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Testosterone replacement therapy induces spermatogenesis and partially restores fertility in luteinizing hormone receptor knockout mice.

T Pakarainen — 2007-03-19T21:06:25-00:00

Endocrinology, Vol. 146, No. 2. (February 2005), pp. 596-606.

Testosterone (T) is essential for spermatogenesis, fertility, and maintenance of the male phenotype. We analyzed in hypogonadal LH receptor knockout (LuRKO) male mice whether T treatment can restore their phenotype, spermatogenesis, and fertility. In LuRKO mice, spermatogenesis is arrested at round spermatids, adult-type Leydig cells are absent, T production is dramatically decreased, the animals are cryptorchid, and their accessory sex organs are atrophic. T replacement therapy from 21 d of life for 60 or 120 d in LuRKO mice induced a male phenotype macroscopically indistinguishable from that of wild-type littermates as well as full spermatogenesis and testicular descent. Thus, the absence of LH-dependent prepubertal androgen priming is not necessary for subsequent maturation of the male phenotype. Conspicuously, some abnormalities remained in epididymal histology after T treatment despite normal expression of several epididymis-specific genes in caput epididymis. The mice displayed normal mating behavior, although at lower frequency than wild-type controls. The spermatozoa were able to fertilize oocytes, but their impaired passage from epididymis to uterus was apparent. The mice remained subfertile, because only 9% of all breedings resulted in pregnancy, and only two of 13 mice (15%) were fertile. Moreover, inflammation in epididymides and prostate was found in many T-treated LuRKO mice, which probably impaired sperm transport and contributed to their high rate of subfertility. In conclusion, T replacement initiated prepubertally only partially restores the fertility of LuRKO mice, even though most features of the male phenotype recover. Full fertility may require higher and/or earlier postnatal T exposure or production of other Leydig cell factors lacking in this model.

A functional transmembrane complex: The luteinizing hormone receptor with bound ligand and G protein

D Puett — 2006-10-26T15:37:01-00:00

Molecular and Cellular Endocrinology, Vol. In Press, Corrected Proof

The luteinizing hormone receptor (LHR) is one of eight members in a cluster of the rhodopsin family of the large G protein-coupled receptor (GPCR) superfamily that contains some 800-900 genes in the human genome. LHR, along with its paralogons, follicle stimulating hormone receptor (FSHR) and thyroid stimulating hormone receptor, form one of the three classes in this cluster; the two other classes contain the relaxin-binding GPCRs and orphan GPCRs. These GPCRs are characterized by a relatively large ectodomain (ECD) containing leucine-rich-repeats (LRRs); in the class of glycoprotein hormone receptors, the LRR region is capped by N-terminal and C-terminal cysteine-rich regions. Binding of human chorionic gonadotropin (hCG) or luteinizing hormone to the LHR-ECD triggers a conformational change of the transmembrane region of the receptor facilitating binding and activation of Gs, followed by effector enzyme activation and subsequent intracellular signaling. Viewing LHR as a transmembrane anchoring protein that sequentially binds hCG and Gs to give the hCG-LHR-Gs complex, numerous interactions and conformational changes must be considered. There is, unfortunately, a paucity of structural data on LHR, but crystal structures exist for hCG, the homologous FSH-FSHR-ECD (N-terminal fragment) complex, rhodopsin (in the inactive state), an active form of G[alpha]s (transducin), and the [beta][gamma] heterodimer. Using a combined experimental (site-directed mutagenesis followed by characterization in transfected cells) and computational (homology modeling and molecular dynamics simulations) approach, good working models are being developed for the protein-protein interaction faces and, in some cases, the ensuing conformational changes induced by complex formation. hCG binding to the LHR-ECD appears to involve several LRRs; LHR activation can be described in terms of disrupting a network of H-bonds in the cytosolic halves of helices 1-3, 6, and 7; and binding of LHR to Gs involves, in large part, intracellular loop 2 binding, presumably to Gs[alpha] at its C-terminus. Major gaps exist in our understanding at the molecular level of the six-polypeptide chain complex, hCG-LHR-Gs, but considerable progress has been made in the past few years.

A molecular dissection of the glycoprotein hormone receptors.

G Vassart — 2006-06-20T11:15:35-00:00

Trends Biochem Sci, Vol. 29, No. 3. (March 2004), pp. 119-126.

In glycoprotein hormone receptors, a subfamily of rhodopsin-like G protein-coupled receptors, the recognition and activation steps are carried out by separate domains of the proteins. Specificity of recognition of the hormones thyrotropin (TSH), lutropin (LH), human chorionic gonadotropin (hCG) and follitropin (FSH) involves leucine-rich repeats (LRRs) present in an N-terminal ectodomain, and can be associated with a limited number of residues at key positions of the LRRs. The mechanism by which binding of the hormones results in activation is proposed to involve switching of the ectodomain from a tethered inverse agonist to a full agonist of the serpentine, rhodopsin-like region of the receptor. Unexpectedly, the picture is complicated by the observation that promiscuous activation of one of the receptors (FSHr) by hCG or TSH can result from activating mutations affecting the serpentine region of the receptors.

An assessment of the hypervariable domains of the 16S rRNA genes for their value in determining microbial community diversity: the paradox of traditional ecological indices.

DK Mills — 2008-05-19T17:03:48-00:00

FEMS microbiology ecology, Vol. 57, No. 3. (September 2006), pp. 496-503.

Amplicon length heterogeneity PCR (LH-PCR) was investigated for its ability to distinguish between microbial community patterns from the same soil type under different land management practices. Natural sagebrush and irrigated mouldboard-ploughed soils from Idaho were queried as to which hypervariable domains, or combinations of 16S rRNA gene domains, were the best molecular markers. Using standard ecological indices to measure richness, diversity and evenness, the combination of three domains, V1, V3 and V1+V2, or the combined V1 and V3 domains were the markers that could best distinguish the undisturbed natural sagebrush communities from the mouldboard-ploughed microbial communities. Bray-Curtis similarity and multidimensional scaling were found to be better metrics to ordinate and cluster the LH-PCR community profiling data. The use/misuse of traditional ecological indices such as diversity and evenness to study microbial community profiles will remain a major point to consider when performing metagenomic studies.

Ovulation detection methods for urinary hormones: precision, daily and intermittent sampling and a combined hierarchical method

KA O'Connor — 2008-02-03T20:07:29-00:00

Hum. Reprod., Vol. 21, No. 6. (1 June 2006), pp. 1442-1452.

BACKGROUND: We evaluate the performance of ovulation detection methods and present new approaches, including evaluation of methods for precision, combining multiple markers into a hierarchical system and using ovulation markers in intermittent sampling designs. METHODS: With serum LH peak day as the gold standard' of ovulation, we estimated accuracy and precision of ovulation day algorithms using 30 ovulatory menstrual cycles with daily urinary and serum hormones and transvaginal ultrasound. Sensitivity and specificity for estimating the presence of ovulation were tested using visually assessed ovulatory (30) and anovulatory (22) cycles. RESULTS: Sensitivity and specificity ranged from 70 to 100% for estimating presence of ovulation with twice-per-cycle, weekly, twice weekly, every-other-day and daily specimens. A combined hierarchical method estimated ovulation day using daily specimens within +/-2 days of the gold standard in 93% of cases. Accuracy of estimating ovulation day within +/-2 days using intermittent sampling ranged from 40% (weekly sampling) to 97% (every-other-day). CONCLUSIONS: A combined hierarchical algorithm using precise and accurate markers allows maximal use of available data for efficient and objective identification of ovulation using daily specimens. In intermittent sampling designs, the presence and the timing of ovulation can be estimated with good sensitivity, specificity and accuracy. 10.1093/humrep/dei497

Serum anti-Mullerian hormone is more strongly related to ovarian follicular status than serum inhibin B, estradiol, FSH and LH on day 3

Renato Fanchin — 2008-02-03T19:50:01-00:00

Hum. Reprod., Vol. 18, No. 2. (1 February 2003), pp. 323-327.

