Activation of a Classic Hunger Circuit Slows Luteinizing Hormone Pulsatility

2019 ◽  
Vol 110 (7-8) ◽  
pp. 671-687 ◽  
Author(s):  
Eulalia A. Coutinho ◽  
Melanie Prescott ◽  
Sabine Hessler ◽  
Christopher J. Marshall ◽  
Allan E. Herbison ◽  
...  
Keyword(s):  
Luteinizing Hormone ◽  
Ex Vivo ◽  
Polycystic Ovary ◽  
Brain Slices ◽  
Pulse Frequency ◽  
Pulse Generation ◽  
Electrophysiological Studies ◽  
The Impact ◽  
Lh Secretion

Introduction: The central regulation of fertility is carefully coordinated with energy homeostasis, and infertility is frequently the outcome of energy imbalance. Neurons in the hypothalamus expressing neuropeptide Y and agouti-related peptide (NPY/AgRP neurons) are strongly implicated in linking metabolic cues with fertility regulation. Objective: We aimed here to determine the impact of selectively activating NPY/AgRP neurons, critical regulators of metabolism, on the activity of luteinizing hormone (LH) pulse generation. Methods: We employed a suite of in vivo optogenetic and chemogenetic approaches with serial measurements of LH to determine the impact of selectively activating NPY/AgRP neurons on dynamic LH secretion. In addition, electrophysiological studies in ex vivo brain slices were employed to ascertain the functional impact of activating NPY/AgRP neurons on gonadotropin-releasing hormone (GnRH) neurons. Results: Selective activation of NPY/AgRP neurons significantly decreased post-castration LH secretion. This was observed in males and females, as well as in prenatally androgenized females that recapitulate the persistently elevated LH pulse frequency characteristic of polycystic ovary syndrome (PCOS). Reduced LH pulse frequency was also observed when optogenetic stimulation was restricted to NPY/AgRP fiber projections surrounding GnRH neuron cell bodies in the rostral preoptic area. However, electrophysiological studies in ex vivo brain slices indicated these effects were likely to be indirect. Conclusions: These data demonstrate the ability of NPY/AgRP neuronal signaling to modulate and, specifically, reduce GnRH/LH pulse generation. The findings suggest a mechanism by which increased activity of this hunger circuit, in response to negative energy balance, mediates impaired fertility in otherwise reproductively fit states, and highlight a potential mechanism to slow LH pulsatility in female infertility disorders, such as PCOS, that are associated with hyperactive LH secretion.

scholarly journals SUN-LB50 Increased In Vivo Pulsatile LH Secretion and Hypothalamic Kisspeptin, NKB, and Dynorphin RNA Levels in a PCOS-Like Mouse Model

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Lourdes Esparza ◽  
Danielle Schafer ◽  
Bryan Ho ◽  
Varykina G Thackray ◽  
Alexander S Kauffman
Keyword(s):  
Mouse Model ◽  
Polycystic Ovary ◽  
Pulse Frequency ◽  
Aromatase Activity ◽  
Polycystic Ovaries ◽  
Neuron Activation ◽  
Lh Pulsatility ◽  
Hypothalamic Arcuate Nucleus ◽  
Lh Secretion

