Voliotis2019-GnRH Pulse Generation
Model Identifier
BIOMD0000000931
Short description
Fertility critically depends on the gonadotropin-releasing hormone (GnRH) pulse generator, a neural construct comprised of hypothalamic neurons coexpressing kisspeptin, neurokoinin-B and dynorphin. Here, using mathematical modeling and in vivo optogenetics we reveal for the first time how this neural construct initiates and sustains the appropriate ultradian frequency essential for reproduction. Prompted by mathematical modeling, we show experimentally using female estrous mice that robust pulsatile release of luteinizing hormone, a proxy for GnRH, emerges abruptly as we increase the basal activity of the neuronal network using continuous low-frequency optogenetic stimulation. Further increase in basal activity markedly increases pulse frequency and eventually leads to pulse termination. Additional model predictions that pulsatile dynamics emerge from nonlinear positive and negative feedback interactions mediated through neurokinin-B and dynorphin signaling respectively are confirmed neuropharmacologically. Our results shed light on the long-elusive GnRH pulse generator offering new horizons for reproductive health and wellbeing.SIGNIFICANCE STATEMENT The gonadotropin-releasing hormone (GnRH) pulse generator controls the pulsatile secretion of the gonadotropic hormones LH and FSH and is critical for fertility. The hypothalamic arcuate kisspeptin neurons are thought to represent the GnRH pulse generator, since their oscillatory activity is coincident with LH pulses in the blood; a proxy for GnRH pulses. However, the mechanisms underlying GnRH pulse generation remain elusive. We developed a mathematical model of the kisspeptin neuronal network and confirmed its predictions experimentally, showing how LH secretion is frequency-modulated as we increase the basal activity of the arcuate kisspeptin neurons in vivo using continuous optogenetic stimulation. Our model provides a quantitative framework for understanding the reproductive neuroendocrine system and opens new horizons for fertility regulation Model is encoded by Johannes and submitted to BioModels by Ahmad Zyoud.
Format
SBML
(L2V4)
Related Publication
-
The Origin of GnRH Pulse Generation: An Integrative Mathematical-Experimental Approach.
- Voliotis M, Li XF, De Burgh R, Lass G, Lightman SL, O'Byrne KT, Tsaneva-Atanasova K
- The Journal of neuroscience : the official journal of the Society for Neuroscience , 12/ 2019 , Volume 39 , Issue 49 , pages: 9738-9747 , PubMed ID: 31645462
- Department of Mathematics and Living Systems Institute, College of Engineering, Mathematics and Physical Sciences, University of Exeter, Exeter EX4 4QF, United Kingdom, M.Voliotis@exeter.ac.uk K.Tsaneva-Atanasova@exeter.ac.uk.
- Fertility critically depends on the gonadotropin-releasing hormone (GnRH) pulse generator, a neural construct comprised of hypothalamic neurons coexpressing kisspeptin, neurokoinin-B and dynorphin. Here, using mathematical modeling and in vivo optogenetics we reveal for the first time how this neural construct initiates and sustains the appropriate ultradian frequency essential for reproduction. Prompted by mathematical modeling, we show experimentally using female estrous mice that robust pulsatile release of luteinizing hormone, a proxy for GnRH, emerges abruptly as we increase the basal activity of the neuronal network using continuous low-frequency optogenetic stimulation. Further increase in basal activity markedly increases pulse frequency and eventually leads to pulse termination. Additional model predictions that pulsatile dynamics emerge from nonlinear positive and negative feedback interactions mediated through neurokinin-B and dynorphin signaling respectively are confirmed neuropharmacologically. Our results shed light on the long-elusive GnRH pulse generator offering new horizons for reproductive health and wellbeing.SIGNIFICANCE STATEMENT The gonadotropin-releasing hormone (GnRH) pulse generator controls the pulsatile secretion of the gonadotropic hormones LH and FSH and is critical for fertility. The hypothalamic arcuate kisspeptin neurons are thought to represent the GnRH pulse generator, since their oscillatory activity is coincident with LH pulses in the blood; a proxy for GnRH pulses. However, the mechanisms underlying GnRH pulse generation remain elusive. We developed a mathematical model of the kisspeptin neuronal network and confirmed its predictions experimentally, showing how LH secretion is frequency-modulated as we increase the basal activity of the arcuate kisspeptin neurons in vivo using continuous optogenetic stimulation. Our model provides a quantitative framework for understanding the reproductive neuroendocrine system and opens new horizons for fertility regulation.