BACKGROUND: The study aim was to compare the relationship between serum anti-Mullerian hormone (AMH) levels and other markers of ovarian function with early antral follicle count on day 3. METHODS: A total of 75 infertile women was studied prospectively. On cycle day 3, serum levels of AMH, inhibin B, estradiol (E2), FSH and LH levels were measured, and the number of early antral follicles (2-10 mm in diameter) estimated at ultrasound scanning to compare the strengths of hormonal-follicular correlations. RESULTS: Median (range) serum levels of AMH, inhibin B, E2, FSH and LH were 1.39 ng/ml (0.24-6.40), 90 (16-182) pg/ml, 31 (15-111) pg/ml, 7.0 (2.9-19.3) mIU/ml and 4.7 (1.2-11.7) mIU/ml respectively, and follicular count was 12 (1-35). Serum AMH levels were more strongly correlated (P < 0.001) with follicular count (r = 0.74, P < 0.0001) than were serum levels of inhibin B (r = 0.29, P < 0.001), E2 (r = -0.08, P = NS), FSH (r = -0.29, P < 0.001) and LH (r = 0.05, P = NS). CONCLUSIONS: Serum AMH levels were more robustly correlated with the number of early antral follicles than inhibin B, E2, FSH and LH on cycle day 3. This suggests that AMH may reflect ovarian follicular status better than the usual hormone markers. 10.1093/humrep/deg042

The ovary-mediated FSH attenuation of the LH surge in the rat involves a decreased gonadotroph progesterone receptor (PR) action but not PR expression

Ana Gordon — 2008-04-10T07:39:17-00:00

J Endocrinol, Vol. 196, No. 3. (1 March 2008), pp. 583-592.

Hyperstimulation of ovarian function with human FSH (hFSH) attenuates the preovulatory surge of LH. These experiments aimed at investigating the mechanism of ovarian-mediated FSH suppression of the progesterone (P4) receptor (PR)-dependent LH surge in the rat. Four-day cycling rats were injected with hFSH, oestradiol benzoate (EB) or vehicle during the dioestrous phase. On pro-oestrus, their pituitaries were studied for PR mRNA and protein expression. Additionally, pro-oestrous pituitaries were incubated in the presence of oestradiol-17 (E2), and primed with P4 and LH-releasing hormone (LHRH), with or without the antiprogestin RU486. After 1 h of incubation, pituitaries were either challenged or not challenged with LHRH. Measured basal and LHRH-stimulated LH secretions and LHRH self-priming were compared with those exhibited by incubated pituitaries on day 4 from ovariectomized (OVX) rats in metoestrus (day 2) injected with hFSH and/or EB on days 2 and 3. The results showed that: i) hFSH lowered the spontaneous LH surge without affecting basal LH and E2 levels, gonadotroph PR-A/PR-B mRNA ratio or immunohistochemical protein expression; ii) incubated pro-oestrous pituitaries from hFSH-treated rats did not respond to P4 or LHRH, and lacked E2-augmenting and LHRH self-priming effects and iii) OVX reversed the inhibitory effects of hFSH on LH secretion. It is concluded that under the influence of hFSH, the ovaries produce a non-steroidal factor which suppresses all PR-dependent events of the LH surge elicited by E2. The action of such a factor seemed to be due to a blockade of gonadotroph PR action rather than to an inhibition of PR expression. 10.1677/JOE-07-0223

Normalization of serum luteinizing hormone levels in women with 46,XX spontaneous primary ovarian insufficiency

Vaishali Popat — 2008-05-08T23:37:39-00:00

Fertility and Sterility, Vol. 89, No. 2. (February 2008), pp. 429-433.

Objective To determine the proportion of women with primary ovarian insufficiency who achieve normal serum LH levels on transdermal E2 therapy.Design Prospective.Setting Clinical research center at a national US health research facility.Patient(s) Women with spontaneous primary ovarian insufficiency (n = 137) and 70 regularly menstruating control women (n = 70).Intervention(s) Blood sampled from controls in the midfollicular phase and from patients while they were off E2 for 2 weeks, then again 3 months later during the E2-only phase of hormone therapy (E2 patch [100 [mu]g/d] and oral medroxyprogesterone acetate [10 mg for 12 d/mo]).Main Outcome Measure(s) Serum LH.Result(s) While on transdermal E2 therapy, significantly more women (51.1%, 70/137; 95% confidence interval, 42%, 60%) had serum LH levels in the normal range (5/137, 3.9% at baseline). Mean (SD) serum E2 level significantly increased on therapy to 95.4 (84.9) pg/mL.Conclusion(s) A regimen of 100 [mu]g/d of transdermal E2 therapy achieves normal serum LH levels in approximately one half of women with spontaneous primary ovarian insufficiency. Theoretically, by avoiding inappropriate luteinization, physiologic E2 therapy may improve follicle function in these women. Controlled studies to assess the effect of transdermal E2 therapy on follicle function in these women are warranted.

Effect of oral administration of dydrogestrone versus vaginal administration of natural micronized progesterone on the secretory transformation of endometrium and luteal endocrine profile in patients with premature ovarian failure: a proof of concept

Fatemi — 2007-06-15T14:46:08-00:00

Human Reproduction, Vol. 22, No. 5. (May 2007), pp. 1260-1263.

The effect of oral estrogen therapy on serum FSH and LH levels in young women with hyper-gonadotrophic ovarian failure

D Leis — 2008-05-08T23:10:12-00:00

Archives of Gynecology and Obstetrics, Vol. 230, No. 3. (1 May 1981), pp. 225-230.

Summary Fourteen women, 18–46 years old (median age: 28 years) with hypergonadotrophic ovarian failure were each treated daily for 21 days with 10 μg, 20 μg, 40 μg, and 60 μg ethinyl estradiol, 2,000 μg estriol, and 1,250 μg conjugated estrogens in six or more consecutive treatment cycles in a randomly assigned sequence. Before treatment and at the beginning of the 3rd week of each of the mentioned estrogen regimens, basal serum FSH and LH levels were measured. During the last 5 days of each treatment cycle, 10 mg of oral norethisterone acetate were given in addition to the estrogen, and after a treatment-free interval of 7 days the next estrogen regimen was begun according to the random list. FSH values were inversely related to the various dosages of ethinyl estradiol; the upper normal range with the exception of the periovulatory phase was reached with 40–60 μg ethinyl estradiol. FSH levels during treatment with 1250 μg of conjugated estrogens were similar to those found during treatment with 20 μg ethinyl estradiol. When 2,000 μg of estriol were given daily, FSH levels rose to pretreatment values. LH behaved similarly except that during treatment with 2,000 μg of estriol and 10 μg of ethinyl estradiol values above pretreatment levels were found.

Ovarian feedback, mechanism of action and possible clinical implications

Messinis — 2006-09-25T05:15:04-00:00

Human Reproduction Update, Vol. 12, No. 5. (September 2006), pp. 557-571.

