A novel mechanism underlying GnRH pulse generation by KNDy neurones
Lead Research Organisation:
UNIVERSITY OF EXETER
Department Name: Mathematics
Abstract
Abstracts are not currently available in GtR for all funded research. This is normally because the abstract was not required at the time of proposal submission, but may be because it included sensitive information such as personal details.
Technical Summary
This project will address one of the most important questions in the field of reproductive biology; what are the neural mechanisms underlying GnRH pulse generation? With a unique combination of expertise in in vivo experimental reproductive neuroendocrinology, in vitro optogenetics-electrophysiology and mathematical systems biology modelling, we will determine the activity parameters of the hypothalamic KNDy neural network, and the intrinsic dynamics of the excitatory (NKB) and inhibitory (Dyn) signalling between KNDy neurones, that controls GnRH pulse generation and modulate its frequency, which is critical for reproduction. Additionally, we will examine the intrinsic modulatory effect of gonadal steroids and the external influence of the amygdala, a key emotional brain centre, on GnRH pulse generator activity. Application of computational methods to the complex KNDy network with continual input of experimental findings will provide a catalyst for systematic model development, emergence of new testable hypotheses and unparalleled advancement in our understanding of the operational characteristics of the GnRH pulse generator. This understanding is hugely important both in humans and animals, because it offers the prospect of better management of fertility in the clinic as well as animal breeding.
Planned Impact
Scientists: Research personnel working within the field of reproductive sciences and mathematical modelling of neuroendocrine systems will receive immediate intellectual benefit. Post-doctoral researchers, technicians, PhD students, undergraduates and pre-university school pupils working on the project will acquire transferrable technical and professional skills that will benefit their future development within scientific and non-scientific arenas. Of particular significance is enhancing capacity in in vivo research, addressing the UK strategic skills needs, which is recognised as a critical limiting resource not only in the UK but in the international biosciences' arena. The scientific community as a whole will benefit from a theoretical viewpoint on the complexity of neuropeptide signalling in the central nervous system, which might lend itself to mathematical modelling in non-biological arenas.
Pharmaceutical Sector: Reproductive potential and stress impacts hugely on Health and Wellbeing in our modern society with significant social and economic consequences. The same is true for commercial farming and breeding, with food security of ever increasing global significance. Although the proposed research focuses on elucidating the mechanisms underlying the central control of reproductive function, it will greatly advance our understanding of this system under both physiologically and pharmacologically relevant paradigms. This understanding is hugely important both in humans and animals, as it will offers the prospect of better understanding and manipulating fertility in the clinic as well as animal breeding. The implications for reproductive function and in particular the adverse effects of environmental perturbation are of critical importance, and the pharmaceutical sector could benefit in the long-term with novel therapeutic for treating global problems associated with stress in humans and animals, with health and wealth sequelae.
Government Environmental/ Health Policy (National and International): Modern society presents many potentially stressful challenges, especially for our children and young people such as, unprecedented 24-hour access to the internet and social media which can lead to increased levels of anxiety, cyberbullying and sleep deprivation. There is growing concern of rising levels of mental health problems, which in turn impact on reproductive health. Our research on modelling the central mechanism controlling reproduction and the impact of psychogenic stress, may provide important information to the many UK Government Health Policies that not only focus on the general public (eg. Public Health England 2017), but our military (eg. Defence People Mental Health and Wellbeing Strategy 2017-2022). Our finding are also relevant to DEFRA's animal health and welfare strategic Policies.
Media, Educational Programmes and Schools: The current interest in Health and Wellbeing TV and radio programmes could benefit from this research by provision of scientific data and knowledge on reproductive health and impact of stress including psychological stress and mental health that could potentially contribute to the general education of viewers and listeners. School curricula might benefit through material provided via social media, websites, mobile apps and events sponsored by the Royal Society of Biology, in partnership with the BBSRC, which receive input from the UK scientific societies including the British Society for Neuroendocrinology and The Physiological Society.
