Kisspeptin Signalling in the Hypothalamic Arcuate Nucleus Regulates GnRH Pulse Generator Frequency in the Rat

Kisspeptin and its G protein-coupled receptor (GPR) 54 are essential for activation of the hypothalamo-pituitary-gonadal axis. In the rat, the kisspeptin neurons critical for gonadotropin secretion are located in the hypothalamic arcuate (ARC) and anteroventral periventricular (AVPV) nuclei. As the ARC is known to be the site of the gonadotropin-releasing hormone (GnRH) pulse generator we explored whether kisspeptin-GPR54 signalling in the ARC regulates GnRH pulses.We examined the effects of kisspeptin-10 or a selective kisspeptin antagonist administration intra-ARC or intra-medial preoptic area (mPOA), (which includes the AVPV), on pulsatile luteinizing hormone (LH) secretion in the rat. Ovariectomized rats with subcutaneous 17β-estradiol capsules were chronically implanted with bilateral intra-ARC or intra-mPOA cannulae, or intra-cerebroventricular (icv) cannulae and intravenous catheters. Blood samples were collected every 5 min for 5–8 h for LH measurement. After 2 h of control blood sampling, kisspeptin-10 or kisspeptin antagonist was administered via pre-implanted cannulae. Intranuclear administration of kisspeptin-10 resulted in a dose-dependent increase in circulating levels of LH lasting approximately 1 h, before recovering to a normal pulsatile pattern of circulating LH. Both icv and intra-ARC administration of kisspeptin antagonist suppressed LH pulse frequency profoundly. However, intra-mPOA administration of kisspeptin antagonist did not affect pulsatile LH secretion.These data are the first to identify the arcuate nucleus as a key site for kisspeptin modulation of LH pulse frequency, supporting the notion that kisspeptin-GPR54 signalling in this region of the mediobasal hypothalamus is a critical neural component of the hypothalamic GnRH pulse generator

An improved analysis of GW150914 using a fully spin-precessing waveform model

This paper presents updated estimates of source parameters for GW150914, a binary black-hole coalescence event detected by the Laser Interferometer Gravitational-wave Observatory (LIGO) on September 14, 2015 [1]. Reference presented parameter estimation [2] of the source using a 13-dimensional, phenomenological precessing-spin model (precessing IMRPhenom) and a 11-dimensional nonprecessing effective-one-body (EOB) model calibrated to numerical-relativity simulations, which forces spin alignment (nonprecessing EOBNR). Here we present new results that include a 15-dimensional precessing-spin waveform model (precessing EOBNR) developed within the EOB formalism. We find good agreement with the parameters estimated previously [2], and we quote updated component masses of $35^{+5}_{-3}\mathrm{M}_\odot$ and $30^{+3}_{-4}\mathrm{M}_\odot$ (where errors correspond to 90% symmetric credible intervals). We also present slightly tighter constraints on the dimensionless spin magnitudes of the two black holes, with a primary spin estimate $0.65$ and a secondary spin estimate $0.75$ at 90% probability. Reference [2] estimated the systematic parameter-extraction errors due to waveform-model uncertainty by combining the posterior probability densities of precessing IMRPhenom and nonprecessing EOBNR. Here we find that the two precessing-spin models are in closer agreement, suggesting that these systematic errors are smaller than previously quoted

Properties of the Binary Black Hole Merger GW150914

On September 14, 2015, the Laser Interferometer Gravitational-Wave Observatory (LIGO) detected a gravitational-wave transient (GW150914); we characterize the properties of the source and its parameters. The data around the time of the event were analyzed coherently across the LIGO network using a suite of accurate waveform models that describe gravitational waves from a compact binary system in general relativity. GW150914 was produced by a nearly equal mass binary black hole of masses 36+5−4M⊙ and 29+4−4M⊙; for each parameter we report the median value and the range of the 90% credible interval. The dimensionless spin magnitude of the more massive black hole is bound to be <0.7 (at 90% probability). The luminosity distance to the source is 410+160−180  Mpc, corresponding to a redshift 0.09+0.03−0.04 assuming standard cosmology. The source location is constrained to an annulus section of 610  deg2, primarily in the southern hemisphere. The binary merges into a black hole of mass 62+4−4M⊙ and spin 0.67+0.05−0.07. This black hole is significantly more massive than any other inferred from electromagnetic observations in the stellar-mass regime

Directly comparing GW150914 with numerical solutions of Einstein's equations for binary black hole coalescence

