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.
PMID: 22214786 CAMSID: cams2589
Cytokine; Inflammation; Seizure; Epilepsy; Synapse; Interleukin; Tumor necrosis factor α; Chemokine; Lipopolysaccharide; Febrile convulsion
17β-estradiol (estradiol or E2) is implicated as a 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.
Estrogen; Brain; Cerebral Ischemia; Stroke; Dementia; Menopause; Critical Period; Hormone Therapy
Gonadal hormones exert neuroprotective actions. In addition, it has become evident that the local synthesis of these molecules in the central nervous system may prevent or reduce neurodegeneration. The neuroprotective actions of steroids involve neurons, glial cells and blood vessels, are exerted via steroid receptor signaling initiated at the nuclear or membrane level and steroid receptor independent mechanisms. They include the regulation of phosphatases and kinases and the regulation of the expression of molecules controlling inflammation and apoptosis. In addition, mitochondria have emerged as new central targets for neuroprotective actions of steroids. These neuroprotective actions have been documented in different experimental models of neurological alterations, including motoneuron injury, Parkinson’s disease, traumatic brain injury, multiple sclerosis, stroke and Alzheimer’s disease. In addition, steroids promote serotonergic neuronal function and protect against affective disorders. This special issue of Frontiers in Neuroendocrinology contains a collection of reviews of the most recent ideas and findings on these various aspects of sex steroid-dependent neuroprotection.
allopregnanolone; apoptosis; aromatase; astroglia; estradiol; microglia; mitochondria; progesterone; testosterone; vitamin-D
The chemical complexity of cell-to-cell communication has emerged as a fundamental challenge to understanding brain systems. This is certainly true for the hypothalamus, where neuropeptide signals are heterogeneous, localized and dynamic. Thus far, most hypothalamic peptidomic studies have centered on the entire structure; however, recent advances in collection strategies and analytical technologies have enabled direct, high-resolution peptidomic profiles focused on two regions of interest, the suprachiasmatic and supraoptic nuclei, including their subregions and individual cells. Suites of peptides now can be identified and probed for function. High spatial and analytical sensitivities reveal that discrete hypothalamic nuclei have distinct peptidomic signatures. Peptidomic discovery not only reveals unanticipated complexity, but also peptides previously unknown that act as key circuit components. Analysis of tissue releasates identifies peptides secreted into the extracellular environment and available for transmitting intercellular signals. Direct sampling techniques define peptide-releasate profiles in spatial, temporal and event-dependent patterns. These approaches are providing remarkable new insights into the complexity of neuropeptidergic cell-to-cell signaling central to neuroendocrine physiology.
Arginine vasopressin (AVP); Gastrin-releasing peptide (GRP); Hypothalamus; Little SAAS; Mass spectrometry (MS); Neuropeptide; Peptidomics; Suprachiasmatic nucleus (SCN); Supraoptic nucleus (SON); Vasoactive intestinal peptide (VIP)
This review highlights our investigations into the neuroprotective efficacy of estradiol and other estrogenic agents in a clinically relevant animal model of transient global ischemia, which causes selective, delayed death of hippocampal CA1 neurons and associated cognitive deficits. We find that estradiol rescues a significant number of CA1 pyramidal neurons that would otherwise die in response to global ischemia, and this is true when hormone is provided as a long-term pretreatment at physiological doses or as an acute treatment at the time of reperfusion. In addition to enhancing neuronal survival, both forms of estradiol treatment induce measurable cognitive benefit in young animals. Moreover, estradiol and estrogen analogs that do not bind classical nuclear estrogen receptors retain their neuroprotective efficacy in middle-aged females deprived of ovarian hormones for a prolonged duration (8 weeks). Thus, non-feminizing estrogens may represent a new therapeutic approach for treating the neuronal damage associated with global ischemia.
stroke; global ischemia; neuroprotection; estradiol; hippocampus; estrogen receptor; insulin-like growth factor-1; GPR30; apoptosis; CREB
Seasonal courtship signals, such as mating calls, are orchestrated by steroid hormones. Sex differences are also sculpted by hormones, typically during brief sensitive periods. The influential organizational-activational hypothesis  established the notion of a strong distinction between long-lasting (developmental) and cyclical (adult) effects. While the dichotomy is not always strict , experimental paradigms based on this hypothesis have indeed revealed long-lasting hormone actions during development and more transient anatomical, physiological and behavioral effects of hormonal variation in adulthood. Sites of action during both time periods include forebrain and midbrain sensorimotor integration centers, hindbrain and spinal cord motor centers, and muscles. African clawed frog (Xenopus laevis) courtship vocalizations follow the basic organization-activation pattern of hormone-dependence with some exceptions, including expanded steroid-sensitive periods. Two highly-tractable preparations—the isolated larynx and the fictively calling brain—make this model system powerful for dissecting the hierarchical action of hormones. We discuss steroid effects from larynx to forebrain, and introduce new directions of inquiry for which Xenopus vocalizations are especially well-suited.
