Showing papers in "Journal of Neuroendocrinology in 2008"

Brain Oxytocin: A Key Regulator of Emotional and Social Behaviours in Both Females and Males

Abstract: In addition to various reproductive stimuli, the neuropeptide oxytocin (OXT) is released both from the neurohypophysial terminal into the blood stream and within distinct brain regions in response to stressful or social stimuli. Brain OXT receptor-mediated actions were shown to be significantly involved in the regulation of a variety of behaviours. Here, complementary methodological approaches are discussed which were utilised to reveal, for example, anxiolytic and anti-stress effects of OXT, both in females and in males, effects that were localised within the central amygdala and the hypothalamic paraventricular nucleus. Also, in male rats, activation of the brain OXT system is essential for the regulation of sexual behaviour, and increased OXT system activity during mating is directly linked to an attenuated anxiety-related behaviour. Moreover, in late pregnancy and during lactation, central OXT is involved in the establishment and fine-tuned maintenance of maternal care and maternal aggression. In monogamous prairie voles, brain OXT is important for mating-induced pair bonding, especially in females. Another example of behavioural actions of intracerebral OXT is the promotion of social memory processes and recognition of con-specifics, as revealed in rats, mice, sheep and voles. Experimental evidence suggests that, in humans, brain OXT exerts similar behavioural effects. Thus, the brain OXT system seems to be a potential target for the development of therapeutics to treat anxiety- and depression-related diseases or abnormal social behaviours including autism.

Cannabinoid Receptors: Where They are and What They do

Abstract: The endocannabinoid system consists of the endogenous cannabinoids (endocannabinoids), cannabinoid receptors and the enzymes that synthesise and degrade endocannabinoids. Many of the effects of cannabinoids and endocannabinoids are mediated by two G protein-coupled receptors (GPCRs), CB(1) and CB(2), although additional receptors may be involved. CB(1) receptors are present in very high levels in several brain regions and in lower amounts in a more widespread fashion. These receptors mediate many of the psychoactive effects of cannabinoids. CB(2) receptors have a more restricted distribution, being found in a number of immune cells and in a few neurones. Both CB(1) and CB(2) couple primarily to inhibitory G proteins and are subject to the same pharmacological influences as other GPCRs. Thus, partial agonism, functional selectivity and inverse agonism all play important roles in determining the cellular response to specific cannabinoid receptor ligands.

Influence of Neonatal Rearing Conditions on Stress-Induced Adrenocorticotropin Responses and Norepinepherine Release in the Hypothalamic Paraventricular Nucleus

Abstract: Postnatal rearing conditions influence the development of hypothalamic-pituitary-adrenal (HPA) responses to stress in the rat. Thus, postnatal handling dampens HPA responsivity to stress, while prolonged periods of maternal separation have the opposite effect. HPA responses to stress are initiated by the release of corticotropin-releasing factor and/or arginine vasopressin from the neurones of the paraventricular nucleus of the hypothalamus (PVNh). A major source of input to the PVNh arises from brainstem noradrenergic neurones with signalling occurring via alpha1 adrenoreceptors. We examined the noradrenergic response to stress in the PVNh in adult animals exposed to daily periods of handling or maternal separation over the first 2 weeks of life using microdialysis in conscious animals. Maternal separation increased, while handling greatly decreased and norepinepherine responses to restraint stress in the PVNh as compared to non-handled controls; the same pattern was observed for plasma adrenocorticotropic hormone (ACTH) responses to stress. Rearing condition did not affect either alpha1 or alpha2 receptor levels in the PVNh. However, alpha2 receptor binding levels in the noradrenergic cell body regions of the locus coeruleus and the n. tractus solitarius were significantly increased in handled animals. These alpha2 receptors are principally located on noradrenergic neurones (i.e. autoreceptors) and inhibit noradrenaline release at terminal sites. The effects on alpha2 receptor levels could serve as a mechanism for the differences in stress-induced noradrenaline levels in the PVNh and in HPA activity among handled vs non-handled and maternal separation animals. Thus, early life events may serve to influence the differentiation of noradrenergic neurones and thus alter HPA responses stress in adulthood.

