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  • 1
    Keywords: brain ; RECEPTOR ; CELL ; Germany ; IN-VIVO ; MODEL ; MODELS ; VIVO ; SYSTEM ; TOOL ; METABOLISM ; MICE ; ACTIVATION ; RESPONSES ; MECHANISM ; mechanisms ; hippocampus ; MOUSE ; NERVOUS-SYSTEM ; DISRUPTION ; STRESS ; MUTATION ; DNA-BINDING ; MUTATIONS ; MOUSE MODEL ; glucocorticoid receptor ; DOMAINS ; DISSECTION ; review ; RE ; RESPONSIVENESS ; FOREBRAIN ; TECHNOLOGY ; LOSSES ; ENGLAND ; steroids ; STEROID-HORMONE RECEPTORS ; CRE RECOMBINASE ACTIVITY ; cortisol/corticosterone ; HPA axis
    Abstract: In the brain, glucocorticoids exert functions in neurogenesis, synaptic plasticity and behavioural responses, as well as in the control of hypothalamic-pituitary-adrenal axis activity. The generation of mice harbouring germline mutations that result either in loss or in gain of glucocorticoid receptor function provided a useful tool for understanding the role of glucocorticoids in the brain in vivo. The improvement of genomic technologies additionally allowed the establishment of mouse models with function-selective point mutations of the receptor as well as the generation of mice harbouring spatially and/or temporally restricted loss of glucocorticoid receptor, specifically within the brain. These models will provide the opportunity to better understand the mechanisms involved in glucocorticoid signalling within the nervous system
    Type of Publication: Journal article published
    PubMed ID: 18513206
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  • 2
    Keywords: DEATH ; DISEASE ; TISSUE ; MICE ; RAT ; MOUSE ; ADRENAL-MEDULLA ; MONITORING AUTOPHAGY ; LABELING INDEX ; PARAGANGLIA
    Abstract: Neuroendocrine chromaffin cells exist in both intra- and extra-adrenal locations; the organ of Zuckerkandl (OZ) constitutes the largest accumulation of extra-adrenal chromaffin tissue in mammals. The OZ disappears postnatally by modes that are still enigmatic but can be maintained by treatment with glucocorticoids (GC). Whether the response to GC reflects a pharmacological or a physiological role of GC has not been clarified. Using mice with a conditional deletion of the GC-receptor (GR) gene restricted to cells expressing the dopamine beta-hydroxylase (DBH) gene [GR(fl/fl) ; DBHCre abbreviated (GR(DBHCre) )], we now present the first evidence for a physiological role of GC signalling in the postnatal maintenance of the OZ: postnatal losses of OZ chromaffin cells in GR(DBHCre) mice are doubled compared to wild-type littermates. We find that postnatal cell loss in the OZ starts at birth and is accompanied by autophagy. Electron microscopy reveals autophagic vacuoles and autophagolysosomes in chromaffin cells. Autophagy in OZ extra-adrenal chromaffin cells is confirmed by showing accumulation of p62 protein, which occurs, when autophagy is blocked by deleting the Atg5 gene (Atg5(DBHCre) mice). Cathepsin-D, a lysosomal marker, is expressed in cells that surround chromaffin cells and are positive for the macrophage marker BM8. Macrophages are relatively more abundant in mice lacking the GR, indicating more robust elimination of degenerating chromaffin cells in GR(DBHCre) mice than in wild-type littermates. In summary, our results indicate that extra-adrenal chromaffin cells in the OZ show signs of autophagy, which accompany their postnatal numerical decline, a process that is controlled by GR signalling.