Abstract Polycystic ovary syndrome (PCOS) is a reproductive disorder in women characterized by hyperandrogenemia, anovulation, cystic ovaries, and LH hyper-pulsatility, but the mechanisms causing the pathophysiology remain incompletely understood. We recently reported a novel mouse model that recapitulates the majority of PCOS phenotypes in adulthood. Females given constant, long-term letrozole to reduce aromatase activity demonstrate PCOS-like phenotypes, including polycystic ovaries, anovulation, elevated circulating testosterone, and increased LH. In vivo LH pulsatile secretion, which is greatly elevated in PCOS women, was not previously studied, nor were possible changes in reproductive neurons known to control GnRH/LH secretion. Here, we used recent technical advances in the field to examine in vivo LH pulse dynamics of freely-moving LET female mice versus control and ovariectomized (OVX) mice. We also studied whether hypothalamic gene expression of several important reproductive regulators, kisspeptin, neurokinin B (NKB), and dynorphin, is altered in LET females. Compared to controls, LET females exhibited very rapid, elevated in vivo LH pulsatility, with increased pulse frequency, amplitude, and basal levels, similar to PCOS women. LET mice also had markedly elevated Kiss1, Tac2, and Pdyn expression along with increased Kiss1 neuron activation in the hypothalamic arcuate nucleus. Although elevated, most hyperactive LH pulse parameters and increased arcuate mRNA measures of LET mice were significantly lower than in OVX littermates. Our findings demonstrate that LET mice, like PCOS women, have markedly elevated LH pulsatility which likely drives increased ovarian androgen secretion. Increased arcuate kisspeptin and NKB levels may be fundamental contributors to the enhanced stimulation of LH pulse secretion in this PCOS-like condition, and perhaps, in some PCOS women.

scholarly journals TMIC-30. MICROGLIA/BRAIN MACROPHAGES PROMOTE GLIOMA GROWTH BY EXPRESSING GLYCOPROTEIN NMB

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi254-vi254
Author(s):  
Fatih Yalcin ◽  
Alice Buonfiglioli ◽  
Ibrahim Efecan Efe ◽  
Hannah Haneke ◽  
Leonard D Kuhrt ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Tumor Growth ◽  
Cellular Localization ◽  
Ex Vivo ◽  
Brain Slices ◽  
Extracellular Domain ◽  
Glioma Growth ◽  
The Impact ◽  
Human And Mouse

Abstract BACKGROUND Glioma-associated microglia and blood-derived macrophages (GAMs) promote tumor growth in experimental mouse glioma models. Using microarray and RNA sequencing, we have previously shown that GAMs upregulate the expression of Glycoprotein NMB/Osteoactivin (GPNMB) when compared to naïve microglia. GPNMB is a type 1 transmembrane glycoprotein expressed intracellularly under healthy conditions. Malignancies such as glioma induce a translocation into the plasma membrane where the extracellular domain can be cleaved and released. METHODS We used qRT-PCR, immunocytochemistry, Western Blot and flow cytometry to determine the cellular localization of GPNMB expression in human and mouse glioblastoma. To test the impact of microenvironment-derived GPNMB on glioma growth, we inoculated GL261 and RCAS-PDGFb glioblastoma cells into organotypic brain slices obtained from wildtype and GPNMB-/- mice. In addition, we quantified glioma growth after injection of RCAS-PDGFb cells into wildtype and GPNMB-/- mice. The soluble extracellular domain of GPNMB was used to stimulate primary human glioblastoma and RCAS-PDGFb cells in vitro. SRB assays were performed to assess proliferation. RESULTS Our data indicate that GAMs are the predominant source of GPNMB in both human and mouse glioblastoma and that the levels of expression in GAMs in the tumor microenvironment is higher than in naïve microglia. In the organotypic brain slice model we found that tumors were significantly smaller in slices derived from GPNMB-/- mice as compared to wildtype. The tumor growth in vivo was nearly completely blocked in the absence of GPNMB. Stimulation of glioma cells with the extracellular domain of GPNMB did not increase proliferation. CONCLUSION Our results show that GPNMB is predominantly expressed in GAMs of human and murine samples. Loss of GPNMB impaired tumor growth ex vivo and glioblastoma progression in vivo. GPNMB seems to play a crucial role in the pro-tumorigenic activity of microglia and blood-derived macrophages in the tumor microenvironment.

scholarly journals Histological, Biomechanical, and Biological Properties of Genipin-Crosslinked Decellularized Peripheral Nerves