Neurodevelopmental and Neurophysiological Actions of Thyroid Hormone

Abstract: For over 100 years, thyroid hormones have been known to be essential for neonatal neurodevelopment but whether they are required by the foetal brain remains a matter of controversy. For decades, the prevailing view was that thyroid hormones are not necessary until after birth because circulating levels in the foetus are very low and the placenta forms an efficient barrier to their transfer from the mother. Clinical observations of good neurological outcome following early treatment of congenital hypothyroidism were used to support the view that thyroid hormones are not required early in neurodevelopment. Nevertheless, the issue remained contentious because of findings that the severity of foetal neurological deficit due to maternal iodine deficiency correlated with the degree of maternal thyroxine (T4) deficiency. Furthermore, neurological damage in these cases could be prevented by correction of maternal T4 deficiency before mid-gestation. This observation led to the opposing view, supported by epidemiological studies of neurological cretinism, that maternal thyroid hormones are important and necessary for early foetal neurodevelopment. It is now clear that thyroid hormones are essential for both foetal and post-natal neurodevelopment and for the regulation of neuropsychological function in children and adults. In recent years, this controversial subject has progressed very rapidly following remarkable progress in understanding of the molecular mechanisms of thyroid hormone action. This article reviews the contributions of molecular biology and genetics to our new understanding of the physiological effects of thyroid hormones on neurodevelopment and in the adult brain.

Measurement of Immediate-Early Gene Activation- c-fos and Beyond

Abstract: Immediate-early genes (IEG) are powerful tools for identifying activated neurosecretory neurones and extended circuits that affect neuroendocrine functions. The generally acknowledged scenario is when cells became activated, IEGs expressed and IEG-encoded transcription factors affect target gene expression. However, there are several examples in which: (i) neuronal activation occurs without induction of IEGs; (ii) IEG induction is not related to challenge-induced neuropeptide expression; and (iii) markers of neuronal activation are not expressed in chronically activated neurones. In spite of these limitations, the use of c-Fos and other regulatory- or effector transcription factors as markers of neuronal activation will continue to be an extremely powerful technique. Recently-developed models, including transgenic mice expressing different marker genes under the regulation of IEG promoters, will help to monitor neuronal activity in vivo or ex vivo and to reveal connection between activated neurones. Furthermore, combinations between novel imaging techniques, such as magnetic resonance and IEG-based mapping strategies, will open new means with which to study functional activity in the neurosecretory systems.

The thyroid-brain interaction in thyroid disorders and mood disorders.

Abstract: Thyroid hormones play a critical role in the metabolic activity of the adult brain, and neuropsychiatric manifestations of thyroid disease have long been recognised. However, it is only recently that methodology such as functional neuroimaging has been available to facilitate investigation of thyroid hormone metabolism. Although the role of thyroid hormones in the adult brain is not yet specified, it is clear that without optimal thyroid function, mood disturbance, cognitive impairment and other psychiatric symptoms can emerge. Additionally, laboratory measurements of peripheral thyroid function may not adequately characterise central thyroid metabolism. Here, we review the relationship between thyroid hormone and neuropsychiatric symptoms in patients with primary thyroid disease and primary mood disorders.

Prenatal alcohol exposure: foetal programming, the hypothalamic-pituitary-adrenal axis and sex differences in outcome.

Abstract: Prenatal exposure to alcohol has adverse effects on offspring neuroendocrine and behavioural functions Alcohol readily crosses the placenta, thus directly affecting developing foetal endocrine organs In addition, alcohol-induced changes in maternal endocrine function can disrupt the normal hormonal interactions between the pregnant female and foetal systems, altering the normal hormone balance and, indirectly, affecting the development of foetal metabolic, physiological and endocrine functions The present review focuses on the adverse effects of prenatal alcohol exposure on offspring neuroendocrine function, with particular emphasis on the hypothalamic-pituitary-adrenal (HPA) axis, a key player in the stress response The HPA axis is highly susceptible to programming during foetal and neonatal development Here, we review data demonstrating that alcohol exposure in utero programmes the foetal HPA axis such that HPA tone is increased throughout life Importantly, we show that, although alterations in HPA responsiveness and regulation are robust phenomena, occurring in both male and female offspring, sexually dimorphic effects of alcohol are frequently observed We present updated findings on possible mechanisms underlying differential effects of alcohol on male and female offspring, with special emphasis on effects at different levels of the HPA axis, and on modulatory influences of the hypothalamic-pituitary-gonadal hormones and serotonin Finally, possible mechanisms underlying foetal programming of the HPA axis, and the long-term implications of increased exposure to endogenous glucocorticoids for offspring vulnerability to illnesses or disorders later in life are discussed

The neuroendocrinology of stress: a never ending story.

