Hormonal Inputs Research Articles

Self-administered and passive cocaine infusions produce different effects on corticosterone concentrations in the medial prefrontal cortex (MPC) of rats

Although our lab, as well as several others, has demonstrated a role for corticosterone in cocaine self-administration, there are no studies of the central dynamics of this hormone over the course of a behavioral session when rats are self-administering cocaine or receiving passive injections. The assay of corticosterone in microdialysates collected during such sessions allows for determinations of changes in brain corticosterone during drug-taking behavior. By using the combination of microdialysis in terminal fields for the mesocorticolimbic dopaminergic system and the yoked-triad model, one can distinguish between the direct cocaine-induced activation of the hypothalamo–pituitary–adrenal (HPA) axis from the activation of the HPA axis related to drug-taking. In these experiments, we measured corticosterone in microdialysis samples collected from probes aimed at the medial prefrontal cortex, nucleus accumbens and basolateral amygdala in rats self-administering cocaine and receiving identical, passive infusions of cocaine or saline. While corticosterone was increased in all three brain regions in rats receiving cocaine, medial prefrontal cortex corticosterone was increased significantly more in rats receiving non-contingent infusions of the drug compared to rats self-administering cocaine. The results of these experiments demonstrate that control over drug delivery can affect the influence of a hormonal input on the functional characteristics of specific anatomical projections of the central nervous system. These results also provide evidence of the role steroid hormones play in shaping the functional activity of the brain.

Microevolution of neuroendocrine mechanisms regulating reproductive timing in Peromyscus leucopus

A key question in the evolution of life history and in evolutionary physiology asks how reproductive and other life-history traits evolve. Genetic variation in reproductive control systems may exist in many elements of the complex inputs that can affect the hypothalamic-pituitary-gonadal (HPG) or reproductive axis. Such variation could include numbers and other traits of secretory cells, the amount and pattern of chemical message released, transport and clearance mechanisms, and the number and other traits of receptor cells. Selection lines created from a natural population of white-footed mice (Peromyscus leucopus) that contains substantial genetic variation in reproductive inhibition in response to short winter daylength (SD) have been used to examine neuroendocrine variation in reproductive timing. We hypothesized that natural genetic variation would be most likely to occur in the inputs to GnRH neurons and/or in GnRH neurons themselves, but not in elements of the photoperiodic pathway that would have pleiotropic effects on nonreproductive functions as well as on reproductive functions. Significant genetic variation has been found in the GnRH neuronal system. The number of GnRH neurons immunoreactive to an antibody to mature GnRH peptide under conditions maximizing detection of stained neurons was significantly heritable in an unselected control (C) line. Furthermore, a selection line that suppresses reproduction in SD (photoperiod responsive, R) had fewer IR-GnRH neurons than a selection line that maintains reproduction in SD (photoperiod nonresponsive, NR). This supports the hypothesis that genetic variation in characteristics of GnRH neurons themselves may be responsible for the observed phenotypic variation in reproduction in SD. The R and NR lines differ genetically in food intake and iodo-melatonin receptor binding, as well as in other characteristics. The latter findings are consistent with the hypothesis that genetic variation occurs in the nutritional and hormonal inputs to GnRH neurons. Genetic variation also exists in the phenotypic plasticity of responses to two combinations of treatments, (1) food and photoperiod, and (2) photoperiod and age, indicating genetic variation in individual norms of reaction within this population. Overall, the apparent multiple sources of genetic variation within this population suggest that there may be multiple alternative combinations of alleles for both the R and NR phenotypes. If that interpretation is correct, we suggest that this offers some support for the evolutionary "potential" hypothesis and is inconsistent with the evolutionary "constraint" and "symmorphosis" hypotheses for the evolution of complex neuroendocrine pathways.

