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  • The hypothalamic-pituitary-adrenal axis as a substrate for stress resilience: Interactions with the circadian clock
    Front. Neuroendocrin. (IF 7.852) Pub Date : 2019-12-19
    Scott A. Kinlein; Ilia N. Karatsoreos

    Stress, primarily processed via the hypothalamic-pituitary-adrenal (HPA) axis, engages biological pathways throughout the brain and body which promote adaptation and survival to changing environmental demands. Adaptation to environmental challenges is compromised when these pathways are no longer functioning optimally. The physiological and behavioral mechanisms through which HPA axis function influences stress adaptation and resilience are not fully elucidated. Our understanding of stress biology and disease must take into account the complex interactions between the endocrine system, neural circuits, and behavioral coping strategies. In addition, further consideration must be taken concerning influences of other aspects of physiology, including the circadian clock which is critical for regulation of daily changes in HPA activity. While adding a layer of complexity, it also offers targets for intervention. Understanding the role of HPA function in mediating these diverse biological responses will lead to important insights about how to bolster successful stress adaptation and promote stress resilience.

  • The Promises and Pitfalls of Sex Difference Research
    Front. Neuroendocrin. (IF 7.852) Pub Date : 2019-12-16
    Liisa AM Galea; Elena Choleris; Arianne YK Albert; Margaret M McCarthy; Farida Sohrabji

    Funding agencies in North America and Europe are recognizing the importance of the integration of sex differences into basic and clinical research. Although these mandates are in place to improve our knowledge of health for both men and women, there have been a number of implementation issues that require vigilance on the part of funders and the research community. Here we discuss issues on simple inclusion of both sexes in studies to specialisation of sex differences with attention paid to statistics and the need for sex-specific treatments. We suggest differing mandates need to be considered regarding simple integration versus the need for studies in the specialisation of sex differences and/or the need for research that recognises the importance of male-specific or female-specific factors that influence subsequent health such as menstruation, menopause or pregnancy.

  • The role of hippocampal estradiol in synaptic plasticity and memory: A systematic review
    Front. Neuroendocrin. (IF 7.852) Pub Date : 2019-12-13
    CA. Finney; A. Shvetcov; RF. Westbrook; NM. Jones; MJ. Morris

    The consolidation of long-term memory is influenced by various neuromodulators. One of these is estradiol, a steroid hormone that is synthesized both in peripheral endocrine tissue and in the brain, including the hippocampus. Here, we examine the evidence regarding the role of estradiol in the hippocampus, specifically, in memory formation and its effects on the molecular mechanisms underlying synaptic plasticity. We conclude that estradiol improves memory consolidation and, thereby, long-term memory. Previous studies have shown that it does this in three, interconnected ways : 1) via functional changes in excitatory activity, 2) signaling changes in calcium dynamics, protein phosphorylation and protein expression, and 3) structural changes to synaptic morphology. Through a functional network analysis of proteins affected by estradiol, we identify potential protein-protein interactions that further support a role for estradiol in modulating synaptic plasticity as well as highlight signaling pathways that may be involved in these changes within the hippocampus.

  • You’ve Got Male: Sex and the Microbiota-Gut Brain Axis Across the Lifespan
    Front. Neuroendocrin. (IF 7.852) Pub Date : 2019-12-02
    Minal Jaggar, Kieran Rea, Simon Spicak, Timothy G. Dinan, John F. Cryan

    Sex is a critical factor in the diagnosis and development of a number of mental health disorders including autism, schizophrenia, depression, anxiety, Parkinson’s disease, multiple sclerosis, anorexia nervosa and others; likely due to differences in sex steroid hormones and genetics. Recent evidence suggests that sex can also influence the complexity and diversity of microbes that we harbour in our gut; and reciprocally that our gut microbes can directly and indirectly influence sex steroid hormones and central gene activation. There is a growing emphasis on the role of gastrointestinal microbiota in the maintenance of mental health and their role in the pathogenesis of disease. In this review, we introduce mechanisms by which gastrointestinal microbiota are thought to mediate positive health benefits along the gut-brain axis, we report how they may be modulated by sex, the role they play in sex steroid hormone regulation, and their sex-specific effects in various disorders relating to mental health.

  • Central aromatization: a dramatic and responsive defense against threat and trauma to the vertebrate brain
    Front. Neuroendocrin. (IF 7.852) Pub Date : 2019-11-28
    Kelli A. Duncan, Colin J. Saldanha

    Aromatase is the requisite and limiting enzyme in the production of estrogens from androgens. Estrogens synthesized centrally have also emerged as a potent neuroprotectant in the vertebrate brain. Studies in rodents and songbirds have identified key mechanisms that underlie both; the injury-dependent induction of central aromatization, and the protective effects of centrally synthesized estrogens. Injury-induced aromatase expression in astrocytes occurs following a broad range of traumatic brain damage including excitotoxic, penetrating, and concussive injury. Responses to neural insult such as edema and inflammation involve signaling pathways the components of which are excellent candidates as inducers of this astrocytic response. Finally, estradiol from astrocytes exerts a paracrine neuroprotective influence via the potent inhibition of inflammatory pathways. Taken together, these data suggest a novel role for neural aromatization as a protective mechanism against the threat of inflammation and suggests that central estrogen provision is a wide-ranging neuroprotectant in the vertebrate brain.

  • In search of optimal resilience ratios: Differential influences of neurobehavioral factors contributing to stress-resilience spectra
    Front. Neuroendocrin. (IF 7.852) Pub Date : 2019-11-15
    Kelly Lambert, Richard G. Hunter, Andrew A. Bartlett, Hannah E. Lapp, Molly Kent

    The ability to adapt to stressful circumstances, known as emotional resilience, is a key factor in the maintenance of mental health. Several individual biomarkers of the stress response (e.g., corticosterone) that influence an animal’s position along the continuum that ranges from adaptive allostasis to maladaptive allostatic load have been identified. Extending beyond specific biomarkers of stress responses, however, it is also important to consider stress-related responses relative to other relevant responses for a thorough understanding of the underpinnings of adaptive allostasis. In this review, behavioral, neurobiological, developmental and genomic variables are considered in the context of emotional resilience [e.g., explore/exploit behavioral tendencies; DHEA/CORT ratios and relative proportions of protein-coding/nonprotein-coding (transposable) genomic elements]. As complex and multifaceted relationships between pertinent allostasis biomediators are identified, translational applications for optimal resilience are more likely to emerge as effective therapeutic strategies.

  • Galanin peptide family regulation of glucose metabolism
    Front. Neuroendocrin. (IF 7.852) Pub Date : 2019-11-06
    Penghua Fang, Mei Yu, Mingyi Shi, Ping Bo, Zhenwen Zhang

    Recent preclinical and clinical studies have indicated that the galanin peptide family may regulate glucose metabolism and alleviate insulin resistance, which diminishes the probability of type 2 diabetes mellitus. The galanin was discovered in 1983 as a gut-derived peptide hormone. Subsequently, galanin peptide family was found to exert a series of metabolic effects, including the regulation of gut motility, body weight and glucose metabolism. The galanin peptide family in modulating glucose metabolism received recently increasing recognition because pharmacological activiation of galanin signaling might be of therapeutic value to improve insuin resistance and type 2 diabetes mellitus. To date, however, few papers have summarized the role of the galanin peptide family in modulating glucose metabolism and insulin resistance. In this review we summarize the metabolic effect of galanin peptide family and highlight its glucoregulatory action and discuss the pharmacological value of galanin pathway activiation for the treatment of glucose intolerance and type 2 diabetes.

  • Individual differences in glucocorticoid regulation: Does it relate to disease risk and resilience?
    Front. Neuroendocrin. (IF 7.852) Pub Date : 2019-11-04
    Jasmine I. Caulfield, Sonia A, Cavigelli

    Glucocorticoid (GC) signaling varies among individuals, and this variation may relate to individual differences in health outcomes. To determine if and which aspects of signaling (basal, circadian, integrative, or reactivity) are associated with specific health outcomes, we reviewed recent studies that relate GCs to health outcomes. We identified papers through PubMed and reviewed 100 original research articles related to mental health, cardiovascular health, cancer, diabetes, obesity, pulmonary health, sleep, and fitness. Many studies reported elevated GC secretion associated with worse health, but this was only particularly true for integrative GC measures. On the other hand, accentuated cortisol awakening response and a steeper circadian rhythm were both associated with positive health outcomes. Overall, relationships between GC secretion and health outcomes were relatively weak. This systematic review of relationships between GC metrics and health outcomes highlights the importance of careful consideration when selecting methods to measure GC regulation in health research.

