Showing papers in "Journal of Neuroendocrinology in 2003"
TL;DR: Four mechanisms underlying resistance of the gonadal axis to stress are suggested, likely genetically determined, and their expression may depend upon a complex interaction with environmental factors.
Abstract: Environmental and social stresses have deleterious effects on reproductive function in vertebrates. Global climate change, human disturbance and endocrine disruption from pollutants are increasingly likely to pose additional stresses that could have a major impact on human society. Nonetheless, some populations of vertebrates (from fish to mammals) are able to temporarily resist environmental and social stresses, and breed successfully. A classical trade-off of reproductive success for potential survival is involved. We define five examples. (i) Aged individuals with minimal future reproductive success that should attempt to breed despite potential acute stressors. (ii) Seasonal breeders when time for actual breeding is so short that acute stress should be resisted in favour of reproductive success. (iii) If both members of a breeding pair provide parental care, then loss of a mate should be compensated for by the remaining individual. (iv) Semelparous species in which there is only one breeding period followed by programmed death. (v) Species where, because of the transience of dominance status in a social group, individuals may only have a short window of opportunity for mating. We suggest four mechanisms underlying resistance of the gonadal axis to stress. (i) Blockade at the central nervous system level, i.e. an individual no longer perceives the perturbation as stressful. (ii) Blockade at the level of the hypothalamic-pituitary-adrenal axis (i.e. failure to increase secretion of glucocorticosteroids). (iii) Blockade at the level of the hypothalamic-pituitary-gonad axis (i.e. resistance of the reproductive system to the actions of glucocorticosteroids). (iv) Compensatory stimulation of the gonadal axis to counteract inhibitory glucocorticosteroid actions. Although these mechanisms are likely genetically determined, their expression may depend upon a complex interaction with environmental factors. Future research will provide valuable information on the biology of stress and how organisms cope. Such mechanisms would be particularly insightful as the spectre of global change continues to unfold.
1,049 citations
TL;DR: Exogenous melatonin can act as soporific agent, a chronohypnotic, and/or a chronobiotic in order to treat sleep or circadian rhythm disorders.
Abstract: The circadian rhythm of pineal melatonin is the best marker of internal time under low ambient light levels. The endogenous melatonin rhythm exhibits a close association with the endogenous circadian component of the sleep propensity rhythm. This has led to the idea that melatonin is an internal sleep ‘facilitator’ in humans, and therefore useful in the treatment of insomnia and the readjustment of circadian rhythms. There is evidence that administration of melatonin is able: (i) to induce sleep when the homeostatic drive to sleep is insufficient; (ii) to inhibit the drive for wakefulness emanating from the circadian pacemaker; and (iii) induce phase shifts in the circadian clock such that the circadian phase of increased sleep propensity occurs at a new, desired time. Therefore, exogenous melatonin can act as soporific agent, a chronohypnotic, and/or a chronobiotic. We describe the role of melatonin in the regulation of sleep, and the use of exogenous melatonin to treat sleep or circadian rhythm disorders.
601 citations
TL;DR: The findings indicate the presence of CART peptide(s) in the hypothalamus, pituitary, and adrenal gland and present evidence for the possible processing of the CART pro‐peptide into smaller peptide fragments.
Abstract: CART peptide specific polyclonal antisera were raised in rabbits. The antisera were raised to CART peptide fragments that span most of the predicted CART protein. The specificity of each antisera was demonstrated by blockade of immunostaining by the immunizing peptide but not by the other CART peptide fragments. In the hypothalamus and pituitary of colchicine and noncolchicine treated rats, immunostaining was observed in cell bodies, fibers and varicosities. Clusters of cells were also stained in the adrenal medulla. It is noteworthy that cellular immunostaining was only found in areas previously shown to express CART mRNA. These findings indicate the presence of CART peptide(s) in the hypothalamus, pituitary, and adrenal gland. Furthermore, we also present evidence for the possible processing of the CART pro-peptide into smaller peptide fragments. These neuroanatomical findings suggest a role of CART peptides in hypothalamic, pituitary and adrenal function.
375 citations
TL;DR: GnIH has the potential to regulate gonadotropin release at more than one level, and its distribution is suggestive of multiple regulatory functions in the central nervous system.
Abstract: Gonadotropin-releasing hormone (GnRH) regulates reproduction in all vertebrates. Until recently, an antagonistic neuropeptide for gonadotropin was unknown. The discovery of an RFamide peptide in quail that inhibits gonadotropin release in vitro raised the possibility of direct hypothalamic inhibition of gonadotropin release. This peptide has now been named gonadotropin-inhibitory hormone (GnIH). We investigated GnIH presence in the hypothalamus of two seasonally breeding songbird species, house sparrows (Passer domesticus) and song sparrows (Melospiza melodia). Using immunocytochemistry (ICC), GnIH-containing neurones were localized in both species in the paraventricular nucleus, with GnIH-containing fibres visible in multiple brain locations, including the median eminence and brainstem. Double-label ICC with light microscopy and fluorescent ICC with confocal microscopy indicate a high probability of colocalization of GnIH with GnRH neurones and fibres within the avian brain. It is plausible that GnIH could be acting at the level of the hypothalamus to regulate gonadotropin release as well as at the pituitary gland. In a photoperiod manipulation experiment, GnIH-containing neurones were larger in birds at the termination of the breeding season than at other times, consistent with a role for this neuropeptide in the regulation of seasonal breeding. We have yet to elucidate the dynamics of GnIH synthesis and release at different times of year, but the data imply temporal regulation of this peptide. In summary, GnIH has the potential to regulate gonadotropin release at more than one level, and its distribution is suggestive of multiple regulatory functions in the central nervous system.
279 citations
TL;DR: Evidence that sleep influences the nocturnal leptin profile is provided, and may have implications for the understanding of the role of sleep in metabolic regulation and the aetiologies of obesity and the night eating syndrome.
