Timing onset of birth: peripheral signals prime oxytocin neurones to burst fire

Lead Research Organisation: University of Edinburgh
Department Name: Biomedical Sciences


Timing onset of birth: peripheral signals prime oxytocin neurones to burst fire
Alison Douglas, Centre for Integrative Physiology, University of Edinburgh
We aim to understand how inappropriate signals from the womb and fetus near the end of pregnancy might trigger preterm labour (and early birth, risking damage to the baby) by driving neuronal pathways to the brain resulting in the early secretion of high amounts of the hormone oxytocin.
We know that the neurones that make oxytocin respond to signals from the womb and oxytocin is normally secreted into the blood during birth and controls womb contractions. However sometimes infection or other unwanted stimuli also trigger the same pathways. We think that these signals start a mechanism that makes the oxytocin neurones more sensitive and respond too early by producing more oxytocin, which then by contracting the womb has the extra effect of causing more unwanted stimuli, resulting in birth happening too early.
We will study the oxytocin neurones using an anaesthised rat model of pregnancy and preterm labour to measure the adaptations of the special neurone activity patterns during late pregnancy and the brain chemicals that mediate this, and the susceptibility of the neurones to unwanted premature signals.
This will contribute to understanding of preterm labour mechanisms and may allow greater precision in prediction and prevention of preterm birth.

Technical Summary

Preterm labour and delivery are relatively common, affecting approximately 10% of births, and are the cause of at least 75% of neonatal deaths. Oxytocin is released from the posterior pituitary into the blood in pulses during labour and parturition, driving co-ordinated and intermittent uterine contractions, and effective treatments for preterm labour include repeated oxytocin antagonist administration. Release of oxytocin from neuronal dendrites in the supraoptic nucleus (SON) is also key during parturition, its actions underlying the newly exhibited synchronised burst firing of the oxytocin cells that generates their peripheral pulsatile secretion. However, the mechanisms facilitating the switch to this activity pattern at the end of pregnancy are unknown. The release and action of dendritic oxytocin requires preparation of the neurones (?priming?). We hypothesise that, at term, uterine signals initiate the preparation of oxytocin neurones, priming them to respond to subsequent stimuli with enhanced intra-SON oxytocin release, which enables burst firing. Uterine signals during preterm labour may also prime oxytocin neurones, making them susceptible to inadvertent unchecked stimuli when they respond inappropriately with large secretory pulses that further drive uterine contraction and birth. We will address the hypothesis by investigating whether priming of oxytocin neurones is present during early labour, whether it is induced by uterine contractions, and whether the known activation of the noradrenergic brainstem input to the SON mediates the priming, using in vivo approaches. We will establish whether noradrenaline induces the priming directly or indirectly via potential intra-SON signals and, if directly, whether it mobilizes intracellular calcium, which is a prerequisite for priming, using in vitro release and calcium imaging studies. Finally, electrophysiological studies will test whether experimentally-induced priming triggers burst firing of oxytocin neurones at the end of pregnancy. Data supporting our hypothesis will indicate an important functional role for priming and reveal its physiological relevance.


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