Neuroendocrine regulation of the reproductive axis during puberty and development

描述(申请人提供)：在哺乳动物中，包括人类，青春期的开始反映了神经内分泌生殖轴的激活，因此青春期是关键的生理、解剖、行为和心理变化的时期。然而，青春期成熟和早期发育阶段生殖轴激活的具体过程、时间和控制仍然知之甚少，女孩的性成熟早于男孩的原因也是如此。同样，女孩的性早熟发生率较高，男孩的青春期延迟的原因尚不清楚。最近，神经肽Kisspeptin及其受体Kiss1R被认为与青春期发育和成年生育有关。Kissspeptin由Kiss1基因编码，可刺激包括人类在内的哺乳动物的GnRH分泌，Kiss1或Kiss1R突变会损害啮齿动物和人类的生育和青春期。尽管有证据表明，下丘脑Kiss1神经元与成年后的生殖控制有关，但最近对成年前Kiss1神经元的作用关注较少。这项建议的总体目标是研究Kiss1系统在性别特异性调节中的作用，生殖轴在出生后和青春期发育中的作用。目的研究Kispeptin信号在生后“关键期”性腺激素分泌中的重要性，这是一个指导性脑性分化的过程。这一目的的实验将评估在缺乏Kisspeptin信号的小鼠中，出生后性腺类固醇分泌是否受损，Kisspeptin治疗是否可以诱导出生后雌性小鼠的性腺类固醇分泌，以及特定脑核中的Kiss1神经元在出生后性腺类固醇分泌过程中是否被激活。目的II探讨Kiss1系统在青春期成熟关键阶段中的作用。这一目标的实验将确定(在大脑中)Kiss1神经元在青春期周围发育期间首次激活的时间和地点，Kiss1R的变化是否包括青春期发育的关键因素，以及急性、短期阻断中枢或外周Kispeptin信号是否会损害青春期的开始。目的研究性腺激素和非性腺因子在青春期发育过程中对Kiss1神经元的调节作用。本实验旨在分析青春期生殖轴激素敏感性的变化是否反映了Kiss1神经元对激素反馈敏感性的发育变化，评估性腺激素非依赖性调节Kiss1神经元发育变化的时间与青春期开始的关系，并阐明青春期周围Kiss1神经元的性别差异是否由出生后早期的激素组织。总体而言，这一建议将更好地理解生殖轴在不同发育关键阶段如何以及何时受到调控，以及这种调控在大脑中的具体来源。这一信息可以为低促性腺激素减退、宝贵的青春期和青春期延迟的机制提供重要的见解。 与公共健康相关：青春期是一个关键的生理、行为和心理变化时期，但青春期发育调控的确切分子、细胞和神经机制仍然是现代科学的谜团之一。这项建议研究了激素和Kispeptin信号在关键发育时期，包括出生后的“关键期”和性成熟(青春期)中对生殖轴的调节作用。这项工作将有助于我们理解激素和神经回路在基本生殖和发育过程中的关键作用，并将进一步深入了解各种人类生殖障碍和疾病的机制，如特发性性腺激素减退症、营养性不孕症、月经过少、多囊卵巢综合征、性早熟或青春期延迟。

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. PUBLIC HEALTH RELEVANCE: Adolescence is a time of critical physiological, behavioral, and psychological changes, but the precise molecular, cellular, and neural mechanisms underlying the regulation of pubertal development remain one of the enigmas of modern science. This proposal investigates the role of hormones and kisspeptin signaling in the regulation of the reproductive axis during key periods of development, including the postnatal "critical period" and sexual maturation (puberty). This work will contribute to our understanding of the critical role of hormones and neural circuits in essential reproductive and developmental processes, and will provide further insight into the mechanisms responsible for various human reproductive disorders and diseases, such as idiopathic hypogonadotropic hypogonadism, nutritional infertility, oligomenorrhea, polycystic ovarian syndrome, and precocious or delayed puberty.