, GABA, glutamate, prostaglandin E2, FAK and paxillin.
120 citations
TL;DR: The data obtained suggest that even mild maternal overnutrition led to increased adiposity, glucose intolerance and altered brain appetite regulators in offspring.
Abstract: Maternal obesity has long-term consequences for the development of hypothalamic neurones involved in energy homeostasis and the metabolic profile in offspring. In the present study, we compared the effects of maternal obesity induced by longstanding high-fat diet (HFD) with milder postnatal overfeeding during suckling induced by litter size reduction. Female Sprague-Dawley rats consumed chow (C) or HFD. On postnatal day 1, litters from chow dams were adjusted to three per dam (small litter, CS) versus 12 control (normal litter, CN). Litters from HFD dams were adjusted to 12 per dam and fed HFD after weaning to induce obesity (HN). Thus, two degrees of maternal overnutrition were produced (CS and HN). To test whether postweaning diet can amplify the effects of maternal obesity, male offspring weaned onto chow or HFD were followed to 21 weeks. Maternal postnatal overnutrition (CS) and HFD-induced maternal obesity (HN) increased body weight and fat mass in offspring compared to those from control dams (CN). Significant glucose intolerance was induced by both degrees of maternal overnutrition, but only in offspring consuming HFD. HFD-induced maternal obesity (HN) was linked to increased offspring leptin, insulin, lipids, insulin resistance and hyperphagia, and was exaggerated by postweaning HFD. No effect of maternal postnatal overnutrition (CS) was seen on these parameters. Hypothalamic signal transducer and activator of transcription-3 and suppressor of cytokine signalling-3 mRNA were significantly elevated by maternal HFD (HN) in the HFD-fed offspring. The data obtained suggest that even mild maternal overnutrition (CS) led to increased adiposity, glucose intolerance and altered brain appetite regulators in offspring. A greater impact of HFD-induced maternal obesity was evident. Marked additive effects were observed when animals consumed a HFD postweaning.
TL;DR: Investigation of the vasopressin and oxytocin systems during maternal care in lactating rats shows that local injection of a selective V1a receptor antagonist bilaterally into the BNST did not affect maternal care, but reduced maternal aggression and tended to lower anxiety‐related behaviour.
Abstract: The neuropeptide arginine vasopressin was recently shown to be an important regulator of female social behaviour, including maternal care and aggression. A key brain site for vasopressin- as well as oxytocin-mediated maternal care is the medial preoptic area (MPOA). Together with the adjacent bed nucleus of the stria terminalis (BNST), these brain regions are considered to form a 'super-region' for maternal behaviour. In the present study, we investigated the vasopressin and oxytocin systems within the MPOA and the BNST during maternal care in lactating rats in more detail. Binding to V1a and oxytocin receptors in the BNST and to oxytocin receptors in the MPOA was increased in lactation. Furthermore, microdialysis revealed that vasopressin release significantly increased (MPOA) or tended to increase (BNST) during different phases of maternal care (i.e. with or without suckling stimulus). In support, manipulations of V1a receptors in the MPOA are known to alter maternal care. We now show that local injection of a selective V1a receptor antagonist bilaterally into the BNST did not affect maternal care, but reduced maternal aggression and tended to lower anxiety-related behaviour. The release of oxytocin did not change in any of the brain regions during maternal care. The results obtained indicate that locally-released vasopressin within the MPOA and the BNST is important for the maintenance of complex maternal behaviours, including maternal care and aggression, respectively.
TL;DR: Comparisons of the distribution of kisspeptin neurone fibres in the female rat brain by comparing precisely the immunoreactive pattern obtained with two antibodies suggest that these peptides play a role in different functions.
