scholarly journals Genetic dissection of the different roles of hypothalamic kisspeptin neurons in regulating female reproduction

2018 ◽  
Author(s):  
Luhong Wang ◽  
Charlotte Vanacker ◽  
Laura L. Burger ◽  
Tammy Barnes ◽  
Yatrik M. Shah ◽  
...  
Keyword(s):  
Negative Feedback ◽  
Knockout Mice ◽  
Positive Feedback ◽  
Gonadotropin Releasing Hormone ◽  
Genetic Dissection ◽  
Female Reproduction ◽  
Releasing Hormone ◽  
Gnrh Neurons ◽  
Reproductive Cycles ◽  
The Brain

AbstractThe brain regulates fertility through gonadotropin-releasing hormone (GnRH) neurons. Estradiol induces negative feedback on pulsatile GnRH/luteinizing hormone (LH) release and positive feedback generating preovulatory GnRH/LH surges. Negative and positive feedback are postulated to be mediated by kisspeptin neurons in arcuate and anteroventral periventricular (AVPV) nuclei, respectively. Kisspeptin-specific ERα knockout mice exhibit disrupted LH pulses and surges. This knockout approach is neither location-specific nor temporally-controlled. We utilized CRISPR-Cas9 to disrupt ERα in adulthood. Mice with ERα disruption in AVPV kisspeptin neurons have typical reproductive cycles but blunted LH surges, associated with decreased excitability of these neurons. Mice with ERα knocked down in arcuate kisspeptin neurons showed disrupted cyclicity, associated with increased glutamatergic transmission to these neurons. These observations suggest activational effects of estradiol regulate surge generation and maintain cyclicity through AVPV and arcuate kisspeptin neurons, respectively, independent from its role in the development of hypothalamic kisspeptin neurons or puberty onset.Significant StatementThe brain regulates fertility through gonadotropin-releasing hormone (GnRH) neurons. Ovarian estradiol regulates GnRH pulses (negative feedback) and the GnRH surge release that ultimately triggers ovulation (positive feedback). Kisspeptin neurons in the arcuate and anteroventral periventricular nuclei are postulated to convey negative and positive feedback to GnRH neurons, respectively. Kisspeptin-specific ERα knockout mice exhibited disrupted negative and positive feedback. However, it is not clear what roles each kisspeptin population plays, and not possible to separate their roles during development vs adulthood in this model. Here we utilized CRISPR-Cas9 to disrupt ERα in each population in adulthood. We found activational effects of estradiol regulate surge generation and maintain cyclicity through AVPV and arcuate kisspeptin neurons, respectively, independent from estradiol action during development.

scholarly journals Genetic dissection of the different roles of hypothalamic kisspeptin neurons in regulating female reproduction

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Luhong Wang ◽  
Charlotte Vanacker ◽  
Laura L Burger ◽  
Tammy Barnes ◽  
Yatrik M Shah ◽  
...  
Keyword(s):  
Gonadotropin Releasing Hormone ◽  
Genetic Dissection ◽  
Glutamatergic Transmission ◽  
Female Reproduction ◽  
Positive Feedbacks ◽  
Pulsatile Gnrh ◽  
Lh Release ◽  
Puberty Onset ◽  
Reproductive Cycles ◽  
The Brain

The brain regulates fertility through gonadotropin-releasing hormone (GnRH) neurons. Estradiol induces negative feedback on pulsatile GnRH/luteinizing hormone (LH) release and positive feedback generating preovulatory GnRH/LH surges. Negative and positive feedbacks are postulated to be mediated by kisspeptin neurons in arcuate and anteroventral periventricular (AVPV) nuclei, respectively. Kisspeptin-specific ERα knockout mice exhibit disrupted LH pulses and surges. This knockout approach is neither location-specific nor temporally controlled. We utilized CRISPR-Cas9 to disrupt ERα in adulthood. Mice with ERα disruption in AVPV kisspeptin neurons have typical reproductive cycles but blunted LH surges, associated with decreased excitability of these neurons. Mice with ERα knocked down in arcuate kisspeptin neurons showed disrupted cyclicity, associated with increased glutamatergic transmission to these neurons. These observations suggest that activational effects of estradiol regulate surge generation and maintain cyclicity through AVPV and arcuate kisspeptin neurons, respectively, independent from its role in the development of hypothalamic kisspeptin neurons or puberty onset.

scholarly journals Lack of sex differences in gonadotropin-releasing hormone (GnRH) neuron potassium currents and excitability

2021 ◽  
Author(s):  
R Anthony DeFazio ◽  
Suzanne M Moenter
Keyword(s):  
Action Potential ◽  
Negative Feedback ◽  
Positive Feedback ◽  
Brain Slices ◽  
Potassium Currents ◽  
Gonadotropin Releasing Hormone ◽  
Releasing Hormone ◽  
Voltage Gated ◽  
Gnrh Neurons ◽  
Gnrh Release

