Neonatal programming of pubertal delay: a novel neural interaction between corticotrophin-releasing hormone and kisspeptin

Puberty remains one of the biggest mysteries in biology with precious little known about what triggers it. The normal age of puberty is about 10.5 years in girls and 11.5 years in boys, but it is very variable. There is considerable public and medical interest in the causes of very early 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. Indeed, recent brain imaging studies have shown that brain maturation extends into the early twenties. Improved diet is thought to underlie the gradual fall in age of puberty onset, but the ever increasing incidence of childhood obesity is accelerating this trend. On the other hand, a delay in puberty can be caused by many factors, including malnutrition, emotional and social deprivation and in particular stress. Early or late onset of puberty can have serious health effects and often raises a great deal of anxiety in the individual or family concerned. Understanding the processes that control the timing of puberty will help in the management and treatment of children affected. Normal puberty starts with activation of a small area in the brain called the hypothalamus that begins to secrete a 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. The hormones from the developing ovaries or testes drive sexual maturation and the many other physical and emotional changes associated with adolescence. What triggers the activation of the GnRH system in the brain remained a mystery until very recently when it was discovered that a genetic mutation of a particular chemical receptor in the brain of humans stopped them from going into puberty. Similar mutations in animal models caused identical problems. These receptors are activated by a brain chemical named 'kisspeptin'. The scientists who discovered this chemical were working at the Pennsylvania State Medical Centre in Hershey USA and they gave it this name because; Hershey is the location of America's famous chocolate factory and the scientists named it after the chocolate company's signature miniature treat chocolate 'kisses'. 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. There is growing awareness that adverse early life environments can have major detrimental effects on health and disease later in life. For example, in humans and animals the immediate period after birth is especially dangerous for bacterial infection because the body's immune system is not yet fully developed. Indeed, more than 40% of all human newborn deaths (~1.7 million per year globally) are due to neonatal bacterial infection. Animals that have been exposed to bacterial substances (endotoxins) during the first week of life are more sensitive to stress when they reach adulthood. Additionally these animals display altered immune, metabolic, anxiety, memory and cognition function as adults, which show that early life exposure to bacteria can exert long-term 'programming' effects on a number of body functions. These and other observations have led to the idea of 'developmental origins of health and disease'. In pilot studies using the animal model of early life infection stress we have shown a delay in the onset of puberty. We have also shown a permanent decrease in brain levels of kisspeptin and an increase in brain levels of corticotrophin-releasing hormone (CRH) receptor, the major stress hormone receptor. This provides a unique opportunity not only to discover key interaction between the stress hormone system (CRH) and the trigger system (kisspeptin) that controls the timing of puberty, but may help future developments of more effective treatments for stress-related disorders of puberty.

This project will address the neural mechanisms by which exposure to bacterial endotoxin in early postnatal life programmes pubertal delay. We will test the hypothesis that neonatal stress-induced upregulation of corticotrophin-releasing hormone (CRH) in the CNS suppresses kisspeptin-GRP54 signalling to delay the onset of puberty. Our multidisciplinary approach will involve a combination of pharmacological, neuroanatomical and molecular biological techniques applied to a well established early life stress model. The project will focus on (i) defining the critical time window during postnatal development when immunological stress (lipopolysaccharide; LPS) results in delayed timing of puberty, (ii) identification of key CRH populations and CRH receptor subtypes programmed by neonatal stressors that regulate Kiss1, the gene for kisspeptin, and its cognate receptor, GRP54, the obligatory activators of the gonadotrophin-releasing hormone (GnRH) neuronal system central to pubertal maturation of the reproductive axis and (iii) determining the precise timing and sequence of neonatal-LPS induced changes in CRH, CRH receptor, Kiss1 and GRP54 expression involved in hypothalamo-pituitary-gonadal axis regulation. This project will not only advance our understanding of the mechanisms by which adverse early life events can have detrimental effects on the major developmental processes of puberty, but help identify critical neural mechanisms that regulate the activity of the kisspeptin-GRP54 system, the newly identified 'gatekeeper' of pubertal activation of the GnRH pulse generator.