Pharmaceutical Sector: Reproductive potential and stress impacts hugely on Health and Wellbeing in our modern society with significant social and economic consequences. The same is true for commercial farming and breeding, with food security of ever increasing global significance. Although the proposed research focuses on elucidating the mechanisms underlying the central control of reproductive function, it will greatly advance our understanding of this system under both physiologically and pharmacologically relevant paradigms. This understanding is hugely important both in humans and animals, as it will offers the prospect of better understanding and manipulating fertility in the clinic as well as animal breeding. The implications for reproductive function and in particular the adverse effects of environmental perturbation are of critical importance, and the pharmaceutical sector could benefit in the long-term with novel therapeutic for treating global problems associated with stress in humans and animals, with health and wealth sequelae.
Government Environmental/ Health Policy (National and International): Modern society presents many potentially stressful challenges, especially for our children and young people such as, unprecedented 24-hour access to the internet and social media which can lead to increased levels of anxiety, cyberbullying and sleep deprivation. There is growing concern of rising levels of mental health problems, which in turn impact on reproductive health. Our research on modelling the central mechanism controlling reproduction and the impact of psychogenic stress, may provide important information to the many UK Government Health Policies that not only focus on the general public (eg. Public Health England 2017), but our military (eg. Defence People Mental Health and Wellbeing Strategy 2017-2022). Our finding are also relevant to DEFRA's animal health and welfare strategic Policies.
Media, Educational Programmes and Schools: The current interest in Health and Wellbeing TV and radio programmes could benefit from this research by provision of scientific data and knowledge on reproductive health and impact of stress including psychological stress and mental health that could potentially contribute to the general education of viewers and listeners. School curricula might benefit through material provided via social media, websites, mobile apps and events sponsored by the Royal Society of Biology, in partnership with the BBSRC, which receive input from the UK scientific societies including the British Society for Neuroendocrinology and The Physiological Society.
Publications
Abbara A
(2020)
Kisspeptin receptor agonist has therapeutic potential for female reproductive disorders.
in The Journal of clinical investigation
Dhillo W
(2019)
SAT-LB040 Measuring LH Pulsatility in Patients with Reproductive Disorders Using a Novel Robotic Aptamer-Enabled Electrochemical Reader (RAPTER)
in Journal of the Endocrine Society
Lass G
(2022)
GnRH pulse generator frequency is modulated by kisspeptin and GABA-glutamate interactions in the posterodorsal medial amygdala in female mice.
in Journal of neuroendocrinology
Liang S
(2019)
Measuring luteinising hormone pulsatility with a robotic aptamer-enabled electrochemical reader.
in Nature communications
McArdle C
(2021)
Cellular Endocrinology in Health and Disease
Plain Z
(2022)
Modelling KNDy neurons and gonadotropin-releasing hormone pulse generation.
in Current opinion in endocrine and metabolic research
Prague JK
(2019)
Determining the Relationship Between Hot Flushes and LH Pulses in Menopausal Women Using Mathematical Modeling.
in The Journal of clinical endocrinology and metabolism
Description | We have investigated the mechanisms underlying the pulsatile release of gonadotropin-releasing hormone (GnRH) using a novel mathematical model hand-in-hand with cutting edge optogenetics and neuropharmacology. The pulsatile release of GnRH into the pituitary gland is driven by a hypothalamic neuronal (KNDy) network, known as the GnRH pulse generator. The operation of the GnRH pulse generator at an appropriate ultradian frequency is critical for maintaining normal reproductive health throughout life and although it has received a great deal of attention from an experimental point of view its dynamic regulation remains poorly understood. We believe our results are novel and of general interest. We are the first to investigate the dynamical behaviour of the GnRH pulse generator combining mathematical modelling and dynamic optic stimulation. Specifically, we propose the first mechanistic model of the GnRH pulse generator revealing that the system behaves as relaxation oscillator: owing to positive and negative feedbacks conveyed via neuropeptide