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Development of an in vitro system for measuring fictive breathing in the neonatal brainstem/spinal cord

Faculty Mentor: Jeffrey Erickson

Student: Robert Myers

Pet-1 gene deletion results in a significant loss of neurons that comprise the brainstem serotonin (5HT) system. This selective loss of 5HT neurons results in abnormal autonomic function, particularly during early postnatal development. Pet-1 mutant (knockout) mice exhibit a lower resting breathing rate, a higher incidence of apneas, and an impaired autoresuscitation response to anoxia-induced apnea, compared to their wild-type littermates, and approximately 25% die within five days of birth. These findings have potential relevance to Sudden Infant Death Syndrome (SIDS) in humans, which has been linked to a deficiency in brainstem 5HT. Recent studies in our lab have focused on the effects of known risk factors for SIDS on cardiorespiratory function in Pet-1 mutants. Currently, the major risk factor for SIDS is exposure to cigarette smoke during prenatal and/or postnatal development, and many believe that nicotine is the causative agent. We have shown through in vivo studies that the breathing abnormalities in the Pet-1 mutants are reversed when the animals are exposed to nicotine prenatally. However, despite this improvement in breathing behavior, early mortality in the knockouts persists. The underlying mechanisms for these surprising results are not known.

This summer, we completed data collection for our initial in vivo study of the effects of prenatal nicotine exposure on Pet-1 knockouts. To explore potential underlying mechanisms, we began to incorporate heart rate measurements into our standard protocol for measuring breathing behavior, since heart rate instability could be the basis for the continued high mortality in the knockouts. In addition, we made significant progress in developing an in vitro system for measuring fictive breathing in the isolated neonatal brainstem/spinal cord in anticipation of more controlled pharmacological studies aimed at defining the role of nicotine in reversing the abnormal breathing phenotype of the 5HT-deficient Pet-1 mutant.

 

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