    Type of Publication: Journal article published
    PubMed ID: 23078542
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  • 3
    Keywords: EXPRESSION ; METABOLISM ; ESCHERICHIA-COLI ; RAT-BRAIN ; ORGANIC ANION TRANSPORTER ; NEURONS ; brain development ; CEREBRAL-CORTEX ; BARRIER GENOMICS ; HYPOTHYROIDISM ; MATERNAL HYPOTHYROXINEMIA ; MONOCARBOXYLATE TRANSPORTER-8 ; solute carrier organic anion transporter 1c1 ; thyroid hormones ; THYROID-HORMONE TRANSPORTERS ; thyroxine transporter
    Abstract: Transporters are essential in thyroid hormone metabolism. Thyroxine (T4) is transported by solute carrier organic anion transporter 1c1 (SLCO1C1, OATP14) into the adult brain, where T4 is converted to 3,5,3'-triiodothyronine (T3). In adults, SLCO1C1 expression is found in two brain barrier structures: the bloodbrain barrier (BBB) and choroid plexus. However, little is known about how T4 is transported in the developing brain, when the BBB is not yet completely formed. We employed bacterial artificial chromosome recombineering to generate transgenic mice carrying Cre recombinase in the Slco1c1 locus (Slco1c1-Cre mice). In Slco1c1-Cre mice Cre was expressed at the sites that have been previously reported for SLCO1C1 in adults. To trace Cre expression during development, we crossed Slco1c1-Cre transgenic mice with Rosa26 reporter mice. beta-galactosidase staining showed Cre activity in neurones of various brain structures, such as cortical layer 2/3 and the hippocampus, suggesting transient Slco1c1 expression during brain development. At embryonic day15, SLCO1C1 was expressed at the same site as TBR2, a marker of neuronal progenitors. Neurones that express SLCO1C1 during their development could be T4 sensitive. In support of this hypothesis, hypothyroxinaemia induced by propylthiouracil treatment of dams decreased the number of beta-galactosidase-positive neurones in cortical layer 2/3 of newborn Slco1c1-Cre/Rosa26 mice. In conclusion, by generating Slco1c1-Cre transgenic mice, we demonstrated that SLCO1C1 is expressed in the neuronal cell lineage during brain development. Expression of SLCO1C1 may underlie the extraordinary sensitivity of specific neuronal populations to hypothyroxinaemia
    Type of Publication: Journal article published
    PubMed ID: 21910767
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  • 4
    Electronic Resource
    Electronic Resource
    Oxford : Blackwell Science Ltd.
    ISSN: 1365-2826
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: This paper summarizes a particular aspect of the stress response — the negative feedback control of anterior pituitary adrenocorticotrophin secretion with special focus on the mechanism of action of protein(s) rapidly induced by glucocorticoids. The main thesis is that the principal intracellular mechanism underlying corticosteroid inhibition of corticotroph secretory function is the opposition of cAMP-mediated activation by calcium ions. An increase of intracellular cAMP levels in corticotrophs produces a rise in intracellular free Ca2+ known to be essential for triggering hormone secretion. In parallel, calcium regulates agonist-induced cAMP accumulation through inhibition of adenylyl cyclase and the stimulation of cAMP-degrading phosphodiesterase. Furthermore, a key action of cAMP is the inhibition of a slow, sustained potassium current which is activated by calcium ions. Collectively, the actions of calcium constitute a powerful intracellular feedback inhibition of cAMP-induced cellular activation. Analysis of corticosteroid action in mouse corticotroph tumour (AtT20) cells indicates that the essence of corticosteroid feedback inhibition is the amplification of intracellular calcium feedback. A common mediator of the inhibitory actions of calcium may be the calcium receptor protein calmodulin the de novo synthesis of which is rapidly stimulated by glucocorticoid hormones. Targets of glucocorticoid-induced calmodulin may include the protein phosphatase calcineurin, calmodulin-activated phosphodiesterase(s), and BK-type potassium channels. The net result of calcium feedback inhibition is a reduction of Ca2+ available for the facilitation of secretory activity i.e. calcium-induced desensitization. It is proposed that the intracellular calcium feedback loop outlined above also operates in the CNS components of negative corticosteroid feedback.