2021 ◽  
Vol 22 (2) ◽  
pp. 674
Author(s):  
Óscar Darío García-García ◽  
Marwa El Soury ◽  
David González-Quevedo ◽  
David Sánchez-Porras ◽  
Jesús Chato-Astrain ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Nerve Repair ◽  
Wistar Rat ◽  
Biomechanical Properties ◽  
Biological Properties ◽  
Suitable Alternative ◽  
Promising Alternative ◽  
Histological Pattern ◽  
The Impact

Acellular nerve allografts (ANGs) represent a promising alternative in nerve repair. Our aim is to improve the structural and biomechanical properties of biocompatible Sondell (SD) and Roosens (RS) based ANGs using genipin (GP) as a crosslinker agent ex vivo. The impact of two concentrations of GP (0.10% and 0.25%) on Wistar rat sciatic nerve-derived ANGs was assessed at the histological, biomechanical, and biocompatibility levels. Histology confirmed the differences between SD and RS procedures, but not remarkable changes were induced by GP, which helped to preserve the nerve histological pattern. Tensile test revealed that GP enhanced the biomechanical properties of SD and RS ANGs, being the crosslinked RS ANGs more comparable to the native nerves used as control. The evaluation of the ANGs biocompatibility conducted with adipose-derived mesenchymal stem cells cultured within the ANGs confirmed a high degree of biocompatibility in all ANGs, especially in RS and RS-GP 0.10% ANGs. Finally, this study demonstrates that the use of GP could be an efficient alternative to improve the biomechanical properties of ANGs with a slight impact on the biocompatibility and histological pattern. For these reasons, we hypothesize that our novel crosslinked ANGs could be a suitable alternative for future in vivo preclinical studies.

scholarly journals Ex Vivo Mitochondrial Respiration Parallels Biochemical Response to Ibrutinib in CLL Cells

Cancers ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 354
Author(s):  
Subir Roy Chowdhury ◽  
Cheryl Peltier ◽  
Sen Hou ◽  
Amandeep Singh ◽  
James B. Johnston ◽  
...  
Keyword(s):  
Mitochondrial Respiration ◽  
Ex Vivo ◽  
Standard Dose ◽  
Cell Receptor ◽  
Lymphocytic Leukemia ◽  
Clinical Tool ◽  
Potential Biomarker ◽  
Apoptotic Pathways ◽  
The Impact

Mitochondrial respiration is becoming more commonly used as a preclinical tool and potential biomarker for chronic lymphocytic leukemia (CLL) and activated B-cell receptor (BCR) signaling. However, respiration parameters have not been evaluated with respect to dose of ibrutinib given in clinical practice or the effect of progression on ibrutinib treatment on respiration of CLL cells. We evaluated the impact of low and standard dose ibrutinib on CLL cells from patients treated in vivo on mitochondrial respiration using Oroboros oxygraph. Cytokines CCL3 and CCL4 were evaluated using the Mesoscale. Western blot analysis was used to evaluate the BCR and apoptotic pathways. We observed no difference in the mitochondrial respiration rates or levels of plasma chemokine (C-C motif) ligands 3 and 4 (CCL3/CCL4), β-2 microglobulin (β-2 M) and lactate dehydrogenase (LDH) between low and standard doses of ibrutinib. This may confirm why clinical observations of the safety and efficacy of low dose ibrutinib are observed in practice. Of interest, we also observed that the mitochondrial respiration of CLL cells paralleled the increase in β-2 M and LDH at progression. Our study further supports mitochondrial respiration as a biomarker for response and progression on ibrutinib in CLL cells and a valuable pre-clinical tool.

scholarly journals PD-L1 Checkpoint Blockade Augments Anti-Tumor Immune Response of GD2 or HER2-Bsab Ex Vivo Armed T-Cells (EVAT) Therapy in Osteosarcoma

