Does kisspeptin in the amygdala control the timing of puberty?

杏仁核中的 Kisspeptin 是否控制青春期的时间？

• 批准号: MR/N022637/1
• 负责人: Kevin O'Byrne
• 金额: $ 67.52万
• 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: 2016
• 资助国家: 英国
• 起止时间: 2016 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FN022637%2F1
• 关键词: Does; kisspeptin; amygdala; control; timing

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.

青春期的发作仍然是生物学中最大的奥秘之一，对生物触发的身份鲜为人知，它引发了它。青春期的正常年龄为10.5岁，男孩为11.5岁。尽管我们达到性成熟的年龄受到父母继承的基因的强烈影响，但环境因素，例如营养，体育锻炼和对社会心理压力的暴露也起着重要作用。青春期时机的干扰会影响超过4％的人口。与心脏病，糖尿病，乳腺癌，焦虑症，抑郁症和其他精神疾病有关，终生的社会，健康和经济影响的联系都太清楚了。 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在卵巢和睾丸中，不仅可以驱动性成熟，而且会触发声音变化，新的身体和与青春期相关的情绪。大约10年前，当发现一种称为Kisspeptin的新脑化学物质或神经肽是激活大脑中GNRH神经细胞的关键联系时，令人兴奋。虽然，毫无疑问，吻肽是GnRH神经细胞中最有效的激活剂，最初被认为是其激活启动开始青春期的触发因素，但我们现在意识到，下丘脑中神经网络的一个至关重要的部分产生了GNRH上的情节性脉冲。在某些试点实验中，我们发现，对青春期的难以捉摸的触发因素仍然有待发现。我们发现，一个称为杏仁核的大脑的一部分控制着情绪和焦虑，这与青春期的时机有关。我们发现的是，杏仁核中的一小部分亲吻肽细胞强烈改变了下丘脑中GnRH的脉动释放。我们还表明，另一种称为GABA的大脑化学物质在整个大脑中广泛分布，并且脑细胞的主要抑制剂在杏仁核中活跃，以影响青春期的时间。总的来说，这些新发现强烈暗示了杏仁核中新型的神经回路，它可能充当难以捉摸的“上游控制器”，以驱动下丘脑中的GnRH脉冲产生系统，因此确定了青春期发作的时机。我们还发现，大脑中的主要压力激素，称为尿皮质素3，被社会心理压力激活，在杏仁核的同一区域中采取了行动，可以延迟青春期。该项目不仅提供了一个独特的机会，不仅可以揭示触发机制的青春期互动，而且还可以与Amygdala的环境建立pue pue的触发条件，从而使punsign puly的环境相互作用。帮助未来对青春期与压力相关的疾病进行更有效治疗的发展，从长远来看，相关疾病的风险降低了。

项目成果

Urocortin3 in the Posterodorsal Medial Amygdala Mediates Stress-induced Suppression of LH Pulsatility in Female Mice.

• DOI: 10.1210/endocr/bqab206
• 发表时间: 2021-12-01
• 期刊: Endocrinology
• 影响因子: 4.8
• 作者: Ivanova D;Li XF;McIntyre C;Liu Y;Kong L;O'Byrne KT
• 通讯作者: O'Byrne KT

Role of posterodorsal medial amygdala urocortin-3 in pubertal timing in female mice

• DOI: 10.1101/2022.01.27.477996
• 发表时间: 2022-03-09
• 期刊: bioRxiv
• 作者: Ivanova, D.;Li, X.;O'Byrne, K.
• 通讯作者: O'Byrne, K.

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

GnRH pulse generator frequency is modulated by kisspeptin and GABA-glutamate interactions in the posterodorsal medial amygdala in female mice.

• DOI: 10.1111/jne.13207
• 发表时间: 2022-11
• 期刊: JOURNAL OF NEUROENDOCRINOLOGY
• 影响因子: 3.2
• 作者: Lass, Geffen;Li, Xiao Feng;Voliotis, Margaritis;Wall, Ellen;de Burgh, Ross A.;Ivanova, Deyana;McIntyre, Caitlin;Lin, Xian-Hua;Colledge, William H.;Lightman, Stafford L.;Tsaneva-Atanasova, Krasimira;O'Byrne, Kevin T.
• 通讯作者: O'Byrne, Kevin T.

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