A novel mechanism underlying GnRH pulse generation by KNDy neurones

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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.