Does kisspeptin in the amygdala control the timing of puberty?

青春期的开始仍然是生物学上最大的谜团之一，对于引发青春期的生物触发器的身份知之甚少。青春期的正常年龄是女孩10.5岁，男孩11.5岁。虽然我们达到性成熟的年龄在很大程度上受到遗传自父母的基因的影响，但环境因素，如营养、体育活动和社会心理压力也起着重要作用。青春期时间紊乱影响了超过4%的人口。青春期过早或过晚的后果是显而易见的，它与心脏病、糖尿病、乳腺癌、焦虑、抑郁和其他对社会、健康和经济产生终身影响的精神疾病有关。因此，至关重要的是，我们要了解是什么驱动了青春期的时间，这样我们才能更好地控制或治疗受影响的儿童和年轻人。正常的青春期开始于大脑中一个叫做下丘脑的小区域的激活，下丘脑开始间歇性地分泌一种叫做促性腺激素释放激素（GnRH）的大脑激素，这种激素会触发一系列激素信号，刺激卵巢和睾丸，不仅会推动性成熟，还会引发声音变化、新的体毛和与青春期相关的喜怒无常。大约10年前，人们发现了一种新的大脑化学物质，或称为kisspeptin的神经肽，它是激活大脑中GnRH神经细胞的关键环节。虽然，kisspeptin无疑是GnRH神经细胞最有效的激活剂，并且最初被认为是触发它们启动青春期的激活，但我们现在意识到，它只是下丘脑神经网络中产生GnRH偶发性脉冲的关键部分。青春期难以捉摸的触发因素仍有待发现。在一些初步实验中，我们发现大脑中控制情绪和焦虑的杏仁核与青春期的时间有关。更值得注意的是，我们发现杏仁核中的一小群kisspeptin细胞强烈地改变下丘脑GnRH的脉动释放。我们还发现了另一种大脑化学物质GABA，它广泛分布于整个大脑，是一种主要的脑细胞抑制剂，在杏仁核中活跃，影响青春期的时间。总的来说，这些新发现强烈表明，杏仁核中存在一种新的神经回路，它可能作为难以捉摸的“上游控制器”，驱动下丘脑的GnRH脉冲产生系统，从而决定青春期开始的时间。我们还发现，大脑中有一种主要的应激激素，叫做尿皮质素，它被社会心理压力激活，在杏仁核的同一区域也有延迟青春期的作用。该项目提供了一个独特的机会，不仅揭示了青春期开始的触发机制，而且建立了杏仁核中调节青春期时间以响应环境条件的压力系统的关键相互作用，从而有助于未来开发更有效的治疗青春期压力相关疾病的方法，并长期降低相关疾病的风险。

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.