Putting the pacemaker channel through its paces to build a better biological pacemaker

Pacemaker channels, as has been appreciated since they were first described, have a most unusual and complex set of properties (DiFrancesco & Borer, 2007). This complexity belies their role in the sinoatrial (SA) node, which is deceivingly simple: to enable nodal myocytes to beat in an efficient and cyclic AMP-sensitive manner. This singularity of purpose has made them a preferred choice to provide a pacing boost to cells with little inclination to beat on their own, in the form of a biological pacemaker (Rosen et al. 2007, 2008), as well as a target for drugs that inhibit heart rate specifically (DiFrancesco & Borer, 2007). Pacemaker channels are also known as ‘funny’ or ‘hyperpolarization-activated cyclic nucleotide-modulated’ (HCN) channels in reference to their uncommon characteristics.

In situ co-distribution and functional interactions of SAP97 with sinoatrial isoforms of HCN channels

The sinoatrial node is a region of specialized cardiomyocytes that is responsible for the repetitive activity of the adult heart. The sinoatrial node is heavily innervated compared to the other regions of the heart, and the specialized cardiomyocytes of this region receive neural and hormonal input from the autonomic nervous system, which leads to changes in heart rate. A key regulator of sinoatrial beating frequency in response to autonomic input is the hyperpolarization-activated cyclic nucleotide gated (HCN) channel, a mixed cationic channel whose activity is increased by the binding of cAMP to its cytoplasmic side. HCN channels localize to distinct regions or “hot spots” on the cell surface of sinoatrial myocytes, but how these regions are formed, whether they correspond to specific signaling domains and the specific HCN isoforms and other proteins therein are not known. In this paper, we show that both HCN2 and HCN4 isoforms co-distribute with the adapter protein SAP97, an important component of distinct punctae in the sinoatrial node of the rabbit heart. HCN4, but not HCN2, also co-distributes with the post-synaptic marker β-catenin, thus identifying diverse organized domains within this tissue. Furthermore, we show, using heterologous expression systems, whole-cell patch clamp electrophysiology and imaging, that SAP97 interacts functionally with HCN in a manner that depends upon the PDZ compatible binding motif of the C-terminus, but that its effects on I f behaviour are HCN isoform and context dependent. Together, the data suggest that SAP97 contributes to isoform specific organization of HCN channels within specific domains in the sinoatrial node of the rabbit.

The central nervous system at the core of the regulation of energy homeostasis

Energy homeostasis is kept through a complex interplay of nutritional, neuronal and hormonal inputs that are integrated at the level of the central nervous system (CNS). A disruption of this regulation gives rise to life-threatening conditions that include obesity and type-2 diabetes, pathologies that are strongly linked epidemiologically and experimentally. The hypothalamus is a key integrator of nutrient-induced signals of hunger and satiety, crucial for processing information regarding energy stores and food availability. Much effort has been focused on the identification of hypothalamic pathways that control food intake but, until now, little attention has been given to a potential role for the hypothalamus in direct control of glucose homeostasis. Recent studies have cast a new light on the role of the CNS in regulating peripheral glucose via a hypothalamic lipid-sensing device that detects nutrient availability and relays, through the autonomic nervous system, a negative feedback signal on food intake, insulin sensitivity and insulin secretion. This review aims to summarize recent discoveries that highlight the brain as a potential target for anti-diabetic strategies.

Regulation of testicular function in the stallion: An intricate network of endocrine, paracrine and autocrine systems

It is well established in many mammalian species, including the horse that normal testicular function is dependent upon a functional hypothalamic–pituitary–testicular (HPT) axis, which involves classic feedback mechanisms. The major HPT hormones involved in the stallion are gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH), follicle stimulating hormone (FSH), testosterone (T), estrogens (Es) and inhibin (INH). Although prolactin (PRL) fluctuates with season in the stallion and both PRL and thyroid hormone (TH) affect reproduction in other male species, their effects on stallion reproduction have not been elucidated. Growth hormone (GH) in the stallion may be involved in sperm motility, production and secretion of insulin-like growth factor-1 (IGF-1) and LH-induced testosterone release. The action of these hormones and the products involved for normal spermatogenesis require cell to cell communication within the testis. The somatic cell types, Leydig, Sertoli and peritubular myoid cells, all support germ cell development, maturation and release into the seminiferous tubule lumen. The cell to cell crosstalk involves an intricate network of paracrine–autocrine systems that support the endocrine input to modulate cell function. In other male species, researchers have demonstrated the reproductive effects of such paracrine–autocrine factors as IGF-1, transferrin, androgens, estrogens, inhibin, insulin like peptide 3 (INSL3), beta-endorphin and oxytocin. The specific nature and relative contribution of these various factors on testicular function in fertile and subfertile stallions are under investigation. This review summarizes current information regarding the nature of the multiple endocrine–paracrine–autocrine systems that may be necessary for normal testicular function in the stallion.