Abstract: Evolutionary success depends on our ability to adapt to changing circumstances. The neuroendocrine response to stress is an excellent example of a plastic system that responds to threats to homeostasis and alters its output to meet current and expected future demands. At the level of the hypothalamus, the corticotroph secretagogues corticotrophin-releasing hormone (CRH) and arginine vasopressin (AVP) respond rapidly to an acute stressor but, following chronic stress, they adapt with a reduction of CRH but a major increase in AVP. The release of CRH and AVP activates pro-opiomelanocortin in anterior pituitary corticotroph cells and the release of adrenocorticotrophic hormone into peripheral blood from where it targets receptors in the adrenal cortex to release glucocorticoid hormones. These hormones (i.e. corticosterone in the rat and cortisol in man) are released in a pulsatile ultradian pattern which defines the normal circadian rhythm. The frequency of the pulses is increased under states of chronic stress, and in rats with genetically determined hyper-responsiveness of the hypothalamic-pituitary-adrenal axis. Interestingly, neonatal influences can also programme alterations in ultradian rhythmicity, implicating epigenetic factors in its regulation. At the level of tissue receptors, the alteration in pattern of glucocorticoid ultradian rhythm has differential effects on mineralocorticoid receptor and glucocorticoid receptor (GR) binding to DNA and offers a mechanism for tissue specific responses to altered glucocorticoid dynamics. The effects of neonatal experience are not only seen at the level of CRH and GR regulation, but also are evident in behavioural responses to stress and in the responsiveness of brain stem serotonergic pathways, as measured by tryptophan hydroxylase mRNA in the brain stem.

Prolactin: a pleiotropic neuroendocrine hormone.

Abstract: The neuroendocrine control of prolactin secretion is unlike that of any other pituitary hormone. It is predominantly inhibited by the hypothalamus and, in the absence of a regulatory feedback hormone, it acts directly in the brain to suppress its own secretion. In addition to this short-loop feedback action in the brain, prolactin has been reported to influence a wide range of other brain functions. There have been few attempts to rationalise why a single hormone might exert such a range of distinct and seemingly unrelated neuroendocrine functions. In this review, we highlight some of the original studies that first characterised the unusual features of prolactin neuroendocrinology, and then attempt to identify areas of new progress and/or controversy. Finally, we discuss a hypothesis that provides a unifying explanation for the pleiotrophic actions of prolactin in the brain.

The Placenta and Intrauterine Programming

Abstract: Intrauterine programming is the process by which the structure and function of tissues are altered permanently by insults acting during early development. In mammals, the placenta controls intrauterine development by supplying oxygen and nutrients, and by regulating the bioavailability of specific hormones involved in foetal growth and development. Consequently, the placenta is likely to have a key role in mediating the programming effects of suboptimal conditions during development. This review examines placental phenotype in different environmental conditions and places particular emphasis on regulation of placental nutrient transfer capacity and endocrine function by insults known to cause intrauterine programming. More specifically, it examines the effects of a range of environmental challenges on the size, morphology, blood flow and transporter abundance of the placenta and on its rate of consumption and production of nutrients. In addition, it considers the role of hormone synthesis and metabolism by the placenta in matching intrauterine development to the prevailing environmental conditions. The adaptive responses that the placenta can make to compensate for suboptimal conditions in utero are also assessed in relation to the strategies adopted to maximise foetal growth and viability at birth. Environmentally-induced changes in placental phenotype may provide a mechanism for transmitting the memory of early events to the foetus later in gestation, which leads to intrauterine programming of tissue development long after the original insult.

Adaptive Responses of the Maternal Hypothalamic-Pituitary-Adrenal Axis during Pregnancy and Lactation

Abstract: Over the past 40 years, it has been recognised that the maternal hypothalamic-pituitary-adrenal (HPA) axis undergoes adaptations through pregnancy and lactation that might contribute to avoidance of adverse effects of stress on the mother and offspring. The extent of the global adaptations in the HPA axis has been revealed and the underlying mechanisms investigated within the last 20 years. Both basal, including the circadian rhythm, and stress-induced adrenocorticotrophic hormone and glucocorticoid secretory patterns are altered. Throughout most of pregnancy, and in lactation, these changes predominantly reflect reduced drive by the corticotropin-releasing factor (CRF) neurones in the parvocellular paraventricular nucleus (pPVN). An accompanying profound attenuation of HPA axis responses to a wide variety of psychological and physical stressors emerges after mid-pregnancy and persists until the end of lactation. Central to this suppression of stress responsiveness is reduced activation of the pPVN CRF neurones. This is consequent on the reduced effectiveness of the stimulation of brainstem afferents to these CRF neurones (for physical stressors) and of altered processing by limbic structures (for emotional stressors). The mechanism of reduced CRF neurone responses to physical stressors in pregnancy is the suppression of noradrenaline release in the PVN by an up-regulated endogenous opioid mechanism, which is induced by neuroactive steroid produced from progesterone. By contrast, in lactation suckling the young provides a neural stimulus that dampens the HPA axis circadian rhythm and reduces stress responses. Reduced noradrenergic input activity is involved in reduced stress responses in lactation, although central prolactin action also appears important. Such adaptations limit the adverse effects of excess glucocorticoid exposure on the foetus(es) and facilitate appropriate metabolic and immune responses.