Abstract: The aim of the current study was to investigate the effects of sleep loss on the diurnal rhythm of circulating leptin levels An indwelling forearm catheter was used to sample blood at 90-min intervals for a total of 120 h, which included 88 h of sustained sleeplessness, in 10 healthy men The diurnal amplitude of leptin was reduced during total sleep deprivation and returned toward normal during the period of recovery sleep This finding provides evidence that sleep influences the nocturnal leptin profile, and may have implications for the understanding of the role of sleep in metabolic regulation and the aetiologies of obesity and the night eating syndrome
262 citations
TL;DR: A review of common themes found between tissues and organisms focuses on some of the striking connections between the molecular core oscillator and aspects of circadian physiology and behaviour, and addresses the limitations of the microarray technology and analyses.
Abstract: Many aspects of physiology and behaviour are organized around a daily rhythm, driven by an endogenous circadian clock. Studies across numerous taxa have identified interlocked autoregulatory molecular feedback loops which underlie circadian organization in single cells. Until recently, little was known of (i) how the core clock mechanism regulates circadian output and (ii) what proportion of the cellular transcriptome is clock regulated. Studies using DNA microarray technology have addressed these questions in a global fashion and identified rhythmically expressed genes in numerous tissues in the rodent (suprachiasmatic nucleus, pineal gland, liver, heart, kidney) and immortalized fibroblasts, in the head and body of Drosophila, in the fungus Neurospora and the higher plant Arabidopsis. These clock controlled genes represent 0.5-9% of probed genes, with functional groups covering a broad spectrum of cellular pathways. There is considerable tissue specificity, with only approximately 10% rhythmic genes common to at least one other tissue, principally consisting of known clock genes. The remaining common genes may constitute genes operating close to the clock mechanism or novel core clock components. Microarray technology has also been applied to understand input pathways to the clock, identifying potential signalling components for clock resetting in fibroblasts, and elucidating the temperature entrainment mechanism in Neurospora. This review explores some of the common themes found between tissues and organisms, and focuses on some of the striking connections between the molecular core oscillator and aspects of circadian physiology and behaviour. It also addresses the limitations of the microarray technology and analyses, and suggests directions for future studies.
239 citations
TL;DR: Data show that although lactating rats showed normal behavioural reactivity to a psychological stress they showed no statisitically significant activation of the HPA axis, suggesting a dissociation of behavioural and neuroendocrine responses to this mild stress.
Abstract: The behavioural and endocrine responses to a 10 min white noise stress have been characterized in female virgin and undisturbed lactating Sprague-Dawley rats. Animals were continuously video-taped and frequent blood samples were collected using an automated sampling system. Noise stress caused hypothalamo-pituitary-adrenal (HPA) activation, as indicated by a rapid increase in plasma corticosterone and ACTH in the virgins: corticosterone concentrations peaked 20 min after initiation of the stress before declining rapidly back to basal concentrations. In contrast, noise stress had no significant effect on either plasma corticosterone or ACTH concentrations in the lactating animals. However, 72 h after weaning the corticosterone response of the ex-lactating rats was of comparable magnitude, but longer duration to that seen in the virgins. Plasma prolactin concentrations were significantly higher in the lactating animals and declined in response to the noise whereas, a transient but reproducible increase was seen in the virgin group. In situ hybridization revealed a significantly lower basal expression of CRF mRNA in the paraventricular nucleus of lactating rats as compared to the virgins, but noise stress had no further effect. Virgin animals showed behavioural responses to the stress, including an increase in the total activity, exploratory behaviours (rearing) and displacement behaviours (grooming). Lactating animals also showed behavioural responses to the noise, but their activities were principally directed towards the pups. These data show that although lactating rats showed normal behavioural reactivity to a psychological stress they showed no statisitically significant activation of the HPA axis, suggesting a dissociation of behavioural and neuroendocrine responses to this mild stress.
232 citations
TL;DR: The present study determined simultaneously the behavioural, neuroendocrine and regional brain activity, using semi‐quantitative analysis of c‐fos mRNA induction, produced by 30 min of auditory stimulation at different white noise intensities in rats.
Abstract: The present study determined simultaneously the behavioural, neuroendocrine and regional brain activity, using semi-quantitative analysis of c-fos mRNA induction, produced by 30 min of auditory stimulation at different white noise intensities (background 60 dB, 70, 80, 90 and 105 dBA), in rats. Only the highest noise intensities (90 and 105 dB) significantly increased corticosterone release after 30 min stimulation. Behaviourally, the 105 dB noise condition reliably reduced overall activity, and moderate noise intensities (70 and 80 dB) increased sleeping time. Three distinct patterns of c-fos mRNA induction were observed. First, following exposure to the experimental cages, a wide pattern of brain activation was obtained in experimental animals irrespective of noise intensity presentation, compared to the naive rats. Second, a number of auditory structures (cochlear nuclei, superior olivary complex, nuclei of the lateral lemniscus, inferior colliculus and the medial division of the medial geniculate body) displayed a clear intensity-dependent increase in c-fos induction. Third, compared to all other conditions, the stressed rats (90 and 105 dB conditions) displayed significantly higher c-fos induction in relatively few areas. Particularly intense c-fos induction was observed in the bed nucleus of the stria terminalis, especially its anterior medial and ventral aspects, the septohypothalamic nucleus, the ventral lateral septum, the ventral portion of the dentate gyrus, a number of hypothalamic nuclei including the lateral preoptic area, the medial preoptic nucleus and the paraventricular nucleus, the median raphe and the pedunculopontine tegmental nucleus. The involvement of a number of these structures in a specific audiogenic stress responsive circuit is discussed.
227 citations
TL;DR: It is concluded that puberty is not merely a time when increasing levels of gonadal steroids activate the neural circuits organized during perinatal development, but also a time of further organization of the CNS, which allows for appropriate behaviours to emerge in adulthood.
