Highly redundant neuropeptide volume co-transmission underlying episodic activation of the GnRH neuron dendron.

The necessity and functional significance of neurotransmitter co-transmission remains unclear. The glutamatergic 'KNDy' neurons co-express kisspeptin, neurokinin B (NKB), and dynorphin and exhibit a highly stereotyped synchronized behavior that reads out to the gonadotropin-releasing hormone (GnRH) neuron dendrons to drive episodic hormone secretion. Using expansion microscopy, we show that KNDy neurons make abundant close, non-synaptic appositions with the GnRH neuron dendron. Electrophysiology and confocal GCaMP6 imaging demonstrated that, despite all three neuropeptides being released from KNDy terminals, only kisspeptin was able to activate the GnRH neuron dendron. Mice with a selective deletion of kisspeptin from KNDy neurons failed to exhibit pulsatile hormone secretion but maintained synchronized episodic KNDy neuron behavior that is thought to depend on recurrent NKB and dynorphin transmission. This indicates that KNDy neurons drive episodic hormone secretion through highly redundant neuropeptide co-transmission orchestrated by differential post-synaptic neuropeptide receptor expression at the GnRH neuron dendron and KNDy neuron

Highly redundant neuropeptide volume co-transmission underlying episodic activation of the GnRH neuron dendron.

The necessity and functional significance of neurotransmitter co-transmission remains unclear. The glutamatergic 'KNDy' neurons co-express kisspeptin, neurokinin B (NKB), and dynorphin and exhibit a highly stereotyped synchronized behavior that reads out to the gonadotropin-releasing hormone (GnRH) neuron dendrons to drive episodic hormone secretion. Using expansion microscopy, we show that KNDy neurons make abundant close, non-synaptic appositions with the GnRH neuron dendron. Electrophysiology and confocal GCaMP6 imaging demonstrated that, despite all three neuropeptides being released from KNDy terminals, only kisspeptin was able to activate the GnRH neuron dendron. Mice with a selective deletion of kisspeptin from KNDy neurons failed to exhibit pulsatile hormone secretion but maintained synchronized episodic KNDy neuron behavior that is thought to depend on recurrent NKB and dynorphin transmission. This indicates that KNDy neurons drive episodic hormone secretion through highly redundant neuropeptide co-transmission orchestrated by differential post-synaptic neuropeptide receptor expression at the GnRH neuron dendron and KNDy neuron

Optimal Delay Time of CT Perfusion for Predicting Cerebral Parenchymal Hematoma After Intra-Arterial tPA Treatment

Background and Purpose: Cerebral hemorrhage is a serious potential complication of stroke revascularization, especially in patients receiving intra-arterial tissue-type plasminogen activator (tPA) therapy. We investigated the optimal pre-intervention delay time (DT) of computed tomography perfusion (CTP) measurement to predict cerebral parenchymal hematoma (PH) in acute ischemic stroke (AIS) patients after intra-arterial tissue plasminogen activator (tPA) treatment.Methods: The study population consisted of a series of patients with AIS who received intra-arterial tPA treatment and had CTP and follow-up computed tomography/magnetic resonance imaging (CT/MRI) to identify hemorrhagic transformation. The association of increasing DT thresholds (>2, >4, >6, >8, and >10 s) with PH was examined using receiver operating characteristic (ROC) analysis and logistic regression.Results: Of 94 patients, 23 developed PH on follow-up imaging. Receiver operating characteristic analysis revealed that the greatest area under the curve for predicting PH occurred at DT > 4 s (area under the curve, 0.66). At this threshold of > 4 s, DT lesion volume ≥ 30.85 mL optimally predicted PH with 70% sensitivity and 59% specificity. DT > 4 s volume was independently predictive of PH in a multivariate logistic regression model (P < 0.05).Conclusions: DT > 4 s was the parameter most strongly associated with PH. The volume of moderate, not severe, hypo-perfusion on DT is more strongly associated and may allow better prediction of PH after intra-arterial tPA thrombolysis