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1959-1959
Author(s):  
Jeong A Park ◽  
Hong fen Guo ◽  
Hong Xu ◽  
Nai-Kong V. Cheung
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Immune Checkpoint ◽  
Bispecific Antibody ◽  
Ex Vivo ◽  
Activated T Cells ◽  
The Impact ◽  
Anti Tumor Activity

Background Ex Vivo Armed T-cells (EVAT) carrying zeptomoles (10-21M) of T-cell engaging GD2-bispecific antibody (GD2-EVAT) or HER2-bispecific antibodies (HER2-EVAT) have potent anti-tumor activity against GD2(+) and/or HER2(+) solid tumors. Strategies to further optimize this approach are highly relevant. PD-1 is a key immune checkpoint receptor expressed mainly by activated T-cells and mediates immune suppression by binding to its ligands PD-L1 or PD-L2. Upregulation of PD-L1 has been found in many cancers including osteosarcoma and associated with aggressive disease and poor outcome. While the use of immune checkpoint inhibitors (ICIs) seems logical, the ideal timing when combined with T-cell engaging bispecific antibody (T-BsAb) or EVAT has yet to be defined. Here, we described the effects of anti-PD-1 or anti-PD-L1 antibodies on GD2-EVAT or HER2-EVAT therapy and explored the impact of its timing in the treatment of osteosarcoma which is GD2(+), HER2(+) and PD-L1(+). Methods GD2-BsAb and HER-BsAb were built using the IgG(L)-scFv format (Can Immunol Res, 3:266, 2015, Oncoimmunology, PMID:28405494). T-cells from healthy volunteer donors were isolated, and cultured ex vivo in the presence of CD3/CD28 beads plus 30 IU/mL of interleukin 2 (IL-2). Between day 7 and day 14, activated T-cells (ATCs) were harvested and armed for 20 minutes at room temperature with GD2-BsAb or HER2-BsAb. In vivo anti-tumor activity against GD2(+), HER2(+), and PD-L1(+) osteosarcoma cell line xenografts was tested in BALB-Rag2-/-IL-2R-γc-KO mice. Anti-human PD-1 antibody (pembrolizumab, anti-PD-1) or anti-human PD-L1 antibody (atezolizumab, anti-PD-L1) were tested for synergy with GD2-EVAT or HER2-EVAT therapy. Results The PD-1 expression increased among T-cells that circulated in the blood, that infiltrated the spleen or the tumor after EVAT therapy. While anti-PD-L1 combination therapy with GD2-EVAT or HER2-EVAT improved anti-tumor response against osteosarcoma (P=0.0123 and P=0.0004), anti-PD-1 did not (all P>0.05). The addition of anti-PD-L1 significantly increased T-cell survival in blood and T-cell infiltration of tumor when compared to GD2-EVAT or HER2-EVAT alone (all P<0.0001). Treatment of GD2-EVAT or anti-PD-L1 plus GD2-EVAT downregulated GD2 expression on tumors, but anti-PD-1 plus GD2-EVAT did not. For the next step we tested the impact of different combination schedules of ICIs on GD2-EVAT therapy. Concurrent anti-PD-1 (6 doses along with GD2-EVAT therapy) interfered with GD2-EVAT, while sequential anti-PD-1 (6 doses after GD2-EVAT) did not make a significant effect (P>0.05). On the other hand, while the concurrent use of anti-PD-L1 did not show benefit on GD2-EVAT, sequentially administered anti-PD-L1 produced a significant improvement in tumor control when compared to anti-PD-L1 or GD2-EVAT alone (P=0.002 and P=0.018). When anti-PD-L1 treatment was extended (12 doses after GD2-EVAT), the anti-tumor effect was most pronounced compared to GD2-EVAT alone (P <0.0001), which translated into improved survival (P=0.0057). These in vivo anti-tumor responses were associated with increased CD8(+) tumor infiltrating lymphocytes (TILs) of tumor. Conclusion In the arming platform, large numbers of target-specific T-cells can be generated, and this EVAT therapy is a highly effective cellular treatment with high potency in preclinical models. In addition, the advantage of ex vivo cytokine release following T-cell arming and activation could reduce or avoid life threatening cytokine storm if such activation was to proceed in vivo. Adoptive T-cell therapy induced immune response upregulates the inhibitory immune checkpoint PD-1/PD-L1 pathway, and combination treatment with anti-PD-L1 antibody, especially when combined as sequential therapy and continuously treated, significantly improved anti-tumor effect of EVAT, partly through increase in CD8(+) TILs infiltration. Disclosures Xu: MSK: Other: co-inventors in patents on GD2 bispecific antibody and HER2 bispecific antibody. Cheung:Ymabs: Patents & Royalties, Research Funding.