Genetic and hormonal control of brain sex differentiation

Sexual differentiation of the brain is a complex developmental phenomenon which, influenced by both the genetic background and sex hormone secretions, leads to several genderspecific physiological and behavioral responses. The developing “sex brain” is feminine by default, unless some specific stimuli drive it to a male phenotype: to achieve a male-specific brain, it is necessary to develop neural circuits responsive to testicular hormones (masculinization) loosing those able to respond to ovarian hormones (defeminization). Genetic and hormonal inputs strictly cooperate in the developing brain, especially in some specific brain areas, as the hypothalamus where marked differences also in the volume and morphology of some selected hypothalamic nuclei, differently enlarged between males and females, occur. The genetic control of brain sexual differentiation is based on recent evidences: some sex differences are already present in tissues before gonadal differentiation; brain cells, that differ in their genetic sex, respond differently to the same hormonal inputs. Even if the “co-primary” role of genes in controlling brain sex differentiation is established, it is generally recognized that the hormonal “milieu”, particularly testosterone, is the leading force controlling this process, at least in rodents. Testosterone is converted in active metabolites by the enzymes 5alpha-reductase (type 1 and 2) and aromatase, giving rise to DHT and estradiol respectively. These two steroids, interacting with specific intracellular receptors, bring about the activation of genes responsible for brain masculinization. Our recent demonstration of a dimorphic expression for aromatase and 5alpha reductase type 2 during embryogenesis, but very likely, not for androgen and estrogen receptors, is consistent with the crucial role of testosterone metabolism in brain differentiation.

Contribution of Noradrenergic and Adrenergic Cell Groups of the Brainstem and Agouti-Related Protein-Synthesizing Neurons of the Arcuate Nucleus to Neuropeptide-Y Innervation of Corticotropin-Releasing Hormone Neurons in Hypothalamic Paraventricular Nucleus of the Rat

CRH-synthesizing neurons in the hypothalamic paraventricular nucleus (PVN) integrate neuronal and hormonal inputs and serve as a final common pathway to regulate the hypothalamic-pituitary-adrenal axis. One of the neuronal regulators of CRH neurons is neuropeptide Y (NPY) contained in axons that densely innervate CRH neurons. The three main sources of NPY innervation of the PVN are the hypothalamic arcuate nucleus and the noradrenergic and adrenergic neurons of the brainstem. To elucidate the origin of the NPY-immunoreactive (NPY-IR) innervation to hypophysiotropic CRH neurons, quadruple-labeling immunocytochemistry for CRH, NPY, dopamine-beta-hydroxylase, and phenylethanolamine-N-methyltransferase was performed. Approximately 63% of NPY-IR varicosities on the surface of CRH neurons were catecholaminergic (22% noradrenergic and 41% adrenergic), and 37% of NPY-IR boutons were noncatecholaminergic. By triple-labeling immunofluorescence detection of NPY, CRH, and agouti-related protein, a marker of NPY axons projecting from the arcuate nucleus, the noncatecholaminergic, NPY-ergic axon population was shown to arise primarily from the arcuate nucleus. When NPY was administered chronically into the cerebral ventricle of fed animals, a dramatic reduction of CRH mRNA was observed in the PVN (NPY vs. control integrated density units, 23.9 +/- 2.7 vs. 77.09 +/- 15.9). We conclude that approximately two thirds of NPY-IR innervation to hypophysiotropic CRH neurons originates from catecholaminergic neurons of the brainstem, whereas the remaining one third arises from the arcuate nucleus. The catecholaminergic NPY innervation seems to modulate the activation of CRH neurons in association with glucoprivation and infection, whereas the NPY input from the arcuate nucleus may contribute to inhibition of CRH neurons during fasting.