Abstract: During perinatal development, steroid hormones act on the central nervous system (CNS) to organize neural circuits. These circuits remain relatively dormant until hormonal stimulation received in adulthood acts on the CNS to activate adult reproductive physiology and behaviour. In this review, the proposal is put forward that, in addition to perinatal development, puberty serves as another period of neural maturation mediated by both steroid-dependent and -independent events that further organize and shape the behavioural potential of the adult organism. In support of this thesis, data are summarized that clearly show the organizational effects of the pubertal rise in gonadal hormones on mating behaviour and other steroid-mediated behaviours exhibited in adulthood, and on the neural pathways that mediate these behaviours. The importance of determining whether this sensitive period of neural development during puberty is a 'critical period' is also discussed, as well as whether perturbations of the nervous system during pubertal development may result in negative behavioural and physiological outcomes in adulthood. It is concluded that puberty is not merely a time when increasing levels of gonadal steroids activate the neural circuits organized during perinatal development, but also a time of further organization of the CNS, which allows for appropriate behaviours to emerge in adulthood.
222 citations
TL;DR: Depression is characterized by an over activity of the hypothalamic‐pituitary‐adrenal (HPA) axis that resembles the neuroendocrine response to stress, and antidepressants directly regulate HPA axis function.
Abstract: Depression is characterized by an over activity of the hypothalamic-pituitary-adrenal (HPA) axis that resembles the neuroendocrine response to stress. These HPA axis abnormalities participate in the development of depressive symptoms. Moreover, antidepressants directly regulate HPA axis function. These novel findings are reshaping our understanding of the causes and treatment of this disabling disorder.
220 citations
TL;DR: The present data show that both stress paradigms induced line‐dependent physiological and neuroendocrine changes, but that the sensory contact stressor produced chronic stress symptoms in LAL mice only, which seems promising to analyse the role of genetic factors in the individual differences in stress‐related psychopathology.
Abstract: Genetically selected aggressive (SAL) and nonaggressive (LAL) male wild house-mice which show distinctly different coping styles, also display a differential regulation of the hypothalamic-pituitary-adrenal axis after exposure to an acute stressor. To test the hypothesis that coping style predicts stressor susceptibility, the present study examined line differences in response to a chronic stressor. Chronic psychosocial stress was evoked using two paradigms. In the first paradigm, a SAL or LAL male was living in sensory contact (except tactile contact) with a dominant SAL male for 25 days (sensory contact stress). In the second paradigm, a SAL or LAL male was, in addition to the first paradigm, defeated by a SAL male for 21 consecutive days (defeat stress). The sensory contact stressor induced in LAL mice chronic body weight loss and increased plasma adrenocorticotropic hormone levels compared to SAL mice and increased corticosterone levels, thymus involution and lower hippocampal mineralocorticoid receptor (MR) : glucocorticoid receptor (GR) ratio compared to LAL controls. The defeat stressor increased corticosterone secretion and caused adrenal hypertrophy and thymus involution in both mouse lines. Defeated LAL mice showed long-lasting body weight loss and higher corticosterone concentrations than SAL mice and lower hippocampal MR : GR ratio and decreased immobility behaviour in the forced swimming test than LAL controls. Hypothalamic corticotropin-releasing hormone mRNA expression was higher in defeated SAL than in controls. The present data show that both stress paradigms induced line-dependent physiological and neuroendocrine changes, but that the sensory contact stressor produced chronic stress symptoms in LAL mice only. This latter stress paradigm therefore seems promising to analyse the role of genetic factors in the individual differences in stress-related psychopathology.
TL;DR: 5‐HT‐induced vasopressin secretion primarily is mediated via 5‐HT2C, 4‐HT4 and 5‐ HT7 receptors, whereas 5-HT2A, 5‐ht3 and 5HT5A receptors seem to be of minor importance.
Abstract: Serotonin (5-HT), 5-HT agonists, the 5-HT precursor 5-hydroxytryptophan, 5-HT-releasers and -reuptake inhibitors stimulate the release of vasopressin and oxytocin. We investigated the involvement of 5-HT receptors in the serotonergic regulation of vasopressin and oxytocin secretion. Vasopressin and oxytocin secretion was stimulated by 5-HT, the 5-HT(1A+1B+5A+7) agonist 5-carboxamidotryptamine (5-CT), the 5-HT(2A+2C) agonist DOI, the 5-HT(2C+2A) agonist mCPP, the 5-HT(2C) agonist MK-212, the 5-HT(3) agonist SR 57277 and the 5-HT(4) agonist RS 67506. The 5-HT(1A) agonist 8-OH-DPAT, which had no effect on vasopressin secretion, stimulated oxytocin secretion. The 5-HT-induced release of vasopressin and oxytocin was inhibited by central infusion of the 5-HT antagonists WAY 100635 (5-HT(1A)), LY 53857 (5-HT(2A+2C)), ICS 205-930 (5-HT(3+4)) and RS 23597 (5-HT(4)). The 5-HT2+6+7 antagonist metergoline in combination with the 5-HT1A+2+7 antagonist methysergide inhibited the stimulatory effect of 5-CT on both hormones, whereas the 5-HT1A+1B antagonist cyanopindolol only inhibited the oxytocin response. The 5-HT(2A) antagonist 4-(4-flourobenzoyl)-1-(4-phenylbutyl)-piperidine oxalate had no effect on DOI-induced hormone response. The 5-HT(2C) antagonist Y 25130 partly inhibited the stimulating effect of MK-212. ICS 205-930 and RS 23597 inhibited vasopressin and oxytocin secretion induced by RS 67506. WAY 100635 inhibited 8-OH-DPAT-induced oxytocin secretion. We conclude that 5-HT-induced vasopressin secretion primarily is mediated via 5-HT(2C), 5-HT(4) and 5-HT(7) receptors, whereas 5-HT(2A), 5-HT(3) and 5-HT(5A) receptors seem to be of minor importance. 5-HT-induced oxytocin secretion involves 5-HT(1A), 5-HT(2C) and 5-HT(4) receptors; in addition an involvement of 5-HT(1B), 5-HT(5A) and 5-HT(7) receptors seems likely, whereas 5-HT(2A) and 5-HT(3) receptors seem to be less important.