Kisspeptin Regulation of Neuronal Activity throughout the Central Nervous System

Kisspeptin signaling at the gonadotropin-releasing hormone (GnRH) neuron is now relatively well characterized and established as being critical for the neural control of fertility. However, kisspeptin fibers and the kisspeptin receptor (KISS1R) are detected throughout the brain suggesting that kisspeptin is involved in regulating the activity of multiple neuronal circuits. We provide here a review of kisspeptin actions on neuronal populations throughout the brain including the magnocellular oxytocin and vasopressin neurons, and cells within the arcuate nucleus, hippocampus, and amygdala. The actions of kisspeptin in these brain regions are compared to its effects upon GnRH neurons. Two major themes arise from this analysis. First, it is apparent that kisspeptin signaling through KISS1R at the GnRH neuron is a unique, extremely potent form or neurotransmission whereas kisspeptin actions through KISS1R in other brain regions exhibit neuromodulatory actions typical of other neuropeptides. Second, it is becoming increasingly likely that kisspeptin acts as a neuromodulator not only through KISS1R but also through other RFamide receptors such as the neuropeptide FF receptors (NPFFRs). We suggest likely locations of kisspeptin signaling through NPFFRs but note that only limited tools are presently available for examining kisspeptin cross-signaling within the RFamide family of neuropeptides

Robust GABAergic Regulation of the GnRH Neuron Distal Dendron.

The amino acid transmitter γ-aminobutyric acid (GABA) is suspected to play an important role in regulating the activity of the gonadotropin-releasing hormone (GnRH) neurons controlling fertility. Rodent GnRH neurons have a novel dendritic compartment termed the "distal dendron" through which action potentials pass to the axon terminals and where inputs from the kisspeptin pulse generator drive pulsatile GnRH secretion. Combining Gnrh1-Cre mice with the Cre-dependent calcium sensor GCaMP6 and confocal imaging of acute brain slices, we examined whether GABA regulated intracellular calcium concentrations ([Ca2+]) in the GnRH neuron distal dendron. Short puffs of GABA on the dendron evoked either a monophasic sustained suppression of [Ca2+] or a biphasic acute elevation in [Ca2+] followed by the sustained suppression. Application of muscimol to the dendron replicated the acute elevation in [Ca2+] while baclofen generated the sustained suppression. Robust GABAB receptor-mediated inhibition was observed in 80% to 100% of dendrons recorded from females across the estrous cycle and from approximately 70% of dendrons in males. In contrast, the GABAA receptor-mediated excitation was rare in males and varied across the estrous cycle, being most prominent at proestrus. The activation of GABAB receptors potently suppressed the stimulatory effect of kisspeptin on the dendron. These observations demonstrate that the great majority of GnRH neuron distal dendrons are regulated by GABAergic inputs in a sex- and estrous cycle-dependent manner, with robust GABAB receptor-mediated inhibition being the primary mode of signaling. This provides a new, kisspeptin-independent, pathway for the regulation of pulsatile and surge modes of GnRH secretion in the rodent.Wellcome Trust New Zealand Health Research Counci

Suppression of potassium channels elicits calcium-dependent plateau potentials in suprachiasmatic neurons of the rat

By using whole-cell recordings in acute and organotypic hypothalamic slices, we found that following K+ channel blockade, sustained plateau potentials can be elicited by current injection in suprachiasmatic neurons. In an attempt to determine the ionic basis of these potentials, ion-substitution experiments were carried out. It appeared that to generate plateau potentials, calcium influx was required. Plateau potentials were also present when extracellular calcium was replaced by barium, but were independent upon an increase in the intracellular free calcium concentration. Substitution of extracellular sodium by the impermeant cation N-methyl-D-glucamine indicated that sodium influx could also contribute to plateau potentials. To gain some information on the pharmacological profile of the Ca++ channels responsible for plateau potentials, selective blocker of various types of Ca++ channel were tested. Plateau potentials were unaffected by isradipine, an L-type Ca++ channel blocker. However, they were slightly reduced by omega-conotoxin GVIA and omega-agatoxin TK, blockers of N-type and P/Q-type Ca++ channels, respectively. These data suggest that R-type Ca++ channels probably play a major role in the genesis of plateau potentials. We speculate that neurotransmitters/neuromodulators capable of reducing or suppressing potassium conductance(s) may elicit a Ca++-dependent plateau potential in suprachiasmatic neurons, thus promoting sustained firing activity and neuropeptide release

