Does kisspeptin in the amygdala control the timing of puberty?

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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.