Serotonin (5-hydroxytryptamine, 5HT)-producing neurons and serotonin neurotransmission are implicated in a spectrum of human disorders ranging from psychiatric disorders of mind and mood such as drug seeking behavior, drug addiction, and pathological anxiety, to childhood developmental disorders such as autism, fetal alcohol syndrome, and the sudden infant death syndrome. Each disorder differs in clinical feature, suggesting heterogeneity in serotonin neuron function. Yet, molecular markers capable of identifying physiologically relevant 5HT neuron subtypes, which might explain this heterogeneity and differential disease susceptibility, are unknown. Consequently lacking, in addition, are means to gain genetic access to specific subsets of 5HT neurons for experimental study. While markers of mature 5HT neuron subtypes are wanting, at hand, however, are markers (transcription factors) that resolve subsets of serotonergic progenitor cells. Such progenitor cell markers, if linked to progeny neurons, would likely define physiologically relevant subgroupings of mature 5HT neurons; this is because developmental programs that define the ultimate fate and function of neurons are often set in motion by the action of transcription factors differentially expressed among their parent progenitor cells. Thus, even in the absence of markers capable of distinguishing mature 5HT neuron subtypes, a molecular framework for the serotonergic system can be constructed through identification of its constituent genetic sublineages. Here we propose to build, for the first time, such a framework, by creating a molecular fate map of rhombomere(r)-defined serotonergic sublineages in mice. We will extend our recently developed paradigm of intersectional and subtractive genetic fate mapping in order to visualize directly and simultaneously the development of 5HT neurons arising from different rhombomeres. Each mature 5HT neuron subtype, defined by its antecedent rhombomere (r)-specific genetic profile, will be analyzed for anatomical position within the brainstem raphe and extra-raphe nuclei. Analyses of cellular morphology, neurochemical profile, and axonal projections will follow. We have transgenics that, depending on the employed combination, should allow us to separately resolve 5HT neurons derived from r1, r2, r3, r5, or r6- r8. We also propose to generate transgenics capable of resolving r6- from r7/8-derived 5HT neurons. From the resultant molecular fate maps, it should be possible to extract information about subsets of 5HT neurons that in humans are likely to have specific disease relevance. This work is innovative and likely of major impact because it has the potential to redefine a critical neural system - the serotonergic system - and to provide a set of reagents that ultimately will permit controlling the activity of discrete 5HT circuits in vivo as a means to assess their roles in development, behavior, and/or cognition. Abnormalities in serotonin (5-hydroxytryptamine, 5-HT) neurotransmission as well as serotonergic neurons are implicated in numerous human disorders ranging from psychiatric disorders of mind, mood, and drug addiction to childhood developmental disorders such as autism and the sudden infant death syndrome. Each disorder differs in clinical feature suggesting heterogeneity in serotonin neuron function, yet the molecular underpinnings of such heterogeneity and differential disease susceptibility are largely unknown. Towards filling this knowledge gap, here we propose to construct the first molecular framework for the 5HT system that, having genetically-defined lineages as its component elements, should have physiological and clinical relevance; moreover, the generated results and genetic tools should have major impact by providing, for the first time, a means to gain genetic access to subgroups of serotonergic neurons to assess their precise roles in behavior, cognition, and/or development. ? ?
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