TL;DR: Investigations of mice that are melatonin‐proficient with mice that do not make melatonin, or alternatively cannot interpret the melatonin message, revealed that melatonin has only minor effects on signal transduction processes within the SCN and sets, at most, the gain for clock error signals mediated via the retino‐hypothalamic tract.
Abstract: In mammals, the circadian system is comprised of three major components: the lateral eyes, the hypothalamic suprachiasmatic nucleus (SCN) and the pineal gland. The SCN harbours the endogenous oscillator that is entrained every day to the ambient lighting conditions via retinal input. Among the many circadian rhythms in the body that are driven by SCN output, the synthesis of melatonin in the pineal gland functions as a hormonal message encoding for the duration of darkness. Dissemination of this circadian information relies on the activation of melatonin receptors, which are most prominently expressed in the SCN, and the hypophyseal pars tuberalis (PT), but also in many other tissues. A deficiency in melatonin, or a lack in melatonin receptors should therefore have effects on circadian biology. However, our investigations of mice that are melatonin-proficient with mice that do not make melatonin, or alternatively cannot interpret the melatonin message, revealed that melatonin has only minor effects on signal transduction processes within the SCN and sets, at most, the gain for clock error signals mediated via the retino-hypothalamic tract. Melatonin deficiency has no effect on the rhythm generation, or on the maintenance of the oscillation. By contrast, melatonin is essential for rhythmic signalling in the PT. Here, melatonin acts in concert with adenosine to elicit rhythms in clock gene expression. By sensitizing adenylyl cyclase, melatonin opens a temporally-restricted gate and thus lowers the threshold for adenosine to induce cAMP-sensitive genes. This interaction, which determines a temporally precise regulation of gene expression, and by endocrine-endocrine interactions possibly also pituitary output, may reflect a general mechanism by which the master clock in the brain synchronizes clock cells in peripheral tissues that require unique phasing of output signals.
TL;DR: It is suggested that ERβ is necessary for the regulation of the expression of oxytocin in the PVN, and region and peptide specific regulation by ERα and ERβ in the mouse hypothalamus is shown.
Abstract: In the female rat, oestrogen receptor (ER) beta is colocalized with both oxytocin- and vasopressin-producing neurones in the paraventricular nucleus of the hypothalamus (PVN). In this study, we demonstrate that the same pattern of colocalization between ERbeta and oxytocin exists in the female mouse. Because this nucleus contains only a negligible quantity of ERalpha, it is likely that the oestrogen-dependent regulation of oxytocin and vasopressin synthesis in the PVN is mediated by ERbeta. Thus, we compared the effect of ovarian hormones on oxytocin and vasopressin mRNA expression in the PVN of wild-type (WT) and ERbeta knockout (betaERKO) mice. We also compared the effects of ovarian hormones on oxytocin receptor (OTR) expression in the medial amygdala (MeA) and ventromedial nucleus of the hypothalamus (VMN) in female WT and betaERKO mice. Ovariectomized mice underwent long-term treatment with oestradiol or oil. Progesterone was given concurrently on the final 7 days of treatment, and all mice were killed 48 h after the final progesterone injection. In the PVN, hormone treatment increased oxytocin mRNA expression in WT but not betaERKO females. These results suggest that ERbeta is necessary for the regulation of the expression of oxytocin in the PVN. Hormone treatment had no effect on vasopressin mRNA expression in the PVN, but significantly increased OTR binding in both the VMN and the MeA in both genotypes. Collectively, our data show region and peptide specific regulation by ERalpha and ERbeta in the mouse hypothalamus.
TL;DR: The results indicate that the expression of PR isoforms is differentially regulated by sex steroid hormones in a regionally specific manner.
Abstract: We studied the effects of oestradiol and progesterone on progesterone receptor (PR) isoform content in the brain of ovariectomized rats and in intact rats during the oestrous cycle by Western blot analysis. In the hypothalamus and the preoptic area of ovariectomized rats, PR-A and PR-B content was increased by oestradiol, whereas progesterone significantly diminished the content of both PR isoforms after 3 h of treatment in the hypothalamus, but not in the preoptic area. In the hippocampus, only PR-A content was significantly increased by oestradiol while progesterone significantly diminished it after 12 h of treatment. In the frontal cortex, no treatment significantly modified PR isoform content. During the oestrous cycle, the lowest content of PR isoforms in the hypothalamus was observed on diestrus day and, by contrast, in the preoptic area, the highest content of both PR isoforms was observed on diestrus day. We observed no changes in PR isoform content in the hippocampus during the oestrous cycle. These results indicate that the expression of PR isoforms is differentially regulated by sex steroid hormones in a regionally specific manner.
TL;DR: Results demonstrate that transcriptional regulation of OTR gene expression mediates changes in receptor density in the brain in a region specific manner during pregnancy and suggests a potential mechanism for some of these changes.
Abstract: Changes in brain oxytocin receptor (OTR) binding sites during the course of pregnancy may influence the sudden onset of maternal behavior in female rats at parturition. In situ hybridization was used to identify changes in OTR messenger ribonucleic acid (mRNA) expression during pregnancy and parturition. Two patterns of mRNA regulation were observed. Relative to diestrus virgin control females, OTR mRNA was elevated in the lateral septum and medial preoptic area at days 13-15 of pregnancy but not on the morning of parturition. In the central nucleus of the amygdala and ventromedial nucleus of the hypothalamus (VMH), OTR mRNA was most abundant on the morning of parturition. Strong signals for OTR mRNA were detected in the bed nucleus of the stria terminalis, hypothalamic paraventricular nucleus, supraoptic nucleus and suprachiasmatic nucleus. However no group differences were detected in these areas. As estrogen and interleukin-6 have been suggested to modulate OTR gene expression and both are elevated at the time of parturition, their effects on OTR mRNA in the brain were examined. Estrogen and interleukin-6, given simultaneously, significantly elevated the concentration of OTR mRNA in the VMH, but not in the amygdala. The increase in the VMH was significantly greater than that produced by estrogen alone, and interleukin-6 alone had no effects. These results demonstrate that transcriptional regulation of OTR gene expression mediates changes in receptor density in the brain in a region specific manner during pregnancy and suggests a potential mechanism for some of these changes.