    Type of Medium: Electronic Resource
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  • 5
    ISSN: 1365-2826
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: The ventrolateral hypothalamus (VLH) in female guinea pigs includes a subset of neurons which contain estrogen and progestin receptors, and which are implicated in the regulation of female sexual behavior by steroid hormones. However, little is known about where these neurons project, and consequently which other brain areas are involved in sexual behavior in female guinea pigs. The anterograde tracer Phaseolus vulgaris-Leucoagglutinin was used to label efferents from the ovarian steroid receptor-containing part of the VLH. To identify the correct placement of the tracer specifically within the group of neurons containing estrogen receptors, medial hypothalamic sections were also immunostained for estrogen receptors. Forebrain areas receiving dense projections from the ventrolateral hypothalamus included the bed nucleus of the stria terminalis, medial preoptic area, anterior hypothalamic area, anterior ventromedial hypothalamus, and caudal ventrolateral hypothalamus. The midbrain central gray was also heavily labeled. Moderate innervation was observed in the forebrain in the basolateral amygdala, medial preoptic nucleus, lateroanterior hypothalamic nucleus, dorsal hypothalamic areas, posterior hypothalamus, zona incerta, and in the midbrain interspersed among the central and lateral tegmental tracts. The major efferent pathways from the VLH appeared to travel rostrally through the mediobasal hypothalamus and preoptic area, and caudally via the medial thalamic nuclei and periventricular fiber system. These findings are similar to those of previous studies tracing the efferents from the ventromedial nucleus in rats and from the lateral hypothalamus in guinea pigs. Many of these areas that receive input from the steroid receptor rich area within the VLH are likely to be involved in the regulation of female sexual behavior.
    Type of Medium: Electronic Resource
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  • 6
    ISSN: 1365-2826
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: This study demonstrates the existence of the putative receptor for the hexapeptide (3–8) fragment of angiotensin II (AngIV) on rat astrocytes and neurons grown in cell culture. Binding of 125I-AngIV was saturable and distinct from that of the AngII receptor subtypes. Equilibrium binding was attained in 15 min in astrocytes and 75 min in neurons at 22 °C. The bound peptide was confirmed by HPLC to be intact AngIV while the bound peptide was substantially degraded, even in the presence of peptidase inhibitors. Scatchard analysis of equilibrium binding was consistent with a two binding site model, revealing a high affinity and a low affinity binding site in both cell types. In neurons, the respective association constants (Ka) were 2.72±0.23 nM−1 and 727± 354 nM−1, with associated receptor densities of 109.30±58.87 and 1723±1167 fmol/mg protein. Similar analyses in astrocytes gave Kas of 5.71±2.85 nM−1 and 277±205 nM−1, and respective densities of 191.1±90.1 and 1425±1250 fmol/mg protein. However, the quantitative reliability of these binding isotherms may be influenced by the degration of unbound peptide. Competitive binding analysis was used to determine the specificity of the receptor site, with the relative order of affinities being AngIV〉AngIII〉AngII(4–8), and no displacement by AngII, losartan and PD123319 in either neurons or astrocytes. Autoradiography with 125I-AngIV performed on neuronal cultures demonstrated that binding was confined to a subpopulation of the total cells. These data support the existence of a specific binding site for AngIV in both neurons and astrocytes, consistent with the properties of binding reported previously in the brain, and distinguish this site from the AngII receptor subtypes.