  • Sex differences in steroid levels and steroidogenesis in the nervous system: physiopathological role
    Front. Neuroendocrin. (IF 7.852) Pub Date : 2019-11-02
    Silvia Giatti, Silvia Diviccaro, Melania Maria Serafini, Donatella Caruso, Luis Miguel Garcia-Segura, Barbara Viviani, Roberto C. Melcangi

    The nervous system, in addition to be a target for steroid hormones, is the source of a variety of neuroactive steroids, which are synthesized and metabolized by neurons and glial cells. Recent evidence indicates that the expression of neurosteroidogenic proteins and enzymes and the levels of neuroactive steroids are different in the nervous system of males and females. We here summarized the state of the art of neuroactive steroids, particularly taking in consideration sex differences occurring in the synthesis and levels of these molecules. In addition, we discuss the consequences of sex differences in neurosteroidogenesis for the function of the nervous system under healthy and pathological conditions and the implications of neuroactive steroids and neurosteroidogenesis for the development of sex-specific therapeutic interventions.

  • Estrogen neuroprotection and the critical period hypothesis.
    Front. Neuroendocrin. (IF 7.852) Pub Date : 2011-11-15
    Erin Scott,Quan-guang Zhang,Ruimin Wang,Ratna Vadlamudi,Darrell Brann

    17β-Estradiol (estradiol or E2) is implicated as a neuroprotective factor in a variety of neurodegenerative disorders. This review focuses on the mechanisms underlying E2 neuroprotection in cerebral ischemia, as well as emerging evidence from basic science and clinical studies, which suggests that there is a "critical period" for estradiol's beneficial effect in the brain. Potential mechanisms underlying the critical period are discussed, as are the neurological consequences of long-term E2 deprivation (LTED) in animals and in humans after natural menopause or surgical menopause. We also summarize the major clinical trials concerning postmenopausal hormone therapy (HT), comparing their outcomes with respect to cardiovascular and neurological disease and discussing their relevance to the critical period hypothesis. Finally, potential caveats, controversies and future directions for the field are highlighted and discussed throughout the review.

  • Dynamic limbic networks and social diversity in vertebrates: from neural context to neuromodulatory patterning.
    Front. Neuroendocrin. (IF 7.852) Pub Date : 2009-06-13
    James L Goodson,David Kabelik

    Vertebrate animals exhibit a spectacular diversity of social behaviors, yet a variety of basic social behavior processes are essential to all species. These include social signaling; discrimination of conspecifics and sexual partners; appetitive and consummatory sexual behaviors; aggression and dominance behaviors; and parental behaviors (the latter with rare exceptions). These behaviors are of fundamental importance and are regulated by an evolutionarily conserved, core social behavior network (SBN) of the limbic forebrain and midbrain. The SBN encodes social information in a highly dynamic, distributed manner, such that behavior is most strongly linked to the pattern of neural activity across the SBN, not the activity of single loci. Thus, shifts in the relative weighting of activity across SBN nodes can conceivably produce almost limitless variation in behavior, including diversity across species (as weighting is modified through evolution), across behavioral contexts (as weights change temporally) and across behavioral phenotypes (as weighting is specified through heritable and developmental processes). Individual neural loci may also express diverse relationships to behavior, depending upon temporal variations in their functional connectivity to other brain regions ("neural context"). We here review the basic properties of the SBN and show how behavioral variation relates to functional connectivity of the network, and discuss ways in which neuroendocrine factors adjust network activity to produce behavioral diversity. In addition to the actions of steroid hormones on SBN state, we examine the temporally plastic and evolutionarily labile properties of the nonapeptides (the vasopressin- and oxytocin-like neuropeptides), and show how variations in nonapeptide signaling within the SBN serve to promote behavioral diversity across social contexts, seasons, phenotypes and species. Although this diversity is daunting in its complexity, the search for common "organizing principles" has become increasingly fruitful. We focus on multiple aspects of behavior, including sexual behavior, aggression and affiliation, and in each of these areas, we show how broadly relevant insights have been obtained through the examination of behavioral diversity in a wide range of vertebrate taxa.

  • The neuroendocrinology of the social brain.
    Front. Neuroendocrin. (IF 7.852) Pub Date : 2009-07-15
    Larry J Young

  • Social buffering of the stress response: diversity, mechanisms, and functions.
    Front. Neuroendocrin. (IF 7.852) Pub Date : 2009-06-24
    Michael B Hennessy,Sylvia Kaiser,Norbert Sachser

    Protracted or repeated activation of the hypothalamic-pituitary-adrenocortical (HPA) system is associated with a variety of physical and psychological pathologies. Studies dating back to the 1970s have documented many cases in which the presence of a social companion can moderate HPA responses to stressors. However, there also are many cases in which this "social buffering" of the HPA axis is not observed. An examination of the literature indicates that the nature of the relationship between individuals is crucial in determining whether or not social buffering of the HPA response will occur. Other factors that affect social buffering, either directly or by influencing the social relationship, include the social organization of the species, previous experience, gender, integration into a social unit, and the developmental stage at which individuals are examined. Current evidence suggests that social buffering involves mechanisms acting at more than one level of the CNS. It is suggested that, in addition to promoting health, social buffering may have evolved to direct the establishment of social relationships, and to facilitate developmental transitions in social interactions appropriate for different life stages.

  • Oxytocin and the neural mechanisms regulating social cognition and affiliative behavior.
    Front. Neuroendocrin. (IF 7.852) Pub Date : 2009-06-02
    Heather E Ross,Larry J Young

    Oxytocin is produced in the hypothalamus and released into the circulation through the neurohypophyseal system. Peripherally released oxytocin facilitates parturition and milk ejection during nursing. Centrally released oxytocin coordinates the onset of maternal nurturing behavior at parturition and plays a role in mother-infant bonding. More recent studies have revealed a more general role for oxytocin in modulating affiliative behavior in both sexes. Oxytocin regulates alloparental care and pair bonding in female monogamous prairie voles. Social recognition in male and female mice is also modulated by oxytocin. In humans, oxytocin increases gaze to the eye region of human faces and enhances interpersonal trust and the ability to infer the emotions of others from facial cues. While the neurohypopheseal oxytocin system has been well characterized, less is known regarding the nature of oxytocin release within the brain. Here we review the role of oxytocin in the regulation of prosocial interactions, and discuss the neuroanatomy of the central oxytocin system.

  • Oxytocin, vasopressin, and human social behavior.
    Front. Neuroendocrin. (IF 7.852) Pub Date : 2009-06-10
    Markus Heinrichs,Bernadette von Dawans,Gregor Domes

    There is substantial evidence from animal research indicating a key role of the neuropeptides oxytocin (OT) and arginine vasopressin (AVP) in the regulation of complex social cognition and behavior. As social interaction permeates the whole of human society, and the fundamental ability to form attachment is indispensable for social relationships, studies are beginning to dissect the roles of OT and AVP in human social behavior. New experimental paradigms and technologies in human research allow a more nuanced investigation of the molecular basis of social behavior. In addition, a better understanding of the neurobiology and neurogenetics of human social cognition and behavior has important implications for the current development of novel clinical approaches for mental disorders that are associated with social deficits (e.g., autism spectrum disorder, social anxiety disorder, and borderline personality disorder). This review focuses on our recent knowledge of the behavioral, endocrine, genetic, and neural effects of OT and AVP in humans and provides a synthesis of recent advances made in the effort to implicate the oxytocinergic system in the treatment of psychopathological states.

  • Neuroendocrinology of social information processing in rats and mice.
    Front. Neuroendocrin. (IF 7.852) Pub Date : 2009-05-16
    Elena Choleris,Amy E Clipperton-Allen,Anna Phan,Martin Kavaliers

    We reviewed oxytocin (OT), arginine-vasopressin (AVP) and gonadal hormone involvement in various modes of social information processing in mice and rats. Gonadal hormones regulate OT and AVP mediation of social recognition and social learning. Estrogens foster OT-mediated social recognition and the recognition and avoidance of parasitized conspecifics via estrogen receptor (ER) alpha (ERalpha) and ERbeta. Testosterone and its metabolites, including estrogens, regulate social recognition in males predominantly via the AVP V1a receptor. Both OT and AVP are involved in the social transmission of food preferences and ERalpha has inhibitory, while ERbeta has enhancing, roles. OT also enhances mate copying by females. ERalpha mediates the sexual, and ERbeta the recognition, aspects of the risk-taking enhancing effects of females on males. Thus, androgens and estrogens control social information processing by regulating OT and AVP. This control is finely tuned for different forms of social information processing.