Stable serum levels of anti-Mullerian hormone during the menstrual cycle: a prospective study in normo-ovulatory women

S Tsepelidis — 2008-02-03T04:04:24-00:00

Hum. Reprod., Vol. 22, No. 7. (1 July 2007), pp. 1837-1840.

BACKGROUNDAnti-Mullerian hormone (AMH), secreted by the granulosa cells of preantral and small antral follicles, has been described as a potential marker of the ovarian reserve. The aim of this prospective study is to investigate the variations of AMH during the menstrual cycle in a young selected population of normo-ovulatory women and to analyse the correlation with other cyclic hormones. METHODSTwenty healthy volunteers from 19 to 35 years old, with regular menstrual cycles (2631 days), normal ovulation (day 1016), normal hormonal profile and normal body mass index (1826 kg/m2) were recruited. AMH, inhibin B, LH, FSH, estradiol and progesterone were measured on days 3, 7, 10, 11, 12, 13, 14, 15, 16, 18, 21 and 25 of a spontaneous cycle. RESULTSAMH serum levels, either expressed by cycle day or aligned according to the ovulation day, did not show any significant variations during the menstrual cycle. CONCLUSIONSNo significant fluctuation of the AMH level during the menstrual cycle was observed. Therefore, this hormone is particularly interesting for clinical evaluation of the ovarian reserve as it may be used at any time during the cycle. 10.1093/humrep/dem101

Serum anti-Mullerian hormone throughout the human menstrual cycle

La Marca — 2006-11-23T11:08:54-00:00

Human Reproduction, Vol. 21, No. 12. (1 December 2006), pp. 3103-3107.

Development of luteinized graafian follicles in patients with karyotypically normal spontaneous premature ovarian failure

Lm Nelson — 2007-11-16T09:27:26-00:00

J Clin Endocrinol Metab, Vol. 79, No. 5. (1 November 1994), pp. 1470-1475.

10.1210/jc.79.5.1470

A randomized, controlled trial of estradiol replacement therapy in women with hypergonadotropic amenorrhea

AE Taylor — 2008-02-28T09:36:18-00:00

J Clin Endocrinol Metab, Vol. 81, No. 10. (1 October 1996), pp. 3615-3621.

10.1210/jc.81.10.3615

The transcription factor NF-ATc is essential for cardiac valve formation.

AM Ranger — 2006-12-09T08:58:06-00:00

Nature, Vol. 392, No. 6672. (12 March 1998), pp. 186-190.

Nuclear factor of activated T cells (NF-AT) is the name of a family of four related transcription factors that may be needed for cytokine gene expression in activated lymphocytes. Here we report that mice with a targeted disruption of the NF-ATc gene show an unexpected and dramatic defect in cardiac morphogenesis, with selective absence of the aortic and pulmonary valves, leading to death in utero from congestive heart failure at days 13.5-17.5 of gestation. In contrast, tricuspid and mitral valve morphogenesis is normal. NF-ATc is the first transcription factor known to be expressed only in the endothelial cells of the heart. As in T cells, nuclear translocation of NF-ATc in cardiac endothelial cells is controlled by the calcium-regulated phosphatase calcineurin: NF-ATc remains cytoplasmic in normal embryos cultured with cyclosporin A, an inhibitor of calcineurin. Abnormal development of the cardiac valves and septae is the most frequent form of birth defect, yet few molecular regulators of valve formation are known. Our results indicate that NF-ATc may play a critical role in signal-transduction processes required for normal cardiac valve formation.

Low-Dose Human Chorionic Gonadotropin Maintains Intratesticular Testosterone in Normal Men with Testosterone-Induced Gonadotropin Suppression

Andrea Coviello — 2007-06-22T12:01:51-00:00

J Clin Endocrinol Metab, Vol. 90, No. 5. (1 May 2005), pp. 2595-2602.

In previous studies of testicular biopsy tissue from healthy men, intratesticular testosterone (ITT) has been shown to be much higher than serum testosterone (T), suggesting that high ITT is needed relative to serum T for normal spermatogenesis in men. However, the quantitative relationship between ITT and spermatogenesis is not known. To begin to address this issue experimentally, we determined the dose-response relationship between human chorionic gonadotropin (hCG) and ITT to ascertain the minimum dose needed to maintain ITT in the normal range. Twenty-nine men with normal reproductive physiology were randomized to receive 200 mg T enanthate weekly in combination with either saline placebo or 125, 250, or 500 IU hCG every other day for 3 wk. ITT was assessed in testicular fluid obtained by percutaneous fine needle aspiration at baseline and at the end of treatment. Baseline serum T (14.1 nmol/liter) was 1.2% of ITT (1174 nmol/liter). LH and FSH were profoundly suppressed to 5% and 3% of baseline, respectively, and ITT was suppressed by 94% (1234 to 72 nmol/liter) in the T enanthate/placebo group. ITT increased linearly with increasing hCG dose (P < 0.001). Posttreatment ITT was 25% less than baseline in the 125 IU hCG group, 7% less than baseline in the 250 IU hCG group, and 26% greater than baseline in the 500 IU hCG group. These results demonstrate that relatively low dose hCG maintains ITT within the normal range in healthy men with gonadotropin suppression. Extensions of this study will allow determination of the ITT concentration threshold required to maintain spermatogenesis in man. 10.1210/jc.2004-0802

The Chimpanzees of the Mahale Mountains: Sexual and Life History Strategies

2005-06-12T19:41:36-00:00

(01 May 1990)

Life-history characters and phylogeny are correlated with extinction risk in the Australian angiosperms

A Sjostrom — 2006-01-20T10:08:00-00:00

Journal of Biogeography, Vol. 33, No. 2. (February 2006), pp. 271-290.

Social structure and life-history patterns in western gorillas (Gorilla gorilla gorilla).

MM Robbins — 2005-05-05T20:15:38-00:00

Am J Primatol, Vol. 64, No. 2. (October 2004), pp. 145-159.

Life-history traits and ecological conditions have an important influence on primate social systems. Most of what we know about the life-history patterns and social structure of gorillas comes from studies of eastern gorillas (Gorilla beringei sp.), which live under dramatically different ecological conditions compared to western gorillas (Gorilla gorilla sp.). In this paper we present new data on western gorilla social structure and life histories from four study sites, and make comparisons with eastern gorilla populations. Data were obtained from two study sites with gorilla groups undergoing the habituation process (Lossi, Democratic Republic of Congo and Bai Hokou, Central African Republic) and two "bai" studies (Maya Nord and Mbeli Bai, Republic of Congo). The size and structure of these groups were similar to those seen in eastern gorillas. However, differences in the occurrence of various group transitions (group formations, changes between one-male and multimale composition, and group disintegrations) exist, and western gorillas notably exhibit much higher rates of male emigration and correspondingly fewer multimale groups compared to mountain gorillas. Certain phenomena have been observed only rarely, including predation by leopards. The preliminary data show no significant differences in birth rates between western gorillas and mountain gorillas. The ecological variability across gorilla habitats likely explains the flexibility in the social system of gorillas, but we need more information on the social relationships and ecology of western gorillas to elucidate the causes for the similarities and differences between western and eastern gorillas on the levels of individuals, social groups, and population dynamics.