signalling (neurokinin B and dynorphin respectively). Our main findings summarised below are based on our model predictions subsequently confirmed by in-vivo optogenetic experiments. We demonstrate that: • we can drive the system from a silent (steady) into a pulsatile (oscillatory) mode of operation via optically stimulating the KNDy population continuously by increasing the frequency of stimulation; • transition into the pulsatile mode is abrupt and occurs above a certain threshold of optic stimulation frequency due to the existence of a tipping point in the system; • blocking dynorphin and neurokinin B signalling modulates the dynamic response of the system by increasing and decreasing the sensitivity of the system to optic stimulation respectively. Taken together, our theoretical and experimental results offer fresh, quantitative insight into the modus operandi of the GnRH pulse generator. For example, our results demonstrate how gonadotropin pulsatility is likely to be modulated through synaptic inputs to the GnRH pulse generator or as a result of changes to the sex steroid-milieu affecting neuropeptide signalling. Therefore, we anticipate our work to shed light on the regulation of pulsatile gonadotropin secretion in various contexts: from lactational amenorrhoea; to stress or starvation induced infertility; to pharmaceutic interventions including the hormone contraceptive pill, and pave the way for manipulating fertility in the clinic. |
Exploitation Route | Taken together, our theoretical and experimental results offer fresh, quantitative insight into the modus operandi of the GnRH pulse generator. For example, our results demonstrate how gonadotropin pulsatility is likely to be modulated through synaptic inputs to the GnRH pulse generator or as a result of changes to the sex steroid-milieu affecting neuropeptide signalling. Therefore, we anticipate our work to shed light on the regulation of pulsatile gonadotropin secretion in various contexts: from lactational amenorrhoea; to stress or starvation induced infertility; to pharmaceutic interventions including the hormone contraceptive pill, and pave the way for manipulating fertility in the clinic. |
Sectors | Healthcare Pharmaceuticals and Medical Biotechnology |
Description | Building a model of the Hypothalamic-Pituitary-Gonadal (HPG) axis |
Amount | £15,009 (GBP) |
Funding ID | 2240721 |
Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
Sector | Public |
Country | United Kingdom |
Start | 09/2019 |
End | 09/2024 |
Description | EPSRC Hub for Quantitative Modelling in Healthcare |
Amount | £1,231,618 (GBP) |
Funding ID | EP/T017856/1 |
Organisation | Engineering and Physical Sciences Research Council (EPSRC) |
Sector | Public |
Country | United Kingdom |
Start | 02/2021 |
End | 08/2025 |
Description | The amygdala, a key upstream regulator of the hypothalamic GnRH pulse generator |
Amount | £391,816 (GBP) |
Funding ID | BB/W005883/1 |
Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
Sector | Public |
Country | United Kingdom |
Start | 02/2022 |
End | 01/2025 |
Description | US Partnering Award: An integrative approach to understanding the GnRH pulse generator: combining in-vitro, in-vivo and in-silico methodologies. |
Amount | £50,613 (GBP) |
Funding ID | BB/S019979/1 |
Organisation | Biotechnology and Biological Sciences Research Council (BBSRC) |
Sector | Public |
Country | United Kingdom |
Start | 03/2019 |
End | 03/2024 |
Title | Modulation of pulsatile GnRH dynamics along the reproductive cycle - the role of excitability within the arcuate kisspeptin network |
Description | Pulsatile LH data set |
Type Of Material | Database/Collection of data |
Year Produced | 2021 |
Provided To Others? | Yes |
URL | https://kcl.figshare.com/articles/dataset/Modulation_of_pulsatile_GnRH_dynamics_along_the_reproducti... |
Title | hormoneBayes |
Description | hormoneBayes is a novel open-access Bayesian framework that can be easily applied to reliably analyze serial LH measurements to assess LH pulsatility. The framework utilizes parsimonious models to simulate hypothalamic signals that drive LH dynamics, together with state-of-the-art (sequential) Monte-Carlo methods to infer key parameters and latent hypothalamic dynamics. We show that this method provides estimates for key pulse parameters including inter-pulse interval, secretion and clearance rates and identifies LH pulses in line with the current gold-standard deconvolution method. We show that these parameters can distinguish LH pulsatility in different clinical contexts including in reproductive health and disease in men and women (e.g., healthy men, healthy women before and after menopause, women with HA or PCOS). A further advantage of hormoneBayes is that our mathematical approach provides a quantified estimation of uncertainty. Our framework will complement methods enabling real-time in-vivo hormone monitoring and therefore has the potential to assist translation of personalized, data-driven, clinical care of patients presenting with conditions of reproductive hormone dysfunction. |
