Neuroendocrine regulation of the reproductive axis during puberty and development

青春期和发育期间生殖轴的神经内分泌调节

• 批准号: 7942648
• 负责人: ALEXANDER S KAUFFMAN
• 金额: $ 31.44万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-10 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7942648
• 关键词: Acute; Address; Adolescence; Adolescent; Adult; Age; Attention; Behavioral; Birth; Brain; Brain region; Cell Nucleus; Cells; Circadian Rhythms; Complex; Cues; Delayed Puberty; Development; Developmental Process; Disease; Elements; Event; Feedback; Female; Fertility; Follicle Stimulating Hormone; Genes; Goals; Gonadal Hormones; Gonadal Steroid Hormones; Gonadotropin Hormone Releasing Hormone; Hormonal; Hormones; Human; Hypothalamic structure; Incidence; Infertility; Kallmann Syndrome; Klinefelter' s Syndrome; Life; Lifting; Link; Location; Luteinizing Hormone; Mammals; Metabolic; Molecular; Mus; Mutation; Neurons; Neuropeptides; Neurosecretory Systems; Nutritional; Oligomenorrhea; Ovarian; Pattern; Peripheral; Physiological; Pituitary Gland; Precocious Puberty; Process; Puberty; Regulation; Relative (related person); Reproduction; Research; Rodent; Role; Science; Sex Characteristics; Sexual Development; Sexual Maturation; Signal Transduction; Site; Staging; Syndrome; System; Testing; Time; Transgenic Mice; Work; boys; brain behavior; critical period; girls; hormone sensitivity; insight; kisspeptin; male; neural circuit; neuromechanism; neuron development; postnatal; prepuberty; psychologic; public health relevance; receptor; relating to nervous system; reproductive; reproductive axis; research study; sex

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.

描述（由申请人提供）：在哺乳动物（包括人类）中，青春期的开始反映了神经内分泌生殖轴的激活，因此青春期是关键生理、解剖、行为和心理变化的时期。然而，对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，女孩性成熟早于男孩的原因也是如此。同样，女孩性早熟和男孩青春期延迟发生率较高的原因也不清楚。最近，神经肽kisspeptin及其受体Kiss 1 R与青春期发育和成年生育力有关。由Kiss1基因编码，kisspeptin刺激哺乳动物（包括人类）的GnRH分泌，Kiss1或Kiss1R突变会损害啮齿动物和人类的生育力和青春期。尽管有证据表明下丘脑Kiss 1神经元与成年期生殖控制有关，但最近对Kiss 1神经元在成年期之前的作用关注较少。本研究的总体目标是探讨Kiss1系统在出生后和青春期发育中对生殖轴的性别特异性调节作用。目的探讨kisspeptin信号在出生后关键期性腺激素分泌中的重要性。在这一目标的实验将评估是否出生后的性腺类固醇分泌受损的小鼠缺乏kisspeptin信号，如果kisspeptin治疗可以诱导性腺类固醇分泌在出生后的女性，以及是否Kiss 1神经元在特定的脑核在出生后的性腺类固醇分泌过程中激活。目的II将探讨Kiss 1系统在青春期成熟的关键阶段的作用。在这一目标的实验将确定何时何地（在大脑中）Kiss1神经元首先成为激活在青春期发育，Kiss1R的变化是否包括青春期发育的关键要素，以及是否急性，中枢或外周kisspeptin信号的短期封锁损害青春期的开始。目的探讨性腺激素和非性腺因素在青春期发育过程中对Kiss 1神经元的调控作用。在这一目标的实验将分析是否青春期生殖轴的激素敏感性的变化反映发育变化的敏感性Kiss1神经元激素反馈，评估的时间发展变化的性腺激素独立调节Kiss1神经元青春期的发病，并阐明是否在青春期前后的Kiss1神经元的性别差异是由激素在出生后早期的生活。总的来说，这一提议将提供一个更好的理解如何以及何时生殖轴在不同的关键发展阶段进行调节，以及在大脑中的这种调节是专门派生。这一信息可以提供重要的深入了解低促性腺激素性腺功能减退症，早熟，青春期延迟的机制。 公共卫生相关性：青春期是一个关键的生理，行为和心理变化的时期，但精确的分子，细胞和神经机制的调节青春期发育仍然是现代科学的谜团之一。该提案调查了激素和kisspeptin信号在发育的关键时期（包括出生后的“关键期”和性成熟（青春期））生殖轴调节中的作用。这项工作将有助于我们了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，如特发性低促性腺激素性腺功能减退症，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。