Frog; Xenopus; vocalization; courtship; reproduction; androgen; estrogen; steroids; central pattern generator; CPG; larynx
The steroid hormone estradiol plays an important role in reproductive development and behavior and modulates a wide array of physiological and cognitive processes. Recently, reports from several research groups have converged to show that estradiol also powerfully modulates sensory processing, specifically, the physiology of central auditory circuits in songbirds. These investigators have discovered that (1) behaviorally-relevant auditory experience rapidly increases estradiol levels in the auditory forebrain; (2) estradiol instantaneously enhances the responsiveness and coding efficiency of auditory neurons; (3) these changes are mediated by a non-genomic effect of brain-generated estradiol on the strength of inhibitory neurotransmission; and (4) estradiol regulates biochemical cascades that induce the expression of genes involved in synaptic plasticity. Together, these findings have established estradiol as a central regulator of auditory function and intensified the need to consider brain-based mechanisms, in addition to peripheral organ dysfunction, in hearing pathologies associated with estrogen deficiency.
17β-Estradiol; Audition; Selectivity; Fadrozole; Estrogen; Aromatase; Behavior; Vocal learning; Selectivity; Auditory coding
Photoperiodism is the ability of plants and animals to measure environmental day length to ascertain time of year. Central to the evolution of photoperiodism in animals is the adaptive distribution of energetically challenging activities across the year to optimize reproductive fitness while balancing the energetic tradeoffs necessary for seasonally- appropriate survival strategies. The ability to accurately predict future events requires endogenous mechanisms to permit physiological anticipation of annual conditions. Day length provides a virtually noise free environmental signal to monitor and accurately predict time of the year. In mammals, melatonin provides the hormonal signal transducing day length. Duration of pineal melatonin is inversely related to day length and its secretion drives enduring changes in many physiological systems, including the HPA, HPG, and brain-gut axes, the autonomic nervous system, and the immune system. Thus, melatonin is the fulcrum mediating redistribution of energetic investment among physiological processes to maximize fitness and survival.
Photoperiod; melatonin; immune; plasticity; seasonality; annual cycles; tradeoffs; life history strategy
The sheep offers a unique mammalian model in which to study paradoxical same-sex sexual partner preferences. Variations in sexual partner preferences occur spontaneously with as many as 8% of rams in a population exhibiting a sexual preference for other rams (male-oriented). The current review presents an overview and update of the male-oriented ram model and discusses several theories that have been invoked to explain same sex preferences in this species. Although our understanding of the biological determinants and underlying neural substrates of sexual attraction and mate selection are far from complete, compelling evidence is discussed that supports the idea that neural substrates regulating sexual partner preferences are organized during prenatal development. The challenge for future research will be to construct an integrated picture of how hormones, genes, and experience shape sexual partner preference.
sheep; rams; sexual partner preferences; sexual orientation; aromatase; sexually dimorphic area; medial preoptic area; gonadal steroids; sexual differentiation
Female sexual behavior in rodents, typified by the lordosis posture, is hormone-dependent and sex-specific. Ovarian hormones control this behavior via receptors in the hypothalamic ventromedial nucleus (VMH). This review considers the sex differences in the morphology, neurochemistry and neural circuitry of the VMH to gain insights into the mechanisms that control lordosis. The VMH is larger in males compared with females, due to more synaptic connections. Another sex difference is the responsiveness to estradiol, with males exhibiting muted, and in some cases reverse, effects compared with females. The lack of lordosis in males may be explained by differences in synaptic organization or estrogen responsiveness, or both, in the VMH. However, given that damage to other brain regions unmasks lordosis behavior in males, a male-typical VMH is unlikely the main factor that prevents lordosis. In females, key questions remain regarding the mechanisms whereby ovarian hormones modulate VMH function to promote lordosis.