  • Neuroendocrinology and sexual differentiation in eusocial mammals.
    Front. Neuroendocrin. (IF 7.852) Pub Date : 2009-05-07
    Melissa M Holmes,Bruce D Goldman,Sharry L Goldman,Marianne L Seney,Nancy G Forger

    Sexual differentiation of the mammalian nervous system has been studied intensively for over 25 years. Most of what we know, however, comes from work on relatively non-social species in which direct reproduction (i.e., production of offspring) is virtually the only route to reproductive success. In social species, an individual's inclusive fitness may include contributions to the gene pool that are achieved by supporting the reproductive efforts of close relatives; this feature is most evident in eusocial organisms. Here, we review what is known about neuroendocrine mechanisms, sexual differentiation, and effects of social status on the brain and spinal cord in two eusocial mammals: the naked mole-rat and Damaraland mole-rat. These small rodents exhibit the most rigidly organized reproductive hierarchy among mammals, with reproduction suppressed in a majority of individuals. Our findings suggest that eusociality may be associated with a relative lack of sex differences and a reduced influence of gonadal hormones on some functions to which these hormones are usually tightly linked. We also identify neural changes accompanying a change in social and reproductive status, and discuss the implications of our findings for understanding the evolution of sex differences and the neuroendocrinology of reproductive suppression.

  • Testosterone release and social context: when it occurs and why.
    Front. Neuroendocrin. (IF 7.852) Pub Date : 2009-05-09
    Erin D Gleason,Matthew J Fuxjager,Temitayo O Oyegbile,Catherine A Marler

    The functions of rapid increases in testosterone seem paradoxical because they can occur in response to different social contexts, such as male-male aggressive encounters and male-female sexual encounters. This suggests that context may impact the functional consequences of changes in testosterone, whether transient or long term. Many studies, including those with California mice (Peromyscus californicus), have addressed these issues using manipulations and species comparisons, but many areas remain to be investigated. We report a study here that suggests transient increases in testosterone after social competition influence future competitive behavior, but social experience alone may also be critical in determining future behavior. In other rodents, a comparable testosterone surge occurs in response to sexual stimulation, but the function is not entirely understood. In addition to competitive and sexual behavior, testosterone impacts other systems instrumental to social behaviors, including paternal behavior and degree of monogamy. Thus, mechanisms regulated by testosterone, such as the vasopressin and aromatase systems, may also be influenced by rapid surges of testosterone in aggressive or sexual contexts. We discuss how the functions of testosterone may overlap in some contexts.

  • The advantage of social living: brain neuropeptides mediate the beneficial consequences of sex and motherhood.
    Front. Neuroendocrin. (IF 7.852) Pub Date : 2009-05-07
    Inga D Neumann

    Living in social groups is clearly beneficial for many species, often resulting in increased survival, enhanced fitness of the group, and progression of brain development and cognitive abilities. The development of the social brain has been promoted on the basis (i) of activation of reward centres by social stimuli, (ii) of positive consequences of close social interactions on emotionality (which is reinforcing by itself) and on general fitness, and (iii) of negative health consequences in the absence or as a result of sudden interruption of social interactions. For example, social interactions as seen between mother and child or between mating partners have beneficial effects on the mental and physical health state, in particular on adaptive processes related to emotional and physiological stress coping in both sexes. Here, the neurobiological basis of social behaviour, in particular the involvement of the brain neuropeptides, oxytocin and prolactin, in mediating such positive health effects will be discussed.

  • Early life stress, the development of aggression and neuroendocrine and neurobiological correlates: what can we learn from animal models?
    Front. Neuroendocrin. (IF 7.852) Pub Date : 2009-04-04
    Alexa H Veenema

    Early life stress (child and adolescent abuse, neglect and trauma) induces robust alterations in emotional and social functioning resulting in enhanced risk for the development of psychopathologies such as mood and aggressive disorders. Here, an overview is given on recent findings in primate and rodent models of early life stress, demonstrating that chronic deprivation of early maternal care as well as chronic deprivation of early physical interactions with peers are profound risk factors for the development of inappropriate aggressive behaviors. Alterations in the hypothalamic-pituitary-adrenocortical (HPA), vasopressin and serotonin systems and their relevance for the regulation of aggression are discussed. Data suggest that social deprivation-induced inappropriate forms of aggression are associated with high or low HPA axis (re)activity and a generally lower functioning of the serotonin system in adulthood. Moreover, genetic and epigenetic modifications in HPA and serotonin systems influence the outcome of early life stress and may even moderate adverse effects of early social deprivation on aggression. A more comprehensive study of aggression, neuroendocrine, neurobiological and (epi)genetic correlates of early life stress using animal models is necessary to provide a better understanding of the invasive aggressive deficits observed in humans exposed to child maltreatment.

  • The biology of gonadotropin hormone-releasing hormone: role in the control of tumor growth and progression in humans.
    Front. Neuroendocrin. (IF 7.852) Pub Date : 2004-01-17
    Patrizia Limonta,Roberta M Moretti,Marina Montagnani Marelli,Marcella Motta

    It is now well known that different forms of GnRH coexist in the same vertebrate species. In humans, two forms of GnRH have been identified so far. The first form corresponds to the hypophysiotropic decapeptide, and is now called GnRH-I. The second form has been initially identified in the chicken brain, and it is referred to as GnRH-II. GnRH-I binds to and activates specific receptors, belonging to the 7 transmembrane (7TM) domain superfamily, present on pituitary gonadotropes. These receptors (type I GnRH receptors) are coupled to the Gq/11/PLC intracellular signalling pathway. A receptor specific for GnRH-II (type II GnRH receptor) has been identified in non-mammalian vertebrates as well as in primates, but not yet in humans. In the last 10-15 years experimental evidence has been accumulated indicating that GnRH-I is expressed, together with its receptors, in tumors of the reproductive tract (prostate, breast, ovary, and endometrium). In these hormone-related tumors, activation of type I GnRH receptors consistently decreases cell proliferation, mainly by interfering with the mitogenic activity of stimulatory growth factors (e.g., EGF, IGF). Recent data seem to suggest that GnRH-I might also reduce the migratory and invasive capacity of cancer cells, possibly by affecting the expression and/or activity of cell adhesion molecules and of enzymes involved in the remodelling of the extracellular matrix. These observations point to GnRH-I as an autocrine negative regulatory factor on tumor growth progression and metastatization. Extensive research has been performed to clarify the molecular mechanisms underlying the peculiar antitumor activity of GnRH-I. Type I GnRH receptors in hormone-related tumors correspond to those present at the pituitary level in terms of cDNA nucleotide sequence and protein molecular weight, but do not share the same pharmacological profile in terms of binding affinity for the different synthetic GnRH-I analogs. Moreover, the classical intracellular signalling pathway mediating the stimulatory activity of the decapeptide on gonadotropin synthesis and secretion is not involved in its inhibitory activity on hormone-related tumor growth. In these tumors, type I GnRH receptors are coupled to the Gi-cAMP, rather than the Gq/11-PLC, signal transduction pathway. Recently, we have reported that GnRH-I and type I GnRH receptors are expressed also in tumors not related to the reproductive system, such as melanoma. Also in melanoma cells, GnRH-I behaves as a negative regulator of tumor growth and progression. Interestingly, the biochemical and pharmacological profiles of type I GnRH receptors in melanoma seem to correspond to those of the receptors at pituitary level. The data so far reported on the expression and on the possible functions of GnRH-II in humans are still scanty. The decapeptide has been identified, together with a 'putative' type II GnRH receptor, both in the central nervous system and in peripheral structures, such as tissues of the reproductive tract (both normal and tumoral). The specific biological functions of GnRH-II in humans are presently under investigation.

  • G-protein coupled receptor oligomerization in neuroendocrine pathways.
    Front. Neuroendocrin. (IF 7.852) Pub Date : 2004-01-17
    Karen M Kroeger,Kevin D G Pfleger,Karin A Eidne

    Protein-protein interactions are fundamental processes for many biological systems including those involving the superfamily of G-protein coupled receptors (GPCRs). A growing body of biochemical and functional evidence supports the existence of GPCR-GPCR homo- and hetero-oligomers. In particular, hetero-oligomers can display pharmacological and functional properties distinct from those of the homodimer or oligomer thus adding another level of complexity to how GPCRs are activated, signal and traffick in the cell. Dimerization may also play a role in influencing the activity of agonists and antagonists. We are only beginning to unravel how and why such complexes are formed, the functional implications of which will have an enormous impact on GPCR biology. Future research that studies GPCRs as dimeric or oligomeric complexes will enhance not only our understanding of GPCRs in cellular function but will also be critical for novel drug design and improved treatment of the vast array of GPCR-related conditions.