Quantifying components of risk for European woody species under climate change

Ralf Ohlemüller — 2006-08-26T03:00:55-00:00

Global Change Biology, Vol. 12, No. 9. (September 2006), pp. 1788-1799.

Estimates of species extinction risk under climate change are generally based on differences in present and future climatically suitable areas. However, the locations of potentially suitable future environments (affecting establishment success), and the degree of climatic suitability in already occupied and new locations (affecting population viability) may be equally important determinants of risk. A species considered to be at low risk because its future distribution is predicted to be large, may actually be at high risk if these areas are out of reach, given the species' dispersal and migration rates or if all future suitable locations are only marginally suitable and the species is unlikely to build viable populations in competition with other species. Using bioclimatic models of 17 representative European woody species, we expand on current ways of risk assessment and suggest additional measures based on (a) the distance between presently occupied areas and areas predicted to be climatically suitable in the future and (b) the degree of change in climatic suitability in presently occupied and unoccupied locations. Species of boreal and temperate deciduous forests are predicted to face higher risk from loss of climatically suitable area than species from warmer and drier parts of Europe by 2095 using both the moderate B1 and the severe A1FI emission scenario. However, the average distance from currently occupied locations to areas predicted suitable in the future is generally shorter for boreal species than for southern species. Areas currently occupied will become more suitable for boreal and temperate species than for Mediterranean species whereas new suitable areas outside a species' current range are expected to show greater increases in suitability for Mediterranean species than for boreal and temperate species. Such additional risk measures can be easily derived and should give a more comprehensive picture of the risk species are likely to face under climate change.

Life history of wild Sumatran orangutans (Pongo abelii).

SA Wich — 2005-05-22T17:48:07-00:00

Journal of Human Evolution, Vol. 47, No. 6. (December 2004), pp. 385-398.

We present life history data on wild Sumatran orangutans gleaned from a 32-year and a 5.5-year study. Estimated age at first reproduction was 15.4 years. At 9.3 years, the average interbirth interval for this population is the longest ever recorded for any great ape population, significantly longer than that of a Bornean orangutan population. We find that age-specific mortality of Sumatran orangutans does not differ between sexes and is significantly lower than that of wild chimpanzees. We conclude that orangutan life history is the slowest among extant great apes. In accordance with their slow life history, longevity in the wild is estimated to be at least 58 years for males and at least 53 for females. We find no evidence for menopause. These data suggest that compared to the ancestral state, humans have undergone less of an increase in longevity than commonly assumed, and have experienced selection on earlier cessation of reproduction.

Mortality rates among wild chimpanzees

K Hill — 2005-06-07T10:30:57-00:00

Journal of Human Evolution, Vol. 40, No. 5. (May 2001), pp. 437-450.

In order to compare evolved human and chimpanzees' life histories we present a synthetic life table for free-living chimpanzees, derived from data collected in five study populations (Gombe, Ta, Kibale, Mahale, Bossou). The combined data from all populations represent 3711 chimpanzee years at risk and 278 deaths. Males show higher mortality than females and data suggest some inter-site variation in mortality. Despite this variation, however, wild chimpanzees generally have a life expectancy at birth of less than 15 years and mean adult lifespan (after sexual maturity) is only about 15 years. This is considerably lower survival than that reported for chimpanzees in zoos or captive breeding colonies, or that measured among modern human hunter-gatherers. The low mortality rate of human foragers relative to chimpanzees in the early adult years may partially explain why humans have evolved to senesce later than chimpanzees, and have a longer juvenile period.

Impact of El Niño and Logging on Canopy Tree Recruitment in Borneo

L Curran — 2005-05-21T19:45:21-00:00

Science, Vol. 286, No. 5447. (10 December 1999), pp. 2184-2188.

Dipterocarpaceae, the dominant family of Bornean canopy trees, display the unusual reproductive strategy of strict interspecific mast-fruiting. During 1986-99, more than 50 dipterocarp species dispersed seed only within a 1- to 2-month period every 3 to 4 years during El Niño-Southern Oscillation events. Synchronous seed production occurred across extensive areas and was essential for satiating seed predators. Logging of dipterocarps reduced the extent and intensity of these reproductive episodes and exacerbated local El Niño conditions. Viable seed and seedling establishment have declined as a result of climate, logging, and predators. Since 1991, dipterocarps have experienced recruitment failure within a national park, now surrounded by logged forest.

Climate envelope, life history traits and the resilience of birds facing global change

Frederic Jiguet — 2007-08-06T11:06:54-00:00

Global Change Biology, Vol. 13, No. 8. (2007), pp. 1672-1684.

Abstract Few studies have examined how life history traits and the climate envelope influence the ability of species to respond to climate change and habitat degradation. In this study, we test whether 18 species-specific variables, related to the climate envelope, ecological envelope and life history, could predict recent population trends (over 17 years) of 71 common breeding bird species in France. Habitat specialists were declining at a much higher rate than generalists, a sign that habitat quality is decreasing globally. The lower the thermal maximum (temperature at the hot edge of the climate envelope), the more negative are the population trends and the less tolerant these species are climate warming, regardless of the thermal range over which these species occur. The life history trait the number of broods per year was positively related to recent trends, suggesting that single-brooded species might be more sensitive to advances in food peak due to climate change, as it increases the risk of mistiming their single-breeding event. Annual fecundity explained long-term declines, as it is a good proxy for most other demographic rates, with shorter-lived species being more sensitive to global change: individuals of species with higher fecundity might have too short a life to learn to adapt to directional changes in their environment. Finally, there was evidence that natal dispersal was a predictor of recent trends, with species with high natal dispersal experiencing smaller population declines than species with low natal dispersal. This is expected if the higher the natal dispersal, the larger the ability to shift spatially when facing changes in local habitat or climate, in order to track optimal conditions and adapt to global change. Identifying decline-promoting factors allow us to infer mechanisms responsible for observed declines in wild bird populations facing global change, and by doing so allow for a more pre-emptive approach to conservation planning.

Reproductive Biology of the Great Apes: Comparative and Biomedical Perspectives

2005-05-24T22:52:55-00:00

(01 November 1981)

Population Dynamics of Wild Bonobos (Pan paniscus) at Wamba

Takeshi Furuichi — 2005-05-24T22:05:04-00:00

International Journal of Primatology, Vol. 19, No. 6. (December 1998), pp. 1029-1043.

Context and Development of Sexual Behavior of Wild Bonobos (Pan paniscus) at Wamba, Zaire

Chie Hashimoto — 2005-05-24T21:56:28-00:00

International Journal of Primatology, Vol. 18, No. 1. (February 1997), pp. 1-21.

Identification of the first germline mutation in the extracellular domain of the follitropin receptor responsible for spontaneous ovarian hyperstimulation syndrome

Anne De Leener — 2007-08-24T09:16:06-00:00

Human Mutation, Vol. 9999, No. 9999. (2007), n/a.