Aromatase in the Brain: Not Just for Reproduction Anymore

Abstract: Aromatase, the enzyme that synthesises oestrogens from androgen precursors, is expressed in the brain, where it has been classically associated with the regulation of neuroendocrine events and behaviours linked with reproduction. Recent findings, however, have revealed new unexpected roles for brain aromatase, indicating that the enzyme regulates synaptic activity, synaptic plasticity, neurogenesis and the response of neural tissue to injury, and may contribute to control nonreproductive behaviours, mood and cognition. Therefore, the function of brain aromatase is not restricted to the regulation of reproduction as previously thought.

Reproduction‐Induced Neuroplasticity: Natural Behavioural and Neuronal Alterations Associated with the Production and Care of Offspring

Abstract: As a female transitions into motherhood, many neurobiological adaptations are required to meet the demands presented by her offspring. In addition to the traditional maternal responses (e.g. crouching, nursing, retrieving, grooming), our laboratories have observed several behavioural modifications accompanying parity, especially in the areas of foraging and emotional resilience. Additionally, brain modifications have been observed in the hippocampus and amygdala, providing support for neural plasticity extending beyond the expected hypothalamic alterations. Interestingly, we have observed parenting-induced neuroplasticity to persist into late adulthood, even providing protection against age-related brain and memory deficits. Although the majority of work on the parental brain has been conducted on females, preliminary research suggests similar changes in the biparental male California deer mouse. Taken together, research suggests that the parental brain is dynamic and changeable as it undergoes diverse and, in some cases, long-lasting, modifications to facilitate the production and care of offspring.

Cytokine Networks and the Regulation of Uterine Function in Pregnancy and Parturition

Abstract: Complex cytokine networks play an important role in a wide range of reproductive and pregnancy related processes. Here, we review the current knowledge concerning the impact of cytokines on uterine physiology and pathophysiology. Cytokines influence a range of uterine functions during the menstrual cycle, implantation, pregnancy and labour. The synergistic interactions between individual cytokines are intricate and dynamic, and modulated by pregnancy hormones. It is not surprising therefore, that perturbations to cytokine signalling are associated with adverse pregnancy outcomes, such as miscarriage, pre-eclampsia, preterm labour and foetal brain injury. Further insight into the complexity of cytokine networks will be required to develop novel therapeutic strategies for the treatment of cytokine imbalances in pregnancy.

Epigenetic programming of phenotypic variations in reproductive strategies in the rat through maternal care.

Abstract: Studies across multiple organisms reveal considerable phenotypic variation in reproductive tactics. In some species, this variation is associated with maternal effects in which variation in maternal investment results in stable individual differences in reproductive function. Recent studies with the rat suggest that maternal effects can alter the function of neuroendocrine systems associated with female sexual behaviour as well as maternal behaviour. These maternal effects appear to be mediated by epigenetic modifications at the promoter for oestrogen receptor alpha (ERalpha) and subsequent effects on gene expression. The tissue-specific nature of such effects may underlie the co-ordinated variation in multiple forms of reproductive function, resulting in distinct reproductive strategies.

Behavioural Assays to Model Cognitive and Affective Dimensions of Depression and Anxiety in Rats

Abstract: Animal models have been used extensively to investigate neuropsychiatric disorders, such as depression, and their treatment. However, the aetiology and pathophysiology of many such disorders are largely unknown, which makes validation of animal models particularly challenging. Furthermore, many diagnostic symptoms are difficult to define, operationalise and quantify, especially in experimental animals such as rats. Thus, rather than attempting to model complex human syndromes such as depression in their entirety, it can be more productive to define and model components of the illness that may account for clusters of co-varying symptoms, and that may share common underlying neurobiological mechanisms. In preclinical investigations of the neural regulatory mechanisms linking stress to depression and anxiety disorders, as well as the mechanisms by which chronic treatment with antidepressant drugs may exert their beneficial effects in these conditions, we have employed a number of behavioural tests in rats to model specific cognitive and anxiety-like components of depression and anxiety disorders. In the present study, we review the procedures for conducting four such behavioural assays: the attentional set-shifting test, the elevated-plus maze, the social interaction test and the shock-probe defensive burying test. The purpose is to serve as a guide to the utility and limitations of these tools, and as an aid in optimising their use and productivity.