  • Leptin signaling in the hypothalamus: emphasis on energy homeostasis and leptin resistance.
    Front. Neuroendocrin. (IF 7.852) Pub Date : 2004-01-17
    Abhiram Sahu

    Leptin, the long-sought satiety factor of adipocytes origin, has emerged as one of the major signals that relay the status of fat stores to the hypothalamus and plays a significant role in energy homeostasis. Understanding the mechanisms of leptin signaling in the hypothalamus during normal and pathological conditions, such as obesity, has been the subject of intensive research during the last decade. It is now established that leptin action in the hypothalamus in regulation of food intake and body weight is mediated by a neural circuitry comprising of orexigenic and anorectic signals, including NPY, MCH, galanin, orexin, GALP, alpha-MSH, NT, and CRH. In addition to the conventional JAK2-STAT3 pathway, it has become evident that PI3K-PDE3B-cAMP pathway plays a critical role in leptin signaling in the hypothalamus. It is now established that central leptin resistance contributes to the development of diet-induced obesity and ageing associated obesity. Central leptin resistance also occurs due to hyperleptinimia produced by exogenous leptin infusion. A defective nutritional regulation of leptin receptor gene expression and reduced STAT3 signaling may be involved in the development of leptin resistance in DIO. However, leptin resistance in the hypothalamic neurons may occur despite an intact JAK2-STAT3 pathway of leptin signaling. Thus, in addition to defective JAK2-STAT3 pathway, defects in other leptin signaling pathways may be involved in leptin resistance. We hypothesize that defective regulation of PI3K-PDE3B-cAMP pathway may be one of the mechanisms behind the development of central leptin resistance seen in obesity.

  • Nutritional status in the neuroendocrine control of growth hormone secretion: the model of anorexia nervosa.
    Front. Neuroendocrin. (IF 7.852) Pub Date : 2003-11-05
    Massimo Scacchi,Angela Ida Pincelli,Francesco Cavagnini

    Growth hormone (GH) plays a key role not only in the promotion of linear growth but also in the regulation of intermediary metabolism, body composition, and energy expenditure. On the whole, the hormone appears to direct fuel metabolism towards the preferential oxidation of lipids instead of glucose and proteins, and to convey the energy derived from metabolic processes towards the synthesis of proteins. On the other hand, body energy stores and circulating energetic substrates take an important part in the regulation of somatotropin release. Finally, central and peripheral peptides participating in the control of food intake and energy expenditure (neuropeptide Y, leptin, and ghrelin) are also involved in the regulation of GH secretion. Altogether, nutritional status has to be regarded as a major determinant in the regulation of the somatotropin-somatomedin axis in animals and humans. In these latter, overweight is associated with marked impairment of spontaneous and stimulated GH release, while acute dietary restriction and chronic undernutrition induce an amplification of spontaneous secretion together with a clear-cut decrease in insulin-like growth factor I (IGF-I) plasma levels. Thus, over- and undernutrition represent two conditions connoted by GH hypersensitivity and GH resistance, respectively. Anorexia nervosa (AN) is a psychiatric disorder characterized by peculiar changes of the GH-IGF-I axis. In these patients, low circulating IGF-I levels are associated with enhanced GH production rate, highly disordered mode of somatotropin release, and variability of GH responsiveness to different pharmacological challenges. These abnormalities are likely due not only to the lack of negative IGF-I feedback, but also to a primary hypothalamic alteration with increased frequency of growth hormone releasing hormone discharges and decreased somatostatinergic tone. Given the reversal of the above alterations following weight recovery, these abnormalities can be seen as secondary, and possibly adaptive, to nutritional deprivation. The model of AN may provide important insights into the pathophysiology of GH secretion, in particular as regards the mechanisms whereby nutritional status effects its regulation.

  • Structure of the GnRH receptor-stimulated signaling network: insights from genomics.
    Front. Neuroendocrin. (IF 7.852) Pub Date : 2003-11-05
    Frederique Ruf,Marc Y Fink,Stuart C Sealfon

    The GnRH receptor influences gene expression in the gonadotrope through activating signaling cascades that modulate transcription factor expression and activity. A longstanding question in neuroendocrinology is how instructions received at the membrane in the form of the pattern of receptor stimulation are processed into specific biosynthetic changes at each gonadotropin promoter. Signal transduction from the membrane to preformed transcription factors relies on recognition of altered conformations. Signal transduction through the layers of the gene network also requires the biosynthesis of new transcription factors. The signal processing of this system depends on its molecular connectivity map and its feedback and feed-forward loops. Review of signal transduction, gene control, and genomic studies provide evidence of key loops that cross between cellular and nuclear compartments. Genomic studies suggest that the signal transduction and gene network form a continuum. We propose that information transfer in the gonadotrope depends on robust signaling modules that serve to integrate events at different time scales across cytoplasmic and nuclear compartments.

  • Central mechanisms of stress integration: hierarchical circuitry controlling hypothalamo-pituitary-adrenocortical responsiveness.
    Front. Neuroendocrin. (IF 7.852) Pub Date : 2003-11-05
    James P Herman,Helmer Figueiredo,Nancy K Mueller,Yvonne Ulrich-Lai,Michelle M Ostrander,Dennis C Choi,William E Cullinan

    Appropriate regulatory control of the hypothalamo-pituitary-adrenocortical stress axis is essential to health and survival. The following review documents the principle extrinsic and intrinsic mechanisms responsible for regulating stress-responsive CRH neurons of the hypothalamic paraventricular nucleus, which summate excitatory and inhibitory inputs into a net secretory signal at the pituitary gland. Regions that directly innervate these neurons are primed to relay sensory information, including visceral afferents, nociceptors and circumventricular organs, thereby promoting 'reactive' corticosteroid responses to emergent homeostatic challenges. Indirect inputs from the limbic-associated structures are capable of activating these same cells in the absence of frank physiological challenges; such 'anticipatory' signals regulate glucocorticoid release under conditions in which physical challenges may be predicted, either by innate programs or conditioned stimuli. Importantly, 'anticipatory' circuits are integrated with neural pathways subserving 'reactive' responses at multiple levels. The resultant hierarchical organization of stress-responsive neurocircuitries is capable of comparing information from multiple limbic sources with internally generated and peripherally sensed information, thereby tuning the relative activity of the adrenal cortex. Imbalances among these limbic pathways and homeostatic sensors are likely to underlie hypothalamo-pituitary-adrenocortical dysfunction associated with numerous disease processes.

  • The orexin/hypocretin system: a critical regulator of neuroendocrine and autonomic function.
    Front. Neuroendocrin. (IF 7.852) Pub Date : 2003-11-05
    Alastair V Ferguson,Willis K Samson

    The hypocretins/orexins are hypothalamic peptides most recognized for their significant effects on feeding and arousal. Indeed, loss of the peptides results in a cataplexy quite similar to that observed canine models of human narcolepsy. However, neurons producing these peptides project to numerous brain sites known to be important in neuroendocrine regulation of pituitary function and autonomic centers as well. Results from numerous laboratories have suggested broad physiological roles for the hypocretins/orexins in neuroendocrine and autonomic regulation as a consequence of actions in the dorsal vagal complex, paraventricular nucleus, and pituitary. This review focuses upon evidence for potential physiologic roles for the peptides in these sites.

  • Molecular determinants and physiological relevance of extrasomatic RNA localization in neurons.
    Front. Neuroendocrin. (IF 7.852) Pub Date : 2003-05-24
    Evita Mohr,Dietmar Richter

    Specific sorting of mRNA molecules to subcellular microdomains is an evolutionarily conserved mechanism by which the polarized nature of eukayotic cells may be established and maintained. The molecular composition of the RNA localization machinery is complex. Sequence motifs within RNA molecules to be transported, called cis-acting elements, and proteins, referred to as trans-acting factors, are essential components. Transport of the resulting ribonucleoprotein complexes to distinct cytoplasmic regions occurs along the cytoskeletal network. The pathway is observed in organisms as diverse as yeast and human and it plays a critical role in development and cell differentiation. Moreover, RNA localization takes place in differentiated cell types including neurons. There is ample evidence to suggest that sorting of defined mRNA species to the neurites of nerve cells and on-site translation has an impact on various aspects of nerve cell biology.