The Role of Nitric Oxide in Erectile Dysfunction: Implications for Medical Therapy

Erectile dysfunction is a common, multifactorial disorder that is associated with aging and a range of organic and psychogenic conditions, including hypertension, hypercholesterolemia, diabetes mellitus, cardiovascular disease, and depression. Penile erection is a complex process involving psychogenic and hormonal input, and a neurovascular nonadrenergic, noncholinergic mechanism. Nitric oxide (NO) is believed to be the main vasoactive nonadrenergic, noncholinergic neurotransmitter and chemical mediator of penile erection. Released by nerve and endothelial cells in the corpora cavernosa of the penis, NO activates soluble guanylyl cyclase, which increases 3',5'-cyclic guanosine monophosphate (cGMP) levels. Acting as a second messenger molecule, cGMP regulates the activity of calcium channels as well as intracellular contractile proteins that affect the relaxation of corpus cavernosum smooth muscle. Impaired NO bioactivity is a major pathogenic mechanism of erectile dysfunction. Treatment of erectile dysfunction often requires combinations of psychogenic and medical therapies, many of which have been only moderately successful in the past. The advent of oral phosphodiesterase type 5 (PDE-5) inhibitors, however, has greatly enhanced erectile dysfunction treatment; patients have demonstrated high tolerability and success rates for improved erectile function. The efficacy of the PDE-5 inhibitors also serves to illustrate the importance of the NO-cGMP pathway in erectile function since these agents counteract the degradation of NO-generated cGMP. Because not all patients respond to PDE-5 inhibitors, additional therapies are being investigated, such as soluble guanylyl cyclase activators and NO donors, which act on NO-independent and NO-dependent pathways, respectively.

Assessment and mechanism of variations in pubertal timing in internationally adopted children: a developmental hypothesis

During the past decades, children migrating for international adoption have increased in number, creating an original condition of dramatic environmental change during development. In several countries, cohorts of these subjects have been shown to experience a global advancement in age at the onset of puberty, and sexual precocity is seen more frequently than in other conditions. Such early or precocious development has been assessed in relatively small cohorts or individual patients using well-defined physical indicators in comparison with updated references in the foster country. Family and adolescent evaluation of pubertal timing could allow for the study of large series of internationally adopted subjects. Also, this type of assessment integrates the physical changes of puberty with the adolescent changes in psychological and social functioning. The pathophysiological mechanisms leading to advancement of puberty in migrating children are still unclear and possibly involve several factors. In the present paper, we hypothesize that the sexual precocity in children migrating for international adoption could represent a developmentally programmed disorder resulting from cumulative anomalies in early remodeling of the central nervous system by communicational, social, nutritional, and hormonal inputs. There is some evidence that the deviations in those inputs can result in altered brain structure, particularly in the limbic system. We discuss the possible association with further disorders of developmental functions, such as cognitive, psychosocial, and sexual maturation. Along this hypothesis, some forms of idiopathic sexual precocity could result from dysfunction of one or several of the environmental programming factors, while other forms may involve predominantly genetic or familial factors.

GLOBAL STUDIES OF CELL TYPE-SPECIFIC GENE EXPRESSION IN PLANTS

Technological advances in expression profiling and in the ability to collect minute quantities of tissues have come together to allow a growing number of global transcriptional studies at the cell level in plants. Microarray technology, with a choice of cDNA or oligo-based slides, is now well established, with commercial full-genome platforms for rice and Arabidopsis and extensive expressed sequence tag (EST)-based designs for many other species. Microdissection and cell sorting are two established methodologies that have been used in conjunction with microarrays to provide an early glimpse of the transcriptional landscape at the level of individual cell types. The results indicate that much of the transcriptome is compartmentalized. A minor but consistent percentage of transcripts appear to be unique to specific cell types. Functional analyses of cell-specific patterns of gene expression are providing important clues to cell-specific functions. The spatial dissection of the transcriptome has also yielded insights into the localized mediators of hormone inputs and promises to provide detail on cell-specific effects of microRNAs.