Abstract: Kisspeptins are a family of small peptides that play a key role in the neuroendocrine regulation of the reproductive function through neural pathways that have not yet been completely identified. The present study aimed to investigate the distribution of kisspeptin neurone fibres in the female rat brain by comparing precisely the immunoreactive pattern obtained with two antibodies: one specifically directed against kisspeptin-52 (Kp-52), the longest isoform, and the other directed against kisspeptin-10 (Kp-10), whose sequence is common to all putative mature isoforms. With both antibodies, immunoreactive cell bodies were exclusively observed in the arcuate nucleus, and immunoreactive fibres were confined to the septo-preoptico-hypothalamic continuum of the brain. Fibres were observed in the preoptic area, the diagonal band of Broca, the septohypothalamic area, the anteroventral periventricular, suprachiasmatic, supraoptic, paraventricular and periventricular nuclei, the dorsal border of the ventromedian nucleus, the dorsomedial and arcuate nuclei, and the median eminence. In the latter structure, varicose fibres were mainly distributed in the internal layer and were detected to a lesser extent throughout the external layer, including around the deeper part of the infundibular recess. Most regions of immunoreactive cells and fibres matched perfectly for the two antibodies. However, fibres in the dorsolateral septum, anterior fornix, accumbens nucleus and the lateral bed nucleus of the stria terminalis were only recognised by antibody anti-Kp-10, suggesting that anti-Kp-10 may recognise a wider range of kisspeptin isoforms than anti-Kp-52 or cross-react with molecules other than kisspeptin in rat tissue. Overall, these results illustrate the variety of projection sites of kisspeptin neurones in the rat and suggest that these peptides play a role in different functions.
TL;DR: The role that RFRP‐3 plays in mammals is summarized and the implications and opportunities for further study with respect to reproductive physiology and the neural control of sexual behaviour and motivation are considered.
Abstract: To maximise reproductive success, organisms restrict breeding to optimal times of the day or year, when internal physiology and external environmental conditions are suitable for the survival of both parent and offspring. To appropriately coordinate reproductive activity, internal and external standing is communicated to the hypothalamic-pituitary-gonadal axis via a coordinated balance of stimulatory and inhibitory neurochemical systems. The cumulative balance of these mediators ultimately drives the pattern of gonadotrophin-releasing hormone secretion, a neurohormone that stimulates pituitary gonadotrophin secretion. Until 2000, a complementary inhibitor of pituitary gonadotrophin secretion had not been identified. At this time, a novel, avian hypothalamic peptide capable of inhibiting gonadotrophin secretion in cultured quail pituitary cells was uncovered and named gonadotrophin-inhibitory hormone (GnIH). Subsequently, the presence and functional role for the mammalian orthologue of GnIH, RFamide-related peptide, (RFRP-3), was examined, confirming a conserved role for this peptide across several rodent species. To date, a similar distribution and functional role for RFRP-3 have been observed across all mammals investigated, including humans. This overview summarises the role that RFRP-3 plays in mammals and considers the implications and opportunities for further study with respect to reproductive physiology and the neural control of sexual behaviour and motivation.
TL;DR: Although measuring ghrelin and obestatin in plasma is challenging because many forms of the peptides circulate, more sensitive and selective assays to detect the different preproghrelin‐derived peptides are being developed and may be the key to obtaining a better understanding of their roles in different physiological and pathological conditions.
Abstract: Ghrelin and obestatin are two gastrointestinal peptides obtained by post-translational processing of a common precursor, preproghrelin. Ghrelin is an orexigenic and adipogenic peptide and a potent growth hormone secretagogue (GHS) modified by the enzyme ghrelin-O-acyl-transferase to bind and activate its receptor, the GHS-R. The ghrelin/GHS-R pathway is complex and the effects of ghrelin on GH secretion, adiposity and food intake appear to be relayed by distinct mechanisms involving different transduction signals and constitutive activity for the GH-R, different cofactors as modulators of endogenous ghrelin signalling and/or alternative ghrelin receptors. The discovery of obestatin in 2005 brought an additional level of complexity to this fascinating system. Obestatin was initially identified as an anorexigenic peptide and as the cognate ligand for GPR39, but its effect on food intake and its ability to activate GPR39 are still controversial. Although several teams failed to reproduce the anorexigenic actions of obestatin, this peptide has been shown to antagonise GH secretion and food intake induced by ghrelin and could be an interesting pharmacological tool to counteract the actions of ghrelin. Ghrelin and obestatin immunoreactivities are recovered in the blood with an ultradian pulsatility and their concentrations in plasma vary with the nutritional status of the body. It is still a matter of debate whether both hormones are regulated by independent mechanisms and whether obestatin is a physiologically relevant peptide. Nevertheless, a significant number of studies show that the ghrelin/obestatin ratio is modified in anorexia nervosa and obesity. This suggests that the ghrelin/obestatin balance could be essential to adapt the body’s response to nutritional challenges. Although measuring ghrelin and obestatin in plasma is challenging because many forms of the peptides circulate, more sensitive and selective assays to detect the different preproghrelin-derived peptides are being developed and may be the key to obtaining a better understanding of their roles in different physiological and pathological conditions.