Electrical properties of kisspeptin neurons and their regulation of GnRH neurons

Kisspeptin neurons are critical components of the neuronal network controlling the activity of the gonadotropin-releasing hormone (GnRH) neurons. A variety of genetically-manipulated mouse models have recently facilitated the study of the electrical activity of the two principal kisspeptin neuron populations located in the rostral periventricular area of the third ventricle (RP3V) and arcuate nucleus (ARN) in acute brain slices. We discuss here the mechanisms and pathways through which kisspeptin neurons regulate GnRH neuron activity. We then examine the different kisspeptin-green fluorescent protein mouse models being used for kisspeptin electrophysiology and the data obtained to date for RP3V and ARN kisspeptin neurons. In light of these new observations on the spontaneous firing rates, intrinsic membrane properties, and neurotransmitter regulation of kisspeptin neurons, we speculate on the physiological roles of the different kisspeptin populations

Geochemical Characterization of the Eocene Coal-Bearing Source Rocks, Xihu Sag, East China Sea Shelf Basin, China: Implications for Origin and Depositional Environment of Organic Matter and Hydrocarbon Potential

Eocene coal-bearing source rocks of the Pinghu Formation from the W-3 well in the western margin of the Xihu Sag, East China Sea Shelf Basin were analyzed using Rock-Eval pyrolysis and gas chromatography–mass spectrometry to investigate the samples’ source of organic matter, depositional environment, thermal maturity, and hydrocarbon generative potential. The distribution patterns of n-alkanes, isoprenoids and steranes, high Pr/Ph ratios, abundant diterpanes, and the presence of non-hopanoid triterpanes indicate predominant source input from higher land plants. The contribution of aquatic organic matter was occasionally slightly elevated probably due to a raised water table. High hopane/sterane ratios and the occurrence of bicyclic sesquiterpanes and A-ring degraded triterpanes suggest microbial activity and the input of microbial organisms. Overwhelming predominance of gymnosperm-derived diterpanes over angiosperm-derived triterpanes suggest a domination of gymnosperms over angiosperms in local palaeovegetation during the period of deposition. The high Pr/Ph ratios, the plot of Pr/n-C17 versus Ph/n-C18, the almost complete absence of gammacerane, and the distribution pattern of hopanes suggest that the samples were deposited in a relatively oxic environment. Generally, fluctuation of redox potential is coupled with source input, i.e., less oxic conditions were associated with more aquatic organic matter, suggesting an occasionally raised water table. Comprehensive maturity evaluation based on Ro, Tmax, and biomarker parameters shows that the samples constitute a natural maturation profile ranging from marginally mature to a near peak oil window. Hydrogen index and atomic H/C and O/C ratios of kerogens suggest that the samples mainly contain type II/III organic matter and could generate mixed oil and gas

Identification and hydrocarbon expulsion history simulation of the effective source rocks in the Dongying Formation, Paleogene, Bohai Sea area, eastern China