  • Molecular defects in the pathogenesis of pituitary tumours.
    Front. Neuroendocrin. (IF 7.852) Pub Date : 2003-05-24
    Andy Levy,Stafford Lightman

    The majority of pituitary adenomas are trophically stable and change relatively little in size over many years. A comparatively small proportion behave more aggressively and come to clinical attention through inappropriate hormone secretion or adverse effects on surrounding structures. True malignant behaviour with metastatic spread is very atypical. Pituitary adenomas that come to surgery are predominantly monoclonal in origin and roughly half are aneuploid, indicating either ongoing genetic instability or transition through a period of genetic instability at some time during their development. Few are associated with the classical mechanisms of tumour formation but it is generally believed that the majority harbour quantitative if not qualitative differences in molecular composition compared to the normal pituitary. Despite their prevalence and the ready availability of biopsy material, at the present time, the precise molecular pathogenesis of the majority of pituitary adenomas remains unclear. This review summarizes current thinking.

  • Mechanisms underlying episodic gonadotropin-releasing hormone secretion.
    Front. Neuroendocrin. (IF 7.852) Pub Date : 2003-05-24
    Suzanne M Moenter,Anthony R DeFazio,Gilbert R Pitts,Craig S Nunemaker

    The episodic secretion of gonadotropin-releasing hormone (GnRH) is crucial for fertility, but the cellular mechanisms and network properties generating GnRH pulses are not well understood. We will explore three primary aspects of this intermittent hormonal signal: the source of rhythm(s), the possible mechanisms comprising oscillator(s), and how GnRH neurons are synchronized to produce a pulse of hormone release into the pituitary portal blood. Current knowledge will be reviewed, and hypotheses and working models proposed for future studies.

  • Gene therapy for pituitary tumors: from preclinical models to clinical implementation.
    Front. Neuroendocrin. (IF 7.852) Pub Date : 2003-03-01
    Maria Castro,Shyam Goverdhana,Jinwei Hu,Nelson Jovel,Xiangpeng Yuan,Pedro Lowenstein

    Gene therapy, which entails the use of nucleic acids as drugs, is a new approach to treat disease. Gene therapy has been successfully implemented in several preclinical animal models, including several paradigms of experimental pituitary tumors. In spite of these successes, several critical issues need to be addressed before gene therapy can become a clinical reality for the treatment of pituitary tumors. These include the development of safer and more effective gene delivery vectors, the uncovering of novel therapeutic targets, the development of molecular switches which will allow turning therapeutic transgene expression "on" and "off" as and when it is needed, and the ability to scale up the vector preparations devoid of any putative contaminants. There are still many basic science developments that must take place in order to allow this new therapeutic technology to make its way successfully into the clinical arena to treat pituitary disease. We envisage these developments taking place within the next five years, gene therapy for pituitary tumors will then form part of the armamentarium available to better treat and manage pituitary tumors.

  • The magnocellular oxytocin system, the fount of maternity: adaptations in pregnancy.
    Front. Neuroendocrin. (IF 7.852) Pub Date : 2003-03-01
    John A Russell,Gareth Leng,Alison J Douglas

    Oxytocin secretion from the posterior pituitary gland is increased during parturition, stimulated by the uterine contractions that forcefully expel the fetuses. Since oxytocin stimulates further contractions of the uterus, which is exquisitely sensitive to oxytocin at the end of pregnancy, a positive feedback loop is activated. The neural pathway that drives oxytocin neurons via a brainstem relay has been partially characterised, and involves A2 noradrenergic cells in the brainstem. Until close to term the responsiveness of oxytocin neurons is restrained by neuroactive steroid metabolites of progesterone that potentiate GABA inhibitory mechanisms. As parturition approaches, and this inhibition fades as progesterone secretion collapses, a central opioid inhibitory mechanism is activated that restrains the excitation of oxytocin cells by brainstem inputs. This opioid restraint is the predominant damper of oxytocin cells before and during parturition, limiting stimulation by extraneous stimuli, and perhaps facilitating optimal spacing of births and economical use of the store of oxytocin accumulated during pregnancy. During parturition, oxytocin cells increase their basal activity, and hence oxytocin secretion increases. In addition, the oxytocin cells discharge a burst of action potentials as each fetus passes through the birth canal. Each burst causes the secretion of a pulse of oxytocin, which sharply increases uterine tone; these bursts depend upon auto-stimulation by oxytocin released from the dendrites of the magnocellular neurons in the supraoptic and paraventricular nuclei. With the exception of the opioid mechanism that emerges to restrain oxytocin cell responsiveness, the behavior of oxytocin cells and their inputs in pregnancy and parturition is explicable from the effects of hormones of pregnancy (relaxin, estrogen, progesterone) on pre-existing mechanisms, leading through relative quiescence at term inter alia to net increase in oxytocin storage, and reduced auto-inhibition by nitric oxide generation. Cyto-architectonic changes in parturition, involving evident retraction of glial processes between oxytocin cells so they get closer together, are probably a response to oxytocin neuron activation rather than being essential for their patterns of firing in parturition.

  • Transgenic studies on the regulation of the anterior pituitary gland function by the hypothalamus.
    Front. Neuroendocrin. (IF 7.852) Pub Date : 2003-03-01
    Sara Wells,David Murphy

    The anterior pituitary gland is composed of five different cell types secreting hormones whose functions include the regulation of post-natal growth (growth hormone, GH), lactation (prolactin, PRL), reproduction (luteinising hormone, LH, and follicle stimulating hormone, FSH), metabolism (thyroid stimulating hormone, TSH), and stress (adrenocorticotrophic hormone, ACTH). The synthesis and secretion of the anterior pituitary hormones is under the control of neuropeptides released from the hypothalamus into a capillary portal plexus which flows through the external zone of the median eminence to the anterior lobe. This review describes the ways that gene transfer technologies have been applied to whole animals in order to study the regulation of anterior pituitary function by the hypothalamus. The extensive studies on these neuronal systems, within the context of the physiological integrity of the intact organism, not only exemplify the successful application of transgenic technologies to neuroendocrine systems, but also illustrate the problems that have been encountered, and the challenges that lie ahead.

  • Insulin and leptin revisited: adiposity signals with overlapping physiological and intracellular signaling capabilities.
    Front. Neuroendocrin. (IF 7.852) Pub Date : 2003-03-01
    Kevin D Niswender,Michael W Schwartz

    The adipocyte-derived hormone leptin and the pancreatic beta cell-derived hormone insulin each function as afferent signals to the hypothalamus in an endocrine feedback loop that regulates body adiposity. Although these two hormones, and the receptors on which they act, are unrelated and structurally distinct, they exert overlapping effects in the arcuate nucleus, a key hypothalamic area involved in energy homeostasis. Defects in either insulin or leptin signaling in the brain result in hyperphagia, disordered glucose homeostasis, and reproductive dysfunction. To explain this striking physiological overlap, we hypothesize that hypothalamic insulin and leptin signaling converge upon a single intracellular signal transduction pathway, known as the insulin-receptor-substrate phosphatidylinositol 3-kinase pathway. Here we synthesize data from a variety of model systems in which such "cross-talk" between insulin and leptin signal transduction has either been observed or can be inferred, discuss our own data demonstrating that insulin and leptin both activate hypothalamic phosphatidylinositol 3-kinase signaling, and discuss the significance of such convergence with respect to neuronal function in normal individuals and in pathological states such as obesity. Identification of the key early molecular events mediating the action of both insulin and leptin in hypothalamic neurons promises new insight into the regulation of these neurons in health and disease.

  • Dynamic neuroendocrine responses to critical illness.
    Front. Neuroendocrin. (IF 7.852) Pub Date : 2002-10-17
    Greet Van den Berghe

    Prolonged critical illness has high morbidity and mortality. The acute neuroendocrine response to critical illness involves an activated anterior pituitary function. In prolonged critical illness, however, a reduced pulsatile secretion of anterior pituitary hormones and the so-called 'wasting syndrome' occur. The impaired pulsatile secretion of growth hormone (GH), thyrotropin and gonadotropin can be re-amplified by relevant combinations of releasing factors, which also substantially increase circulating levels of insulin-like growth factor (IGF)-I, GH-dependent IGF-binding proteins, thyroxine, tri-iodothyronine, and testosterone. Anabolism is clearly re-initiated when GH secretagogues, thyrotropin-releasing and gonadotropin-releasing hormones are co-administered but the effect on survival remains unknown. A lethal outcome of critical illness is predicted by a high serum concentration of IGF-binding protein 1, pointing to impaired insulin effect rather than pituitary function, and survival was recently shown to be dramatically improved by strict normalization of glycemia with exogenous insulin. The recent progress in the knowledge of the neuroendocrine response to critical illness and its interrelation with peripheral hormonal and metabolic alterations during stress allows for potential new therapeutic perspectives to safely reverse the wasting syndrome and improve survival. These novel insights will be reviewed herein.