Endogenous Cannabinoids: Structure and Metabolism

Abstract: The finding of specific binding sites for Delta(9)-tetrahydrocannabinol, the psychoactive component of Cannabis sativa, has led to the discovery of the endocannabinoid system and has emphasised the physiological and pathological relevance of endocannabidoid lipid signalling. Subsequently, an increasing number of papers have been published on the biochemistry and pharmacology of endocannabinoids. An overview of the current understanding of structure and metabolism of the best studied endocannabinoids is provided, with a focus on the mechanisms responsible for their biosynthesis and inactivation.

The mechanisms and regulation of placental amino acid transport to the human foetus.

Abstract: The mechanisms by which amino acids are transferred across the human placenta are fundamental to our understanding of foetal nutrition. Amino acid transfer across the human placenta is dependent on transport across both the microvillous and basal plasma membranes of the placental syncytiotrophoblast, and on metabolism within the syncytiotrophoblast. Although the principles underlying uptake of amino acids across the microvillous plasma membrane are well understood, the extent to which amino acids are metabolised within human placenta and the mechanisms by which amino acids are transported out of the placenta across the basal plasma membrane are not well understood. Understanding the mechanisms and regulation of amino acid transport is necessary to understand the causes of intrauterine growth restriction in human pregnancy.

RFamide-related peptide and its cognate receptor in the sheep: cDNA cloning, mRNA distribution in the hypothalamus and the effect of photoperiod.

Abstract: Photoperiodic responses enable animals to adapt their physiology to predictable patterns of seasonal environmental change. In mammals, this depends on pineal melatonin secretion and effects in the hypothalamus, but the cellular and molecular substrates of its action are poorly understood. The recent identification of a mammalian orthologue of the avian gonadotrophin-inhibitory hormone gene has led to interest in its possible involvement in seasonal breeding. In long-day breeding Syrian hamsters, hypothalamic RFamide-related peptide (RFRP) expression is increased by exposure to long photoperiod. Because, opposite to hamsters, sheep are short-day breeders, we predicted that a conserved role in mammalian reproductive activation would decrease RFRP expression in sheep under a long photoperiod. We cloned the ovine RFRP cDNA and examined its expression pattern in Soay sheep acclimated to a 16 : 8 h or 8 : 16 h light /dark cycle (LP and SP, respectively). RFRP was expressed widely in the sheep hypothalamus and increased modestly overall with exposure to LP. Interestingly, RFRP expression in the ependymal cells surrounding the base of the third ventricle was highly photoperiodic, with levels being undetectable in animals held on SP but consistently high under LP. These data are inconsistent with a conserved reproductive role for RFRP across mammals. Additionally, we cloned the ovine homologue of the cognate RFRP receptor, rfr-2 (NPFF1) and found localised expression in the suprachiasmatic nuclei and in the pars tuberalis. Taken together, these data strengthen the emerging view that interplay between ependymal cells and the pars tuberalis might be important for the seasonal timing system.

Sex steroids and cognitive function.

Abstract: Gonadal hormones, most notably oestradiol, enhance some aspects of cognitive function in animal and human models. However, the demonstrated effects are often not large and inconsistent across studies. Nonetheless, because increased numbers of women are living longer in a state of oestrogen deprivation, research on this topic continues to be important. This review traces major developments concerning hormonal influences on cognition and provides some insights from recent studies that may be fruitful for future research.

KiSS-1 and GPR54 Genes are Co-Expressed in Rat Gonadotrophs and Differentially Regulated In Vivo by Oestradiol and Gonadotrophin-Releasing Hormone