estradiol; estrogen receptor; hypothalamus; lordosis; reproductive behavior; sexual differentiation; ventromedial nucleus
The auditory system exhibits differences by sex and by sexual orientation, and the implication is that relevant auditory structures are altered during prenatal development, possibly by exposure to androgens. The otoacoustic emissions (OAEs) of newborn male infants are weaker than those of newborn females, and these sex differences persist through the lifespan. The OAEs of nonheterosexual females also are weaker than those of heterosexual females, suggesting an atypically strong exposure to androgens some time early in development. Auditory evoked potentials (AEPs) also exhibit sex differences beginning early in life. Some AEPs are different for heterosexual and nonheterosexual females, and other AEPs are different for heterosexual and nonheterosexual males. Research on non-humans treated with androgenic or anti-androgenic agents also suggests that OAEs are masculinized by prenatal exposure to androgens late in gestation. Collectively, the evidence suggests that prenatal androgens, acting globally or locally, affect both nonheterosexuality and the auditory system.
Sexual orientation; otoacoustic emissions (OAEs); auditory evoked potentials (AEPs); prenatal androgen exposure; prenatal development; localized effects of hormones; nonmonotonic effects of hormones; homosexuality; heterosexuality
Over fifty years of rigorous empirical attention to the study of sexual differentiation of the brain has produced sufficient data to reveal fundamental guiding principles, but has also required the generation of new hypotheses to explain non-conforming observations. An early emphasis on the powerful impact and essential role of gonadal steroids is now complemented by an appreciation for genetic contributions to sex differences in the brain. The organizing effects of early steroid hormones on reproductively relevant brain regions and endpoints are largely dependent upon neuronal aromatization of androgens to estrogens. The effect of estradiol is mediated via estrogen receptors (ER). The presence or absence of ER can restrict hormone action to select cells and either prevent or invoke cell death. Alternatively, ER activation can initiate signaling cascades that induce cell-to-cell communication and thereby transduce organizational steroid effects to large numbers of cells. However, the specific details by which cell death and cell-to-cell communication are achieved appear to be locally, even cellularly, unique and specific to that particular subpopulation. As the field moves forward the increasingly specific and detailed elucidation of mechanism challenges us to generate new guiding principles in order to gain a holistic understanding of how the brain develops in males and females.
Biological differences between men and women contribute to many sex-specific illnesses and disorders. Historically, it was argued that such differences were largely, if not exclusively, due to gonadal hormone secretions. However, emerging research has shown that some differences are mediated by mechanisms other than the action of these hormone secretions and in particular by products of genes located on the X and Y chromosomes, which we refer to as direct genetic effects. This paper reviews the evidence for direct genetic effects in behavioral and brain sex differences. We highlight the `four core genotypes' model and sex differences in the midbrain dopaminergic system, specifically focusing on the role of Sry. We also discuss novel research being done on unique populations including people attracted to the same sex and people with a cross-gender identity. As science continues to advance our understanding of biological sex differences, a new field is emerging that is aimed at better addressing the needs of both sexes: gender-based biology and medicine. Ultimately, the study of the biological basis for sex differences will improve healthcare for both men and women.
Sexual differentiation; brain anatomy; sex differences; sexual orientation; gender identity; sex chromosomes; SRY; dopamine; behavior
Both sexual orientation and sex-typical childhood behaviors, such as toy, playmate and activity preferences, show substantial sex differences, as well as substantial variability within each sex. In other species, behaviors that show sex differences are typically influenced by exposure to gonadal steroids, particularly testosterone and its metabolites, during early development (prenatally or neonatally). This article reviews the evidence regarding prenatal influences of gonadal steroids on human sexual orientation, as well as sex-typed childhood behaviors that predict subsequent sexual orientation. The evidence supports a role for prenatal testosterone exposure in the development of sex-typed interests in childhood, as well as in sexual orientation in later life, at least for some individuals. It appears, however, that other factors, in addition to hormones, play an important role in determining sexual orientation. These factors have not been well-characterized, but possibilities include direct genetic effects, and effects of maternal factors during pregnancy. Although a role for hormones during early development has been established, it also appears that there may be multiple pathways to a given sexual orientation outcome and some of these pathways may not involve hormones.
hormones; sexual orientation; androgen; testosterone; toy preferences; sex-typical behavior; estrogen; diethylstilbestrol; gonadal steroids; fetal development
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.