Type Of Material | Computer model/algorithm |
Year Produced | 2022 |
Provided To Others? | Yes |
Impact | Too early to say. |
URL | https://git.exeter.ac.uk/mv286/hormonebayes |
Description | BBSRC (BB/S000550/1) A novel mechanism underlying GnRH pulse generation by KNDy neurones |
Organisation | King's College London |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | This is a collaborative BBSRC grant that has two sites - KCL and Exeter |
Collaborator Contribution | Providing data and expertise |
Impact | Publications and further collaborative awards |
Start Year | 2017 |
Description | BBSRC US Partnering Award BB/S019979/1, Title: An integrative approach to understanding the GnRH pulse generator: combining in-vitro, in-vivo and in-silico methodologies |
Organisation | King's College London |
Country | United Kingdom |
Sector | Academic/University |
PI Contribution | Mathematical modelling and data analysis |
Collaborator Contribution | Experimental data and expertise |
Impact | None |
Start Year | 2019 |
Title | hormoneBayes |
Description | hormoneBayes is a novel open-access Bayesian framework that can be easily applied to reliably analyze serial LH measurements to assess LH pulsatility. The framework utilizes parsimonious models to simulate hypothalamic signals that drive LH dynamics, together with state-of-the-art (sequential) Monte-Carlo methods to infer key parameters and latent hypothalamic dynamics. We show that this method provides estimates for key pulse parameters including inter-pulse interval, secretion and clearance rates and identifies LH pulses in line with the current gold-standard deconvolution method. We show that these parameters can distinguish LH pulsatility in different clinical contexts including in reproductive health and disease in men and women (e.g., healthy men, healthy women before and after menopause, women with HA or PCOS). A further advantage of hormoneBayes is that our mathematical approach provides a quantified estimation of uncertainty. Our framework will complement methods enabling real-time in-vivo hormone monitoring and therefore has the potential to assist translation of personalized, data-driven, clinical care of patients presenting with conditions of reproductive hormone dysfunction. |
Type Of Technology | Software |
Year Produced | 2022 |
Open Source License? | Yes |
Impact | Too early to say. |
URL | https://git.exeter.ac.uk/mv286/hormonebayes |
Description | Brain Awareness Week, public talk on 15th March 2018 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Undergraduate students |
Results and Impact | The Brain Awareness Week is a global campaign which aims to increase the public's awareness of current brain research. It is taking place from the 12 - 18 March 2018 and the University of Exeter has been awarded funding from the British Neuroscience Association to host a range of workshops and events on brain-related topics. One of our public events is called "Neuroscience: Is it all in our minds?", which is a seminar series introducing a diverse audience to a range of neuroscience ideology and research findings, with an opportunity for questions and networking. |
Year(s) Of Engagement Activity | 2018 |
Description | Exeter Maths School INSPIRE lectures on 18th January 2019 |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Local |
Primary Audience | Schools |
Results and Impact | An INSPIRE lecture delivered by Research Co-I Margaritis Voliotis to A-level students at the specialist Exeter Mathematics School on modelling the reproductive system. These lectures are designed to expose and illustrate the deep links between all things and Mathematics, whilst also breaking down the traditionally rigid boundaries between, for example, Biology and Physics. They also provide students with inspiration for their own future; in the summer term of year 12 the focus shifts towards careers based topics with speakers from industry, degree apprenticeship providers and our own alumni. |
Year(s) Of Engagement Activity | 2019 |
Description | School visit |
Form Of Engagement Activity | A talk or presentation |
Part Of Official Scheme? | No |
Geographic Reach | Regional |
Primary Audience | Schools |
Results and Impact | Title: "Mathematical models of hormonal rhythms" seminar by Dr Margaritis Voliotis Date: 04/03/2022 Venue: South Gloucester and Strout College (SGS), STEM Seminar series |
Year(s) Of Engagement Activity | 2022 |