Abstract: Kisspeptin, the product derived from KiSS-1, and its cognate receptor, GPR54, both exert a role in the neuroendocrine control of reproduction by regulating gonadotrophin-releasing hormone (GnRH) secretion. In the present study, we demonstrate, using dual immunofluorescence with specific antibodies, that the KiSS-1 and GPR54 genes are both expressed in rat gonadotrophs. All luteinising hormone beta-immunoreactive (LH beta-ir) cells were stained by the KiSS-1 antibody but some kisspeptin-ir cells were not LH beta positive; thus, we cannot exclude the possibility that kisspeptins are expressed in other pituitary cells. All GPR54-ir are co-localised with LH beta cells, but only a subset of LH beta cells are stained with the GPR54 antibody. Using the real-time reverse transcription-polymerase chain reaction (RT-PCR), we found that the expression of KiSS-1 and GPR54 is differentially regulated by steroids. In the female, KiSS-1 mRNA levels dramatically decreased following ovariectomy (OVX), and this decrease was prevented by administration of 17beta-oestradiol (E(2)), but not by administration of GnRH antagonist or agonist. Administration of E(2) in OVX rats receiving either GnRH antagonist or agonist clearly shows that E(2) acts directly on the pituitary to positively control KiSS-1 expression. In OVX rats, administration of the selective oestrogen receptor (ER)alpha ligand propylpyrazoletriol, but not the selective ER beta ligand diarylpropionitrile, mimics this effect. By contrast, our study shows that GPR54 expression is positively regulated by GnRH and negatively controlled by chronic exposure to E(2). In summary, our data document for the first time that, in the female rat pituitary, KiSS-1 expression is up-regulated by oestradiol, similarly to that seen in the anteroventral periventricular nucleus of the hypothalamus. Conversely, GPR54 is up-regulated by GnRH, which exclusively targets gonadotrophs.

Interplay between endocannabinoids, steroids and cytokines in the control of human reproduction.

Abstract: The use of marijuana, which today is the most used recreational drug, has been demonstrated to affect adversely reproduction. Marijuana smokers, both men and women, show impaired fertility, owing to defective signalling pathways, aberrant hormonal regulation, or wrong timing during embryo implantation. Anandamide (N-arachidonoylethanolamine, AEA) and 2-arachidonoylglycerol (2-AG) mimic Delta(9)-tetrahydrocannabinol (THC), the psychoactive principle of Cannabis sativa, by binding to both the brain-type (CB(1)) and the spleen-type (CB(2)) cannabinoid receptors. These 'endocannabinoids' exert several actions either in the central nervous system or in peripheral tissues, and are metabolised by specific enzymes that synthesise or hydrolyse them. In this review, we shall describe the elements that constitute the endocannabinoid system (ECS), in order to put in a better perspective the role of this system in the control of human fertility, both in females and males. In addition, we shall discuss the interplay between ECS, sex hormones and cytokines, which generates an endocannabinoid-hormone-cytokine array critically involved in the control of human reproduction.

Two decades of circadian time.

Abstract: Circadian rhythms coordinate our physiology at a fundamental level. Over the last 20 years, we have witnessed a paradigm shift in our perception of what the clocks driving such rhythms actually are, moving from 'black boxes' to talking about autoregulatory transcriptional/post-translational feedback loops with identified molecular components. We also now know that the pacemaker of the suprachiasmatic nuclei (SCN) is not our only clock but quite the opposite because circadian clocks abound in our bodies, driving local rhythms of cellular metabolism, and synchronised to each other and to solar time, by cues from the SCN. This discovery of dispersed local clocks has far-reaching implications for understanding our physiology and the pathological consequences of clock dysfunction, revealing that clocks are critical in a variety of metabolic and neurological conditions, all of which have long-term morbidity attributable to them. Without the currently available molecular framework, these insights would have not have been possible. In the circadian future, a growing appreciation of the systems-level functioning of these clocks and their various cerebral and visceral outputs, will likely stimulate the development of novel therapies for major illnesses.

Biology of Post‐Traumatic Stress Disorder in Childhood and Adolescence

Abstract: Diverse patterns of cortisol secretion with consistently high circulating catecholamines have been reported in post-traumatic stress disorder (PTSD), an anxiety state that develops after exposure to traumatic life events. Indeed, peripheral cortisol levels have been reported to be low or normal in the majority of adult chronic PTSD studies, whereas, in most paediatric studies, high cortisol values have been documented. Longitudinal studies on PTSD biology, including the transition from childhood to adulthood, may shed light on these discrepancies. In children, elevated evening salivary cortisol in the aftermath of the trauma was predictive of PTSD development 6 months later, whereas plasma interleukin-6 correlated positively with evening cortisol and was equally predictive of later PTSD. Longitudinal assessment of PTSD children 1 and 6 months later revealed progressive normalisation of cortisol levels, whereas noradrenaline concentrations became gradually higher. We hypothesise that, in adults with chronic PTSD, low cortisol levels, together with high catecholamines, may reflect a late event in the natural history of the disorder, months or years after the trauma. The progressive divergence of cortisol and noradrenaline concentrations over time may be responsible for PTSD maintenance in children and explain the differences between the child and adult PTSD endophenotypes. In adults studied immediately after the trauma, and by contrast to children, low cortisol levels are predictive of later PTSD development. Our hypothesis that low cortisol levels may reflect a previous trauma, earlier in development, is supported by the well established observation that prior trauma is a risk factor for a new PTSD diagnosis. The developmental stage of an individual in relation to previous exposure to trauma and PTSD vulnerability are crucial variables that may determine clinical and biological PTSD phenotypes and explain the discrepancies between adults and children in reported cortisol levels.