TL;DR: Oxytocin is actively involved in the neurobiological response to predator scent stress processes and thus warrants further study as a potential therapeutic avenue for the treatment of anxiety‐related disorders.
Abstract: The neurohypophysial hormone oxytocin acts as a central nervous system neurotransmitter/neuromodulator. We evaluated the effects of oxytocin on behavioural responses to stress, as well as associated biophysiological responses, in a controlled, prospective animal model. The long-term effects of exogenous oxytocin microinjected to the hippocampus of male rats were assessed. Animals were exposed to predator scent stress and treated 1 h or 7 days later with oxytocin or vehicle. Behaviours were assessed with the elevated plus-maze and acoustic startle response tests, 7 days after microinjection and freezing behaviour upon exposure to a trauma-related cue on day 8. These data served for classification into behavioural response groups. Trauma cue response, circulating corticosterone and oxytocin, hippocampal expression of glucocorticoid and mineralocorticoid receptors, and oxytocin receptor mRNA levels were assessed. The interplay between oxytocin, corticosterone and norepinephrine was assessed. Microinfusion of oxytocin both immediately after predator scent stress exposure or 7 days later, after exposure to trauma cue significantly reduced the prevalence rates of extreme responders and reduced trauma cue freezing responses. Post-exposure treatment with oxytocin significantly corrected the corticosterone stress response, decreased glucocorticoid receptor expression and increased mineralocorticoid receptor expression in the hippocampus compared to vehicle treatment. High-dose corticosterone administration together with norepinephrine caused release of plasma oxytocin and hippocampal oxytocin receptor. Oxytocin is actively involved in the neurobiological response to predator scent stress processes and thus warrants further study as a potential therapeutic avenue for the treatment of anxiety-related disorders.
TL;DR: The results suggest that secretion of oxytocin into the brain in a CD38‐dependent manner may play an important role in the development of social behaviour.
Abstract: Oxytocin in the hypothalamus is the biological basis of social recognition, trust, love and bonding. Previously, we showed that CD38, a proliferation marker in leukaemia cells, plays an important role in the hypothalamus in the process of oxytocin release in adult mice. Disruption of Cd38 (Cd38 (-/-)) elicited impairment of maternal behaviour and male social recognition in adult mice, similar to the behaviour observed in Oxt and oxytocin receptor (Oxtr) gene knockout (Oxt (-/-) and Oxtr (-/-), respectively) mice. Locomotor activity induced by separation from the dam was higher and the number of ultrasonic vocalisation calls was lower in Cd38 (-/-) than Cd38( +/+) pups. However, these behavioural changes were much milder than those observed in Oxt (-/-) and Oxtr (-/-) mice, indicating less impairment of social behaviour in Cd38 (-/-) pups. These phenotypes appeared to be caused by the high plasma oxytocin levels during development from the neonatal period to 3-week-old juvenile mice. ADP-ribosyl cyclase activity was markedly lower in the knockout mice from birth, suggesting that weaning for mice is a critical time window of plasma oxytocin differentiation. Breastfeeding was an important exogenous source of plasma oxytocin regulation before weaning as a result of the presence of oxytocin in milk and the dam's mammary glands. The dissimilarity between Cd38 (-/-) infant behaviour and those of Oxt (-/-) or Oxtr (-/-) mice can be explained partly by this exogenous source of oxytocin. These results suggest that secretion of oxytocin into the brain in a CD38-dependent manner may play an important role in the development of social behaviour.
TL;DR: In adult females, prior to the preovulatory surge of GnRH, the retraction of specialised ependymoglial cells lining the floor of the third ventricle named tanycytes allows for the juxtaposition of Gn RH nerve terminals with the adjacent pericapillary space of the pituitary portal vasculature, thus forming direct neurohaemal junctions.
