Prenatal photoperiod action in hypothalamic development

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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