Date of Award

5-4-2020

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Neuroscience Institute

First Advisor

Nancy G. Forger

Second Advisor

Geert De Vries

Third Advisor

Javier E. Stern

Fourth Advisor

Aaron Roseberry

Abstract

A vaginal birth is a dramatic event for the mammalian fetus. Birth is accompanied by hormonal surges, mechanical forces from uterine contractions, and activation of the hypothalamic-pituitary axis to prepare the fetus to survive ex utero. For example, respiration, thermoregulation, and mature circulation are triggered by birth. However, virtually nothing is known about how, or if, the brain responds to the challenges of birth. Moreover, some important neurodevelopmental events, including developmental neuronal cell death, coincide with the timing of birth, but it is unclear whether birth influences these processes. Here, using a variety of histological, molecular, and pharmacological approaches, we investigate the response of the brain to birth. First, we find that a vaginal birth triggers neural activation in specific brain areas, including discrete nuclei within the hypothalamus. Based on c-Fos immunoreactivity, activation in the paraventricular, suprachiasmatic, and supraoptic nuclei of the hypothalamus increases up to 500% 3h after birth compared to one day before or one day after birth. Second, using carefully controlled experiments to isolate the events associated with labor and delivery, we demonstrate that neural activation occurs as a result of the exposure of the fetus to the extrauterine environment regardless of gestational length or birth mode, and that a large portion of the activated neurons are vasopressinergic. Given that vasopressin is elevated in plasma samples of human neonates on the day of birth, we next measured perinatal levels of vasopressin using the more stable surrogate marker, copeptin, and found that copeptin is elevated perinatally compared to adult samples. To determine possible functions of vasopressin at birth, we examined plasma osmolality and neuronal cell death. We show that plasma osmolality is acutely decreased following a vaginal birth, but not a Cesarean birth, and that vasopressin decreases cell death in specific hypothalamic areas of Cesarean-delivered pups, likely acting via oxytocin receptors. Collectively, these studies provide support for the hypothesis that a vaginal birth triggers a neuroendocrine response that provides neuroprotection to the newborn via vasopressinergic signaling. Furthermore, our results suggest that modifications in the normal progression of birth (i.e. birth mode) may alter brain development.

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