Prenatal photoperiod action in hypothalamic development

摘要 人类的季节性或光周期性变化会影响荷尔蒙模式，大脑功能，并且是一种潜在的 导致了几种心理疾病。出生季节对出生体重有明显的影响， 对疾病的易感性（例如，儿童糖尿病、精神疾病和阿尔茨海默病）。暴露于“冬季- 比如”怀孕期间光照时间短会延迟季节性物种后代的发育轨迹。 这种作用由经胎盘褪黑激素作用介导，导致出生后下丘脑甲状腺的变化。 激素（TH）调节。在脊椎动物中，胚后脑发育严重依赖于TH， 在神经发生和神经元分化的控制中至关重要。光周期是否影响大脑 非季节性物种的发展仍然未知。我们假设光周期影响围产期 通过TH调节的局部变化的下丘脑发育。在啮齿类动物中， 下丘脑神经发生在妊娠结束时完成，而胶质细胞生成持续到妊娠早期。 产后时期TH的增加促进神经祖细胞增殖的结束，并有利于它们的增殖。 神经元而不是神经胶质分化。短光周期-与下丘脑TH含量降低相关- 促进细胞增殖和增加的神经祖细胞标志物的成年季节性物种。在这 应用，我们将首先使用单细胞RNA测序，以确定不同的光周期的影响， 妊娠期暴露对下丘脑中基底层细胞类型特化和分化的影响 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物 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 细胞命运程序和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 高度验证的野生小鼠模型，其中光周期影响新生儿下丘脑TH调节。 该小鼠模型（Mus musculus molossinus）显示褪黑激素和成体的光周期性变化。 生理学（即，体重和性腺大小的变化）。我们在这一探索性和 开发研究应用是为了评估我们的模型的准确性，以验证实验小鼠 了解下丘脑单细胞转录组在生后早期发育过程中的变化。 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天地，并且 这将为科学和临床理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类健康

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