Project IV seeks to identify molecular programs and gestational stages in mice that, if compromised, may cause homeostatic dysfunction, and, by extrapolation to humans, may underlie an increase in risk for the sudden infant death syndrome (SIDS) or other clinical disorders of homeostasis. Life- sustaining homeostatic responses to cardiorespiratory and thermal challenges are regulated by brain serotonergic (5-HT) neurons. Using novel mouse transgenics, we recently established that different homeostatic functions, for example respiratory control In response to CO2 elevation or body temperature control In response to cold, map to distinct ontogenetically defined subtypes of 5-HT neurons. This suggests that molecularly distinct 5-HT neurons mediate distinct functions. In addition, we now know that mice experience a window of heightened vulnerability to homeostatic stressors, spanning postnatal day (P)~5-12, reflecting that these homeostatic functions are developmentally regulated, and may be analogous to the critical period where human SIDS risk is elevated. We also know that male mice show a greater homeostatic sensitivity to 5-HT disruptions. In-line with the higher rate of SIDS in male Infants. Armed with these functional parameters - 5-HT neuron subtype, vulnerable postnatal stage, and gender - and our novel circuitry mapping tools, we propose to Identify molecular programs underlying these homeostatic specializations and vulnerabilities In mice. We hypothesize that critical molecular differences driving homeostatic specializations and their temporal development in 5-HT neurons stem from differences in gene expression and that they can be revealed through systematic comparison among transcriptomes generated from each of our Identified functional classes of medullary 5-HT neurons across postnatal windows Identified as especially vulnerable to homeostatic challenge and across gender (Aim 1). Further, we hypothesize that gestational exposures which elevate SIDS risk do so by perturbing the expression of critical homeostatic specializations, and that these perturbations Involve, at least in part, transcript alterations which are identifiable by comparative transcripfional profiling (Aim 2). Such gestational exposures may not only affect gene expression but also 5-HT neuron activity in the embryo, which in turn may affect the long-term development and postnatal function of homeostatic circuits. Using inducible genetic neuronal 'silencing'tools recently engineered In our lab, we will Identify, In mice, embryonic stages during which 5-HT neuron activity is most critical for development and function of circuits essential for postnatal homeostasis (Aim 3).
Expected outcomes of significant relevance to public health Include discovery of molecular mechanisms underlying life-sustaining neuronal networks and possibly SIDS, and the Identification of molecular pathways of potential value for developing therapeutics for preventing this devastating disorder or biomarkers for diagnosing risk. The Impact on basic science will likely be substantial as well because this integrative work (involving Projects l-IV) templates a new physiological genomics approach to developmental neuroscience and brain circuitry mapping that is applicable across numerous brain regions, physiologies, and behaviors.
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