TL;DR: Findings indicate a receptor‐mediated positive feedback action of oxytocin on its own release within the supraoptic nucleus during parturition, which seems to be involved in the progress of parturitions without significantly affecting circulating oxytocIn levels.
Abstract: Oxytocin is released within the supraoptic nucleus during parturition and suckling. During suckling, such release is important in positive feedback stimulation of oxytocin neurons. We have investigated whether oxytocin released within this hypothalamic nucleus during parturition (1) acts on local receptors to further amplify its own release in a positive feedback manner and (2) is critically involved in the regulation of the delivery process. To examine the effect of the oxytocin antagonist on oxytocin release within the supraoptic nucleus, microdialysates were sampled before and during parturition and either vehicle or the antagonist was infused adjacent to the microdialysis probe directly into the supraoptic nucleus after delivery of the second pup. Intranuclear infusion of an oxytocin receptor antagonist (des-Gly-NH2d(CH2)5[Tyr(Me)2Thr4]OVT; 50 ng/0.5 microliters) significantly (P < 0.01) diminished the parturition-related rise in oxytocin release within the supraoptic nucleus and reduced the number of pups delivered during the first and second 30-min dialysis period compared to vehicle-treated controls. Bilateral infusion of the oxytocin receptor antagonist into the supraoptic nucleus after delivery of the second pup significantly slowed parturition (P < 0.05), although the parturition-related rise in plasma oxytocin concentration was unchanged. In addition, the onset of suckling was significantly affected by the antagonist as indicated by fewer liver pups and fewer surviving pups with milk in their stomachs 24 hours after parturition (P < 0.05). To seek other, periventricular sites of oxytocin action during parturition, oxytocin or the oxytocin antagonist was infused into the lateral cerebral ventricle from the birth of pup 2. Via this route, oxytocin speeded up parturition, but the antagonist was ineffective; thus it appears that periventricular oxytocin-sensitive sites are not normally active in promoting parturition, and can do so. The findings indicate a receptor-mediated positive feedback action of oxytocin on its own release within the supraoptic nucleus during parturition, which seems to be involved in the progress of parturition without significantly affecting circulation oxytocin levels. Oxytocin released within the supraoptic nucleus might be important for the coordinated activation of oxytocin neurons and for the synergistic central and peripheral oxytocin effects involved in the regulation of parturition-related events necessary for the survival of the newborn, including the onset of lactation.
TL;DR: It is suggested that MPOA and VBST efferents project to a variety of regions to promote full maternal responsiveness.
Abstract: Medial preoptic area (MPOA) and ventral bed nucleus of the stria terminalis (VBST) neurons are involved in maternal behavior, but the neural sites to which the maternally relevant neurons project have not been determined. Since MPOA and VBST neurons express Fos during maternal behavior, we used a double-labeling immunocytochemical procedure to detect both Fos and a retrograde tracer, wheat germ agglutinin (WGA), in order to determine where these Fos neurons project. On Day 4 postpartum, fully maternal females were separated from their litters. On Day 5, WGA was iontophoretically injected into one of the following regions known to receive MPOA and/or VBST input: Lateral septum, medial hypothalamus at the level of the ventromedial nucleus, lateral habenula, ventral tegmental area, retrorubral field, or periaqueductal gray. On Day 7, females received a 2-h test with either pups or candy, after which they were perfused and their brains were processed for the detection of Fos and WGA. As expected, females tested with pups had more Fos-containing neurons in the MPOA and VBST than did females tested with candy. After WGA injections into several brain sites, the number of double-labeled cells observed in the MPOA and VBST was greater for the maternal females when compared to the non-maternal females. Therefore, these results pinpointed neural circuits that were activated during maternal behavior. For the maternal females, Fos-containing neurons in the MPOA projected most strongly to the medial hypothalamus at the level of the ventromedial nucleus and to the lateral septum, while Fos-containing neurons in the VBST projected most strongly to the retrorubral field, ventral tegmental area, and medial hypothalamus. Although relatively few MPOA and VBST neurons which expressed Fos during maternal behavior projected to the periaqueductal gray, these Fos-expressing neurons made up a relatively large proportion of the MPOA and VBST projection to the periaqueductal gray. This study suggests that MPOA and VBST efferents project to a variety of regions to promote full maternal responsiveness.
TL;DR: The current state of knowledge within a physiological perspective with emphasis on human biological rhythms is outlined, and the significance of circadian phase and period is highlighted.
Abstract: The pineal hormone melatonin is a remarkable molecule, with a conserved time-keeping function across species. It is extensively used as a self-administered remedy for sleep disturbance in countries where it is freely available, and to some extent when it is available on prescription, as in the UK. In some circumstances, notably free-running sleep disorder of the blind, it is the treatment of choice. It is also the marker rhythm of choice for the determination of circadian phase and period. This review outlines the current state of knowledge within a physiological perspective with emphasis on human biological rhythms.
TL;DR: The presence of ER beta immunoreactivity in the lateral septum, medial amygdala, hippocampus and paraventricular nucleus of ovariectomized rats indicates that ER beta may be of physiological significance in the regulation of hypothalamic parvocellular oxytocin neurons by estrogen.
