Does kisspeptin in the amygdala control the timing of puberty?

The onset of puberty remains one of the biggest mysteries in biology with precious little known about the identity of the biological trigger which sets it off. The normal age of puberty is 10.5 years in girls and 11.5 years in boys. Although the age at which we reach sexual maturity is strongly influenced by the genes inherited from our parents, environmental factors, such as nutrition, physical activity and exposure to psychosocial stress also play a major role. Disturbances of pubertal timing affect over 4% of the population. The consequences of early or late puberty are all too clear with links to heart disease, diabetes, breast cancer, anxiety, depression and other mental illnesses with lifelong social, health and economic implications. It is critical therefore that we understand what drives the timing of puberty so that we can better control or treat affected children and young adults.
Normal puberty starts with activation of a small area in the brain called the hypothalamus that begins to secrete intermittent pulses of a brain hormone called gonadotrophin-releasing hormone (GnRH), which sets in motion a cascade of hormonal signals that lead to stimulation of both the ovaries and the testes that not only drives sexual maturation but triggers voice changes, new body hair and the moodiness associated with adolescence. About 10 years ago there was great excitement when a new brain chemical, or neuropeptide, called kisspeptin was found to be a critical link in activating the GnRH nerve cell in the brain. Although, kisspeptin is undoubtedly the most potent activator of the GnRH nerve cells, and was initially thought to be the trigger for their activation to kick start puberty, we now realise that it is just a crucial part of the nerve network in the hypothalamus that generates the episodic pulses on GnRH. The elusive trigger for puberty still remains to be discovered.
In some pilot experiments, we have discovered that a part of the brain called the amygdala which controls emotions and anxiety is involved in the timing of puberty. Even more remarkable is our discovery that a small population of kisspeptin cells in the amygdala strongly alter the pulsatile release of GnRH in the hypothalamus. We have also shown that another brain chemical called GABA that is widely distributed throughout the brain and a major inhibitor of brain cells is active in the amygdala to affect the timing of puberty. Collectively, these new findings strongly suggest a novel nerve circuit in the amygdala that may function as the elusive "upstream controller" to drive the GnRH pulse generating system in the hypothalamus and therefore determine the timing of puberty onset. We have also discovered that a major stress hormone in the brain, called urocortin3 that is known to be activated by psychosocial stress has an action in the same region of the amygdala to delay puberty.
This project provides a unique opportunity not only to unravel the triggering mechanism for puberty onset, but establish the key interactions with the stress system in the amygdala that modulate the timing of puberty in response to environmental conditions, thereby helping future developments of more effective treatments for stress-related disorders of puberty and in the long term reduced risk of associated diseases.

Although it is recognised that hypothalamic kisspeptin plays an integral role in the gonadotrophin-releasing hormone (GnRH) pulse generating neural network, and is obligatory for puberty, the upstream regulatory mechanisms that drive the GnRH pulse generator to trigger the onset of puberty have remained stubbornly elusive, as have those underlying its delay by stress. We have recently discovered that the posterodorsal subnucleus of the medial amygdala (MePD) plays a key role in pubertal timing, involving intrinsic GABA and glutamate receptor mechanisms, and that kisspeptin signalling in this extra-hypothalamic structure surprisingly exerts a profound influence on GnRH pulse generator frequency. Additionally, activation of MePD corticotrophin-releasing factor type 2 receptor (CRF-R2) by the endogenous ligand urocortin3 delays puberty. We aim to test the hypothesis that in the amygdala the kisspeptin and GABA/glutamate neural circuits are interdependent and form a higher-order regulator of the GnRH pulse generator that is critical for triggering puberty. Our multidisciplinary approach will involve a combination of neuropharmacological, optogenetic, neuroanatomical and molecular biological techniques applied to well established animal models. The project will focus on (i) determining the anatomical and functional relationship between the kisspeptin and GABA/glutamate systems in the MePD and hypothalamic kisspeptin-GnRH neuronal signalling to regulate pubertal timing and, (ii) determine the neural mechanisms by which the urocortin3/CRF-R2 system alters MePD kisspeptin and/or GABAergic signalling to delay puberty. This project will not only provide novel insight to key upstream regulatory mechanisms that activate the GnRH pulse generator to trigger puberty onset, but may provide new insights into the control and treatment of early and late puberty and hence lessen the burden of many adverse outcomes on health and wellbeing that persist and emerge in adulthood.

Scientists: Research personnel working within the field of stress and reproductive sciences 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.
Clinical Practice and Government Health/Environmental Policy (National and International): Reproductive potential and stress impacts on Health and Wellbeing in our modern society with significant social and economic consequences. Although the proposed research focuses on elucidating the mechanisms underlying the control of pubertal timing and the impact of stress on pubertal development, these studies have broader relevance to Health and Wellbeing in general because of the long-term consequences of altered pubertal timing, including gynaecological disorders, cardiovascular disease, autoimmune disease, diabetes, mental health disease and cancer.
Through associations between stress and puberty onset this proposal is also relevant to the increasing concern, as demonstrated by UK Government's report on anti-poverty strategies, on the long-term social and health consequences of early dysfunctional family life and child poverty. Modern society presents many other potentially stressful challenges 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. High levels of anxiety and exam-related stress in schools has led to a 200% rise in requests for counselling (NSPCC, May 2015). Psychosocial stress, especially, parental dysfunction, divorce, parent-child conflict, and physical, sexual and emotional abuse, impact on children's health and wellbeing, as acknowledged in the Department of Health's report, "Future in Mind" (17 March 2015) and other UK Government reports, and there is clear evidence linking these life events to heightened risk of early or delayed puberty. Additionally, mode of action for several herbicides and environmental contaminants on reproductive potential is via stress related hormones and the research has the potential to benefit environmental agencies and could influence policy and legislation within local government. Overall, this project has the potential to have an impact on the health of the nation, and of relevance to the MRC's Strategic important area of 'lifelong health and ageing'.
Pharmaceutical Sector: The implications for adult reproductive function and in particular the adverse effects of environmental perturbation on puberty onset could benefit the pharmaceutical sector in the long-term with the potential for development of novel therapeutics to precipitate or delay puberty, and for treating global problems associated with stress in humans, with health and wealth sequelae.
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 stress and reproductive physiology that could potentially contribute to the general education of viewers and listeners. School curricula might benefit through material provided via websites such as "Practical Biology" sponsored by the Royal Society of Biology, British Society for Neuroendocrinology and others.