Abstract: Although coordinated actions of several areas within the hypothalamus are involved in the secretion of gonadotrophin-releasing hormone (GnRH), the median eminence of the hypothalamus, where the nerve terminals are located, plays a particularly critical role in the release of GnRH. In adult females, prior to the preovulatory surge of GnRH, the retraction of specialised ependymoglial cells lining the floor of the third ventricle named tanycytes allows for the juxtaposition of GnRH nerve terminals with the adjacent pericapillary space of the pituitary portal vasculature, thus forming direct neurohaemal junctions. These morphological changes occur within a few hours and are reversible. Such remodelling may promote physiological conditions to enhance the central release of GnRH and potentiate oestrogen-activated GnRH release. This plasticity involves dynamic cell interactions that bring into play tanycytes, astrocytes, vascular endothelial cells and GnRH neurones themselves. The underlying signalling pathways responsible for these structural changes are comprised of highly diffusible gaseous molecules, such as endothelial nitric oxide, and paracrine communication processes involving receptors of the erbB tyrosine kinase family, transforming growth factor beta 1 and eicosanoids, such as prostagladin E2. Some of these molecules, as a result of their ability to diffuse within the median eminence, may also serve as synchronising cues allowing for the occurrence of functionally meaningful episodes of GnRH secretion by coordinating GnRH release from the GnRH neuroendocrine terminals.
TL;DR: Observations indicate that the nervous system adapts its local levels of neuroactive steroids in response to changes in gonadal hormones with sex and regional specificity and depending on the duration of the peripheral modifications.
Abstract: Significant levels of neuroactive steroids are still detected in the nervous system of rodents after the removal of peripheral steroidogenic glands. However, the influence of the plasma levels of gonadal steroids on the levels of neuroactive steroids in the nervous system has not so far been clarified in detail. Accordingly, by liquid chromatography tandem mass spectrometry, we have analysed the levels of neuroactive steroids in the sciatic nerve, in three central nervous system (CNS) regions (i.e. cerebellum, cerebral cortex and spinal cord) and in the plasma of male and female animals. The levels present in gonadally intact animals were compared with those present in short- and long-term gonadectomised animals. We observed that: (i) changes in neuroactive steroid levels in the nervous system after gonadectomy do not necessarily reflect the changes in plasma levels; (ii) long-term gonadectomy induces changes in the levels of neuroactive steroids in the peripheral nervous system (PNS) and the CNS that, in some cases, are different to those induced by short-term gonadectomy; (iii) the effect of gonadectomy on neuroactive steroid levels is different between the PNS and the CNS and within different CNS regions; and (iv) the effects of gonadectomy on neuroactive steroid levels in the nervous system show sex differences. Altogether, these observations indicate that the nervous system adapts its local levels of neuroactive steroids in response to changes in gonadal hormones with sex and regional specificity and depending on the duration of the peripheral modifications.
TL;DR: Results indicate that the CRH‐urocortin‐CRH‐R2 pathway in the PVN and connected areas mediates the long‐term effects of BDNF to depress feeding and promote lipolysis.
Abstract: Brain-derived neurotrophic factor (BDNF) has been implicated in learning, depression and energy metabolism However, the neuronal mechanisms underlying the effects of BDNF on energy metabolism remain unclear The present study aimed to elucidate the neuronal pathways by which BDNF controls feeding behaviour and energy balance Using an osmotic mini-pump, BDNF or control artificial cerebrospinal fluid was infused icv at the lateral ventricle or into the paraventricular nucleus of the hypothalamus (PVN) for 12 days Intracerebroventricular BDNF up-regulated mRNA expression of corticotrophin-releasing hormone (CRH) and urocortin in the PVN TrkB, the receptor for BDNF, was expressed in the PVN neurones, including those containing CRH Both icv and intra-PVN-administered BDNF decreased food intake and body weight These effects of BDNF on food intake and body weight were counteracted by the co-administration of alpha-helical-CRH, an antagonist for the CRH and urocortin receptors CRH-R1/R2, and partly attenuated by a selective antagonist for CRH-R2 but not CRH-R1 Intracerebroventricular BDNF also decreased the subcutaneous and visceral fat mass, adipocyte size and serum triglyceride levels, which were all attenuated by alpha-helical-CRH Furthermore, BDNF decreased the respiratory quotient and raised rectal temperature, which were counteracted by alpha-helical-CRH These results indicate that the CRH-urocortin-CRH-R2 pathway in the PVN and connected areas mediates the long-term effects of BDNF to depress feeding and promote lipolysis
TL;DR: Evidence is provided that in rats, 6 weeks of daily or intermittent exercise constrains the HPA axis response to mild, but not more intense stressors, and that this regulation may be mediated at a central level beyond the primary sensory input.
