Search Results - (Author, Cooperation:A. Gore)

2018-06-20

BMJ Publishing

2044-6055

Medicine

Open access, Mental health

2018-02-16

American Society of Hematology (ASH)

0006-4971

1528-0020

Biology

Medicine

Myeloid Neoplasia, Clinical Trials and Observations

2011-10-08

Nature Publishing Group (NPG)

0028-0836

1476-4687

Biology

Chemistry and Pharmacology

Medicine

Natural Sciences in General

Physics

Adult ; Blastocyst/cytology/metabolism ; Cell Differentiation ; *Cellular Reprogramming ; DNA Methylation ; Epigenesis, Genetic ; Female ; Gene Expression Profiling ; Gene Expression Regulation, Developmental ; Genome, Human/genetics ; Germ Layers/cytology/embryology/metabolism ; Humans ; Induced Pluripotent Stem Cells/*cytology/*metabolism ; Oocyte Donation ; Oocytes/*cytology/growth & development/*physiology ; Primary Cell Culture ; Transcription, Genetic ; Triploidy ; Young Adult

2011-03-04

Nature Publishing Group (NPG)

0028-0836

1476-4687

Biology

Chemistry and Pharmacology

Medicine

Natural Sciences in General

Physics

Cells, Cultured ; Cellular Reprogramming/*genetics ; DNA Mutational Analysis ; Epistasis, Genetic/genetics ; Fibroblasts/cytology/metabolism ; Humans ; Induced Pluripotent Stem Cells/cytology/*metabolism ; Male ; Middle Aged ; Models, Genetic ; Mutagenesis/*genetics ; Open Reading Frames/genetics ; Point Mutation/*genetics

0269-0403

Musicology

0269-0403

Musicology

0269-0403

Musicology

1365-2826

Blackwell Publishing Journal Backfiles 1879-2005

Medicine

Insulin-like growth factor-I (IGF-I) is thought to play a role in the onset of reproductive ability at puberty and the control of reproductive function throughout adult life. It is believed that these effects are mediated at least in part by the activation of gonadotropin releasing hormone (GnRH) neurones by IGF-I, but the interactions of IGF-I with GnRH neurones in vivo are largely unknown. We first examined the anatomical relationship between GnRH and IGF-I cells in neuroendocrine regions. Using double-label immunocytochemistry, we observed that in the preoptic area-anterior hypothalamus (POA-AH), the site of GnRH perikarya, the majority (78%) of GnRH cell bodies expressed IGF-I immunoreactivity. IGF-I immunoreactivity was also high in the median eminence, the site of GnRH release, and GnRH neuroterminals were seen to interweave among IGF-I-immunopositive cells. Due to this substantial overlap of GnRH and IGF-I immunoreactive elements, we then tested the hypothesis that changes in IGF-I may regulate the GnRH system. Animals were examined at the two important reproductive life transitions: puberty and reproductive senescence. IGF-I mRNA levels were measured in POA-AH and medial basal hypothalamus-median eminence (MBH-ME) and effects of IGF-I treatment on GnRH mRNA levels were quantified by RNase protection assay. Although IGF-I treatment did not alter GnRH gene expression, there were significant alterations in hypothalamic IGF-I gene expression at both puberty and reproductive senescence. During puberty, IGF-I mRNA levels in the MBH-ME of rats increased from the juvenile stage (P25) to the day of vaginal opening (P35), and from the day of vaginal opening to young adulthood (P45) in the POA-AH. During reproductive ageing, IGF-I mRNA levels were significantly lower in middle-aged than young rats, particularly in the MBH-ME. At all ages, IGF-I expression was greater in the MBH-ME than in the POA-AH. These experiments demonstrate that: (i) the majority of adult GnRH neurones are immunopositive for the IGF-I protein; (ii) hypothalamic IGF-I levels increase at the onset of reproductive function and decrease at reproductive senescence in a regionally specific manner; and (iii) despite the presence of IGF-I in GnRH perikarya, IGF-I does not affect GnRH gene expression, suggesting that IGF-I may act at the level of GnRH release rather than gene expression.