    Type of Medium: Electronic Resource
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  • 7
    ISSN: 1365-2826
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Two types of cDNAs encoding thyrotropin-releasing hormone (TRH) precursors (TRH-A andTRH-B) were amplified from hypothalamic mRNA of sockeye salmon by reverse transcriptase-polymerase chain reaction (RT-PCR). The amplification was achieved using two primers which correspond to TRH progenitor sequence (Lys/Arg-Arg-Gln-His-Pro-Gly-Lys/Ag-Arg). A full length cDNA encoding TRH-A was obtained by 5′- and 3′-RACE methods. It has a length of 1324 base pairs (bp) that contains sequences of 5′ and 3′ untranslated regions and an open reading frame of 259 codons. The sockeye salmon TRH-A deduced from the nucleotide sequence tandemly contains 8 copies of TRH progenitor sequences. Another cDNA which encodes a part of TRH-B consists of 242 bp, and the sequence homology between TRH-A and -B cDNAs is 90%. The result of Southern blot analysis of sockeye and masu salmon genomic DNAs supported the evidence that there are at least two TRH genes in the salmonid. A RT-PCR analysis of TRH gene expression in various tissues of sockeye salmon showed that strong expression was observed only in the brain. The primary structure of the sockeye salmon TRH-A shares low similarity to those of human, rat and Xenopus TRH precursors (35, 27 and 44%, respectively). However, their hydropathy profiles were almost the same with each other. The profile of sockeye salmon TRH-A showed the presence of two discrete hydrophobic regions, one in the N-terminal region which corresponds to the signal peptide and the other in the C-terminal region. All of the repetitive TRH progenitor sequences are included in three hydrophilic regions easily recognizable. The present results thus suggest that the three-dimensional structures of TRH precursors are highly conserved, although the primary structures of TRH precursors have diverged through the evolutionary pathway of vertebrates.
    Type of Medium: Electronic Resource
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  • 8
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    ISSN: 1365-2826
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Type of Medium: Electronic Resource
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  • 9
    ISSN: 1365-2826
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Using quantitative autoradiography, melatonin receptors have been studied during post-natal and pubertal development of the rat in 2 brain and 2 pituitary structures. In the pars distalis of anterior pituitary, melatonin receptors decrease gradually in density after birth and disappear in 30 day-old animals. In contrast melatonin binding is only expressed in the paraventricular nuclei of the thalamus at the age of 21–23 days and is always present in adult animals. In the suprachiasmatic nuclei and in the pars tuberalis of the pituitary, melatonin receptor density decreases after birth, remains stable for approximately 1 month and increases again at puberty to reach the birth values in the adult. This increase was absent in pinealectomized and in castrated animals but present in castrated animals receiving testosterone suggesting that it depends upon circulating testosterone and melatonin levels. These results show that melatonin receptors are differentially regulated during post-natal development in each of the 4 structures studied, and that melatonin and testosterone are 2 factors which could be involved in the regulation of melatonin receptor density in the suprachiasmatic nuclei and pars tuberalis.
    Type of Medium: Electronic Resource
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  • 10
    ISSN: 1365-2826
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Medicine
    Notes: Neurotensin (NT) has been shown to be involved in neuroendocrine regulation, and the presence of both the peptide and its receptors has been demonstrated in the hypothalamus. In the present study, we show that hypothalamic neurons in primary cultures express the neurotensin receptor (NTR) and we examined a possible regulation of this receptor by glucocorticoids and activators of adenylate cyclase. In the hypothalamic cultures, 125I-NT bound to a single class of binding sites, presenting a selectivity similar to that observed for the high-affinity NTR previously described in the adult rat brain. Radioautographic studies demonstrated that these 125I-NT binding sites were present on 3% of the neurons. A 48-h treatment with forskolin (fsk) decreased 125I-NT binding by 30%. No effect of dexamethasone (dex) alone was found on that parameter. However, a combined treatment with both agents led to a 40% decrease in 125I-NT binding, corresponding to a reduced number of binding sites, and to a 68% decrease in the amount of NTR mRNA. In parallel, the dex plus forsk treatment increased NT release in the incubation medium. Moreover, the decreases in 125I-NT binding and NTR mRNA induced by this treatment were abolished in the presence of an anti-NT antibody or SR 48692, a non-peptidic antagonist of NTR, suggesting that the down-regulation of NTR observed after dex plus fsk treatment was mediated by the release of endogenous NT. Agonist-induced down-regulation of the NTR in this system was confirmed by the application of an exogenous NT analogue, JMV 449. The present findings indicate that, in hypothalamic cultures, dex and fsk indirectly down-regulate NTR expression via the release of endogenous NT.
    Type of Medium: Electronic Resource
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