Abstract 401: Experimental Aneurysm in Rats Excluded by Stent Graft: A New Model to Assess the Impact of Endovascular Aneurysm Repair on the Pathophysiology of Abdominal Aortic Aneurysm.

2012 ◽  
Vol 32 (suppl_1) ◽  
Author(s):  
Martin Rouer ◽  
Martin Rouer ◽  
Jean-Marc Alsac ◽  
Jean-Baptiste Michel
Keyword(s):  
Experimental Model ◽  
Ex Vivo ◽  
Endovascular Aneurysm Repair ◽  
Small Animal ◽  
Normal Diet ◽  
Biological Study ◽  
Experimental Aneurysm ◽  
Midline Laparotomy ◽  
The Impact

Introduction Biological study of the impact of endovascular aortic repair (EVAR) on pathophysiology of aortic abdominal aneurysms (AAA) can only be performed indirectly in humans, by imaging or search for peripheral biomarkers in the circulating blood. Therefore biological mechanism’s modifications into the aneurismal wall related to its endovascular exclusion are still to be elucidated, and small animal models should bring a valuable help in this field. We describe a new experimental model of stentgraft implantation for the exclusion of AAA in rats. Methods Aneurysms were induced as previously described by intra-aortic elastase injection in Wistar rats, or by aortic decellularized xenograft transplantation in Lewis rats. At least 15 days later, the midline laparotomy was reopened, and 3mm covered stentgraft were inserted and deployed in the AAA to obtain its exclusion. The patency of the graft and the AAA exclusion could be assessed by a global arteriogram through the carotid artery. After closure of the laparotomy, the rats were awakened and returned to a normal diet. Results This experimental model of AAA exclusion by a stentgraft allows many in vivo and ex vivo studies of the pathophysiology of AAA after EVAR. Histological modifications of the aortic wall and the intra-luminal thrombus could be assessed. The impact of EVAR on the adventitial immuno-inflammatory activity could be studied by different imaging such as MRI, scintigraphy or PET-scan. In situ biological and enzymatic activities could be evaluated to better understand the local mechanisms leading to AAA shrinkage or expansion after EVAR. Conclusion Exclusion by stentgraft of experimental AAA in rats is the first described model of EVAR in small animals. It is feasible and reproducible for both elastase and xenograft experimental AAA models. This model will definitely help to a better analysis and understanding of the impact of stentgrafting on biological mechanisms in the aneurismal wall, that lead to EVAR success with shrinkage of aneurismal sac or EVAR failure with its continuing expansion.

scholarly journals Understanding the Effects of General Anesthetics on Cortical Network Activity Using Ex Vivo Preparations

2019 ◽  
Vol 130 (6) ◽  
pp. 1049-1063 ◽  
Author(s):  
Logan J. Voss ◽  
Paul S. García ◽  
Harald Hentschke ◽  
Matthew I. Banks
Keyword(s):  
Molecular Mechanisms ◽  
Ex Vivo ◽  
Brain Slices ◽  
Brain Regions ◽  
Cortical Network ◽  
Network Activity ◽  
Common Mechanism ◽  
General Anesthetics ◽  
Neural Basis