The receptors for follitropin (FSHR), thyrotropin (TSHR), and lutropin/chorionic gonadotropin (LHCGR) are the members of the glycoprotein hormone (GPH) receptors (GPHR) family. They present a bipartite structure with a large extracellular amino-terminal domain (ECD), responsible for high-affinity hormone binding, and a carboxyl-terminal serpentine region, implicated in transduction of the activation signal. Spontaneous ovarian hyperstimulation syndrome (sOHSS) is a rare genetic condition in which human chorionic gonadotropin (hCG) promiscuously stimulates the FSHR during the first trimester of pregnancy. Surprisingly, germline FSHR mutations responsible for the disease have so far been found only in the transmembrane helices of the serpentine region of the FSHR, outside the hormone binding domain. When tested functionally, all mutants were abnormally sensitive to both hCG and thyrotropin (TSH) while displaying constitutive activity. This loss of ligand specificity was attributed to the lowering of an intramolecular barrier of activation rather than to an increase of binding affinity. Here we report the first germline mutation responsible for sOHSS (c.383C>A, p.Ser128Tyr), located in the ECD of the FSHR. Contrary to the mutations described previously, the p.Ser128Tyr FSHR mutant displayed increase in affinity and sensitivity toward hCG and did not show any constitutive activity, nor promiscuous activation by TSH. Thus, sOHSS can be achieved from different molecular mechanisms involving each functional domains of the FSHR. Based on the structure of the FSHR/FSH complex and site-directed mutagenesis studies, we provide robust molecular models for the GPH/GPHR complexes and we propose a molecular explanation to the binding characteristics of the p.Ser128Tyr mutant. Hum Mutat 0,1-8, 2007. © 2007 Wiley-Liss, Inc.

Molecular mechanism of LH/CG receptor activation

Ryu — 2006-12-18T15:21:32-00:00

Molecular and Cellular Endocrinology, Vol. 125, No. 1-2. (20 December 1996), pp. 93-100.

It is known that the N-terminal half of the LH/CG receptor is responsible for high hCG binding whereas the C-terminal half is capable of receptor activation. Our results suggest that initial hCG binding at the high affinity site in the N-half receptor induces conformational adjustments. This leads to low affinity secondary contacts of the complex of hCG/the N-half receptor with the C-half receptor. This low affinity secondary contact is responsible for activating the receptor. This is based on the following observations. The C-terminal tail of hCG[alpha] is known to be involved in activation of the LH/CG receptor. In addition to hCG, we examined the C-terminal three residues (His90-Lys91-Ser92) of the common [alpha] subunit of FSH and TSH. The results show their differential roles in the three hormones. Ser92 is important for binding and cAMP induction of TSH but not for hCG and FSH. Lys91 is important for binding and cAMP induction of hCG, and cAMP induction but not binding of FSH. It is not important for binding or cAMP induction of TSH. His90 is important for all three hormones. When all three residues were truncated, FSH and TSH lose their affinity for binding and cAMP induction, whereas hCG is still capable of binding but not cAMP induction. Therefore, the three amino acids contribute differently in receptor binding and cAMP induction of hCG, FSH and TSH. Our data also indicate that the evolution of the [alpha] subunit has been constrained in order not to impair any one of the hormones. This suggests that each hormone can be independently engineered to improve the potency. To chemically identify the contact site of the [alpha] C-tail of hCG in the LH/>CG receptor, a decamer peptide corresponding to the [alpha] subunit sequence from His83 to Ser92 (peptide [alpha]83-92) was derivatized with UV sensitive reagent, ABG and radio-iodinated. The resulting ABG-125I-peptide [alpha]83-92 was capable of binding and activating the LH/CG receptor. Furthermore, it specifically photoaffinity-labeled the LH/CG receptor. In addition, the amino group of [alpha]Lys91 of peptide [alpha]83-92 is crosslinked to a carboxyl group of the receptor, an indication of close association. Reciprocal mutagenesis of [alpha]Lys91 and Asp397 in exoloop 1 of the LH/CG receptor suggests the complementary of this pair in receptor activation but not the high affinity interaction of hCG and the receptor. In addition, Lys583 of exoloop 3 is also crucial for receptor activation. To test the conformational adjustment, ABG was attached to hCG[alpha] and reassociated with untreated [beta] to produce ABG-125I-[alpha]/[beta]. The extent of inter-subunit crosslinking of ABG-125I-[alpha]/[beta] bound to the receptor was two to three fold less than unbound ABG-125I-[alpha]/[beta]. This result indicates structural change at the subunit interface in response to hCG binding to the receptor.

Heterodimeric Fly Glycoprotein Hormone-alpha2 (GPA2) and Glycoprotein Hormone-beta5 (GPB5) Activate Fly Leucine-Rich Repeat-Containing G Protein-Coupled Receptor-1 (DLGR1) and Stimulation of Human Thyrotropin Receptors by Chimeric Fly GPA2 and Human GPB5

Satoko Sudo — 2008-02-27T15:46:06-00:00

Endocrinology, Vol. 146, No. 8. (1 August 2005), pp. 3596-3604.

Glycoprotein hormones play important roles in thyroid and gonadal function in vertebrates. The glycoprotein hormone alpha-subunit forms heterodimers with different beta-subunits to activate TSH or gonadotropin (LH and FSH) receptors. Recent genomic analyses allowed the identification of another alpha-subunit, GPA2, and another beta-subunit, GPB5, in human, capable of forming heterodimers to activate TSH receptors. Based on comparative genomic searches, we isolated the fly orthologs for human GPA2 and GPB5, each consisting of 10 cysteine residues likely involved in cystine-knot formation. RT-PCR analyses in Drosophila melanogaster demonstrated the expression of GPA2 and GPB5 at different developmental stages. Immunoblot analyses further showed that fly GPA2 and GPB5 subunit proteins are of approximately 16 kDa, and coexpression of these subunits yielded heterodimers. Purified recombinant fly GPA2/GPB5 heterodimers were found to be glycoproteins with N-linked glycosylated alpha-subunits and nonglycosylated beta-subunits, capable of stimulating cAMP production mediated by fly orphan receptor DLGR1 but not DLGR2. Although the fly GPA2/GPB5 heterodimers did not activate human TSH or gonadotropin receptors, chimeric fly GPA2/human GPB5 heterodimers stimulated human TSH receptors. These findings indicated that fly GPA2/GPB5 is a ligand for DLGR1, thus showing the ancient origin of this glycoprotein hormone-seven transmembrane receptor-G protein signaling system. The fly GPA2 also could form heterodimers with human GPB5 to activate human TSH receptors, indicating the evolutionary conservation of these genes and suggesting that the GPA2 subunit may serve as a scaffold for the beta-subunit to activate downstream G protein-mediated signaling. 10.1210/en.2005-0317

Structure-function relationships of the luteinizing hormone receptor.

D Puett — 2006-02-13T15:51:44-00:00

Ann N Y Acad Sci, Vol. 1061 (December 2005), pp. 41-54.

Of the 800-900 genes in the human genome that appear to encode G-protein-coupled receptors (GPCRs), two are known to encode receptors that bind the three heterodimeric human gonadotropins, luteinizing hormone (LH), chorionic gonadotropin (CG), and follicle-stimulating hormone (FSH). LH and CG bind to a common receptor, LHR, and FSH binds to a paralogous receptor. These GPCRs contain a relatively large ectodomain (ECD), responsible for high-affinity ligand binding, and a transmembrane portion, as in the other GPCRs. The ECD contains nine leucine-rich repeats capped by N-terminal and C-terminal cysteine-rich regions. The overall goal of this research is to elucidate the molecular mechanisms by which CG and LH bind to and activate LHR and the latter, in turn, activates Gsalpha. A combination of molecular modeling and site-directed mutagenesis, coupled with binding and signaling studies in transiently transfected HEK 293 cells expressing wild-type and mutant forms of LHR, has been used to develop and test models for the LHR ECD, the CG-LHR ECD complex, and the structural changes in the transmembrane helices and intracellular loops, particularly loop 2, that accompany receptor activation. In addition, a single-chain CG-LHR complex was designed in which a fusion protein of the two subunits of human CG was linked to full-length LHR. This ligand-receptor complex was shown to be constitutively active in cellular models and in transgenic mice, the latter of which exhibit precocious puberty. From a combination of molecular modeling, site-directed mutagenesis, genetic/protein engineering, and receptor characterization in cellular and animal models, considerable insight is being developed on the mechanisms of normal and aberrant activation of LHR.

