Multiple abnormalities have been identified by our group in the serotonergic system in the medulla of SIDScases. These data are exciting and compelling in light of a large body of experimental data from our groupand others that indicate that serotonin (5-HT) neurons are involved in maintaining cardiovascular andrespiratory homeostasis and in regulating sleep and arousal. There is strong evidence in particular that 5-HTneurons contribute to the ventilatory and arousal response to hypercapnia, as well as the response to temperaturechallenges. Thus, a defect in 5-HT neurons fits well with long-standing theories of SIDS proposingthat there are defects in cardiorespiratory control, arousal and thermoregulation. Preliminary data from ourgroup also indicate that there are defects in the GABA system in SIDS cases. This is intriguing, becausethere is a subset of GABA neurons within the raphe nuclei that may also be central chemoreceptors.The work proposed in this project will use in vitro approaches to address cellular and network mechanismsinvolved in 5-HT and GABA function. We will use state-of-the art in vitro electrophysiological methods toexamine the effects of CO2/pH, O2, temperature, gender and nicotine on 5-HT and GABA neurons duringdevelopment in medullary slices from genetically engineered mice in which all or subsets of serotonin orGABA neurons are fluorescent. With the Neuroanatomy Core, we will also use immunohistochemistry andtract tracing to define the neurochemical organization and connectivity of the medullary 5-HT system relativeto the GABA system and the respiratory network. The goal is to use an in vitro approach to provide insightinto how a defect in 5-HT and GABA neurons impairs the response of an infant to hypercarbia, hypoxiaand/or a temperature challenge, why this defect is expressed only during a critical developmental period,how gender and prenatal exposure to nicotine modifies it, and why death typically occurs during sleep.To accomplish this, we propose the following aims: 1) Define the properties of GABA neurons in themedullary raphe. 2) Characterize how hypoxia, temperature, prenatal nicotine, gender and pH interact toaffect different subsets of 5-HT neurons in the medulla at different postnatal ages. 3) Define how networkinteractions between the raphe, ventrolateral medulla, retrotrapezoid nucleus and pre-B6tzinger Complexinfluence the response to pH and neuromodulators. The cellular and network experiments proposed hereare interdigitated with those in the other Projects of this PPG, and are an intermediate step between themolecular approach of Project 5 and the human and whole animal work of Projects 1-3. Together our resultswill provide critical insight, we believe, into how a defect in the 5 HT system could lead to SIDS.
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