Abstract General anesthetics have been used to ablate consciousness during surgery for more than 150 yr. Despite significant advances in our understanding of their molecular-level pharmacologic effects, comparatively little is known about how anesthetics alter brain dynamics to cause unconsciousness. Consequently, while anesthesia practice is now routine and safe, there are many vagaries that remain unexplained. In this paper, the authors review the evidence that cortical network activity is particularly sensitive to general anesthetics, and suggest that disruption to communication in, and/or among, cortical brain regions is a common mechanism of anesthesia that ultimately produces loss of consciousness. The authors review data from acute brain slices and organotypic cultures showing that anesthetics with differing molecular mechanisms of action share in common the ability to impair neurophysiologic communication. While many questions remain, together, ex vivo and in vivo investigations suggest that a unified understanding of both clinical anesthesia and the neural basis of consciousness is attainable.

scholarly journals Intestinal IgA Regulates Expression of a Fructan Polysaccharide Utilization Locus in Colonizing Gut Commensal Bacteroides thetaiotaomicron

mBio ◽  
2019 ◽  
Vol 10 (6) ◽  
Author(s):  
Payal Joglekar ◽  
Hua Ding ◽  
Pablo Canales-Herrerias ◽  
Pankaj Jay Pasricha ◽  
Justin L. Sonnenburg ◽  
...  
Keyword(s):  
Gut Microbiota ◽  
Ex Vivo ◽  
Microbial Colonization ◽  
Bacteroides Thetaiotaomicron ◽  
Content Type ◽  
Microbial Utilization ◽  
Polysaccharide Utilization Locus ◽  
The Impact

ABSTRACT Gut-derived immunoglobulin A (IgA) is the most abundant antibody secreted in the gut that shapes gut microbiota composition and functionality. However, most of the microbial antigens targeted by gut IgA remain unknown, and the functional effects of IgA targeting these antigens are currently understudied. This study provides a framework for identifying and characterizing gut microbiota antigens targeted by gut IgA. We developed a small intestinal ex vivo culture assay to harvest lamina propria IgA from gnotobiotic mice, with the aim of identifying antigenic targets in a model human gut commensal, Bacteroides thetaiotaomicron VPI-5482. Colonization by B. thetaiotaomicron induced a microbe-specific IgA response that was reactive against diverse antigens, including capsular polysaccharides, lipopolysaccharides, and proteins. IgA against microbial protein antigens targeted membrane and secreted proteins with diverse functionalities, including an IgA specific against proteins of the polysaccharide utilization locus (PUL) that are necessary for utilization of fructan, which is an important dietary polysaccharide. Further analyses demonstrated that the presence of dietary fructan increased the production of fructan PUL-specific IgA, which then downregulated the expression of fructan PUL in B. thetaiotaomicron, both in vivo and in vitro. Since the expression of fructan PUL has been associated with the ability of B. thetaiotaomicron to colonize the gut in the presence of dietary fructans, our work suggests a novel role for gut IgA in regulating microbial colonization by modulating their metabolism. IMPORTANCE Given the significant impact that gut microbes have on our health, it is essential to identify key host and environmental factors that shape this diverse community. While many studies have highlighted the impact of diet on gut microbiota, little is known about how the host regulates this critical diet-microbiota interaction. In our present study, we discovered that gut IgA targeted a protein complex involved in the utilization of an important dietary polysaccharide: fructan. While the presence of dietary fructans was previously thought to allow unrestricted growth of fructan-utilizing bacteria, our work shows that gut IgA, by targeting proteins responsible for fructan utilization, provides the host with tools that can restrict the microbial utilization of such polysaccharides, thereby controlling their growth.