We compare GW150914 directly to simulations of coalescing binary black holes in full general relativity, including several performed specifically to reproduce this event. Our calculations go beyond existing semianalytic models, because for all simulations – including sources with two independent, precessing spins – we perform comparisons which account for all the spin-weighted quadrupolar modes, and separately which account for all the quadrupolar and octopolar modes. Consistent with the posterior distributions reported in LVC-PE[1] (at the 90% credible level), we find the data are compatible with a wide range of nonprecessing and precessing simulations. Followup simulations performed using previously-estimated binary parameters most resemble the data, even when all quadrupolar and octopolar modes are included. Comparisons including only the quadrupolar modes constrain the total redshifted mass Mz ∈ [64M� − 82M�], mass ratio 1/q = m2/m1 ∈ [0.6, 1], and effective aligned spin χeff ∈ [−0.3, 0.2], where χeff = (S1/m1 + S2/m2) · Lˆ /M. Including both quadrupolar and octopolar modes, we find the mass ratio is even more tightly constrained. Even accounting for precession, simulations with extreme mass ratios and effective spins are highly inconsistent with the data, at any mass. Several nonprecessing and precessing simulations with similar mass ratio and χeff are consistent with the data. Though correlated, the components’ spins (both in magnitude and directions) are not significantly constrained by the data: the data is consistent with simulations with component spin magnitudes a1,2 up to at least 0.8, with random orientations. Further detailed followup calculations are needed to determine if the data contain a weak imprint from transverse (precessing) spins. For nonprecessing binaries, interpolating between simulations, we reconstruct a posterior distribution consistent with previous results. The final black hole’s redshifted mass is consistent with Mf,z in the range 64.0M� − 73.5M� and the final black hole’s dimensionless spin parameter is consistent with af = 0.62 − 0.73. As our approach invokes no intermediate approximations to general relativity and can strongly reject binaries whose radiation is inconsistent with the data, our analysis provides a valuable complement to LVC-PE[1]

High-Fat Diet Increases LH Pulse Frequency and Kisspeptin-Neurokinin B Expression in Puberty-Advanced Female Rats

To investigate whether the advancement of puberty in response to high-fat diet (HFD) results from a concomitant increase in LH pulse frequency and kisspeptin (Kiss1) and neurokinin B (NKB) signaling in the hypothalamus, blood samples were collected on postnatal day (pnd) 28, 32, or 36 for LH measurement and vaginal opening monitored as a marker of puberty in female rats fed with HFD or standard chow from weaning. Quantitative RT-PCR was used to determine Kiss1 and kisspeptin receptor (Kiss1r) mRNA levels in brain punches of the medial preoptic area and the arcuate nucleus (ARC), and NKB and NKB receptor (NK3R) mRNA levels in the ARC. There was a gradual increase in LH pulse frequency from pnd 28, reaching significance by pnd 36 in control diet-fed rats. The advancement of puberty by approximately 6 d (average pnd 34) in rats fed HFD was associated with an earlier onset of the higher LH pulse frequency that was already extant on pnd 28. The increased levels of expression of Kiss1 in the medial preoptic area and ARC, and NKB in the ARC, associated with pubertal onset were similarly advanced in HFD-fed rats. These data suggest that the earlier accelerated GnRH pulse generator frequency and advanced puberty with obesogenic diets might be associated with premature up-regulation of kisspeptin and NKB signaling in the hypothalamus of the female rat.</jats:p

The Inhibitory Effects of Neurokinin B on GnRH Pulse Generator Frequency in the Female Rat

Neurokinin B (NKB) and its receptor (neurokinin-3 receptor) are coexpressed with kisspeptin and dynorphin A (Dyn) within neurons of the hypothalamic arcuate nucleus, the suggested site of the GnRH pulse generator. It is thought that these neuropeptides interact to regulate gonadotropin secretion. Using the ovariectomized (OVX) and OVX 17β-estradiol-replaced rat models, we have carried out a series of in vivo neuropharmacological and electrophysiological experiments to elucidate the hierarchy between the kisspeptin, NKB, and Dyn signaling systems. Rats were implanted with intracerebroventricular cannulae and cardiac catheters for frequent (every 5 min) automated serial blood sampling. Freely moving rats were bled for 6 h, with intracerebroventricular injections taking place after a 2-h control bleeding period. A further group of OVX rats was implanted with intra-arcuate electrodes for the recording of multiunit activity volleys, which coincide invariably with LH pulses. Intracerebroventricular administration of the selective neurokinin-3 receptor agonist, senktide (100–600 pmol), caused a dose-dependent suppression of LH pulses and multiunit activity volleys. The effects of senktide did not differ between OVX and 17β-estradiol-replaced OVX animals. Pretreatment with a selective Dyn receptor (κ opioid receptor) antagonist, norbinaltorphimine (6.8 nmol), blocked the senktide-induced inhibition of pulsatile LH secretion. Intracerebroventricular injection of senktide did not affect the rise in LH concentrations after administration of kisspeptin (1 nmol), and neither did kisspeptin preclude the senktide-induced suppression of LH pulses. These data show that NKB suppresses the frequency of the GnRH pulse generator in a Dyn/κ opioid receptor-dependent fashion.</jats:p