  • Regulation of gene promoters of hypothalamic peptides.
    Front. Neuroendocrin. (IF 7.852) Pub Date : 2002-10-17
    J Peter H Burbach

    In order to fulfill their roles in neuroendocrine regulation, specific hypothalamic neurons are devoted to produce and deliver biologically active peptides to the pituitary gland. The biosynthesis and release of peptides are strictly controlled by afferents to these hypothalamic neurons. Cell-specific expression and biosynthetic regulation largely relies on transcription from the gene promoter for which the 5(')-flanking regions of the peptidergic genes contain essential elements. Cell-specific transcription factors employ these regulatory elements to exert their control over the expression of the peptidergic gene. This article explores the properties of regulatory elements of the major hypothalamic peptides, somatostatin, growth hormone-releasing hormone, gonadotropin-releasing hormone, thyrotropin-releasing hormone, corticotropin-releasing hormone, vasopressin and oxytocin, and the transcription factors acting on them. These transcription factors are often endpoints of signal transduction pathways that can be activated by neurotransmitters or steroid hormones. Others are essential to provide cell-specific expression of the peptidergic gene during development and mature regulation.

  • Behavioral neuroendocrinology of vasotocin and vasopressin and the sensorimotor processing hypothesis.
    Front. Neuroendocrin. (IF 7.852) Pub Date : 2002-10-17
    James D Rose,Frank L Moore

    Vasotocin (AVT) and vasopressin (AVP) are potent modulators of social behaviors in diverse species of vertebrates. This review addresses questions about how and where AVT and AVP act to modulate social behaviors, focusing on research with an amphibian model (Taricha granulosa). In general, the behaviorally important AVT and AVP neurons occur in the forebrain and project to sites throughout the brain. Social behaviors are modulated by AVT and AVP acting at multiple sites in the brain and at multiple levels in the behavioral sequence. This review proposes that AVT and AVP can act on sensory pathways to modulate the responsiveness of neurons to behaviorally relevant sensory stimuli and also can act on motor pathways in the brainstem and spinal cord to modulate the neuronal output to behavior-specific pattern generators. This neurobehavioral model, in which AVT and AVP are thought to modulate social behaviors by affecting sensorimotor processing, warrants further research.

  • Development of the neuroendocrine hypothalamus.
    Front. Neuroendocrin. (IF 7.852) Pub Date : 2002-07-20
    Eleni A Markakis

    The development of the neuroendocrine hypothalamus has been studied using a variety of neuroanatomical and molecular techniques. Here, the major findings that mold our understanding of hypothalamic development are reviewed. The rat hypothalamus is generated predominantly from the third ventricular neuroepithelium in a "lateral early to medial late" pattern dictated perhaps by the medially receding third ventricle. Neuroendocrine neurons seem to exhibit a delayed migrational strategy, showing relatively early birthdates, although they are located in the latest-generated, periventricular nuclei. Several homeobox genes seem to play a role in hypothalamic development, and gene knockout experiments implicate a number of genes of importance in the generation of the neuroendocrine cell type.

  • Development of gonadotropin-releasing hormone-1 neurons.
    Front. Neuroendocrin. (IF 7.852) Pub Date : 2002-07-20
    S Wray

    Gonadotropin releasing hormone-1 (GnRH-1) neurons, critical for reproduction, are derived from the nasal placode and migrate into the brain during prenatal development. Once within the brain, GnRH-1 cells become integral components of the CNS-pituitary-gonadal axis, essential for reproductive maturation and maintenance of reproductive function in adults. This review focuses on the lineage and development of the GnRH-1 neuroendocrine system. Although the migration of these cells from nose to brain has been well documented in a variety of species, many questions remain concerning the melecules and cues directing GnRH-1 cell differentiation, migration, axon targeting, and establishment and control of GnRH-1 secretion. These process most likely involve multiple and redundant cues because if these mechanisms fail, reproduction dysfunction will ensue and guarantee that this defect does not remain in the gene pool.

  • Integration of the regulation of reproductive function and energy balance: lactation as a model.
    Front. Neuroendocrin. (IF 7.852) Pub Date : 2002-07-20
    M Susan Smith,Kevin L Grove

    Lactation is a physiological model for studying how the hypothalamus integrates peripheral signals, such as sensory signals (suckling stimulus) and those denoting energy balance (leptin), to alter hypothalamic function regulating food intake/energy balance and reproduction. The characteristics of food intake/energy balance during lactation are extreme hyperphagia, coupled with negative energy balance. The arcuate nucleus Neuropeptide Y (ARH-NPY) system is activated by: (1) brainstem projections specifically activated by the suckling stimulus, and (2) the decrease in leptin in response to the metabolic drain of milk production. NPY neurons from the ARH make direct contact with GnRH neurons and with CRH neurons in the PVH. NPY neurons also make contact with orexin and MCH neurons in the LHA, which, in turn, make contacts with GnRH neurons. Thus, the ARH-NPY system provides a neuroanatomical framework by which to integrate changes in food intake/energy with the regulation of cyclic reproductive function.

    Front. Neuroendocrin. (IF 7.852) Pub Date : 1997-01-01

  • Epigenetic regulation of female puberty.
    Front. Neuroendocrin. (IF 7.852) Pub Date : 2014-08-31
    Alejandro Lomniczi,Hollis Wright,Sergio R Ojeda

    Substantial progress has been made in recent years toward deciphering the molecular and genetic underpinnings of the pubertal process. The availability of powerful new methods to interrogate the human genome has led to the identification of genes that are essential for puberty to occur. Evidence has also emerged suggesting that the initiation of puberty requires the coordinated activity of gene sets organized into functional networks. At a cellular level, it is currently thought that loss of transsynaptic inhibition, accompanied by an increase in excitatory inputs, results in the pubertal activation of GnRH release. This concept notwithstanding, a mechanism of epigenetic repression targeting genes required for the pubertal activation of GnRH neurons was recently identified as a core component of the molecular machinery underlying the central restraint of puberty. In this chapter we will discuss the potential contribution of various mechanisms of epigenetic regulation to the hypothalamic control of female puberty.

  • Regulation of the human menstrual cycle.
    Front. Neuroendocrin. (IF 7.852) Pub Date : 1998-07-17
    N Chabbert Buffet,C Djakoure,S C Maitre,P Bouchard

    Our understanding of the regulation of the menstrual cycle has recently improved with the development of various tools of investigation. The cycle is now thought to be determined mainly by the ovary itself, which sends various signals to the pituitary and the hypothalamus. The aim of the cycle is to produce a single mature oocyte each month from puberty to menopause. However, the most common evolution of a follicle is atresia, a consequence of the genetically controlled, ovarian apotosis (or "programmed cell death"). Follicular growth and maturation are mostly independent of gonadotropins, from the stage of primordial follicles to antral follicles. A complete intraovarian paracrine system is implied in this gonadotropin-independent follicular growth, and in the modulation of the actions of the gonadotropins in the ovary. FSH allows the rescue of a minority of follicles from atresia and is indispensable to only the final maturation of the preovulatory follicle. The cyclical variations of the gonadotropins are under the control of ovarian steroids (estradiol and progesterone) and peptides (inhibin). The cycle length is determined by follicular growth and by the fixed life span of the corpus luteum. The mechanism of action of gonadotropins is much better understood since the gonadotropins and their receptor cDNA have been cloned. The recent description of naturally occurring mutations has lead to a better understanding of the role of each gonadotropin, demonstrating the crucial role of FSH in the terminal maturation of the follicles. The ovarian cycle can also be monitored at the level of target tissues of steroids such as the endometrium. The cellular mechanisms of endometrial maturation, under the control of estradiol and progesterone, are better understood. The endometrial maturation is synchronized to follicular development and allows implantation of the conceptus. The genes implied in the implantation of the embryo are being identified (e.g., integrins). Last but not least, the mechanisms of endometrial shedding are being elucidated, especially the role of metalloproteases and angiogenic factors. These concepts will allow the development of new treatments for infertility, the design of new contraceptive techniques, and a better tolerance of treatments using sex steroids, particularly progestin-only pill.

