Prenatal photoperiod action in hypothalamic development

摘要 人类的季节性或光周期变化会影响荷尔蒙模式、大脑功能，并是潜在的 几种心理障碍的起因。出生季节对出生体重和出生动机有明显影响 对疾病的易感性(例如，儿童糖尿病、精神病和阿尔茨海默病)。暴露在“冬天-- 比如“怀孕期间的短光周期会延缓季节性物种后代的发育轨迹。 这种作用是通过胎盘褪黑激素的作用，导致出生后下丘脑甲状腺的变化。 激素调节。在脊椎动物中，胚胎后大脑的发育严重依赖于TH， 在控制神经发生和神经元分化方面是必不可少的。光周期是否影响大脑 非季节性物种的发展仍然未知。我们假设光周期对围产期的影响 下丘脑通过调节TH的局部变化而发育。在啮齿动物中，胚胎程序 下丘脑的神经发生在妊娠结束时完成，而神经胶质的形成持续到妊娠早期。 产后期。TH的增加促进了神经前体细胞增殖的结束，并有利于其 神经元而不是神经胶质分化。短光周期与下丘脑TH含量降低有关- 促进季节性物种成体的细胞增殖和神经前体标志物的增加。在这 应用，我们将首先使用单细胞RNA测序来确定不同光周期的影响 孕期暴露对下丘脑内侧基底区细胞类型和分化的影响 出生后早期发育(目标1)。在目标2中，我们将使用组织学技术和细胞标记 分化以确定妊娠期间暴露于短光周期是否影响细胞增殖，新生儿 细胞命运程序与出生后下丘脑发育的变化。为了实现我们的目标，我们将使用 光周期影响新生儿下丘脑TH调节的高度有效的野生型小鼠模型。 这个小鼠模型(小鼠肌肉)显示了褪黑素和成体的光周期变化 生理(即体重和性腺大小的变化)。我们在这次探索和研究中的总体目标 开发研究的应用是评估我们模型的准确性，验证实验小鼠 并在出生后早期获得有关单细胞下丘脑转录组程序的知识。 如果得到证实，我们的模型将在光周期对发育中的大脑的影响方面开辟新的天地，并且 这将为科学和临床了解这些机制提供新的机会 季节性环境改变下丘脑发育、神经内分泌功能和人体健康

ABSTRACT Seasonal or photoperiodic changes in humans affect hormonal patterns, brain function, and are an underlying cause of several psychological disorders. Season of birth has a clear impact on birth weight and ulterior susceptibility to disease (e.g., childhood diabetes, psychiatry disorders and Alzheimer). Exposure to “winter- like” short photoperiod during pregnancy delays the developmental trajectory in offspring of seasonal species. This effect, mediated by transplacental melatonin action, leads to postnatal changes in hypothalamic thyroid hormone (TH) regulation. In vertebrates, postembryonic brain development is critically dependent on TH, essential in the control of neurogenesis and neuronal differentiation. Whether photoperiod affects brain development in non-seasonal species remains unknown. We hypothesize that photoperiod impacts perinatal hypothalamic development via local changes in TH regulation. In rodents, the embryonic program of hypothalamic neurogenesis is completed by the end of gestation, while gliogenesis continues into the early postnatal period. Increased TH promotes the end of proliferation of neural progenitors and favors their neuronal instead of glial differentiation. Short photoperiod – associated with lower hypothalamic TH content – promotes cell proliferation and increase in neural progenitor markers in adults of seasonal species. In this application, we will initially use single cell RNA sequencing to determine the impact of distinct photoperiod exposure during gestation on cell type specification and differentiation of the mediobasal hypothalamus during early postnatal development (Aim 1). In Aim 2, we will use histological techniques and markers of cell differentiation to determine if exposure to short photoperiod during gestation affects cell proliferation, newborn cell fate program and changes in postnatal hypothalamic development. To accomplish our goals, we will use a highly validated wild-derived mouse model in which photoperiod affects neonatal hypothalamic TH regulation. This mouse model (Mus musculus molossinus) shows photoperiodic changes in melatonin and adult physiology (i.e., changes in body weight and gonads size). Our overall objectives in this exploratory and development research application are to assess the accuracy of our model, to validate the experimental mouse and to gain knowledge on single cell hypothalamic transcriptome program during early postnatal development. If demonstrated, our model will break new ground on the impact of photoperiod on the developing brain, and will open new opportunities for the scientific and clinical understanding of the mechanisms by which the seasonal environment alters hypothalamic development, neuroendocrine function, and human’s health