Stress and timing of puberty: is the amygdala the key?

Puberty remains one of the biggest mysteries in biology with precious little known about what triggers it all off. The normal age of puberty is 10.5 years in girls and 11.5 years in boys. Chronic malnutrition, illness and social deprivation are the most common causes of delayed puberty, in a global context. However, there is considerable public and medical interest in the falling age of puberty because of the consequences of a mismatch between the psychological and body changes caused by the early rise in 'the hormones' and the actual level of maturity of the individual. Although obesity and overweightness, which are reaching epidemic proportions in children in the UK and other countries, are considered the principal culprit, there is increasing evidence that psychosocial stress also plays a role. Early puberty is associated with stress in the family domain, especially, absence of father, parental dysfunction, parent-child conflict and sexual abuse. Early onset of puberty puts girls at increased risk of earlier sexual activity and first pregnancy, in addition to gynaecological disorders including cancer, depression and many other health problems, which have long-term consequences for Women's Health in general. The recent report (Dec. 3, 2010) from the UK Government's poverty advisor, Frank Field, advocates that 'Britain must not pussyfoot around with feckless parents and dysfunctional families, and children's needs are more important than that of the mothers'. Normal puberty starts with activation of a small area in the brain called the hypothalamus that begins to secrete 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. Recently 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 single most important activator of the GnRH system it now remains to be discovered what triggers the kisspeptin system at puberty. We have recently discovered that the major stress hormone in the brain, corticotrophin-releasing factor (CRF), has a direct inhibitory action on the kisspeptin system in adults that may explain reproductive disorders including infertility. In addition, we have found that at the time of puberty there is a reduction in the activity of the CRF system in the hypothalamus that is responsible for activating the adrenal glands that release the stress hormone, cortisol, into the blood. Moreover, blockade of CRF actions in the brain with an anti-CRF drug causes earlier puberty suggesting that normally CRF may play a key role in the triggering of puberty onset. However, there is another major CRF system in the brain that controls emotion, called the amygdala. The amygdala not only enhances the stress response, but controls anxiety, especially stress-related reward seeking behaviour that includes the increased consumption of energy rich foods or 'comfort foods'. We have recently discovered that the amygdala also sends inhibitory signals to the reproductive centres and previous studies showed an inhibitory influence of the amygdala on the timing of puberty. In pilot studies using animal models of delayed puberty (early life infection stress) or advanced puberty (eating energy rich foods) we have discovered that the CRF system in the amygdala was activated or inhibited respectively. These models provide a unique opportunity not only to discover the key interactions between the emotional stress areas in the brain (amygdala) and the reproductive centres (containing kisspeptin-GnRH) that controls the timing of puberty in response to the environment, but may help future developments of more effective treatments for stress-related disorders of puberty.

This project will address the neural mechanisms by which the amygdala controls the timing of puberty in response to environmental perturbations. We will test the hypothesis that variable effects of stress on the timing of puberty, both delay and advance, are critically dependent on levels of corticotrophin-releasing factor (CRF) activity in the amygdala. Our multidisciplinary approach will involve a combination of pharmacological, neuroanatomical and molecular biological techniques applied to well established early life stress and metabolic models. The project will focus on (i) determining the functional relationship between amygdala CRF and CRF receptor systems, and hypothalamic kisspeptin-gonadotrophin releasing hormone (GnRH) neuronal signalling that underlie stress-induced delay or advancement of puberty, (ii) establish the differential role of the medial (MeA) and central (CeA) amygdala in early life stress, maternal care or high caloric diet induced regulation of pubertal timing and (iii) determine whether advanced puberty is due to modulatory impact of food-related stimuli on amygdala CRF tone or direct metabolic change. This project will not only provide novel insight of key neural mechanisms integrating limbic brain stress and reward-emotional eating centres with hypothalamic reproductive kisspeptin-GnRH systems that regulate the impact of common diverse environmental factors on the timing of puberty, but may help future development of more effective treatments for stress-related disorders of puberty.

Scientists: Research personnel working within the field of stress and reproductive sciences will receive immediate intellectual benefit. The scientific community as a whole will benefit from a theoretical view point on the complexity of neuropeptide signalling in the central nervous system, which might lend itself to mathematical modelling in non-biological arenas. Pharmaceutical Sector: 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. Although the proposed research focuses on elucidating the mechanisms underlying 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 delayed but particularly advanced puberty, including gynaecological disorders, cardiovascular disease, autoimmune disease, mental health disease and cancer. Thus the pharmaceutical sector could benefit in the long-term with new therapeutic for treating global problems associated with stress in humans and animals, with health and wealth sequelae. Government Environmental Agencies (National and International): There is increasing concern as demonstrated by the recent UK Government's report on anti-poverty strategies, highlighting the long-term social and health consequences of early dysfunctional family life. Additionally, mode of action for several herbicides and environmental contaminants on reproductive potential is via stress related hormones. Thus the proposed research has an immediate and direct benefit to environmental agencies and could influence policy and legislation within local government and farming community. Research Staff working on the project: Post-doctoral researchers, PhD students, undergraduates and pre-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. 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 enhance quality of life for viewers and listeners. School curricula might benefit through material provided via websites such as 'Practical Biology' sponsored by the Society of Biology and others.