Abstract: An understanding of the functional significance of the newly identified estrogen receptor (ER beta) in the brain will require definition of its expression pattern and relationship to ER alpha. Using an antibody generated against the C-terminus of rat ER beta, we report the presence of ER beta immunoreactivity in the lateral septum, medial amygdala, hippocampus and paraventricular nucleus (PVN) of ovariectomized rats. Double labelling studies in the PVN revealed that approximately 35% of oxytocin neurons located principally in the medial and lateral parvocellular divisions of the caudal PVN were immunoreactive for ER beta while vasopressin, somatostatin and magnocellular oxytocin neurons exhibited no ER beta staining with this antibody. No ER alpha immunoreactive cells were identified in the caudal PVN. These observations provide direct evidence for the differential expression of ER sub-types within neurons and indicate that ER beta may be of physiological significance in the regulation of hypothalamic parvocellular oxytocin neurons by estrogen.
TL;DR: The data indicate that aggression is mediated in part by OT in mice and that increased aggressiveness is not an obligatory phenotypic result of targeted genetic disruption of any gene.
Abstract: Oxytocin (OT) has been reported to mediate aggressive and affiliative behaviours in several species. The behavioural role of OT has been established with physiological manipulations that potentially affected blood pressure, which may have indirectly affected the behaviours under study. To provide converging evidence of the physiological role of OT in aggressive behavior, wild type (WT), heterozygous (OT-/+), and homozygous (OT-/-) mutant mice were tested in two aggression paradigms. In general, there was no significant difference in aggressiveness between WT and OT-/+ mice. However, there were significant reductions in the duration of aggressive behaviors among OT-/- animals, especially in agonistic encounters within neutral arenas. The OT-/- mice did not exhibit any sensorimotor deficits or display any altered general anxiety levels that may have accounted for the observed reduction in aggressive behavior. These data indicate that aggression is mediated in part by OT in mice and that increased aggressiveness is not an obligatory phenotypic result of targeted genetic disruption of any gene.
TL;DR: The results lend support to the hypothesis that both androgen receptor activation and aromatization are necessary for the restoration of male sexual behavior in rats and found that estradiol is neither necessary nor sufficient for the restored of partner preference.
Abstract: This study assessed the role of aromatization in the expression of male reproductive behavior by testing the effects of the aromatase inhibitor, fadrozole, on the restoration of male sexual behavior and partner preference in testosterone-treated gonadectomized rats. We measured nuclear estrogen receptor occupation to determine whether fadrozole blocked brain aromatase. In addition, nuclear androgen receptor assays were used to verify that fadrozole does not block androgen receptors. Mini-osmotic pumps fitted to brain infusion cannulas were used to deliver fadrozole (20 micrograms/day) into the right lateral ventricle. The majority of animals receiving fadrozole treatment with two, 10 mm testosterone filled Silastic capsules (T/F group) failed to display any sexual behavior 7 and 13 days following implant surgery. In contrast, animals receiving fadrozole treatment which were implanted with two, 10 mm testosterone capsules and one, 5 mm 1% estradiol capsule (T/F/E group) copulated normally, indicating that fadrozole's inhibition of male sex behavior was specifically due to blocking aromatase activity. Moreover, the animals which received only one, 5 mm 1% estradiol capsule (E group) also failed to exhibit male sexual behavior. Partner preference for either a sexually receptive female or a non-receptive female was measured in a three chambered apparatus for an index of sexual motivation. Repeated measures contrasts on the group x test interaction indicated that the T/F group was not significantly different from the T group. In addition, the E group did not show a preference for the receptive females and was significantly different from the T group. Fadrozole treatment resulted in a 59% decrease in brain nuclear estrogen receptor occupation relative to the T group. Fadrozole had no significant effect on brain nuclear androgen receptor occupation. Our results lend support to the hypothesis that both androgen receptor activation and aromatization are necessary for the restoration of male sexual behavior in rats. However, we found that estradiol is neither necessary nor sufficient for the restoration of partner preference.
TL;DR: The view is presented that the SCN uses different routes to maintain daily glucose balance and set the level of the endocrine response to abrupt blood glucose changes.
Abstract: The body has developed several control mechanisms to maintain plasma glucose concentrations within strict boundaries Within those physiological boundaries, a clear daily rhythm in plasma glucose concentrations is present; this rhythm depends on the biological clock, which is located in the hypothalamic suprachiasmatic nucleus (SCN), and is independent of the daily rhythm in food intake Interestingly, there is also a daily rhythm in glucose uptake, which also depends on the SCN and follows the same pattern as the daily rhythm in plasma glucose concentrations; both rise before the onset of activity Thus, the SCN prepares the individual for the upcoming activity period in two different ways: by increasing plasma glucose concentrations and by facilitating tissue glucose uptake In addition to this anticipation of glucose metabolism to expected glucose demands, the SCN also influences, depending on the time of the day, the responses of pancreas and liver to abrupt glucose changes (such as a glucose rise after a meal or hypoglycaemia) This review presents the view that the SCN uses different routes to (i) maintain daily glucose balance and (ii) set the level of the endocrine response to abrupt blood glucose changes
TL;DR: In this paper, the central nervous system (CNS) plays a major role in the hitherto unexplained regulation of body fat distribution, leading to the development of metabolic disorders such as hypertriglyceridemia, diabetes mellitus type 2 and lipodystrophy syndromes.
Abstract: Neuroendocrine research has altered the traditional perspective of white adipose tissue (WAT) as a passive store of triglycerides. In addition to fatty acids, WAT produces many hormones and can therefore be designated as a traditional endocrine gland actively participating in the integrative physiology of fuel and energy metabolism, eating behaviour and the regulation of hormone secretion and sensitivity. WAT is controlled by humoral factors, para- and intracrine factors and by neural regulation. Sympathetic nerve fibres innervate WAT and stimulate lipolysis, leading to the release of glycerol and free fatty acids. In addition, recent research in rats has clearly shown a functional parasympathetic innervation of WAT. There appears to be a distinct somatotopy within the parasympathetic nuclei: separate sets of autonomic neurones in the brain stem innervate either the visceral or the subcutaneous fat compartment. We therefore propose that the central nervous system (CNS) plays a major role in the hitherto unexplained regulation of body fat distribution. Parasympathectomy induces insulin resistance with respect to glucose and fatty acid uptake in the innervated fat depot and has selective effects on local hormone synthesis. Thus, the CNS is involved not only in the regulation of hormone production by WAT, but also in its hormone sensitivity. The developments in this research area are likely to increase our insights in the pathogenesis of metabolic disorders such as hypertriglyceridemia, diabetes mellitus type 2 and lipodystrophy syndromes.