Targeting Fatty Acid Metabolism in the Treatments of Obesity and Disorders of CNS Cellular Energy Balance

The regulation of cellular energy homeostasis within the CNS is crucial not only to neuronal survival, but to the brains function as an integrator of hormonal and neural inputs that regulate many functions, such as feeding behavior. The sensing and regulation of CNS cellular energy balance is altered in many diseases. Recent studies have suggested that fatty acid metabolism plays a significant role in regulating cellular energy balance in the brain. This hypothesis is supported by observations that the pharmacological manipulation of fatty acid metabolism alters food intake and causes weight loss. Fatty acid levels are determined by fatty acid synthase (FAS), which catalyzes the de novo synthesis of longchain fatty acids that are stored as triglycerides during energy surplus, and carnitine palmitoyltransferase-1 (CPT-1), the rate-limiting enzyme for entry of long-chain acyl-CoAs into the mitochondria for fatty acid oxidation during energy deficit. Most recently, it has been reported that pharmacological manipulation of fatty acid metabolism can also alter cellular energy balance in a stroke model, thus providing neuroprotection. While the physiological contribution of fatty acid metabolism is a hypothesis that awaits further testing, here, we review studies from a number of laboratories investigating fatty acid metabolism as a therapeutic approach for obesity and disorders of CNS energy balance such as stroke.

The magnocellular medial preoptic nucleus I. sources of afferent input

The magnocellular medial preoptic nucleus plays a crucial role in the regulation of male sexual behavior in Syrian hamsters. Histological and behavioral studies suggest that the magnocellular medial preoptic nucleus regulates male mating behavior by integrating chemosensory and hormonal signals. The present study is the first to systematically identify the afferent connections of the magnocellular medial preoptic nucleus by tracing the uptake of cholera toxin B from deposits in the magnocellular medial preoptic nucleus of adult male Syrian hamsters. Our findings indicate that the magnocellular medial preoptic nucleus receives 1) chemosensory input from areas in the main and accessory olfactory pathways including the posterior medial bed nucleus of the stria terminalis, anterior medial, anterior cortical and posterior cortical nuclei of the amygdala; 2) input from steroid responsive structures such as the posterior medial nucleus of the amygdala, bed nucleus of the stria terminalis, lateral septum, anteroventral periventricular nucleus, medial preoptic nucleus, ventromedial nucleus of the hypothalamus and arcuate nucleus; 3) input from structures in the brainstem such as the subparafascicular thalamic nucleus, peripeduncular nucleus and the premamillary nucleus in the hypothalamus that carry sensory information from the genitalia. The major afferent input to the magnocellular medial preoptic nucleus was confirmed by injecting anterograde tracer biotinylated dextran amine into the anterior medical nucleus of the amygdala, the posterodorsal part of the medial nucleus of the amygdala, the posteromedial part of the bed nucleus of the stria terminalis and the posterointermediate part of the bed nucleus of the stria terminalis. Our results support the hypothesis that the magnocellular medial preoptic nucleus is part of the chemosensory pathway that receives chemosensory and hormonal input to regulate mating behavior and suggest that the magnocellular medial preoptic nucleus may utilize information from the genitalia to regulate male mating behavior.

Hormonal and sensory inputs regulate distinct neuroblast cell cycle properties in adult cricket brain

From invertebrates to humans, it has been demonstrated that new neurons are added to specific brain structures throughout adult life. In the house cricket, adult neurogenesis occurs in the mushroom bodies, the main sensory integrative center of the brain, often considered an analogue of vertebrate hippocampus. We have previously shown that this neurogenesis can be modulated by hormones through the polyamine pathway and by environmental conditions through sensory inputs and the nitric oxide pathway. Environment-induced neurogenesis is independent of juvenile hormone levels, so we addressed the roles of sensory inputs and hormones in the control of neuroblast proliferation. Here, by using double labelling of cells specifically in S phase (5-bromo-2'-deoxyuridine) together with labelling of mitotically active cells in any phase (proliferating cell nuclear antigen), we show that juvenile hormone acts on progenitor cell proliferation by inducing quiescent neuroblasts to enter the cell cycle, whereas sensory inputs act by shortening the cell cycle. Thus, in the adult house cricket, regulation of neuroblast proliferation by hormonal and environmental cues occurs through two independent modes of action.