Gonadotropin-releasing hormone (GnRH) drives pituitary secretion of luteinizing hormone (LH) and follicle-stimulating hormone, which in turn regulate gonadal functions including steroidogenesis. The pattern of GnRH release and thus fertility depend on gonadal steroid feedback. Under homeostatic (negative) feedback conditions, removal of the gonads from either females or males increases the amplitude and frequency of GnRH release and alters the long-term firing pattern of these neurons in brain slices. The neurobiological mechanisms intrinsic to GnRH neurons that are altered by homeostatic feedback are not well studied and have not been compared between sexes. During estradiol positive feedback, which is unique to females, there are correlated changes in voltage-gated potassium currents and neuronal excitability. We thus hypothesized these same mechanisms would be engaged in homeostatic negative feedback. Voltage-gated potassium channels play a direct role in setting excitability and action potential properties. Whole-cell patch-clamp recordings of GFP-identified GnRH neurons in brain slices from sham-operated and castrated adult female and male mice were made to assess fast (IA) and slow (IK) inactivating potassium currents as well as action potential properties. Surprisingly, no changes were observed in most potassium current properties, input resistance or capacitance and this was reflected in a lack of differences in excitability and specific action potential properties. These results support the concept that, in contrast to positive feedback, steroid negative feedback regulation of GnRH neurons in both sexes is likely conveyed to GnRH neurons via mechanisms that do not induce major changes in the biophysical properties of these cells.

scholarly journals Live View of Gonadotropin-Releasing Hormone Containing Neuron Migration

Endocrinology ◽  
2005 ◽  
Vol 146 (1) ◽  
pp. 463-468 ◽  
Author(s):  
Elizabeth P. Bless ◽  
Heather J. Walker ◽  
Kwok W. Yu ◽  
J. Gabriel Knoll ◽  
Suzanne M. Moenter ◽  
...  
Keyword(s):  
Real Time ◽  
Direct Evidence ◽  
Gonadotropin Releasing Hormone ◽  
Releasing Hormone ◽  
Reproductive Axis ◽  
Gnrh Neurons ◽  
Migratory Route ◽  
The Brain

Neurons that synthesize GnRH control the reproductive axis and migrate over long distances and through different environments during development. Prior studies provided strong clues for the types of molecules encountered and movements expected along the migratory route. However, our studies provide the first real-time views of the behavior of GnRH neurons in the context of an in vitro preparation that maintains conditions comparable to those in vivo. The live views provide direct evidence of the changing behavior of GnRH neurons in their different environments, showing that GnRH neurons move with greater frequency and with more changes in direction after they enter the brain. Perturbations of guiding fibers distal to moving GnRH neurons in the nasal compartment influenced movement without detectable changes in the fibers in the immediate vicinity of moving GnRH neurons. This suggests that the use of fibers by GnRH neurons for guidance may entail selective signaling in addition to mechanical guidance. These studies establish a model to evaluate the influences of specific molecules that are important for their migration.

scholarly journals Gonadotropin-Releasing Hormone (GnRH) Activates the M-Current in GnRH Neurons: An Autoregulatory Negative Feedback Mechanism?

Endocrinology ◽  
2008 ◽  
Vol 149 (5) ◽  
pp. 2459-2466 ◽  
Author(s):  
Chun Xu ◽  
Troy A. Roepke ◽  
Chunguang Zhang ◽  
Oline K. Rønnekleiv ◽  
Martin J. Kelly
Keyword(s):  
Negative Feedback ◽  
Feedback Mechanism ◽  
Gonadotropin Releasing Hormone ◽  
Releasing Hormone ◽  
M Current ◽  
Negative Feedback Mechanism ◽  
Gnrh Neurons

Hypothalamic Control of Female Reproduction

2017 ◽  
Author(s):  
Brian P. Kenealy ◽  
Ei Terasawa
Keyword(s):  
Neuronal Activity ◽  
Gonadotropin Releasing Hormone ◽  
Female Reproduction ◽  
Animal Kingdom ◽  
Neurokinin B ◽  
Ovarian Steroid ◽  
Large Numbers ◽  
Hypothalamic Control ◽  
Gnrh Neurons ◽  
The Brain

Female reproduction is an interplay between the hypothalamus, pituitary, and ovaries. While the gonadotropin releasing hormone (GnRH) neuron in the hypothalamus regulates gonadal function through the pituitary, GnRH neuronal activity is also profoundly influenced by ovarian steroid hormones. GnRH is released from GnRH neurons in a pulsatile manner after integration of a diverse array of internal and external milieus. Since the discovery of the mammalian GnRH molecule, over a dozen GnRH forms have been identified in the animal kingdom, and large numbers of publications in various lab animal and human studies suggest that GnRH neurons are regulated by multiple neuromodulators in the brain, such as kisspeptin, neurokinin B, β-dynorphin, neuropeptide Y, GnIH, GABA, glutamate, and glial factors. A recent emerging concept is that steroids synthesized locally in the hypothalamus, namely, neuroestradiol and neuroprogesterone, also contribute to the regulation of GnRH neuronal activity, and hence female reproduction. Together with modulation by various inputs and ovarian steroid feedback, GnRH neurons are responsible for puberty, cyclic ovulation, and menopause.

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