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

青春期的压力和时间：杏仁核是关键吗？

• 批准号: BB/J002232/1
• 负责人: Kevin O'Byrne
• 金额: $ 94.42万
• 依托单位: King's College London
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2012
• 资助国家: 英国
• 起止时间: 2012 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FJ002232%2F1
• 关键词: Stress; timing; puberty; amygdala; 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.

青春期仍然是生物学中最大的谜团之一，对于是什么引发了这一切，我们知之甚少。青春期的正常年龄是女孩10.5岁，男孩11.5岁。在全球范围内，长期营养不良、疾病和社会剥夺是青春期延迟的最常见原因。然而，由于“荷尔蒙”的过早上升所引起的心理和身体变化与个体的实际成熟水平之间的不匹配，公众和医学界对青春期年龄的下降有相当大的兴趣。尽管肥胖和超重在英国和其他国家的儿童中已达到流行病的比例，但人们认为这是罪魁祸首，但越来越多的证据表明，心理社会压力也发挥了作用。青春期提前与家庭压力有关，特别是父亲的缺失、父母功能障碍、亲子冲突和性虐待。青春期提前使女孩更有可能过早进行性活动和初次怀孕，此外还有包括癌症、抑郁症和许多其他健康问题在内的妇科疾病，这些疾病对妇女的总体健康产生长期影响。英国政府贫困问题顾问弗兰克·菲尔德（Frank Field）最近的一份报告（2010年12月3日）主张，“英国绝不能对不负责任的父母和功能失调的家庭犹豫不决，孩子的需求比母亲的需求更重要”。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，它开始分泌一种叫做促性腺激素释放激素（GnRH）的大脑激素，它启动了一系列激素信号，导致卵巢和睾丸的刺激，不仅促进性成熟，还引发了声音变化，新的体毛和青春期相关的喜怒无常。最近，一种新的大脑化学物质或神经肽被发现是激活大脑中GnRH神经细胞的关键环节。虽然，kisspeptin无疑是GnRH系统最重要的激活剂，但现在仍有待发现在青春期触发kisspeptin系统的因素。我们最近发现，大脑中的主要应激激素，促肾上腺皮质激素释放因子（CRF），对成年人的kisspeptin系统有直接的抑制作用，这可能解释包括不育在内的生殖疾病。此外，我们发现，在青春期的时候，下丘脑中的CRF系统的活动减少，该系统负责激活肾上腺，肾上腺释放应激激素皮质醇进入血液。此外，用抗CRF药物阻断大脑中的CRF作用会导致青春期提前，这表明通常CRF可能在触发青春期发作中起关键作用。然而，大脑中还有另一个控制情绪的主要CRF系统，称为杏仁核。杏仁核不仅能增强压力反应，还能控制焦虑，尤其是与压力有关的寻求奖励的行为，包括增加能量丰富的食物或“安慰食物”的消费。我们最近发现，杏仁核也向生殖中心发送抑制信号，以前的研究表明杏仁核对青春期的时间有抑制作用。在使用青春期延迟（早期生活感染应激）或青春期提前（食用富含能量的食物）的动物模型的初步研究中，我们发现杏仁核中的CRF系统分别被激活或抑制。这些模型提供了一个独特的机会，不仅可以发现大脑（杏仁核）中的情绪压力区域与生殖中心（包含kisspeptin-GnRH）之间的关键相互作用，这些生殖中心控制青春期对环境的反应时间，而且可能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。

项目成果

GPR54-dependent stimulation of luteinizing hormone secretion by neurokinin B in prepubertal rats.

• DOI: 10.1371/journal.pone.0044344
• 发表时间: 2012
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Grachev P;Li XF;Lin YS;Hu MH;Elsamani L;Paterson SJ;Millar RP;Lightman SL;O'Byrne KT
• 通讯作者: O'Byrne KT

Hypothalamic Prolactin Regulation of Luteinizing Hormone Secretion in the Female Rat.

下丘脑催乳素对雌性大鼠黄体激素分泌的调节。

• DOI: 10.1210/en.2015-1040
• 发表时间: 2015
• 期刊: Endocrinology
• 影响因子: 4.8
• 作者: Grachev P

Stress regulation of kisspeptin in the modulation of reproductive function.

• DOI: 10.1007/978-1-4614-6199-9_20
• 发表时间: 2013
• 期刊: Advances in experimental medicine and biology
• 作者: P. Grachev;Xiao Feng Li;K. O'Byrne

Kisspeptin in the medial amygdala and sexual behavior in male rats.

• DOI: 10.1016/j.neulet.2016.05.042
• 发表时间: 2016-08-03
• 期刊: Neuroscience letters
• 影响因子: 2.5
• 作者: Gresham R;Li S;Adekunbi DA;Hu M;Li XF;O'Byrne KT
• 通讯作者: O'Byrne KT

Kisspeptin signaling in the amygdala modulates reproductive hormone secretion.

• DOI: 10.1007/s00429-015-1024-9
• 发表时间: 2016-05
• 期刊: Brain structure & function
• 影响因子: 3.1
• 作者: Comninos AN;Anastasovska J;Sahuri-Arisoylu M;Li X;Li S;Hu M;Jayasena CN;Ghatei MA;Bloom SR;Matthews PM;O'Byrne KT;Bell JD;Dhillo WS
• 通讯作者: Dhillo WS