  • The history of neuropeptides 1.
    Front. Neuroendocrin. (IF 7.852) Pub Date : 1995-10-01
    M M Klavdieva

  • The impact of physiological stimuli on the expression of corticotropin-releasing hormone (CRH) and other neuropeptide genes.
    Front. Neuroendocrin. (IF 7.852) Pub Date : 1996-07-01
    A G Watts

    The article reviews some of the recent work showing how physiological stimuli act to alter neuropeptide gene expression. It describes how neural and humoral factors activated by physiological stimuli interact with the mechanisms regulating neuropeptide gene expression in neurons with either vascular (neurosecretory) or cellular (centrally directed) synapses. Although the focus will be on corticotropin-releasing hormone (CRH) in the hypothalamic paraventricular nucleus, comparisons will be made between this neurosecretory cell group and others that express this gene. The regulation of neuropeptide genes colocalized in neurons that synthesize CRH is also considered. The review begins with a brief historical introduction, placing peptides in the overall functional perspective of neurosecretory and centrally directed neurons. It then describes studies using in vitro preparations that reveal details of the signal transduction mechanisms responsible for altering the expression of neuropeptide genes. For the CRH gene they are providing the foundations for future work on how physiological stimuli alter mRNA levels in the whole animal. Physiological stimuli provide a very broad range of signals to neuropeptide neurons commensurate with the wide variety of motor responses they initiate. One important humoral signal impacting neuropeptide neurons is plasma corticosterone, and many workers have addressed this aspect of its function. Corticosterone appears capable of interacting with at least two different neuronal mechanisms to regulate CRH mRNA levels: one is clearly seen in paraventricular neurosecretory neurons, where increasing plasma corticosteroid reduces CRH mRNA levels; the other, seen in neurons in the central nucleus of the amygdala, acts to increase them. Since physiological stimuli present a complex mixture of humoral and neural signals to the CNS, integration of these two signal types is a critical aspect of peptide metabolism that requires detailed attention. Studies that are beginning to address this important question are described. Circadian influences play an important role in organizing homeostatic processes, and their influence on CRH gene expression is considered. The viscerosensory-motor integration associated with dehydration offers a useful model for investigating the role of peptides in neuronal function and motor architecture. Much of our work has concentrated on how peptide genes are regulated by alterations to fluid homeostasis, and these studies, along with those of other investigators, are described in this integrative context. Finally, consideration is given to the many studies that have addressed the impact of nonviscerosensory stimulation on neuropeptide gene expression.

  • Octreotide and related somatostatin analogs in the diagnosis and treatment of pituitary disease and somatostatin receptor scintigraphy.
    Front. Neuroendocrin. (IF 7.852) Pub Date : 1993-01-01
    S W Lamberts,L J Hofland,W W de Herder,D J Kwekkeboom,J C Reubi,E P Krenning

    Clinical introduction of octreotide, a long-acting somatostatin analog, has opened a new era in the medical therapy of patients with growth hormone (GH)- and thyroid-stimulating hormone (TSH)-secreting pituitary tumors. Good control of hormonal hypersecretion occurred in most patients, and tumor shrinkage has been observed in more than half of them. Octreotide therapy is of no value in most patients with Prolactin (PRL)- and adrenocorticotrophic (ACTH)-secreting pituitary tumors. However patients with Cushing's syndrome caused by ectopic ACTH secretion from a variety of endocrine tumors benefit from octreotide administration. In patients with visual disturbances related to chiasmal compression by nonfunctioning pituitary tumors, somatostatin analog administration has been reported to result in rapid improvement in visual acuity. This beneficial effect might not be related to a direct action of octreotide, but may reflect an effect on the retina and/or optic nerve. The presence of somatostatin receptors on a wide variety of pituitary tumors as well as on a number of parasellar tumors allows their in vivo visualization with radionucleotide-labelled somatostatin analogs. A positive scan in patients with GH- and TSH-secreting pituitary tumors is predictive of a good suppressive effect of octreotide on hormone release by these tumors. PRL- and ACTH-secreting pituitary adenomas cannot be visualized, but clinically nonfunctioning pituitary adenomas are visualized in 75% of cases with 111In-DTPA-octreotide. At present it is unclear whether this has consequences with regard to the medical treatment of these last group of patients. Somatostatin receptor scintigraphy can be successfully used in the differential diagnosis between pituitary hypersecretion of GH and/or ACTH and the ectopic secretion of growth hormone-releasing hormone (GHRH) and ACTH by peripherally localized endocrine tumors. Again the visualization of such tumors also predicts successful control of hormonal hypersecretion by octreotide.

  • Early life origins of metabolic disease: Developmental programming of hypothalamic pathways controlling energy homeostasis.
    Front. Neuroendocrin. (IF 7.852) Pub Date : 2015-08-25
    Laura Dearden,Susan E Ozanne

    A wealth of animal and human studies demonstrate that perinatal exposure to adverse metabolic conditions - be it maternal obesity, diabetes or under-nutrition - results in predisposition of offspring to develop obesity later in life. This mechanism is a contributing factor to the exponential rise in obesity rates. Increased weight gain in offspring exposed to maternal obesity is usually associated with hyperphagia, implicating altered central regulation of energy homeostasis as an underlying cause. Perinatal development of the hypothalamus (a brain region key to metabolic regulation) is plastic and sensitive to metabolic signals during this critical time window. Recent research in non-human primate and rodent models has demonstrated that exposure to adverse maternal environments impairs the development of hypothalamic structure and consequently function, potentially underpinning metabolic phenotypes in later life. This review summarizes our current knowledge of how adverse perinatal environments program hypothalamic development and explores the mechanisms that could mediate these effects.

  • GnRH, anosmia and hypogonadotropic hypogonadism--where are we?
    Front. Neuroendocrin. (IF 7.852) Pub Date : 2014-10-14
    Paolo E Forni,Susan Wray

    Gonadotropin releasing hormone (GnRH) neurons originate the nasal placode and migrate into the brain during prenatal development. Once within the brain, these cells become integral components of the hypothalamic-pituitary-gonadal axis, essential for reproductive function. Disruption of this system causes hypogonadotropic hypogonadism (HH). HH associated with anosmia is clinically defined as Kallman syndrome (KS). Recent work examining the developing nasal region has shed new light on cellular composition, cell interactions and molecular cues responsible for the development of this system in different species. This review discusses some developmental aspects, animal models and current advancements in our understanding of pathologies affecting GnRH. In addition we discuss how development of neural crest derivatives such as the glia of the olfactory system and craniofacial structures control GnRH development and reproductive function.

  • Cytokines and brain excitability.
    Front. Neuroendocrin. (IF 7.852) Pub Date : 2012-01-05
    Michael A Galic,Kiarash Riazi,Quentin J Pittman

    Cytokines are molecules secreted by peripheral immune cells, microglia, astrocytes and neurons in the central nervous system. Peripheral or central inflammation is characterized by an upregulation of cytokines and their receptors in the brain. Emerging evidence indicates that pro-inflammatory cytokines modulate brain excitability. Findings from both the clinical literature and from in vivo and in vitro laboratory studies suggest that cytokines can increase seizure susceptibility and may be involved in epileptogenesis. Cellular mechanisms that underlie these effects include upregulation of excitatory glutamatergic transmission and downregulation of inhibitory GABAergic transmission.

  • The molecular physiology of CRH neurons.
    Front. Neuroendocrin. (IF 7.852) Pub Date : 2011-08-30
    Greti Aguilera,Ying Liu

    Corticotropin releasing hormone (CRH) is essential for stress adaptation by mediating hypothalamic-pituitary-adrenal (HPA) axis, behavioral and autonomic responses to stress. Activation of CRH neurons depends on neural afferents from the brain stem and limbic system, leading to sequential CRH release and synthesis. CRH transcription is required to restore mRNA and peptide levels, but termination of the response is essential to prevent pathology associated with chronic elevations of CRH and HPA axis activity. Inhibitory feedback mediated by glucocorticoids and intracellular production of the repressor, Inducible Cyclic AMP Early Repressor (ICER), limit the magnitude and duration of CRH neuronal activation. Induction of CRH transcription is mediated by the cyclic AMP/protein kinase A/cyclic AMP responsive element binding protein (CREB)-dependent pathways, and requires cyclic AMP-dependent nuclear translocation of the CREB co-activator, Transducer of Regulated CREB activity (TORC). This article reviews current knowledge on the mechanisms regulating CRH neuron activity.