Spatiotemporal analysis of exocytosis in mouse parotid acinar cells

Exocrine cells of the digestive system are specialized to secrete protein and fluid in response to neuronal and/or hormonal input. Although morphologically similar, parotid and pancreatic acinar cells exhibit important functional divergence in Ca(2+) signaling properties. To address whether there are fundamental differences in exocytotic release of digestive enzyme from exocrine cells of salivary gland versus pancreas, we applied electrophysiological and optical methods to investigate spatial and temporal characteristics of zymogen-containing secretory granule fusion at the single-acinar cell level by direct or agonist-induced Ca(2+) and cAMP elevation. Temporally resolved membrane capacitance measurements revealed that two apparent phases of exocytosis were induced by Ca(2+) elevation: a rapidly activated initial phase that could not be resolved as individual fusion events and a second phase that was activated after a delay, increased in a staircaselike fashion, was augmented by cAMP elevation, and likely reflected both sequential compound and multivesicular fusion of zymogen-containing granules. Optical measurements of exocytosis with time-differential imaging analysis revealed that zymogen granule fusion was induced after a minimum delay of approximately 200 ms, occurred initially at apical and basolateral borders of acinar cells, and under strong stimulation proceeded from apical pole to deeper regions of the cell interior. Zymogen granule fusions appeared to coordinate subsequent fusions and produced persistent structures that generally lasted several minutes. In addition, parotid gland slices were used to assess secretory dynamics in a more physiological context. Parotid acinar cells were shown to exhibit both similar and divergent properties compared with the better-studied pancreatic acinar cell regarding spatial organization and kinetics of exocytotic fusion of zymogen granules.

Follicle-Stimulating Hormone Activates p70 Ribosomal Protein S6 Kinase by Protein Kinase A-Mediated Dephosphorylation of Thr 421/Ser 424 in Primary Sertoli Cells

FSH is a major hormonal input that drives Sertoli cells to their fully differentiated function in male reproduction. It is a physiologically important issue to define how FSH mediates its effects at the cellular level to regulate gene expression. FSH biological activities are transduced via a seven-spanned transmembrane receptor, the FSH-R, primarily leading to cAMP-dependent protein kinase A (PKA) activation and cAMP response element binding protein-mediated transcriptional responses. Nevertheless, the intracellular mechanisms interacting with PKA to control Sertoli cell differentiation by FSH are still incompletely defined. Here, we report that, in primary cultures of Sertoli cells isolated from prepubertal rats, FSH enhanced p70S6K enzymatic activity, in a PKA-dependent manner. p70S6K was constitutively phosphorylated on Thr 389, in a manner sensitive to inhibitors of phosphatidyl-inositide-3 kinase and mammalian target of rapamycin. But FSH could not enhance p70S6K phosphorylation on Thr 389. Rather, the hormone induced the dephosphorylation of Thr 421/Ser 424, located in the autoinhibitory domain of p70S6K, in a PKA-dependent manner. Consistently, FSH-induced phosphorylation of the S6 ribosomal protein, a cellular substrate of p70S6K, required PKA activity. In conclusion, these results show that FSH triggers unexpected regulations of p70S6K by dephosphorylation of Thr 421/Ser 424 mediated by PKA, and stimulates S6 phosphorylation, in Sertoli cells.

A protocol for in vitro germination and sustainable growth of two tropical mistletoes

We report a protocol for in vitro germination and sustainable growth of two tropical mistletoes, Dendrophthoe pentandra and Macrosolen cochinchinensis . Normal mistletoe shoots with haustoria have been produced using Murashige and Skoog (MS) media supplemented with coconut water (15–20% v/v) in ventilated culture vessels. Germination of mistletoes took place on hormone-free basal MS media, and the time needed for germination was much shorter for Macrosolen than for Dendrophthoe . After germination, further development of the mistletoes required a hormonal input from the medium. We found that 20 μM 6-benzylaminopurine (BA) did allow normal development of only Dendrophthoe , while coconut water (15–20% v/v) gave complete development of both species in ventilated culture vessels. Multiplication of these mistletoes is also possible via the callus stage using half-strength MS media supplemented with BA at various concentrations in ventilated culture vessels. This is probably the first report of a successful culture for the mistletoe genus of Macrosolen . Compared to Macrosolen , the nutritional and hormonal requirements for Dendrophthoe are less demanding, making the latter a useful model for further mistletoe research.