TL;DR: Evidence is provided that OT is released in the PVN during parturition and is important for the induction of maternal behaviour and it seems probable that OT release at this site has a positive feedback effect on both parvocellular and magnocellular OT neurones to facilitate co‐ordinated OT release.
Abstract: Oxytocin (OT) release within the brain is thought to play a major role in inducing maternal behaviour in a number of mammalian species but little is known about the sites of release which are important in this respect. We have investigated whether the paraventricular nucleus of the hypothalamus (PVN) is a site of OT action on maternal behaviour in the sheep. In vivo microdialysis and retrodialysis was used to determine whether OT is released in the region of the PVN during the post-partum induction of maternal behaviour and if its release at this site can stimulate maternal behaviour in non-pregnant animals. In vivo sampling showed that OT concentrations increased significantly in the region of PVN at birth. When OT was retrodialysed bilaterally into the PVN (1 or 10 microM) of multiparous ewes treated with progesterone and oestradiol to stimulate lactation, maternal behaviour was induced in a significant number of animals (1 microM, 6/8 and 10 microM, 5/8) compared with controls (0/8 ewes). Similar infusions of the ring structure of OT, tocinoic acid (TOC-10 microM), also induced maternal behaviour in a significant proportion of animals (5/6 ewes) as did intracerebroventricular (ICV) OT (6/8 ewes) and artificial stimulation of the vagina and cervix (VCS, 8/9 ewes). On the other hand, vasopressin (AVP) 1 microM did not induce maternal behaviour in any ewes and a 10 microM dose only induced it in 2/8 animals. The neurochemical changes accompanying the above treatments were also investigated. Noradrenaline concentrations increased in the PVN after the retrodialysis administration of OT 1 microM and 10 microM, TOC 10 microM and AVP 1 microM, OT ICV and VCS. Dopamine concentrations were also increased by OT 10 microM, TOC 10 microM, AVP 1microM and OT ICV. Aspartate and glutamate concentrations were significantly reduced by retrodialysis infusions of OT 1 microM and AVP 1 and 10 microM but not by any other treatment. Finally, the retrodialysis infusion of OT and TOC, as well as ICV OT, significantly increased plasma OT release whereas AVP infusions did not. These results provide evidence that OT is released in the PVN during parturition and is important for the induction of maternal behaviour. It seems probable that OT release at this site has a positive feedback effect on both parvocellular and magnocellular OT neurons to facilitate co-ordinated OT release both in central OT terminal regions (to facilitate maternal behaviour) and peripherally into the blood (to facilitate uterine contractions/milk let down). The potential functional roles for the actions of OT on monoamine and amino acid transmitter release in the PVN are discussed.
TL;DR: It is hypothesized that the presence of pups with their mothers at the time of exposure to an intruder or a predator odour is an effective way to increase the emotional salience of the psychological stressor, thus eliminating the stress hyporesponsiveness in lactating females.
Abstract: Blunted neuroendocrine responses to stress are reported in lactating females after exposure to various stressors. However, many of the stimuli used in these studies have little ethological relevance for maternal protection of the litter in a threatening environment. The question that arises is whether the relevance of the stressor to the infant is critical in the 'gating' of the neuroendocrine response. We hypothesized that the presence of pups with their mothers at the time of exposure to an intruder or a predator odour is an effective way to increase the emotional salience of the psychological stressor, thus eliminating the stress hyporesponsiveness in lactating females. We first compared neuroendocrine responses [corticotropin-releasing factor (CRF) mRNA in the paraventricular nucleus of the hypothalamus (PVN) and central nucleus of the amygdala (CeA), plasma adrenocorticotropic hormone (ACTH) and corticosterone] between early (EL, PPD3-5), late (LL, PPD 15) lactating and virgin (V) females to a male intruder in the home cage. We next investigated the effect of pups' presence at the time of stressor exposure on the magnitude of the hormonal response to a male intruder in the home cage or to a predator odour (fox urine) in a novel environment. In the male intruder paradigm, levels of CRF mRNA expression in the PVN and CeA were lower in LL compared to EL or V females and plasma ACTH and corticosterone secretion was not as elevated in LL compared to EL females. Aggression towards the intruder was high in EL females in the presence of their pups and a positive correlation was found with the integrated ACTH response. Aggression rapidly declined after pup separation (2.5 h or 48 h) or in LL nursing females. In EL females, the presence of the pups with their mothers (EL + pups) at the time of stress significantly increased plasma ACTH and corticosterone responses to either male intruder or predator odour compared to EL females without their pups for 2.5 h or 48 h (EL - pups). Plasma ACTH response to fox urine in EL + pups females was comparable to that of virgin females, suggesting that increasing the salience of emotionally relevant stimuli by keeping the pups present in the cage could eliminate the hyporesponsiveness detected for EL females without their pups. These studies indicate the critical role of the pups in modulating the maternal response to stressors that represent a threat for the litter. We hypothesize that the amygdala, because of its ability to process olfactory stimuli and stimuli with affective properties, might play an essential role in 'gating' the neuroendocrine response to stress during lactation.
TL;DR: Immunocytochemistry with quantitative image analysis, for both GnRH and its precursor proGnRH‐GAP, was used in male European starlings to investigate four stages of a photoperiodically‐induced reproductive cycle.