Abstract: Regular physical exercise is beneficial for both physical and mental health. By contrast, stress is associated with deleterious effects on health and there is growing evidence that regular physical exercise counteracts some of the effects of stress. However, most previous studies have suggested that prior exercise does not alter the acute hypothalamic pituitary adrenal (HPA) axis responses to stress. The present series of studies provides evidence that in rats, 6 weeks (but not 1 or 3 weeks) of voluntary wheel running reduces the HPA axis responses to lower-intensity stressors such as an i.p. saline injection, exposure to a novel environment or exposure to moderate intensity noise, but not to more intense stressors such as predator odour exposure or restraint. Daily exercise does not appear to be necessary for the reduction in HPA axis responses, with intermittent access (24 h out of each 72-h period) to a running wheel for 6 weeks, resulting in similar decrements in adrenocorticotrophic hormone and corticosterone release in response to 85 dBA noise exposure. Data from in situ hybridisation for c-fos mRNA are consistent with the hypothesis that voluntary exercise results in a decrease in HPA axis responsiveness to a low-intensity stressor at a central level, with no changes in primary sensory processing. Together, these data suggest that 6 weeks of daily or intermittent exercise constrains the HPA axis response to mild, but not more intense stressors, and that this regulation may be mediated at a central level beyond the primary sensory input.
TL;DR: A role in the regulation of adult reproduction rather that prepubertal infertility is suggested, and the levels of RFRP and Kiss1 gene expression and their G protein‐coupled receptors (GPR147 and GPR54, respectively) in various brain areas and the pituitary gland are quantified.
Abstract: RFamide related peptides (RFRPs) have been extensively implicated in the neuroendocrine control of reproduction. While steroid hormones strongly regulate the closely-related kisspeptin gene and protein expression, the regulation of RFRPs or their receptor by steroid hormones is almost unknown. The present study aimed to quantify relative levels of RFRP and Kiss1 gene expression and their G protein-coupled receptors (GPR147 and GPR54, respectively) in various brain areas and the pituitary gland, and to determine the effects of differing levels of oestradiol and pubertal development on levels of these gene products. In Experiment 1, the treatment groups examined were: dioestrus, ovariectomised and ovariectomised with replacement oestradiol to induce a preovulatory-like luteinising hormone surge. Micropunched brain regions and whole pituitary glands were processed for measurement of RFRP, Kiss1, GPR147 and GPR54 mRNA by quantitative reverse transcriptase-polymerase chain reaction. As expected, Kiss1 gene expression was low in the rostral periventricular area of the third ventricle of ovariectomised animals, whereas levels were highest in the arcuate nucleus in this situation. No such oestrogenic effects were observed for RFRP gene expression. GPR147 gene expression was highest in the rostral periventricular region of the third ventricle. The levels of GPR147 and GPR54 mRNA were markedly lower in the pituitary gland than in the hypothalamic regions, and RFRP and Kiss1 mRNA were virtually undetectable in the pituitary gland. These data imply that the actions of RFamides are likely to be predominantly central in nature. In Experiment 2, hypothalamic RFRP and GPR147 mRNA levels were measured in male and female rats aged 2, 4, 6 and 8 weeks. In females, RFRP gene expression increased with developmental age, peaking around the time of puberty, whereas in males gene expression increased between 2 and 4 weeks of age. These results suggest a role in the regulation of adult reproduction rather that prepubertal infertility.
TL;DR: This work considers the decoding of hormone pulsatility by taking the HPG axis as a model system and focussing on molecular mechanisms of frequency decoding by pituitary gonadotrophs, which involves steroid feedback‐dependent endogenous rhythmic activity throughout the HPA axis.