Brain angiotensin II modulates sympathoadrenal and hypothalamic pituitary adrenocortical activation during stress.

Abstract: Angiotensin II (Ang II) type-1 (AT1) receptors are present in areas of the brain controlling autonomic nervous activity and the hypothalamic-pituitary-adrenal (HPA) axis, including CRH cells in the hypothalamic paraventricular nucleus (PVN). To determine whether brain AT1 receptors are involved in the activation of the HPA axis and sympathetic system during stress, we studied the effects of acute immobilization stress on plasma catecholamines, ACTH and corticosterone, and mRNA levels of CRH and CRH receptors (CRH-R) in the PVN in rats under central AT1 receptor blockade by the selective antagonist, Losartan. While basal levels of epinephrine, norepinephrine and dopamine in plasma were unaffected 30 min after i.c.v. injection of Losartan (10 microg), the increases after 5 and 20 min stress were blunted in Losartan treated rats (P < 0.05 for norepinephrine, and P < 0.01 for epinephrine and dopamine, vs controls). Basal or stress-stimulated plasma ACTH and corticosterone levels were unaffected by i.c.v. Losartan treatment. Using in situ hybridization studies, basal levels of CRH mRNA and CRH-R mRNA in the PVN were unchanged after i.c.v. Losartan. While Losartan had no effect on the increases in CRH-R mRNA levels 2 or 3 h after 1 h immobilization, it prevented the increases in CRH mRNA. The blunted plasma catecholamine responses after central AT1 receptor blockade indicate that endogenous Ang II in the brain is required for sympathoadrenal activation during immobilization stress. While Ang II appears not to be involved in the acute secretory response of the HPA axis, it may play a role in regulating CRH expression in the PVN.

Glial-gonadotrophin hormone (GnRH) neurone interactions in the median eminence and the control of GnRH secretion

Abstract: A wealth of information now exists showing that glial cells are actively involved in the cell–cell communication process generating and disseminating information within the central nervous system. In the hypothalamus, two types of glial cells, astrocytes and ependymal cells lining the latero-ventral portion of the third ventricle (known as tanycytes), regulate the secretory activity of neuroendocrine neurones. This function, initially described for astrocytes apposing magnocellular neurones, has been more recently characterised for neurones secreting gonadotrophin hormone-releasing hormone (GnRH). The available evidence suggests that glial cells of the median eminence regulate GnRH secretion via two related mechanisms. One involves the production of growth factors acting via receptors with tyrosine kinase activity. The other involves plastic rearrangements of glia–GnRH neurone adhesiveness. GnRH axons reach the median eminence, at least in part, directed by basic fibroblast growth factor. Their secretory activity is facilitated by insulin-like growth factor 1 and members of the epidermal growth factor family. A structural complement to these soluble molecules is provided by at least three cell–cell adhesion systems endowed with signalling capabilities. One of them uses the neuronal cell adhesion molecule (NCAM), another employs the synaptic cell adhesion molecule (SynCAM), and the third one consists of neuronal contactin interacting with glial receptor-like protein tyrosine phosphatase-β. It is envisioned that, within the median eminence, soluble factors and adhesion molecules work coordinately to control delivery of GnRH to the portal vasculature.

Maternal antenatal anxiety and amniotic fluid cortisol and testosterone: possible implications for foetal programming.

Abstract: Both animal and human studies have shown that maternal stress or anxiety during pregnancy is associated with increased risk of disturbance in offspring neurodevelopment and behaviour. In animal models, increased foetal exposure to glucocorticoids has been found to be one mechanism for such foetal programming. Little is understood of the mediating mechanisms in humans, and one aim of our research programme is to investigate this further. This review presents a synopsis of some of our recent results. We aimed to test the hypothesis that maternal anxiety was associated with raised maternal cortisol, and that this in turn was related to increased foetal exposure to cortisol. We studied this by recruiting women at amniocentesis, obtained their Spielberger State Anxiety scores, and assessed maternal plasma cortisol and amniotic fluid cortisol. We also examined maternal plasma and amniotic fluid testosterone levels. Awaiting amniocentesis was in general anxiogenic, but with a wide range of anxiety scores. Maternal anxiety was significantly associated with plasma cortisol before 17 weeks, albeit of modest magnitude (r = 0.0.23), and not after 17 weeks of gestation. This is probably due to the known attenuation of the maternal hypothalamic-pituitary-adrenal axis with increasing gestation. We found a strong correlation between maternal plasma and amniotic fluid cortisol levels, which increased with gestation and became robust after 18 weeks. This correlation increased with maternal anxiety, suggesting a possible effect of maternal mood on placental function. There was a positive correlation between cortisol and testosterone in amniotic fluid, in both male and female foetuses independent of maternal anxiety, plasma testosterone, gestational age, and time of collection. Foetal stress may be associated with increased foetal exposure to testosterone. However, maternal anxiety did not predict amniotic fluid cortisol or testosterone level. Thus, the role of these hormones in mediating the effect of maternal mood on foetal development in humans remains to be demonstrated.