This paper discusses a new method for identification and simulation of the hydrocarbon expulsion history of Effective Source Rocks (ESR) in the Dongying Formation (E3d), Bohai sea area, Bohai Bay basin, eastern China. This new method enables us to reliably identify the distribution and quantitatively determine the hydrocarbon expulsion history of ESR in petroliferous basins. ESR are the material basis for hydrocarbon accumulation, having important implications for oil and gas exploration prospects. The Bohai Bay basin is one of the most petroliferous basins in China, with nearly one third of the total oil production of the country. However, insufficient research on the ESR in the Dongying Formation (E3d), Bohai sea area, Bohai Bay basin obstructs further exploration. In this paper, ESR of E3d are identified with the new "two-stage and three-step" method, and their planar distribution is predicted by combining well data with sedimentary facies, and structure distribution. On that basis, the hydrocarbon expulsion history of ESR in the 2nd Member (E3d2) and 3rd Member (E3d3) of E3d was systematically simulated by using the hydrocarbon generation potential method. The results show that the ESR of E3d2 are distributed in four sags of Bohai Sea area, while the ESR of E3d3 occur in seven sags. Hydrocarbon expulsion from the ESR of E3d2 began during the deposition period of the Minghuazhen Formation (N1m) (12 Ma) with a hydrocarbon expulsion quantity of 42×108 t. The hydrocarbon expulsion centers were located in the Bozhong, Huanghekou, Qikou and Bodong sags. Hydrocarbon expulsion from the ESR of E3d3 began around 16.6 Ma ago (hydrocarbon expulsion quantity of 84×108 t), and the hydrocarbon expulsion centers were located in the Bozhong, Qinnan, Huanghekou, Liaozhong, Nanpu and Qikou sags. In conclusion, the hydrocarbon expulsion centers of the ESR of E3d are mainly located in Bozhong, Huanghekou, Qikou and Bodong sags, with late-stage hydrocarbon expulsion (16.6�2 Ma), which is advantageous to hydrocarbon accumulation and preservation. The uplifts and slope belts around the hydrocarbon expulsion centers would be favorable exploration targets.En este artículo se discute un nuevo método para la identificación y simulación de la historia de expulsión de hidrocarburos de la Roca Madre Efectiva (RME) en la Formación Dongying (E3d), área del Mar de Bohai, cuenca de la Bahía de Bohai, este de China. Este nuevo método permite identificar de manera confiable la distribución y determinar cuantitativamente la historia de expulsión de hidrocarburos de las RME en cuencas petrolíferas. Las RME son la base material para la acumulación de hidrocarburos y tienen implicaciones importantes para prospectos de exploración de petróleo y gas. La cuenca de la Bahía de Bohai es una de las más ricas en petróleo de China, con cerca de un tercio de la producción total de petróleo en el país. Sin embargo, la investigación de las RME de la Formación Dongying (E3d) en la cuenca de la Bahía de Bohai es aún insuficiente, lo que ha obstruido el avance de la exploración. En este trabajo, se indentifican las RME de E3d con el nuevo método de "dos etapas y tres pasos", y su distribución planar se predice por medio de la combinación de datos de pozos con facies sedimentarias y distribución de estructuras. Con base en lo anterior se simuló sistemáticamente la historia de expulsión de hidrocarburos de las RME en el 2° Miembro (E3d2) y el 3er Miembro (E3d3) de E3d por medio de la aplicación del método de potencial de generación de hidrocarburos. Los resultados muestran que las RME de E3d2 están distribuidas en cuatro depresiones ("sags") del área del Mar de Bohai, mientras que las RME de E3d3 se presentan en siete depresiones. La expulsión de hidrocarburos de las RME de E3d2 inició en el periodo de depósito de la Formación Minghuazhen (N1m) (12 Ma) con la expulsión de 42× 108 t. Los centros de expulsión se localizan en las depresiones de Bozhong, Huanghekou, Qikou y Bodong. La expulsión de hidrocarburos de las RME de E3d3 inició a ~16.6 Ma con la expulsión de 84×108 t, y los centros de expulsión se localizaron en las depresiones Bozhong, Qinnan, Huanghekou, Liaozhong, Nanpu y Qikou. En conclusión, los centros de expulsión de hidrocarburos de las RME de E3d se localizan principalmente en las depresiones Bozhong, Huanghekou, Qikou y Bodong, con expulsión de hidrocarburos tardía (16.6�2 Ma), lo cual es ventajoso para la acumulación y preservación de hidrocarburos. Los levantamientos ("uplifts") y cinturones de talud que rodean a los centros de expulsión de hidrocarburos serían blancos de exploración favorables