Neuroendocrine regulation of the reproductive axis during puberty and development

描述（由申请人提供）：在包括人类在内的哺乳动物中，青春期的开始反映了神经内分泌生殖轴的激活，因此青春期是生理、解剖、行为和心理发生关键变化的时期。然而，在青春期成熟和早期发育阶段，生殖轴激活的具体时间和控制过程仍然知之甚少，女孩比男孩性成熟早的原因也是如此。同样，女孩性早熟和男孩性早熟发生率较高的原因尚不清楚。最近，神经肽kisspeptin及其受体Kiss1R与青春期发育和成年生育能力有关。kisspeptin由Kiss1基因编码，可以刺激哺乳动物（包括人类）的GnRH分泌，而Kiss1或Kiss1R的突变会损害啮齿动物和人类的生育能力和青春期。尽管有证据表明下丘脑的Kiss1神经元与成年期的生殖控制有关，但最近对Kiss1神经元在成年期之前的作用的关注较少。本研究的总体目标是研究Kiss1系统在出生后和青春期发育中生殖轴的性别特异性调节中的作用。目的：探讨kisspeptin信号在出生后“关键时期”性腺激素分泌中的重要性，这一过程指导大脑的性别分化。本实验将评估缺乏kisspeptin信号的小鼠出生后性腺类固醇分泌是否受损，kisspeptin治疗是否能诱导雌性出生后性腺类固醇分泌，以及特定脑核中的Kiss1神经元是否在出生后性腺类固醇分泌过程中被激活。目的二将探讨Kiss1系统在青春期成熟的关键阶段的作用。该实验旨在确定Kiss1R神经元在青春期发育期间何时何地（在大脑中）首次被激活，Kiss1R的变化是否构成青春期发育的关键因素，以及急性、短期阻断中枢或外周kisspeptin信号是否会损害青春期的发生。目的III将探讨性腺激素和非性腺因子在青春期周围发育过程中调节Kiss1神经元的作用。本实验旨在分析生殖轴激素敏感性的青春期变化是否反映了Kiss1神经元对激素反馈敏感性的发育变化，评估Kiss1神经元性腺激素非依赖性调节与青春期开始相关的发育变化时间，并阐明青春期周围Kiss1神经元的性别差异是否在出生后早期由激素组织。总的来说，这一建议将更好地理解生殖轴在发育的不同关键阶段是如何以及何时受到调节的，以及这种调节在大脑中的具体来源。这一信息可以为了解促性腺功能低下、青春期珍贵和青春期延迟的机制提供重要的见解。

DESCRIPTION (provided by applicant): In mammals, including humans, puberty onset reflects the activation of the neuroendocrine reproductive axis, and adolescence is therefore a time of key physiological, anatomical, behavioral, and psychological changes. However, the specific processes timing and governing the activation of the reproductive axis during pubertal maturation and earlier developmental stages remain poorly understood, as does the reason for earlier sexual maturation in girls than boys. Similarly, the reason for a higher incidence of precocious puberty in girls and delayed puberty in boys is unclear. Recently, the neuropeptide kisspeptin, and its receptor Kiss1R, have been implicated in pubertal development and adulthood fertility. Encoded by the Kiss1 gene, kisspeptin stimulates GnRH secretion in mammals, including humans, and mutations in Kiss1 or Kiss1R impair fertility and puberty in rodents and humans. Despite evidence linking hypothalamic Kiss1 neurons to the control of reproduction in adulthood, less attention has recently been given to the role of Kiss1 neurons prior to adulthood. The overall goal of this proposal is to investigate the role of the Kiss1 system in the sex-specific regulation the reproductive axis in postnatal and pubertal development. Aim I will investigate the importance of kisspeptin signaling in the secretion of gonadal steroids during the postnatal "critical period", a process which directs sexual differentiation of the brain. Experiments in this aim will assess whether postnatal gonadal steroid secretion is impaired in mice lacking kisspeptin signaling, if kisspeptin treatment can induce gonadal steroid secretion in postnatal females, and whether Kiss1 neurons in specific brain nuclei are activated during postnatal gonadal steroid secretion. Aim II will explore the role of the Kiss1 system in key stages of pubertal maturation. Experiments in this aim will determine when and where (in the brain) Kiss1 neurons first become activated during peripubertal development, whether changes in Kiss1R comprise a key element of pubertal development, and whether acute, short-term blockade of central or peripheral kisspeptin signaling impairs puberty onset. Aim III will investigate the role of both gonadal hormones and non-gonadal factors in regulating Kiss1 neurons during peripubertal development. Experiments in this aim will analyze whether pubertal changes in hormone sensitivity of the reproductive axis reflect developmental changes in the sensitivity of Kiss1 neurons to hormone feedback, assess the timing of developmental changes in gonadal hormone-independent regulation of Kiss1 neurons in relation to puberty onset, and elucidate whether sex differences in peripubertal Kiss1 neurons are organized by hormones during early postnatal life. Overall, this proposal will provide a better understanding of how and when the reproductive axis is regulated during different critical stages of development, as well as where in the brain such regulation is specifically derived. This information could provide important insight into the mechanisms underlying hypogonadotropic hypogonadism, precious puberty, and delayed puberty.