Electronic Resource

1365-2826

Blackwell Publishing Journal Backfiles 1879-2005

Medicine

Polychlorinated biphenyls (PCBs) cause abnormal development and physiology of the reproductive system. We hypothesized that these effects may be mediated, at least in part, by neuroendocrine cells in the hypothalamus that integrate inputs to and outputs from the central nervous system and reproductive systems. The effects of two PCB mixtures, Aroclor 1221 and Aroclor 1254, were tested on the hypothalamic GT1-7 cells, which synthesize and secrete the key hypothalamic hormone, gonadotropin-releasing hormone (GnRH). GT1-7 cells were treated for 24 h in dose–response experiments and GnRH gene expression and release were quantified. Aroclor 1221 was stimulatory to GnRH gene expression, particularly at post-transcriptional levels (GnRH cytoplasmic mRNA), and increased GnRH peptide levels, suggesting a post-translational regulation of GnRH biosynthesis. It also caused a qualitative increase in GT1-7 neurite outgrowth and cell confluency. Aroclor 1254 had very different effects from Aroclor 1221. It inhibited GnRH nuclear mRNA levels at high dosages, and stimulated GnRH mRNA at low doses, suggesting a post-transcriptional mechanism of regulation. Aroclor 1254 did not alter GnRH peptide levels. Qualitatively, Aroclor 1254 caused a retraction of GT1-7 cell processes and neurotoxicity at high dosages. In order to gauge the involvement of the oestrogen receptor in these responses, the oestrogen receptor antagonist, ICI 182,780 (ICI) was coadministered in other studies with the PCBs. While effects of Aroclor 1221 on GnRH gene expression were not blocked by ICI, its effects on GnRH peptide levels were blocked by ICI, indicating that some but not all of the effects of Aroclor 1221 are mediated by the classical oestrogen receptor α and/or β. The inhibitory effects of Aroclor 1254 on GnRH gene expression were not prevented by ICI, although ICI itself had stimulatory effects on GnRH gene expression that were blocked by cotreatment with Aroclor 1254. These results demonstrate a novel mechanism for effects of the two PCBs directly on GnRH gene expression, and indicate a hypothalamic level for endocrine disruption by these environmental toxicants.

Electronic Resource

1365-2826

Blackwell Publishing Journal Backfiles 1879-2005

Medicine

Successful reproduction requires precise temporal coordination among various endocrine and behavioural events. The circadian system regulates daily temporal organization in behaviour and physiology, including neuroendocrine rhythms. The main circadian pacemaker in mammals is located in the suprachiasmatic nuclei (SCN) of the anterior hypothalamus. The SCN sends direct efferents to the reproductive axis via monosynaptic projections to gonadotropin-releasing hormone (GnRH) neurones. This communication generates circadian endocrine rhythms as well as the preovulatory luteinizing hormone (LH) surge necessary for successful ovulation. One SCN peptide thought to be important for the regulation of oestrous cycles is vasoactive intestinal polypeptide (VIP). VIP neurones from the SCN contact GnRH cells, and these cells are preferentially activated during an LH surge in rats. Unlike adult rats, prepubertal females do not exhibit oestrous cycles, nor do they exhibit an LH surge in response to oestradiol positive-feedback. The present study was undertaken to determine the extent to which the development of a ‘mature’ reproductive axis in female rats is associated with modifications in VIP contacts on GnRH neurones. The brains of diestrus adult (approximately 60 days of age) and prepubertal (21 days of age) female rats were examined using double-label fluorescence immunohistochemistry for VIP and GnRH, with light and confocal microscopy. Although the total number of GnRH-immunoreactive neurones did not differ between adult and prepubertal females, adults had a significant increase in the percentage of GnRH cells receiving VIP contacts compared to juveniles. These data suggest that the development of reproductive hormone rhythms and oestrous cyclicity may be, in part, due to modifications of VIP input to the GnRH system.

Electronic Resource

1365-2826

Blackwell Publishing Journal Backfiles 1879-2005

Medicine

Reproduction in vertebrates is controlled by hypophysiotropic gonadotropin-releasing hormone (GnRH) neurones. Pulsatile GnRH release increases during reproductive development, resulting in the onset and progression of puberty and, ultimately, the acquisition and maintenance of adult reproductive function. These changes in GnRH release are largely due to inputs to GnRH cells from other factors, including the neurotrophic factor, insulin-like growth factor-1 (IGF-1). Here, molecular studies were undertaken to quantify expression of IGF-1 receptor (IGF-1R) mRNA in the preoptic area-anterior hypothalamus (POA-AH) and mediobasal hypothalamus (MBH)-median eminence (ME), the sites of GnRH perikarya and neuroterminals, respectively. Immunocytochemical studies were also carried out to study the anatomical relationship between the IGF-1R and GnRH neurones. Experiments were performed in a developmental context using neonatal (P5), peripubertal (∼P30) and adult (P60) male and female mice. We found that IGF-1R mRNA levels in the POA-AH were significantly different among all age groups, with levels higher at P60 then P5 or ∼P30. Levels of IGF-1R mRNA in the MBH-ME were lower at P5 than ∼P30 or P60. Qualitative observations suggested that IGF-1R immunoreactivity in POA-AH increased from P5 through P60. Quantitative double-label immunocytochemistry studies showed that GnRH perikarya expressed IGF-1R. Taken together, the results demonstrate expression of, and developmental changes in, IGF-1R gene and protein in brain regions containing GnRH and other neuroendocrine cells. Moreover, the novel finding that the IGF-1R is expressed on GnRH perikarya in vivo suggests a potential direct anatomical locus where IGF-1 can regulate reproductive development and function.