Abstract: Ultradian pulsatile hormone secretion underlies the activity of most neuroendocrine systems, including the hypothalamic-pituitary adrenal (HPA) and gonadal (HPG) axes, and this pulsatile mode of signalling permits the encoding of information through both amplitude and frequency modulation. In the HPA axis, glucocorticoid pulse amplitude increases in anticipation of waking, and, in the HPG axis, changing gonadotrophin-releasing hormone pulse frequency is the primary means by which the body alters its reproductive status during development (i.e. puberty). The prevalence of hormone pulsatility raises two crucial questions: how are ultradian pulses encoded (or generated) by these systems, and how are these pulses decoded (or interpreted) at their target sites? We have looked at mechanisms within the HPA axis responsible for encoding the pulsatile mode of glucocorticoid signalling that we observe in vivo. We review evidence regarding the 'hypothalamic pulse generator' hypothesis, and describe an alternative model for pulse generation, which involves steroid feedback-dependent endogenous rhythmic activity throughout the HPA axis. We consider the decoding of hormone pulsatility by taking the HPG axis as a model system and focussing on molecular mechanisms of frequency decoding by pituitary gonadotrophs.
TL;DR: Data are consistent with recent observations in sheep, and suggest that the PT TSH third ventricle‐ependymal cell relay plays a conserved role in initiating the photoperiodic response in both long‐ and short‐day breeding mammals.
Abstract: Recent studies have characterised a retrograde mechanism whereby the pineal hormone melatonin acts in the pars tuberalis (PT) of the pituitary gland to control thyroid hormone action in the hypothalamus, leading to changes in seasonal reproductive function. This involves the release of thyroid-stimulating hormone (TSH) from PT that activates type II deiodinase (DIO2) gene expression in hypothalamic ependymal cells, locally generating biologically active T3, and thus triggering a neuroendocrine cascade. In the present study, we investigated whether a similar regulatory mechanism operates in the European hamster. This species utilises both melatonin signalling and a circannual timer to time the seasonal reproductive cycle. We found that expression of βTSH RNA in the PT was markedly increased under long compared to short photoperiod, whereas TSH receptor expression was localised in the ependymal cells lining the third ventricle, and in the PT, where its expression varied with time and photoperiod. In the ependymal cells at the base of the third ventricle, DIO2 and type III deiodinase (DIO3) expression was reciprocally regulated, with DIO2 activated under long and repressed under short photoperiod, and the reverse case for DIO3. These data are consistent with recent observations in sheep, and suggest that the PT TSH third ventricle-ependymal cell relay plays a conserved role in initiating the photoperiodic response in both long- and short-day breeding mammals.
TL;DR: It is proposed that male‐typical neural and behavioural differentiation occurs prenatally in genetic males under the influence of oestradiol, which is avoided in foetal genetic females by the neuroprotective actions of α‐fetoprotein, whereas female‐Typical neuraland behavioural differentiation normally occurs postnatallyIn genetic females under the Influence of ostradiol that is presumably produced by the ovaries.
Abstract: A central tenet of contemporary theories on mammalian brain and behavioural sexual differentiation is that an organisational action of testosterone, secreted by the male's testes, controls male-typical aspects of brain and behavioural development, whereas no active perinatal sex hormone signalling is required for female-typical sexual differentiation. Furthermore, the available evidence suggests that many, although not all, of the perinatal organisational actions of testosterone on the development of the male brain result from the cellular effects of oestradiol formed via neural aromatisation of testosterone. However, a default developmental programme for the female brain has been criticised. Indeed, we review new results obtained in aromatase knockout mice indicating that oestradiol actively contributes to the differentiation of female-typical aspects of brain and behavioural sexual differentiation. Furthermore, we propose that male-typical neural and behavioural differentiation occurs prenatally in genetic males under the influence of oestradiol, which is avoided in foetal genetic females by the neuroprotective actions of alpha-fetoprotein, whereas female-typical neural and behavioural differentiation normally occurs postnatally in genetic females under the influence of oestradiol that is presumably produced by the ovaries.
TL;DR: In male rodent models, NKB andkisspeptin have different effects upon gonadotrophin release and appear to interact in a complex manner, and co‐administration of NKB with kisspeptin abrogated the effect of kisspeptide, producing no GnRH release above basal state.
