A novel mechanism underlying GnRH pulse generation by KNDy neurones

The ability to reproduce, which is absolutely essential for survival of our species, depends on an amazing "clock" in the brain. This clock is responsible for driving the intermittent secretion of pulses of a brain hormone called gonadotrophin-releasing hormone (GnRH), which controls a cascade of hormonal signals that not only triggers puberty, but is responsible for fertile egg and sperm production across the life course. This neural clock is called the "GnRH Pulse Generator". Despite the fact that is was discovered over half a century ago, and was shown to be located in a very small area in the brain called the hypothalamus, the components of this timepiece have remained elusive until very recently. About 15 years ago there was great excitement when a new brain chemical called kisspeptin was found in the hypothalamus and shown to be a critical link in activating the GnRH nerve cells in the brain. What was even more astonishing was the discovery that these neurones producing Kisspeptin were also making two additional chemicals; a stimulatory one called Neurokinin-B (NKB) and an inhibitory one called Dynorphin-A (Dyn)(hence their name KNDy neurones). The KNDy neurones are a crucial part of the nerve network that can drive the pulses of GnRH and so drive reproduction. However, we still do not understand how the KNDy network generate the stream of kisspeptin pulses (like the ticks of a clock) to drive the GnRH pulses. Because of the complexity of this system, we have developed a mathematical model of the KNDy network to help us understand the relationships of all the key elements of this complex neural system, rather like the weather forecast models help us understand complex meteorological data.
Surprisingly one of the main predictions of our mathematical model is that low level of constant activity within the KNDy network is the primary cause of the GnRH pulses. Our pilot laboratory experiments indicate that this is actually the way that the living system works and justifies a full scale examination of the model and its implications. These novel findings provide the first insight into the control of the ticking function of the GnRH pulse generator. With continued development of our mathematical model and complementary laboratory experimentation we will discover how the pulses of hormone release are controlled and also discover how other parts of the brain, most notably the emotional centres in a region called the amygdala, can influence or modulate the GnRH pulse generator and reproduction in humans
This project provides a unique opportunity not only to unravel the mechanism underlying the pulsatile nature of GnRH secretion, which is essential for reproduction, but to establish the key interactions with the emotional stress systems in the amygdala that modulate the pulse generator, thereby helping future developments of more effective treatments for stress-related disorders of fertility and health.

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.

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.