Comparison of melanin-concentrating hormone and hypocretin/orexin mRNA expression patterns in a new parceling scheme of the lateral hypothalamic zone.

LW Swanson — 2006-11-13T02:28:40-00:00

Neurosci Lett, Vol. 387, No. 2. (21 October 2005), pp. 80-84.

A high-resolution spatial distribution analysis of hypothalamic neurons expressing melanin-concentrating hormone or hypocretin/orexin was performed in adult male rats with in situ hybridization cytochemistry. For the analysis, a new parcellation of the lateral zone with some two-dozen regions was used, and distributions were plotted on 15 transverse reference levels through the hypothalamus. Qualitatively the results confirm earlier, much lower resolution mapping studies, although some discrepancies are clarified. Previous work indicates that each of these cell populations is far from homogeneous, and the present results should help establish a framework for clarifying more precisely how they are differentiated and organized in terms of axonal input-output relationships and gene expression patterns, and for defining precise relationships with other hypothalamic neuron populations.

Orexin (hypocretin) neurons contain dynorphin

TC Chou — 2006-11-10T20:10:40-00:00

The Journal Of Neuroscience: The Official Journal Of The Society For Neuroscience, Vol. 21, No. 19. (1 October 2001), pp. RC168-RC168.

Orexins (also called hypocretins) are peptide neurotransmitters expressed in neurons of the lateral hypothalamic area (LHA). Mice lacking the orexin peptides develop narcolepsy-like symptoms, whereas mice with a selective loss of the orexin neurons develop hypophagia and severe obesity in addition to the narcolepsy phenotype. These different phenotypes suggest that orexin neurons may contain neurotransmitters besides orexin that regulate feeding and energy balance. Dynorphin neurons are common in the LHA, and dynorphin has been shown to influence feeding; hence, we studied whether dynorphin and orexin are colocalized. In rats, double-label in situ hybridization revealed that nearly all (94%) neurons expressing prepro-orexin mRNA also expressed prodynorphin mRNA. The converse was also true: 96% of neurons in the LHA containing prodynorphin mRNA also expressed prepro-orexin mRNA. Double-label immunohistochemistry confirmed that orexin-A and dynorphin-A peptides were highly colocalized in the LHA. Wild-type mice and orexin knock-out mice showed abundant prodynorphin mRNA-expressing neurons in the LHA, but orexin/ataxin-3 mice with a selective loss of the orexin neurons completely lacked prodynorphin mRNA in this area, further confirming that within the LHA, dynorphin expression is restricted to the orexin neurons. These findings suggest that dynorphin-A may play an important role in the function of the orexin neurons. [Journal Article; In English; United States; MEDLINE]

Hypothalamic orexin (hypocretin) neurons express vesicular glutamate transporters VGLUT1 or VGLUT2.

DL Rosin — 2006-11-10T19:59:10-00:00

J Comp Neurol, Vol. 465, No. 4. (27 October 2003), pp. 593-603.

Initially recognized for their importance in control of appetite, orexins (also called hypocretins) are neuropeptides that are also involved in regulating sleep, arousal, and cardiovascular function. Loss of orexin appears to be the primary cause of narcolepsy. Cells expressing the orexins are restricted to a discrete region of the hypothalamus, but their terminal projections are widely distributed throughout the brain. With the diversity of function and broad distribution of orexin terminals, it is not known whether the orexin cells constitute a homogeneous population. Because orexins produce neuroexcitatory effects, we hypothesized that orexin-containing neurons are glutamatergic. In the present study we used digoxigenin-labeled cRNA probes for the vesicular glutamate transporters, VGLUT1 and VGLUT2, for in situ hybridization studies in combination with immunohistochemical detection of orexin cell bodies in the hypothalamus. In general, cells in the hypothalamus expressed low levels of the vesicular glutamate transporters relative to other areas of the forebrain, such as the cortex and thalamus. Light labeling for VGLUT2 mRNA was detected in about 50% of the orexin-immunoreactive neurons, and a much smaller percentage (approximately 13%) of orexin-immunoreactive cells was found to express VGLUT1. Despite the fact that intense labeling for GAD67 mRNA was found in a large number of cells throughout the hypothalamus, none of the orexin-immunoreactive cells was found to be GABAergic. These findings, showing that many of the orexin neurons are glutamatergic, are consistent with the neuroexcitatory effects of orexin but suggest that another neurochemical phenotype may define the remaining subset of orexin neurons.

Regulation of orexin neurons by the monoaminergic and cholinergic systems

Akihiro Yamanaka — 2006-11-10T19:52:25-00:00

Biochemical and Biophysical Research Communications, Vol. 303, No. 1. (28 March 2003), pp. 120-129.

Orexins are a pair of neuropeptides implicated in energy homeostasis and arousal. Here we characterize the electrophysiological properties of orexin neurons using slice preparations from transgenic mice in which orexin neurons specifically express green fluorescent protein. Orexin neurons showed high frequency firing with little adaptation by injecting a positive current. The hyperpolarization-activated current was observed in orexin neurons by a negative current injection. The neurotransmitters, which were implicated in sleep/wake regulation, affected the activity of orexin neurons; noradrenaline and serotonin hyperpolarized, while carbachol depolarized orexin neurons in either the presence or absence of tetrodotoxin. It has been reported that orexins directly or indirectly activate the nuclei that are the origin of the neurons containing these neurotransmitters. Our data suggest that orexin neurons have reciprocal neural circuitries between these nuclei for either a positive or negative feedback loop and orchestrate the activity of these neurons to regulate the vigilance states.

Chemical coding of GABA(B) receptor-immunoreactive neurones in hypothalamic regions regulating body weight.

M Bäckberg — 2006-11-10T19:40:33-00:00

J Neuroendocrinol, Vol. 15, No. 1. (January 2003), pp. 1-14.

Gamma-aminobutyric acid (GABA) interacts with hypothalamic neuronal pathways regulating feeding behaviour. GABA has been reported to stimulate feeding via both ionotropic GABA(A) and metabotropic GABA(B) receptors. The functional form of the GABA(B) receptor is a heterodimer consisting of GABA(B) receptor-1 (GABA(B)R1) and GABA(B) receptor-2 (GABA(B)R2) proteins. Within the heterodimer, the GABA-binding site is localized to GABA(B)R1. In the present study, we used an antiserum to the GABA(B)R1 protein in order to investigate the cellular localization of GABA(B)R1-immunoreactive neurones in discrete hypothalamic regions implicated in the control of body weight. The colocalization of GABA(B)R1 immunoreactivity with different chemical messengers that regulate food intake was analysed. GABA(B)R1-immunoreactive cell bodies were found in the periventricular, paraventricular (PVN), supraoptic, arcuate, ventromedial hypothalamic, dorsomedial hypothalamic, tuberomammillary nuclei and lateral hypothalamic area (LHA). Direct double-labelling showed that glutamic acid decarboxylase (GAD)-positive terminals were in close contact with GABA(B)R1-containing cell bodies located in all these regions. In the ventromedial part of the arcuate nucleus, GABA(B)R1-immunoreactive cell bodies were found to contain neuropeptide Y, agouti-related peptide (AGRP) and GAD. In the ventrolateral part of the arcuate nucleus, GABA(B)R1-immunoreactive cell bodies were shown to contain pro-opiomelanocortin and cocaine- and amphetamine-regulated transcript. In the LHA, GABA(B)R1 immunoreactivity was present in both melanin-concentrating hormone- and orexin-containing cell populations. In the tuberomammillary nucleus, GABA(B)R1-immunoreactive cell bodies expressed histidine decarboxylase, a marker for histamine-containing neurones. In addition, GAD and AGRP were found to be colocalized in some nerve terminals surrounding GABA(B)R1-immunoreactive cell bodies in the parvocellular part of the PVN. The results may provide a morphological basis for the understanding of how GABA regulates the hypothalamic control of food intake and body weight via GABA(B) receptors.