Electronic Resource

1365-2826

Blackwell Publishing Journal Backfiles 1879-2005

Medicine

During reproductive ageing, the oestrous cycles of female rats become irregular and eventually cease. The mechanisms for reproductive senescence in rodents are believed to involve changes in hypothalamic neurones, including gonadotropin-releasing hormone (GnRH) cells and their afferent inputs. In addition, effects of oestrogen on hypothalamic function may vary in animals of different ages. These issues were addressed using young (aged 4–5 months), middle-aged (12–14 months) and old (24–26 months) female Sprague-Dawley rats. Animals were ovariectomized and given oestrogen or vehicle replacement. They were killed and the preoptic area-anterior hypothalamus (POA-AH) and the medial basal hypothalamus-median eminence (MBH-ME) were dissected out, RNA extracted, and RNase protection assay used to quantify gene expression of several hypothalamic molecules. In the first experiment, GnRH RNA levels were measured in the POA-AH. No effects of ageing or oestrogen were observed on GnRH gene expression. This finding suggests that ageing and oestrogen may affect GnRH release from neuroterminals independently of de novo biosynthesis, and that this may involve other neurones that affect GnRH neurosecretory function. In the second experiment, we investigated changes in N-methyl-d-aspartate (NMDA) receptor subunit mRNA levels. These receptors play an important regulatory role in mediating effects of glutamate on GnRH function, and are themselves regulated by oestrogen and ageing. NMDA receptor subunit (NR) 1, 2a and 2b mRNA levels were quantified in the POA-AH and MBH-ME, the sites of GnRH perikarya and neuroterminals, respectively. In general, oestrogen had inhibitory effects on NR1 and NR2a, and differential effects on NR2b subunit mRNA levels. NMDA receptor subunit mRNA levels also changed during ageing: age-related decreases in NR1 mRNA occurred in the MBH-ME, and an age-related increase in NR2b mRNA occurred in the POA-AH. Taken together, these results demonstrate subunit- and region-specific changes in hypothalamic NMDA receptor subunit gene expression with oestrogen and ageing. These alterations could have implications for the physiological effects of glutamate on its NMDA receptor, and impact the regulation of reproductive and other neuroendocrine and autonomic functions by hypothalamic glutamatergic inputs.

Electronic Resource

1365-2826

Blackwell Publishing Journal Backfiles 1879-2005

Medicine

Pheromones are an important class of environmental cues that affect the hypothalamic-pituitary-gonadal axis in a variety of vertebrate species, including humans. When male mice contact female-soiled bedding, or urine, they display a reflexive luteinizing hormone (LH) surge within 30 min. Aside from the requirement that males have gonads to show this response, the physiological mechanisms that underlie this pituitary response are unknown. In this experiment, we asked if female pheromones acted at the level of gonadotropin-releasing hormone (GnRH) gene expression to affect this hormone response. In addition, we also examined the contribution of one of the oestrogen receptors (ERα) by studying this neuroendocrine reflex in wild-type and oestrogen receptor-α knockout (ERαKO) males. Both ERαKO and wild-type males showed the expected LH surge, 45 and 90 min after contact with female pheromones. Males housed in clean bedding or bedding soiled by another adult male did not display the LH elevation. Interestingly, this dramatic change in LH concentrations was not accompanied by any alterations in GnRH mRNA expression or levels of primary transcript in the preoptic area-anterior hypothalamus. The one exception to this was a significant increase in GnRH mRNA expression in tissue collected from wild-type males exposed to bedding from another male. This is particularly intriguing since LH was not elevated in these males. These data replicate and extend our previous finding that ERαKO males do exhibit an LH surge in response to female pheromones. Thus, this neuroendocrine response is regulated by a steroid receptor other than ERα and does not require alterations in GnRH mRNA expression.

Electronic Resource

1365-2826

Blackwell Publishing Journal Backfiles 1879-2005

Medicine

We studied three neurotransmitters involved in the regulation of pulsatile luteinizing hormone (LH) release: opioid peptides, serotonin and norepinephrine, using the ovariectomized guinea-pig. This is an attractive animal model due to the regularity of its LH pulses, enabling any disruptions to be clearly ascertained. In all experiments, a specific agonist or antagonist was administered, either alone or serially to enable detection of interactions, and effects on mean LH concentrations, pulse amplitude and interpulse interval were determined by PULSAR analysis. In the ovariectomized guinea-pig, catecholamines are stimulatory (acting through the α1 and α2 but not β receptors, unlike other species), opioids inhibitory and serotonin permissively stimulatory to pulsatile LH release. Stimulatory effects of the opiate antagonist were not blocked by pretreatment with an α1- or α2-adrenergic antagonist. Similarly, pretreatment with the opiate antagonist did not prevent the suppression of LH release by α1 and α2 antagonists. This suggests that, in the guinea-pig, effects of opiates and catecholamines on LH release are exerted by independent pathways to luteinizing hormone releasing hormone (LHRH) neurones. For the opiate–serotonin interactions, pretreatment with the serotonergic antagonist did not block the stimulatory effect of the opiate antagonist on LH release. However, pretreatment with the opiate agonist could not be overcome by the serotonergic agonist. This suggests that the effects of the serotonin system on LHRH release may be indirectly mediated by opioid neurones. Taken together, these studies demonstrate that the three neurotransmitter systems studied are critically involved in normal pulsatile LH release in the female guinea-pig, and demonstrate novel functional relationships between the opioid and the adrenergic and serotonergic systems.

Electronic Resource