Abstract: Growing evidence suggests the tachykinin neurokinin B (NKB) may modulate gonadotrophin secretion and play a role in sex-steroid feedback within the reproductive axis. NKB signalling has recently been identified as being necessary for normal human reproductive function, although the precise mechanisms underpinning this role remain to be established. We have used rodents to explore further the role of NKB within the reproductive axis. In particular, we have studied its interactions with kisspeptin, a neuropeptide essential for reproductive function in rodent and human with close anatomical links to NKB within the hypothalamus. Intraperitoneal administration of NKB (50 nmol) to male mice had no effect on circulating luteinsing hormone (LH) levels and, although i.p. kisspeptin (15 nmol) increased LH five-fold, co-administration of NKB and kisspeptin was indistinguishable from kisspeptin alone. Intracerebroventricular administration of NKB (10 nmol) to male mice also had no effect on LH levels, with 1 nmol kisspeptin i.c.v. significantly increasing LH compared to control (0.37 +/- 0.18 versus 5.11 +/- 0.28 ng/ml, respectively). Interestingly, i.c.v. co-administration of NKB and kisspeptin caused a significant increase in LH concentrations compared to kisspeptin alone (8.96 +/- 1.82 versus 5.11 +/- 0.28 ng/ml respectively). We used hypothalamic explants from rats to assess the effect of NKB on gonadotrpohin-releasing hormone (GnRH) secretion ex vivo. Doses of NKB up to 1000 nm failed to stimulate GnRH secretion, whereas 100 nm kisspeptin robustly increased GnRH secretion. Of note, co-administration of NKB with kisspeptin abrogated the effect of kisspeptin, producing no GnRH release above basal state. Finally, we analysed the expression of Tac2/Tacr3 (genes encoding NKB and NK3R, respectively) within the arcuate nucleus in different nutritional states. After a 48-h fast, the expression of both Tac2 and Tacr3 showed a significant increase, in contrast to levels of Kiss1 and Kiss1r mRNA, which remained unchanged. In male rodent models, NKB and kisspeptin have different effects upon gonadotrophin release and appear to interact in a complex manner.
TL;DR: In the pathogenesis of inner ear hydrops resulting in Meniere’s attacks, pAVP elevation as a result of stress and subsequent V2R‐cAMP‐PKA‐AQP2 activation and endosomal trapping of AQP2 in the endolymphatic sac, might be important as a basis of this disease.
Abstract: Meniere's disease, characterised by episodic vertigo, fluctuating hearing loss and tinnitus, can occur under conditions of stress. Its pathology was first revealed to be inner ear hydrops through temporal bone studies in 1938. Although its pathogenesis has been proposed to be a disorder of water transport in the inner ear, subsequently, it remains unsolved, until now. A recent study revealed that both plasma stress hormone, vasopressin (pAVP) and its receptor, V2 (V2R) expression in the inner ear endolymphatic sac were significantly higher in Meniere's patients. In the present study, to link V2R-related molecules and inner ear hydrops, we examined V2R-linked water channel molecule, aquaporin-2 (AQP2) expression and translocation in human endolymphatic sac. AQP2 mRNA expression in the endolymphatic sac was significantly higher in Meniere's patients by using real-time polymerase chain reaction, as further confirmed by western blotting. AQP2-like immunoreactivity (-LIR) was translocated from luminal to basolateral side with endosomal trapping in the endolymphatic sac at the time of AVP exposure in human endolymphatic sac tissue culture. The similar AQP2-LIR translocation was also demonstrated by forskolin and blocked by vasopressin/V2R specific antagonist, OPC31260 and protein kinase A (PKA) specific antagonists, H-89 and KT-5720. We concluded that in the pathogenesis of inner ear hydrops resulting in Meniere's attacks, pAVP elevation as a result of stress and subsequent V2R-cAMP-PKA-AQP2 activation and endosomal trapping of AQP2 in the endolymphatic sac, might be important as a basis of this disease. Further experimental and clinical studies are needed to better clarify the neuroscientific relationship between stress and Meniere's disease.
TL;DR: Pharmacological and anatomical data are consistent with GABA‐ and glutamate‐containing afferents controlling A15 activity in anoestrus, with E2 inhibiting GABA and stimulating glutamate release at this time of year.