Cellular localization of GABA receptor alpha subunit immunoreactivity in the rat hypothalamus: relationship with neurones containing orexigenic or anorexigenic peptides.

M Bäckberg — 2006-11-10T19:35:48-00:00

J Neuroendocrinol, Vol. 16, No. 7. (July 2004), pp. 589-604.

gamma-Aminobutyric acid (GABA), the major inhibitory neurotransmitter in the brain, acts via two different type of GABA receptors. GABA(A) receptors are composed of five subunits that belong to eight different classes. Depending on their subunit composition, distinct pharmacological and electrophysiological properties are obtained. GABA is produced in certain hypothalamic neurones known to be involved in control of feeding behaviour. We report the detailed immunohistochemical localization of four GABA(A)R alpha subunits in hypothalamic regions associated with the regulation of feeding behaviour. Immunoreactive structures for all studied GABA(A)R alpha subunits were observed in the hypothalamus, but with subunit-specific staining patterns. GABA(A)R alpha(1) immunoreactivity was most prominent in the dorsomedial hypothalamic nucleus and in the lateral hypothalamic area (LHA), whereas GABA(A)R alpha(2), alpha(3) and alpha(5) subunits exhibited particularly strong immunoreactivity in the ventromedial hypothalamic nucleus. In comparison, GABA(A)R alpha subunit immunoreactivities were generally weak in the arcuate nucleus. In the ventromedial part of the arcuate nucleus, neuropeptide Y- and agouti-related peptide-containing cell bodies, which also are known to be GABAergic, were immunoreactive for only the GABA(A)R alpha(3) subunit, whereas pro-opiomelanocortin- and cocaine- and amphetamine-regulated transcript- containing cell bodies located in the ventrolateral subdivision of the arcuate nucleus, showed GABA(A)R alpha(1), alpha(2) and alpha(3) subunit immunoreactivity. In the LHA, GABA(A)R alpha(3) subunit immunoreactivity was demonstrated in both melanin-concentrating hormone (MCH) and orexin-containing neurones. In addition, MCH neurones contained GABA(A)R alpha(2) immunoreactivity. In neurones of the tuberomammillary nucleus, GABA(A)R alpha(2) and alpha(5) subunits were colocalized with histidine decarboxylase, a marker for histamine-containing neurones.

Melanin concentrating hormone depresses synaptic activity of glutamate and GABA neurons from rat lateral hypothalamus.

XB Gao — 2006-11-10T19:31:13-00:00

J Physiol, Vol. 533, No. Pt 1. (15 May 2001), pp. 237-252.

The neuropeptide melanin concentrating hormone (MCH) is synthesised only by neurons of the lateral hypothalamic (LH) area in the CNS. MCH cells project widely throughout the brain. Despite the growing interest in this peptide, in part related to its role in feeding, little has been done to characterise its physiological effects in neurons. Using whole-cell recording with current and voltage clamp, we examined the cellular actions in neurons from the LH. MCH induced a consistent decrease in the frequency of action potentials and reduced synaptic activity. Most fast synaptic activity in the hypothalamus is mediated by GABA or glutamate. MCH inhibited the synaptic activity of both glutamatergic and GABAergic LH neurons, each tested independently. MCH reduced the amplitude of glutamate-evoked currents and reduced the amplitude of miniature excitatory currents, indicating an inhibitory modulation of postsynaptic glutamate receptors. In the presence of tetrodotoxin to block action potentials, MCH caused a depression in the frequency of miniature glutamate-mediated postsynaptic currents, suggesting a presynaptic site of receptor expression. In voltage clamp experiments, MCH depressed the amplitude of calcium currents, suggesting that a mechanism of inhibition may involve a reduced calcium-dependent release of amino acid transmitter. Previous reports have suggested that MCH activated potassium channels in non-neuronal cells transfected with the MCH receptor gene. We found no effect of MCH on voltage-dependent potassium channels in LH neurons. Baclofen, a GABAB receptor agonist, activated G-protein gated inwardly rectifying potassium (GIRK)-type channels; in the same neurons, MCH had no effect on GIRK channels. MCH showed no modulation of sodium currents. Blockade of the Gi/Go protein with pertussis toxin eliminated the actions of MCH. The inhibitory actions of MCH on both excitatory and inhibitory synaptic events, coupled with opposing excitatory actions of hypocretin, another LH peptide that projects to many of the same loci, suggest a substantial level of complexity in neuropeptide modulation of LH actions.

Leptin receptor- and STAT3-immunoreactivities in hypocretin/orexin neurones of the lateral hypothalamus.

M Håkansson — 2006-11-10T19:22:24-00:00

J Neuroendocrinol, Vol. 11, No. 8. (August 1999), pp. 653-663.

Hypocretins/orexins are recently characterized peptides that are synthesized in neurones of the lateral hypohalamus and stimulate food intake in rats. To clarify whether leptin may interact with hypocretin/orexin to reduce ingestive behaviour, the presence of leptin receptor-immunoreactivity in hypocretin/orexin-containing neurones was examined. Many leptin receptor-and hypocretin/orexin-immunoreactive neurones were demonstrated in the lateral hypothalamic area and perifornical region. Both direct double-labelling and elution-restaining methods showed that leptin receptor-immunoreactivity was present in the vast majority of hypocretin/orexin-containing neurones. Immunoreactivity for STAT3, a transcription factor activated by leptin, was also demonstrated in hypocretin/orexin-containing neurones. Isolated hypocretin/orexin cell bodies in the dorsal part of the lateral hypothalamic area and the ventral perifornical region were shown to contain immunoreactivity for galanin, another peptide known to affect feeding. Galanin neurones were also seen to contain leptin receptor-and STAT3-immunoreactivity. Melanin-concentrating hormone (MCH)-containing neurones constituted a cell population within the lateral hypothalamus distinct from the one containing hypocretin/orexin-immunoreactivity, as shown by elution-restaining methodology. The presence of leptin receptor-and STAT3-immunoreactivities in hypocretin/orexin-containing neurones of the lateral hypothalamus suggests that leptin may directly regulate these hypothalamic neurones, most likely via an inhibitory action on hypocretin/orexin expression and/or secretion resulting in reduced food intake.

Glucose-sensing neurons of the hypothalamus.

D Burdakov — 2006-11-10T19:21:00-00:00

Philos Trans R Soc Lond B Biol Sci, Vol. 360, No. 1464. (29 December 2005), pp. 2227-2235.