Sex chromosome; X chromosome; Y chromosome; Sex differences; Sexual differentiation; Nociception; Neural tube closure; Autoimmune disease; Addiction
Galanin-like peptide (GALP) was discovered in 1999 in the porcine hypothalamus and was found to be a 60 amino-acid neuropeptide. GALP shares sequence homology to galanin (1–13) in position 9–21 and can bind to, as well as activate, the three galanin receptor subtypes (GalR1-3). GALP-expressing cells are limited, and are mainly found in the arcuate nucleus of the hypothalamus (ARC) and the posterior pituitary. GALP-positive neurons in the ARC project to several brain regions where they appear to make contact with multiple neuromodulators. These neuromodulators are involved in the regulation of energy homeostasis and reproduction, anatomical evidence that suggests a role for GALP in these physiological functions. In support of this idea, GALP gene expression is regulated by several factors that reflect metabolic state including the metabolic hormones leptin and insulin, thyroid hormones, and blood glucose. Considerable evidence now exists to support the hypothesis that GALP has a role in the regulation of energy homeostasis and reproduction; and, that GALP’s role may be independent of the known galanin receptors. In this review we (1) provide an overview of the distribution of GALP, and discuss the potential relationship between GALP and other neuromodulators of energy homeostasis and reproduction, (2) discuss the metabolic factors that regulate GALP expression, (3) review the evidence for the role of GALP in energy homeostasis and reproduction, (4) discuss the potential downstream mediators and mechanisms underlying GALP’s effects, and (5) discuss the possibility that GALP may mediate it’s effects via an as yet unidentified GALP-specific receptor.
GnRH neurons follow a carefully orchestrated journey from their birth in the olfactory placode area. Initially, they migrate along with the vomeronasal nerve into the brain at the cribriform plate, then progress caudally to sites within the hypothalamus where they halt and send projections to the median eminence to activate pituitary gonadotropes. Many factors controlling this precise journey have been elucidated by the silencing or over expression of candidate genes in mouse models. Importantly, a number of these factors may not only play a role in normal physiology of the hypothalamic-pituitary-gonadal axis but also be mis-expressed to cause human disorders of GnRH deficiency, presenting as a failure to undergo normal pubertal development. This review outlines the current cadre of candidates thought to modulate GnRH neuronal migration. The further elucidation and characterization of these factors that impact GnRH neuron development may shed new light on human reproductive disorders and provide potential targets to develop new pro-fertility or contraceptive agents.
The formation of enduring relationships between adult mates (i.e., pair bonds) is an integral aspect of human social behavior and has been implicated in both physical and psychological health. However, due to the inherent complexity of these bonds and the relative rarity with which they are formed in other mammalian species, we know surprisingly little about their underlying neurobiology. Over the past few decades, the prairie vole (Microtus ochrogaster) has emerged as an animal model of pair bonding. Research in this socially monogamous rodent has provided valuable insights into the neurobiological mechanisms that regulate pair bonding behaviors. Here, we review these studies and discuss the neural regulation of three behaviors inherent to pair bonding: the formation of partner preferences, the subsequent development of selective aggression toward unfamiliar conspecifics, and the bi-parental care of young. We focus on the role of vasopressin, oxytocin, and dopamine in the regulation of these behaviors, but also discuss the involvement of other neuropeptides, neurotransmitters, and hormones. These studies may not only contribute to the understanding of pair bonding in our own species, but may also offer insight into the underlying causes of social deficits noted in several mental health disorders.
Social attachment; aggression; paternal behavior; vasopressin; oxytocin; dopamine; prairie vole; monogamy
Fibroblast growth factor (FGF) signaling is pivotal to the formation of numerous central regions. Increasing evidence suggests FGF signaling also directs the development of the neuroendocrine hypothalamus, a collection of neuroendocrine neurons originating primarily within the nose and the ventricular zone of the diencephalon. This review outlines evidence for a role of FGF signaling in the prenatal and postnatal development of several hypothalamic neuroendocrine systems. The emphasis is placed on the nasally derived gonadotropin- releasing hormone neurons, which depend on neurotrophic cues from FGF signaling throughout the neurons' lifetime. Although less is known about neuroendocrine neurons derived from the diencephalon, recent studies suggest they also exhibit variable levels of dependence on FGF signaling. Overall, FGF signaling provides a broad spectrum of cues that ranges from genesis, cell survival/death, migration, morphological changes, to hormone synthesis in the neuroendocrine hypothalamus. Abnormal FGF signaling will deleteriously impact multiple hypothalamic neuroendocrine systems, resulting in the disruption of diverse physiological functions.