GABAergic transmission in the rat paraventricular nucleus of the hypothalamus is suppressed by corticosterone and stress

Parvocellular neurons in the hypothalamic paraventricular nucleus receive hormonal inputs mediated by corticosterone as well as neuronal inputs, prominent among which is a GABAergic inhibitory projection. In the present study we examined the functional properties of this GABAergic innervation when corticosteroid levels fluctuate. Frequency, amplitude and kinetic properties of miniature inhibitory postsynaptic potentials (mIPSCs), mediated by gamma amino butyric acid (GABA) were studied with whole cell recording in parvocellular neurons. Injection of a high dose of corticosterone in vivo suppressed the frequency but did not change the amplitude and kinetic properties of mIPSCs recorded 1-5 h later in vitro. Similar effects were observed after restraint stress. The corticosteroid actions do not require involvement of extrahypothalamic brain regions, because in vitro administration of 100 nM corticosterone (20 min) directly to a hypothalamic slice also suppressed the frequency of mIPSCs recorded several hours later. Corticosterone administration to hypothalamic slices from restraint rats did not result in stronger reduction of mIPSC frequency than either treatment alone, pointing to a common underlying mechanism. Paired pulse response inhibition was reduced by corticosterone, suggesting that the hormone decreases the release probability of GABA-containing vesicles. Unlike neurosteroids, corticosterone induced no rapid effects on mIPSC properties. These results indicate that increases in glucocorticoid level due to stress can slowly but persistently inhibit the GABAergic tone on parvocellular hypothalamic neurons via a hitherto unknown local mechanism independent of limbic projections.

Nutrient, Neural and Endocrine Control of Glucagon-like Peptide Secretion

The intestinal glucagon-like peptides, GLP-1 and GLP-2, are important regulators of nutrient intake, digestion, absorption and metabolism. Extensive studies have shown that the co-secretion of GLP-1 and GLP-2 is regulated by a variety of dietary nutrient, neural and endocrine inputs. Furthermore, secretion of these peptides is altered in a number of pathological conditions, including type 2 diabetes and obesity. The purpose of this review is to discuss the regulation of GLP-1 and GLP-2 secretion in both health and disease.

Multiple and overlapping combinatorial codes orchestrate hormonal responsiveness and dictate cell-specific expression of the genes encoding luteinizing hormone.

Normal reproductive function in mammals requires precise control of LH synthesis and secretion by gonadotropes of the anterior pituitary. Synthesis of LH requires expression of two genes [alpha-glycoprotein subunit (alphaGSU) and LHbeta] located on different chromosomes. Hormones from the hypothalamus and gonads modulate transcription of both genes as well as secretion of the biologically active LH heterodimer. In males and females, the transcriptional tone of the genes encoding alphaGSU and LHbeta reflects dynamic integration of a positive signal provided by GnRH from hypothalamic neurons and negative signals emanating from gonadal steroids. Although alphaGSU and LHbeta genes respond transcriptionally in the same manner to changes in hormonal input, different combinations of regulatory elements orchestrate their response. These hormone-responsive regulatory elements are also integral members of much larger combinatorial codes responsible for targeting expression of alphaGSU and LHbeta genes to gonadotropes. In this review, we will profile the genomic landscape of the promoter-regulatory region of both genes, depicting elements and factors that contribute to gonadotrope-specific expression and hormonal regulation. Within this context, we will highlight the different combinatorial codes that control transcriptional responses, particularly those that mediate the opposing effects of GnRH and one of the sex steroids, androgens. We will use this framework to suggest that GnRH and androgens attain the same transcriptional endpoint through combinatorial codes unique to alphaGSU and LHbeta. This parallelism permits the dynamic and coordinate regulation of two genes that encode a single hormone.