  • G protein-coupled receptors in the hypothalamic paraventricular and supraoptic nuclei--serpentine gateways to neuroendocrine homeostasis.
    Front. Neuroendocrin. (IF 7.852) Pub Date : 2011-08-02
    Georgina G J Hazell,Charles C Hindmarch,George R Pope,James A Roper,Stafford L Lightman,David Murphy,Anne-Marie O'Carroll,Stephen J Lolait

    G protein-coupled receptors (GPCRs) are the largest family of transmembrane receptors in the mammalian genome. They are activated by a multitude of different ligands that elicit rapid intracellular responses to regulate cell function. Unsurprisingly, a large proportion of therapeutic agents target these receptors. The paraventricular nucleus (PVN) and supraoptic nucleus (SON) of the hypothalamus are important mediators in homeostatic control. Many modulators of PVN/SON activity, including neurotransmitters and hormones act via GPCRs--in fact over 100 non-chemosensory GPCRs have been detected in either the PVN or SON. This review provides a comprehensive summary of the expression of GPCRs within the PVN/SON, including data from recent transcriptomic studies that potentially expand the repertoire of GPCRs that may have functional roles in these hypothalamic nuclei. We also present some aspects of the regulation and known roles of GPCRs in PVN/SON, which are likely complemented by the activity of 'orphan' GPCRs.

  • The pros and cons of phytoestrogens.
    Front. Neuroendocrin. (IF 7.852) Pub Date : 2010-03-30
    Heather B Patisaul,Wendy Jefferson

    Phytoestrogens are plant derived compounds found in a wide variety of foods, most notably soy. A litany of health benefits including a lowered risk of osteoporosis, heart disease, breast cancer, and menopausal symptoms, are frequently attributed to phytoestrogens but many are also considered endocrine disruptors, indicating that they have the potential to cause adverse health effects as well. Consequently, the question of whether or not phytoestrogens are beneficial or harmful to human health remains unresolved. The answer is likely complex and may depend on age, health status, and even the presence or absence of specific gut microflora. Clarity on this issue is needed because global consumption is rapidly increasing. Phytoestrogens are present in numerous dietary supplements and widely marketed as a natural alternative to estrogen replacement therapy. Soy infant formula now constitutes up to a third of the US market, and soy protein is now added to many processed foods. As weak estrogen agonists/antagonists with molecular and cellular properties similar to synthetic endocrine disruptors such as Bisphenol A (BPA), the phytoestrogens provide a useful model to comprehensively investigate the biological impact of endocrine disruptors in general. This review weighs the evidence for and against the purported health benefits and adverse effects of phytoestrogens.

  • 更新日期:2019-11-01
  • The regulation of reproductive neuroendocrine function by insulin and insulin-like growth factor-1 (IGF-1).
    Front. Neuroendocrin. (IF 7.852) Pub Date : 2014-06-15
    Andrew Wolfe,Sara Divall,Sheng Wu

    The mammalian reproductive hormone axis regulates gonadal steroid hormone levels and gonadal function essential for reproduction. The neuroendocrine control of the axis integrates signals from a wide array of inputs. The regulatory pathways important for mediating these inputs have been the subject of numerous studies. One class of proteins that have been shown to mediate metabolic and growth signals to the CNS includes Insulin and IGF-1. These proteins are structurally related and can exert endocrine and growth factor like action via related receptor tyrosine kinases. The role that insulin and IGF-1 play in controlling the hypothalamus and pituitary and their role in regulating puberty and nutritional control of reproduction has been studied extensively. This review summarizes the in vitro and in vivo models that have been used to study these neuroendocrine structures and the influence of these growth factors on neuroendocrine control of reproduction.

  • Sex differences in cardiovascular disease - Impact on care and outcomes.
    Front. Neuroendocrin. (IF 7.852) Pub Date : 2017-04-22
    K H Humphries,M Izadnegahdar,T Sedlak,J Saw,N Johnston,K Schenck-Gustafsson,R U Shah,V Regitz-Zagrosek,J Grewal,V Vaccarino,J Wei,C N Bairey Merz

  • Estrogen-BDNF interactions: implications for neurodegenerative diseases.
    Front. Neuroendocrin. (IF 7.852) Pub Date : 2006-10-31
    Farida Sohrabji,Danielle K Lewis

    Since its' discovery over 20 years ago, BDNF has been shown to play a key role in neuronal survival, in promoting neuronal regeneration following injury, regulating transmitter systems and attenuating neural-immune responses. Estrogen's actions in the young and mature brain, and its role in neurodegenerative diseases in many cases overlaps with those observed for BDNF. Reduced estrogen and BDNF are observed in patients with Parkinson's disease and Alzheimer's disease, while high estrogen levels are a risk factor for development of multiple sclerosis. Estrogen receptors, which transduce the actions of estrogen, colocalize to cells that express BDNF and its receptor trkB, and estrogen further regulates the expression of this neurotrophin system. This review describes the distribution of BDNF and trkB expressing cells in the forebrain, and the roles of estrogen and the BDNF-trkB neurotrophin system in Parkinson's disease, Alzheimer's disease and multiple sclerosis.

  • What does the "four core genotypes" mouse model tell us about sex differences in the brain and other tissues?
    Front. Neuroendocrin. (IF 7.852) Pub Date : 2008-11-26
    Arthur P Arnold,Xuqi Chen

    The "four core genotypes" (FCG) model comprises mice in which sex chromosome complement (XX vs. XY) is unrelated to the animal's gonadal sex. The four genotypes are XX gonadal males or females, and XY gonadal males or females. The model allows one to measure (1) the differences in phenotypes caused by sex chromosome complement (XX vs. XY), (2) the differential effects of ovarian and testicular secretions, and (3) the interactive effects of (1) and (2). Thus, the FCG model provides new information regarding the origins of sex differences in phenotype that has not been available from studies that manipulate gonadal hormone levels in normal XY males and XX females. Studies of the FCG model have uncovered XX vs. XY differences in behaviors (aggression, parenting, habit formation, nociception, social interactions), gene expression (septal vasopressin), and susceptibility to disease (neural tube closure and autoimmune disease) not mediated by gonadal hormones. Some sex chromosome effects are mediated by sex differences in dose of X genes or their parental imprint. Future studies will identify the genes involved and their mechanisms of action.

  • Development of the HPA axis: where and when do sex differences manifest?
    Front. Neuroendocrin. (IF 7.852) Pub Date : 2014-03-19
    Leonidas Panagiotakopoulos,Gretchen N Neigh

    Sex differences in the response to stress contribute to sex differences in somatic, neurological, and psychiatric diseases. Despite a growing literature on the mechanisms that mediate sex differences in the stress response, the ontogeny of these differences has not been comprehensively reviewed. This review focuses on the development of the hypothalamic-pituitary-adrenal (HPA) axis, a key component of the body's response to stress, and examines the critical points of divergence during development between males and females. Insight gained from animal models and clinical studies are presented to fully illustrate the current state of knowledge regarding sex differences in response to stress over development. An appreciation for the developmental timelines of the components of the HPA axis will provide a foundation for future areas of study by highlighting both what is known and calling attention to areas in which sex differences in the development of the HPA axis have been understudied.

  • Estrogens facilitate memory processing through membrane mediated mechanisms and alterations in spine density.
    Front. Neuroendocrin. (IF 7.852) Pub Date : 2012-09-18
    Victoria N Luine,Maya Frankfurt

    Estrogens exert sustained, genomically mediated effects on memory throughout the female life cycle, but here we review new studies documenting rapid effects of estradiol on memory, which are exerted through membrane-mediated mechanisms. Use of recognition memory tasks in rats shows that estrogens enhance memory consolidation within 1h. 17α-Estradiol is more potent than 17β-estradiol, and the dose response relationship between estrogens and memory is an inverted U shape. Use of specific estrogen receptor (ER) agonists suggests mediation by an ERβ-like membrane receptor. Enhanced memory is associated with increased spine density and altered noradrenergic activity in the medial prefrontal cortex and hippocampus within 30 min of administration. The environmental chemical, bisphenol-A, rapidly antagonizes enhancements in memory in both sexes possibly through actions on spines. Thus, estradiol and related compounds exert rapid alterations in cognition through non-genomic mechanisms, a finding which may provide a basis for better understanding and treating memory impairments.

  • 更新日期:2019-11-01
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