Contributors
Submitter of the first revision: Ahmad Zyoud
Submitter of this revision: Tung Nguyen
Modellers: Tung Nguyen, Ahmad Zyoud
Submitter of this revision: Tung Nguyen
Modellers: Tung Nguyen, Ahmad Zyoud
Metadata information
is (2 statements)
isDescribedBy (1 statement)
hasTaxon (1 statement)
hasProperty (4 statements)
isDescribedBy (1 statement)
hasTaxon (1 statement)
hasProperty (4 statements)
Mathematical Modelling Ontology
Ordinary differential equation model
NCIt Fertility
NCIt Endocrine
NCIt Gonadotrophin Releasing Hormone
NCIt Fertility
NCIt Endocrine
NCIt Gonadotrophin Releasing Hormone
Curation status
Curated
Modelling approach(es)
Tags
Connected external resources
SBGN view in Newt Editor
| Name | Description | Size | Actions |
|---|---|---|---|
Model files |
|||
| Voliotis2019.xml | SBML L2V4 Voliotis2019-GnRH Pulse Generation_Curated_Fig1A | 36.24 KB | Preview | Download |
Additional files |
|||
| Voliotis2019-original.xml | SBML L2V4 Voliotis2019-GnRH Pulse Generation_Original | 36.24 KB | Preview | Download |
| Voliotis2019.cps | COPASI version 4.27 (Build 217) Voliotis2019-GnRH Pulse Generation_Curated_Fig1A | 68.55 KB | Preview | Download |
| Voliotis2019.sedml | SBML L2V4 Voliotis2019-GnRH Pulse Generation_Curated_Fig1A | 1.80 KB | Preview | Download |
- Model originally submitted by : Ahmad Zyoud
- Submitted: Mar 19, 2020 9:02:54 PM
- Last Modified: Jan 20, 2022 10:39:22 AM
Revisions
-
Version: 4
- Submitted on: Jan 20, 2022 10:39:22 AM
- Submitted by: Tung Nguyen
- With comment: Renamed one of the additional files to resolve the main and that file having the same name
-
Version: 3
- Submitted on: Apr 7, 2020 6:08:48 PM
- Submitted by: Ahmad Zyoud
- With comment: Automatically added model identifier BIOMD0000000931
-
Version: 1
- Submitted on: Mar 19, 2020 9:02:54 PM
- Submitted by: Ahmad Zyoud
- With comment: Import of Voliotis2019-GnRH Pulse Generation
(*) You might be seeing discontinuous
revisions as only public revisions are displayed here. Any private revisions
of this model will only be shown to the submitter and their collaborators.
Legends
: Variable used inside SBML models
: Variable used inside SBML models
Species
| Species | Initial Concentration/Amount |
|---|---|
| N | 0.07764 item |
| v | 300.0 item |
| D | 2.348 item |
Reactions
| Reactions | Rate | Parameters |
|---|---|---|
| => N | compartment*f_N | f_N = 0.302353418222975 |
| N => | compartment*d_N*N | d_N = 1.0 |
| => v | compartment*f_v | f_v = 3016.26432543932 |
| D => | compartment*d_D*D | d_D = 0.25 |
| => D | compartment*f_D | f_D = 0.439705882352941 |
| v => | compartment*d_v*v | d_v = 10.0 |
Curator's comment:
(added: 07 Apr 2020, 18:08:23, updated: 07 Apr 2020, 18:08:23)
(added: 07 Apr 2020, 18:08:23, updated: 07 Apr 2020, 18:08:23)
Fig1A has been reproduced using Copasi 4.27 ( Build 217).
The unit of the Firing Rate in the figure is Hz (spikes/sec), while in the model is spikes/min