The Tissue‐Specific Processing of Pro‐Opiomelanocortin

Abstract: It is just over 30 years since the definitive identification of the adrenocorticotrophin (ACTH) precursor, pro-opiomelanocotin (POMC). Although first characterised in the anterior and intermediate lobes of the pituitary, POMC is also expressed in a number of both central and peripheral tissues including the skin, central nervous tissue and placenta. Following synthesis, POMC undergoes extensive post-translational processing producing not only ACTH, but also a number of other biologically active peptides. The extent and pattern of this processing is tissue-specific, the end result being the tissue dependent production of different combinations of peptides from the same precursor. These peptides have a diverse range of biological roles ranging from pigmentation to adrenal function to the regulation of feeding. This level of complexity has resulted in POMC becoming the archetypal model for prohormone processing, illustrating how a single protein combined with post-translational modification can have a diverse number of roles.

Endocannabinoids and the regulation of bone metabolism.

Abstract: In mammals, including humans, bone metabolism is manifested as an ongoing modelling/remodelling process whereby the bone mineralised matrix is being continuously renewed. Recently, the main components of the endocannabinoid system have been reported in the skeleton. Osteoblasts, the bone forming cells, and other cells of the osteoblastic lineage, as well as osteoclasts, the bone resorbing cells, and their precursors, synthesise the endocannabinoids anandamide and 2-arachidonoylglycerol (2-AG). CB(1) cannabinoid receptors are present in sympathetic nerve terminals in close proximity to osteoblasts. Activation of these CB(1) receptors by elevated bone 2-AG levels communicates brain-to-bone signals as exemplified by traumatic brain injury-induced stimulation of bone formation. In this process, the retrograde CB(1) signalling inhibits noradrenaline release and alleviates the tonic sympathetic restrain of bone formation. CB(2) receptors are expressed by osteoblasts and osteoclasts. Their activation stimulates bone formation and suppresses bone resorption. CB(2)-deficient mice display a markedly accelerated age-related bone loss. Ovariectomy-induced bone loss can be both prevented and rescued by a CB(2) specific agonist. Hence, synthetic CB(2) ligands, which are stable and orally available, provide a basis for developing novel anti-osteoporotic therapies, free of psychotropic effects. The CNR2 gene (encoding CB(2)) in women is associated with low bone mineral density, offering an assay for identifying females at risk of developing osteoporosis.

Pregnancy-Induced Adaptation in the Neuroendocrine Control of Prolactin Secretion

Abstract: During pregnancy, neuroendocrine control of prolactin secretion is markedly altered to allow a state of hyperprolactinaemia to develop. Prolactin secretion is normally tightly regulated by a short-loop negative-feedback mechanism, whereby prolactin stimulates activity of tuberoinfundibular dopamine (TIDA) neurones to increase dopamine secretion into the pituitary portal blood. Dopamine inhibits prolactin secretion, thus reducing prolactin concentrations in the circulation back to the normal low level. Activation of this feedback secretion by placental lactogen during pregnancy maintains relatively low levels of prolactin secretion during early and mid-pregnancy. Despite the continued presence of placental lactogen, however, dopamine secretion from TIDA neurones is reduced during late pregnancy. Moreover, the neurones become completely unresponsive to endogenous or exogenous prolactin at this time, allowing a large nocturnal surge of prolactin to occur from the maternal pituitary gland during the night before parturition. In this review, we describe the changing patterns of prolactin secretion during pregnancy in the rat, and discuss the neuroendocrine mechanisms controlling these changes. The loss of response to prolactin is an important maternal adaptation to pregnancy, allowing the prolonged period of hyperprolactinaemia required for mammary gland development and function and for maternal behaviour immediately after parturition, and possibly also contributing to a range of other adaptive responses in the mother.