Specialized subgroups of hypothalamic neurons exhibit specific excitatory or inhibitory electrical responses to changes in extracellular levels of glucose. Glucose-excited neurons were traditionally assumed to employ a 'beta-cell' glucose-sensing strategy, where glucose elevates cytosolic ATP, which closes KATP channels containing Kir6.2 subunits, causing depolarization and increased excitability. Recent findings indicate that although elements of this canonical model are functional in some hypothalamic cells, this pathway is not universally essential for excitation of glucose-sensing neurons by glucose. Thus glucose-induced excitation of arcuate nucleus neurons was recently reported in mice lacking Kir6.2, and no significant increases in cytosolic ATP levels could be detected in hypothalamic neurons after changes in extracellular glucose. Possible alternative glucose-sensing strategies include electrogenic glucose entry, glucose-induced release of glial lactate, and extracellular glucose receptors. Glucose-induced electrical inhibition is much less understood than excitation, and has been proposed to involve reduction in the depolarizing activity of the Na+/K+ pump, or activation of a hyperpolarizing Cl- current. Investigations of neurotransmitter identities of glucose-sensing neurons are beginning to provide detailed information about their physiological roles. In the mouse lateral hypothalamus, orexin/hypocretin neurons (which promote wakefulness, locomotor activity and foraging) are glucose-inhibited, whereas melanin-concentrating hormone neurons (which promote sleep and energy conservation) are glucose-excited. In the hypothalamic arcuate nucleus, excitatory actions of glucose on anorexigenic POMC neurons in mice have been reported, while the appetite-promoting NPY neurons may be directly inhibited by glucose. These results stress the fundamental importance of hypothalamic glucose-sensing neurons in orchestrating sleep-wake cycles, energy expenditure and feeding behaviour.

Neuronal interactions between galanin-like-peptide- and orexin- or melanin-concentrating hormone-containing neurons

Fumiko Takenoya — 2006-11-10T19:19:07-00:00

Regulatory Peptides, Vol. 126, No. 1-2. (15 March 2005), pp. 79-83.

Galanin-like peptide (GALP) is a novel orexigenic neuropeptide that is recently isolated from the porcine hypothalamus. GALP-containing neurons predominantly locate in the hypothalamic arcuate nucleus (ARC). The expression of GALP mRNA within the ARC is increased after the administration of leptin. GALP-containing neurons express leptin receptor and contain [alpha]-melanocyte-stimulating hormone. We have recently reported that neuropeptide Y (NPY)- and orexin-containing axon terminals are in close apposition with GALP-containing neurons in the ARC. In addition, GALP-containing neurons express orexin-1 receptor (OX1-R). Thus, GALP may function under the influence of leptin and orexin. However, the target neurons of GALP have not yet been clarified. To clarify the neuronal interaction between GALP-containing and other feeding regulating neurons, double-immunostaining method using antibodies against GALP- and orexin- or melanin-concentrating hormone (MCH) was performed in the rat lateral hypothalamus (LH). GALP-immunoreactive fibers appeared to project to the LH around the fornix. They were also found from the rostral to the caudal part of the ARC, paraventricular nucleus (PVH), stria terminalis (BST), medial preoptic area (MPA), and lateral septal nucleus (LSV). Moreover, GALP-like immunoreactive nerve fibers were directly contacted with orexin- and melanin-concentrating hormone (MCH)-like immunoreactive neurons in the LH. Our findings strongly suggest that GALP-containing neurons interact with orexin- and/or MCH-containing neurons in the lateral hypothalamus and that it participates in the regulation of feeding behavior in harmony with other feeding-regulating neurons in the hypothalamus.

Anatomical substrates of orexin-dopamine interactions: lateral hypothalamic projections to the ventral tegmental area

J Fadel — 2006-11-26T21:19:41-00:00

Neuroscience, Vol. 111, No. 2. (10 May 2002), pp. 379-387.

Dopaminergic projections to the forebrain arising from the mesencephalic ventral tegmentum modulate information processing in cortical and limbic sites. The lateral hypothalamus is crucial for the coordination of behavioral responses to interoceptive cues. The presence of a hypothalamic input to the ventral tegmental area has been known for some time, but the organization of this pathway has received little attention. Among the neuropeptides found in the hypothalamus are the orexins, which are selectively expressed in the lateral hypothalamus and adjacent perifornical area and are critically involved in homeostatic regulatory processes, including arousal and feeding. We examined the anatomical relationships between orexin and dopamine neurons in rats, with particular attention to characterizing the lateral hypothalamic projection to midbrain dopamine neurons.Iontophoretic deposits of the retrograde tracer FluoroGold into the ventral tegmental area revealed a large number of retrogradely-labeled cells that formed a band extending from the medial perifornical area arching dorsally over the fornix and then ventrolaterally into the lateral hypothalamus; approximately 20% of these cells expressed orexin A-like immunoreactivity. Moreover, axons that were anterogradely labeled from the lateral hypothalamus were seen throughout the ventral tegmental area, and were often in close proximity to the dendrites and somata of dopamine neurons. Dopamine and orexin fibers were found to codistribute in the medial prefrontal cortex; orexin fibers were present in lower density in the medial shell of the nucleus accumbens, and the central and posterior basolateral nuclei of the amygdala.We conclude that the lateral hypothalamic/perifornical projection represents an anatomical substrate by which interoceptive-related signals may influence forebrain dopamine function.

Arousal and reward: a dichotomy in orexin function

Glenda Harris — 2006-11-15T22:19:06-00:00

Trends in Neurosciences, Vol. 29, No. 10. (October 2006), pp. 571-577.

The orexins (or hypocretins) are neuropeptide transmitters made exclusively in hypothalamic neurons that have extensive CNS projections. Previous studies reported that this system is most strongly associated with feeding, arousal and the maintenance of waking. We review here recent studies that reveal a novel and important role for the orexin/hypocretin neuronal system in reward processing and addiction. We propose that the current evidence indicates a dichotomy in orexin function, such that orexin neurons in the lateral hypothalamus regulate reward processing for both food and abused drugs, whereas those in the perifornical and dorsomedial hypothalamus regulate arousal and response to stress. Evidence also indicates roles for lateral hypothalamus orexin neurons and ventral tegmental orexin receptors in reward-based learning and memory.

Left-handed leaky wave antenna for millimeter-wave applications

S Matsuzawa — 2007-11-27T10:23:40-00:00

Antenna Technology: Small Antennas and Novel Metamaterials, 2005. IWAT 2005. IEEE International Workshop on (2005), pp. 183-186.

In this paper, we have designed microstrip left-handed leaky wave antennas (LH LWAs) working from 75 to 82 GHz, and we have conformed beam scanning by MoM simulation. A conventional LH LWA for microwave applications consists of series interdigital capacitors and shunt stubs connected with vias to the ground. Manufacturing the interdigital capacitor and meander-line inductor working at mm-wave frequencies is very hard because of the etching tolerance. In the case of the mm-wave antenna, the value of capacitance, and inductance becomes smaller than that of the microwave antenna, so the interdigital capacitor and shunt meander-line inductor can be replaced with a simple gap capacitor and line inductor. In this paper, we have designed a planar mm-wave frequency LH LWA. In order to maximize the fabrication tolerance, we have chosen a via-free LH structure with a simple series gap and a straight shunt inductor connected with a virtual ground patch in the unit cell, which will contribute to reducing conductor losses as well.