FGF signaling; GnRH neurons; olfactory placode; ventricular zone; diencephalon; oxytocin; vasopressin; hypothalamic nuclei
► The paraventricular and supraoptic nuclei of the hypothalamus are regulators of homeostasis. ► Over one hundred G protein-coupled receptors are expressed in each of these nuclei. ► The receptors have many functions including modulating neuropeptide synthesis and release. ► 20–30% of the receptors are ‘orphans’ whose endogenous ligand and function is unknown.
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.
G protein-coupled receptor; Paraventricular nucleus; Supraoptic nucleus; Vasopressin; Oxytocin; Corticotropin-releasing factor; Hypothalamo-neurohypophysial system (HNS); Hypothalamus–pituitary–adrenal (HPA) axis
Spatiotemporal patterns of parvicellular neurosecretory neuron generation (birthdates) were determined in the young adult male rat using a triple fluorescence labeling method. The six classic phenotypes were identified in histological sections with rabbit antisera to neurotransmitters (or related enzymes), nuclear bromodeoxyuridine was detected with a mouse monoclonal antibody, and an axonal projection to the median eminence was determined with the fluorescent retrograde tracer fast blue. The vast majority of triply labeled neurons are generated between embryonic days 12–14, during the time when magnocellular neurosecretory neurons are also generated. This pattern of neurogenesis is distinct from the well-known ‘outside-in’ pattern of hypothalamic neurogenesis, where the peak of lateral zone birthdates occurs on embryonic days 12 and 13, the peak of medial zone birthdates occurs on embryonic days 14 and 15, and the peak of periventricular zone birthdates occurs on embryonic days 16 and 17. Thus, neuroendocrine motoneurons may constitute ‘pioneer neurons’ for the various anatomically distinct regions of the periventricular zone. In addition, many intermixed neurons that express the same neurotransmitters as parvicellular neurosecretory neurons but do not send an axon to the median eminence, also appear to be generated sbetween embryonic days 12 and 14. What these results imply about mechanisms underlying neuroendocrine motor zone differentiation is discussed.
Bromodeoxyuridine; Corticotropin-releasing hormone; Dopamine; Growth hormone-releasing hormone; Hypothalamus; Neuroendocrine; Parvicellular neurosecretory; Somatostatin; Thyrotropin-releasing hormone
The potential adverse effects of Bisphenol A (BPA), a synthetic xenoestrogen, have long been debated. Although standard toxicology tests have revealed no harmful effects, recent research highlighted what was missed so far: BPA-induced alterations in the nervous system. Since 2004, our laboratory has been investigating one of the central effects of BPA, which is interference with gonadal steroid-induced synaptogenesis and the resulting loss of spine synapses. We have shown in both rats and nonhuman primates that BPA completely negates the ~70–100% increase in the number of hippocampal and prefrontal spine synapses induced by both estrogens and androgens. Synaptic loss of this magnitude may have significant consequences, potentially causing cognitive decline, depression, and schizophrenia, to mention those that our laboratory has shown to be associated with synaptic loss. Finally, we discuss why children may particularly be vulnerable to BPA, which represents future direction of research in our laboratory.
The link between in utero and neonatal exposure to environmental toxicants, such as endocrine-disrupting chemicals (EDCs) and adult female reproductive disorders is well established in both epidemiological and animal studies. Recent studies examining the epigenetic mechanisms involved in mediating the effects of EDCs on female reproduction are gathering momentum. In this review, we describe the developmental processes that are susceptible to EDC exposures in female reproductive system, with a special emphasis on the ovary. We discuss studies with select EDCs that have been shown to have physiological and correlated epigenetic effects in the ovary, neuroendocrine system, and uterus. Importantly, EDCs that can directly target the ovary can alter epigenetic mechanisms in the oocyte, leading to transgenerational epigenetic effects. The potential mechanisms involved in such effects are also discussed.
epigenetics; techniques; DNA methylation; ovary; transgenerational epigenetic effects; EDC; DES; BPA; genistein; methoxychlor