Abstract: Immunocytochemistry with quantitative image analysis, for both GnRH and its precursor proGnRH-GAP, was used in male European starlings (Sturnus vulgaris) to investigate four stages of a photoperiodically-induced reproductive cycle. Four different groups of birds were examined: photosensitive buy sexually immature, sexually mature, undergoing gonadal regression, and after the completion of regression and fully photorefractory. The size of cells staining for GnRH and proGnRH-GAP increased during gonadal maturation. A reduction in the number of cells staining for GnRH and the size of cells staining for both GnRH and proGnRH-GAP occurred during gonadal regression, though staining for GnRH and proGnRH-GAP in the median eminence remained high at this stage. Birds examined after completion of regression showed significantly reduced staining for both GnRH and its precursor. These observations suggest that photorefractoriness is promoted by a reduction in proGnRH-GAP production and in GnRH synthesis, rather than requiring inhibition of release of GnRH at the median eminence.
TL;DR: The data suggest that melatonin exerts its seasonal effects in the PT by signalling to PT specific‐cells through the MT1 receptor subtype.
Abstract: Melatonin, secreted only during the night by the pineal gland, transduces the photoperiodic message to the organism. One important target for the hormone is the pars tuberalis (PT) of the adenohypophysis which displays a very high number of melatonin binding sites in mammals and is implicated in the seasonal regulation of prolactin secretion. To gain insight into the mechanism by which the melatonin signal is decoded in the PT, we studied the effect of photoperiod on the PT cells expressing the MT1 melatonin receptor in a highly photoperiodic species, the European hamster. Recently, we showed that, in the rat, the MT1 receptor mRNA is expressed in PT-specific cells characterized by their expression of beta-thyroid stimulating hormone (beta-TSH) along with the alpha-glycoprotein subunit (alpha-GSU). As the cellular composition of the PT shows variability among species, we first identified the cell type expressing the MT1 receptor in the European hamster by combining immunocytochemistry and nonradioactive in situ hybridization for the MT1 receptor mRNA. Our results show that, in the European hamster, as in the rat, the MT1 receptor is only expressed by the PT-specific-cells, beta-TSH and alpha-GSU positive. In a second step, we analysed the effects of photoperiod on the MT1 mRNA, and on beta-TSH and alpha-GSU both at the mRNA and protein levels. Our data show that, compared to long photoperiod, short photoperiod induces a dramatic decrease of MT1, beta-TSH and alpha-GSU expression. Protein levels of beta-TSH and alpha-GSU were also dramatically reduced in short photoperiod. Together, our data suggest that melatonin exerts its seasonal effects in the PT by signalling to PT specific-cells through the MT1 receptor subtype.
TL;DR: The mobilization of fat by leptin in short‐day housed hamsters is not associated with changes in expression in either anorexic or anabolic peptides expressed in leptin‐receptor rich structures in the arcuate region of the hypothalamus, and suggests that leptin may target other structures.
Abstract: Seasonal mammals commonly exhibit robust annual cycles of adiposity, food intake and energy metabolism These cycles are driven by changes in the external daylength signal, which generates a diurnal melatonin profile and acts on neuroendocrine pathways The white adipose tissue hormone leptin reflects overall adiposity in seasonal mammals, and consequently undergoes significant seasonal fluctuations in secretion The seasonally breeding Siberian (Djungarian) hamster is a convenient laboratory model to study the effect of a seasonal time-keeping clock on energy metabolism, appetite regulation and the control of adiposity We have shown that administration of exogenous leptin at physiological doses induces significant loss of adipose tissue for short-day housed winter-like hamsters in which endogenous adipose tissue and leptin concentrations are already low By contrast, long-day housed hamsters with high adipose tissue reserves are refractory to the effects of leptin This phenomenon of seasonal leptin resistance appears to be a general feature of other seasonally breeding mammals, and may reflect the operation of an annual timer controlling leptin uptake and/or action on central nervous system signal transduction pathways The mobilization of fat by leptin in short-day housed hamsters is not associated with changes in expression in either anorexic or anabolic peptides expressed in leptin-receptor rich structures in the arcuate region of the hypothalamus, and suggests that leptin may target other structures These data contrast with studies, which show that homeostatic mechanisms in response to feed-restriction induce changes in hypothalamic peptides in a similar manner to nonphotoperiodic species Thus, the long-term seasonal regulation of body weight set point and leptin feedback may operate through separate pathways to those responsible for acute responses to food restriction
TL;DR: Observations indicate that, in male and female rats under normal conditions, noradrenergic afferents innervate each type of neurosecretory somata, in both magnocellular nuclei, in a similar fashion, and reveal, moreover, that nor adrenergic Afferents participate in lactation‐induced structural plasticity of synapses impinging on oxytocinergic somata.
Abstract: Despite several studies showing that the rat supraoptic (SON) and paraventricular (PVN) nuclei are innervated by noradrenergic afferents, the respective contribution of these inputs to the oxytocinergic and vasopressinergic neuronal populations remains to be clearly defined. In the present study, we used the unbiased disector method to estimate the numerical density of noradrenergic varicosities on identified oxytocinergic and vasopressinergic somata in the rat SON and PVN. The analysis was carried out on semithin (1 micron) plastic sections cut from vibratome slices (50 microns) of the SON and PVN which had been double-labelled for noradrenaline (NA) and oxytocin- or vasopressin-related neurophysin. These preparations displayed many noradrenergic varicosities which electron microscopy showed to represent, in the main, synaptic boutons. Our quantitative analysis revealed that noradrenergic varicosities contacted oxytocinergic and vasopressinergic somata to a similar extent in male and female rats, under basal conditions of hormone secretion. The incidence of these axo-somatic contacts was similar in the SON and PVN. In contrast, in lactating rats, in which oxytocin secretion is enhanced, there was a significant increase in the density of noradrenergic varicosities apposed to oxytocinergic somata, in both nuclei. Our observations indicate that, in male and female rats under normal conditions, noradrenergic afferents innervate each type of neurosecretory somata, in both magnocellular nuclei, in a similar fashion. They reveal, moreover, that noradrenergic afferents participate in lactation-induced structural plasticity of synapses impinging on oxytocinergic somata.