Abstract: Reproduction is unique among physiological systems in that it can be shut down completely for prolonged periods. In females, the most common instances of such reversible infertility are the anovulation that occurs prior to puberty, during lactation, and annually in seasonally breeding species. Although the afferent signals inhibiting reproduction vary among these three conditions, the basic changes in hypothalamic function appear to be similar. Specifically two distinct, but not mutually exclusive, alterations in the control of gonadotrophin-releasing hormone (GnRH) secretion have been described. First, there is a change in responsiveness to the negative feedback actions of oestradiol (E2) so that during anovulatory periods E2 exerts a potent inhibition of GnRH secretion that wanes as ovulatory ovarian cycles begin. Second, there is a steroid-independent inhibition of GnRH that is evident as unexpectedly low levels of luteinising hormone (LH) concentrations in ovariectomised (OVX) animals and agonadal girls. Although such instances of physiological infertility occur in all species, the underlying alterations in hypothalamic function remain largely unknown. One exception to this generalization is the ewe, in which a testable hypothesis has been developed for specific hypothalamic alterations to account for the seasonal suppression of reproductive function. In this review, we will first briefly consider the mechanisms by which the external environment controls the timing of ovulation in the ewe, and then describe the neural circuitry that appears to be responsible for seasonal changes in GnRH secretion.
TL;DR: The data obtained suggest that the MeA modulates the neuroendocrine responses to acute but not chronic stress, and suggest that it may be an important neural component for the control of body weight in the face of chronic stress.
Abstract: Stress pathologies such as depression and eating disorders (i.e. anorexia nervosa) are associated with amygdalar dysfunction, which are linked with hypothalamic-pituitary-adrenal axis (HPA) axis hyperactivity. The medial amygdaloid nucleus (MeA), a key output nucleus of the amygdaloid complex, promotes HPA axis activation to acute psychogenic stress and is in a prime position to mediate the deleterious effects of chronic stress on physiology and behaviour. The present study tests the hypothesis that the MeA is necessary for the development of maladaptive physiological changes caused by prolonged stress exposure. Male rats received bilateral ibotenate or sham lesions targeting the MeA and one half underwent 2 weeks of chronic variable stress (CVS) or served as home cage controls. Sixteen hours post CVS, all animals were exposed to an acute restraint challenge. CVS induced thymic involution, adrenal hypertrophy, and attenuated body weight gain and up-regulation of hypothalamic corticotrophin-releasing hormone mRNA expression. Consistent with previous literature, lesions of the MeA dampened stress-induced increases in corticosterone after 30 min of exposure to acute restraint stress. However, this effect was independent of CVS exposure, suggesting that the MeA may not be critical for modulating neuroendocrine responses after chronic HPA axis drive. Interestingly, lesion of the MeA modestly exaggerated the stress-induced attenuation of weight gain. Overall, the data obtained suggest that the MeA modulates the neuroendocrine responses to acute but not chronic stress. In addition, the data suggest that the MeA may be an important neural component for the control of body weight in the face of chronic stress.
TL;DR: A model of graded T4 reductions using doses of propylthiouracil that were 200‐ to 67‐fold lower than the dose traditionally used to produce hypothyroidism in rats did not support the currently envisioned concept of the developing brain being capable of compensating for low T4.
Abstract: Thyroid hormone is essential for normal brain development, although the degree to which the developing brain is sensitive to small perturbations in serum thyroxin is not clear. An important concept related to this is that the developing brain possesses potent mechanisms to compensate for low serum thyroid hormone, and this concept is routinely employed in discussions concerning clinical treatments or public health. However, experimental studies have not directly tested whether (or the degree to which) putative compensatory mechanisms can ameliorate the consequences of small reductions in serum thyroxin (T(4)). To formally test this concept, we employed a model of graded T(4) reductions using doses of propylthiouracil (PTU) that were 200- to 67-fold lower than the dose traditionally used to produce hypothyroidism in rats. PTU produced a stepwise decrease in serum total T(4), and a stepwise increase in serum thyroid-stimulating hormone (TSH), in type 2 deiodinase mRNA expression and enzyme activity in the brain, and in the expression of the mRNA encoding the tri-iodothyronine (T(3)) transporter MCT8 in the postnatal day (P) 15 cortex. However, the mRNA encoding RC3/neurogranin, a direct target of T(3) action, exhibited a strong negative linear correlation with serum total T(4) despite these adaptive responses. In addition, single-cell analysis of RC3 mRNA levels in cortical neurones demonstrated that the co-expression of MCT8 did not alter the relationship between RC3 mRNA and serum T(4). These findings do not support the currently envisioned concept of the developing brain being capable of compensating for low T(4).