The role of seasonal changes in light on the reproductive axis in female mice

项目摘要 在人类和实验室啮齿动物中，出生和后代死亡率、生殖 激素释放，体外受精成功。目前还不清楚女性的生育力对时间的反应 在非季节性繁殖者中是一年。照明的季节变化的特点是强度高，夏季长 白天和低强度冬季白天较短。光质的季节性变化，特别是光持续时间(光周期) 和强度，是驱动一年中雌性生殖的非季节性季节变化的候选变量 饲养员。由于人类和非季节性实验室啮齿动物的繁殖不受特定时间段的限制 年，光质变化，特别是光周期或光强度的变化可能通过哪些机制 调节荷尔蒙释放和卵巢功能未作检查。光周期是最显著和最好的- 已建立的暗示季节性变化的信号。然而，随着广泛的人工照明，许多现代 人类不会经历光周期的季节性变化，但会经历光的季节性变化 强度。通过增加我们对季节性调节繁殖者如何适应光照的理解 条件，该项目将为开发治疗干预措施奠定必要的基础 在一年中生育率和繁殖成功率下降的时候提高生育率。至 证明了非季节性小鼠的生殖轴受光周期的调节，我建立了一个 在LD12：12和Long采集发情间期雌性动物连续血液样本的纵向实验方案 天数(LD19：5)，室内采光强度(300勒克斯)。我发现LD19：5的女性搏动减少 卵巢所需的两种激素--黄体生成素和卵泡刺激素的释放 功能和生育能力。光影响黄体生成素和卵泡刺激素最直接的途径是通过神经元群体 视交叉上核表达血管活性肠肽(VIP)。光线进入眼睛，并被 传递给VIP神经元，再投射到促性腺激素释放激素(GnRH)神经元，调节促黄体生成素和 他妈的。基于这些数据，我假设VIP-GnRH-垂体通路适应光周期的变化 和光线强度，在长白天(LD19：5)和明亮强度(1000)时此电路的功能降低 Lux)光照，导致黄体生成素和卵泡刺激素释放模式减少，卵巢功能降低 (路5：19)天和昏暗的(50勒克司)光。目标1将确定光强度和光周期的程度 诱导黄体生成素和卵泡刺激素释放及卵巢功能的改变。目标2将确定VIP-GnRH-垂体 连通性和功能适应光周期和光照强度。这些研究将提供对 光质量调节下丘脑和下游内分泌通路的神经机制。这个 在我的赞助商和指导委员会的指导下，根据这项计划进行的培训将为我的 作为一名研究光在调节生殖成功中的作用的学术研究人员，成功的职业生涯。

Project Summary In humans and laboratory rodents, there are seasonal patterns in birth and offspring mortality rates, reproductive hormone release, and in vitro fertilization success. It is unknown how female fertility is responding to time-of- year in non-seasonal breeders. Seasonal changes in lighting are characterized by high intensity long summer days and low intensity short winter days. Seasonal changes in light quality, notably light duration (photoperiod) and intensity, are candidate variables to drive the time-of year changes in female reproduction of non-seasonal breeders. As human and non-seasonal laboratory rodents do not exhibit breeding restricted to specific times of year, potential mechanisms by which variations in light quality, specifically photoperiod or light intensity, may modulate hormone release and ovarian function are unexamined. Photoperiod is the most salient and well- established cue signaling seasonal changes. However, with extensive artificial lighting, many modern-day humans do not experience seasonal changes in photoperiod, but do experience seasonal changes in light intensity. By increasing our understanding of how seasonally-modulated breeders adapt their physiology to light conditions, this project will lay the foundation necessary for the development of therapeutic interventions to improve reproduction during times of year when fertility and reproductive success are decreased. To demonstrate that the reproductive axis is modulated by photoperiod in non-seasonal mice, I established a longitudinal experimental protocol to collect serial blood samples from diestrus females on LD12:12 and long days (LD19:5) with indoor lighting intensity (300 Lux). I found that females on LD19:5 have reduced pulsatile release of luteinizing hormone (LH) and follicle stimulating hormone (FSH), two hormones required for ovarian function and fertility. The most direct pathway by which light influences LH and FSH is via a neuronal population expressing vasoactive intestinal peptide (VIP) of the suprachiasmatic nucleus. Light enters the eye and is transmitted to VIP neurons that project to gonadotropin releasing hormone (GnRH) neurons to modulate LH and FSH. Based on these data, I hypothesize that the VIP-GnRH-pituitary pathway adapts to changes in photoperiod and light intensity, with reduced functionality of this circuit on long days (LD19:5) and in bright intensity (1000 Lux) light, leading to reduced LH and FSH release patterns and reduced ovarian function compared to short (LD5:19) days and dim (50 lux) light. Aim 1 will determine the degree by which light intensity and photoperiod induce changes in LH and FSH release and ovarian function. Aim 2 will determine how VIP-GnRH-Pituitary connectivity and function adapt to photoperiod and light intensity. These studies will provide key insights into the neuronal mechanisms by which light qualities modulate hypothalamic and downstream endocrine pathways. The training from this proposal, with guidance from my Sponsors and mentoring committee, will prepare me for a successful career as an academic researcher investigating the role of light in modulating reproductive success.