An Anatomical and Functional Dissection of the Role Pet1 Raphe Neurons Play in Neonatal Cardiorespiratory Homeostasis
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CitationDosumu-Johnson, Ryan T. 2016. An Anatomical and Functional Dissection of the Role Pet1 Raphe Neurons Play in Neonatal Cardiorespiratory Homeostasis. Doctoral dissertation, Harvard University, Graduate School of Arts & Sciences.
AbstractLife-sustaining cardiorespiratory homeostasis requires the dynamic response of brainstem neural circuits. Apneas - the cessation of breathing often accompanied by bradycardia - can reflect defects in these circuits, and if frequent or prolonged can be life-threatening. During early postnatal life, mammals exhibit a higher frequency of spontaneous apneas, thus needing to engage this respiratory circuitry frequently, robustly, and reliably. Dysfunction can lead to sudden unexpected death and is hypothesized to be one underlying cause of the Sudden Infant Death Syndrome (SIDS), which is the leading cause of postneonatal infant mortality in the western world. Brainstem abnormalities have been observed in most SIDS cases, with the predominant defect being an abnormality in medullary raphe serotonergic neurons, also referred to as Pet1 raphe neurons for their intrinsic expression of the transcription factor Pet1. Even with this finding, the precise role of Pet1 raphe neu- rons in cardiorespiratory homeostatic reflexes remains unclear. Here, I show that disrupting Pet1 raphe neuron activity in mouse neonates, either chronically or acutely, results in an altered home- ostatic baseline and a decreased ability to survive apneas during a critical developmental window (bracketing postnatal day 8). I also provide evidence that disruption of Pet1 raphe neurons primarily affects respiratory not cardiac components of the apnea response, and that these defects in respira- tory control might predict higher risk for apnea-associated mortality. In addition to analyzing Pet1 neurons functionally, gene expression analyses were performed resulting in the identification of a previously uknown subset of Pet1 raphe neurons lacking normal transcript and protein levels for serotonergic genes, suggestive of a reserve neuronal population poised to become more serotonergic on demand. These findings allow for a more complete model of the role Pet1 raphe neurons play in modulating cardiorespiratory homeostasis in neonates, their possible plasticity, and by extension to humans, how their dysfunction might increase SIDS risk.
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