A new implantable tool for repeated assessment of supraventricular electrophysiology and atrial fibrillation susceptibility in freely moving rats

2020 ◽  
Author(s):  
Michael Murninkas ◽  
Roni Gillis ◽  
Danielle I Lee ◽  
Sigal Elyagon ◽  
Nikhil Suresh Bhandarkar ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Ex Vivo ◽  
Adult Rats ◽  
Electrophysiological Properties ◽  
Multiple Risk Factors ◽  
Electrophysiological Studies ◽  
Cycle Lengths ◽  
Major Factors

The complex pathophysiology of atrial fibrillation (AF) is governed by multiple risk factors in ways that are still elusive. Basic electrophysiological properties including atrial effective refractory period (AERP) and conduction velocity are major factors determining the susceptibility of the atrial myocardium to AF. Although there is a great need for affordable animal models in this field of research, in-vivo rodent studies are limited by technical challenges. Recently, we introduced an implantable system for long-term assessment of AF susceptibility in ambulatory rats. However, technical considerations did not allow us to perform concomitant supraventricular electrophysiology measurements. Here, we designed a novel quadripolar-electrode specifically adapted for comprehensive atrial studies in ambulatory rats. Electrodes were fabricated from medical-grade silicone, four platinum-iridium poles and stainless steel fixating pins. Initial quality validation was performed ex-vivo, followed by implantation in adult rats and repeated electrophysiological studies 1, 4 and 8 weeks post implantation. Capture threshold was stable. Baseline AERP values (38.1±2.3 and 39.5±2.0 using 70ms and 120ms S1-S1 cycle lengths, respectively) confirmed the expected absence of rate-adaptation in the unanesthetized state and validated our prediction that markedly higher values reported under anesthesia are non-physiological. Evaluation of AF substrate in parallel with electrophysiological parameters validated our recent finding of a gradual increase in AF susceptibility over-time and demonstrated that this phenomenon is associated with an electrical remodeling process characterized by AERP shortening. Our findings indicate that the miniature quadripolar-electrode is a potent new tool, which opens a window of opportunities for better utilization of rats in AF research.

scholarly journals Neural Determinants of Pulsatile Luteinizing Hormone Secretion in Male Mice

Endocrinology ◽  
2020 ◽  
Vol 161 (2) ◽  
Author(s):  
Su Young Han ◽  
Isaiah Cheong ◽  
Tim McLennan ◽  
Allan E Herbison
Keyword(s):  
Luteinizing Hormone ◽  
High Frequency ◽  
Pulse Generator ◽  
Hormone Secretion ◽  
Pulse Frequency ◽  
Male Mice ◽  
Intact Male ◽  
Luteinizing Hormone Secretion ◽  
Pulse Profile ◽  
Lh Secretion

Abstract The gonadotrophin-releasing hormone (GnRH) pulse generator drives pulsatile luteinizing hormone (LH) secretion essential for fertility. However, the constraints within which the pulse generator operates to drive efficient LH pulsatility remain unclear. We used optogenetic activation of the arcuate nucleus kisspeptin neurons, recently identified as the GnRH pulse generator, to assess the efficiency of different pulse generator frequencies in driving pulsatile LH secretion in intact freely behaving male mice. Activating the pulse generator at 45-minute intervals generated LH pulses similar to those observed in intact male mice while 9-minute interval stimulation generated LH profiles indistinguishable from gonadectomized (GDX) male mice. However, more frequent activation of the pulse generator resulted in disordered LH secretion. Optogenetic experiments directly activating the distal projections of the GnRH neuron gave the exact same results, indicating the pituitary to be the locus of the high frequency decoding. To evaluate the state-dependent behavior of the pulse generator, the effects of high-frequency activation of the arcuate kisspeptin neurons were compared in GDX and intact mice. The same stimulus resulted in an overall inhibition of LH release in GDX mice but stimulation in intact males. These studies demonstrate that the GnRH pulse generator is the primary determinant of LH pulse profile and that a nonlinear relationship exists between pulse generator frequency and LH pulse frequency. This may underlie the ability of stimulatory inputs to the pulse generator to have opposite effects on LH secretion in intact and GDX animals.

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