Gene Expression and Drug Targets in the Rostromedial Tegmentum

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DESCRIPTION (provided by applicant): In 2009, we and others recently identified a previously overlooked brain region, the rostromedial tegmental nucleus (RMTg). These neurons play key roles in aversive learning, behavior, and addiction, via their dense projections to dopamine neurons, and major inputs from the lateral habenula, extended amygdala, and other regions implicated in affect and motivation. RMTg neurons are critically required for many (though not all) aversive behaviors related to fear, anxiety, pain, and drug withdrawal. Despite the rapid recent growth of knowledge regarding RMTg anatomic, physiological, and behavioral characteristics, the genetic properties of these neurons are almost entirely unknown. It is unknown what neurotransmitters (besides GABA) they contain, nor whether they exhibit receptors, uptake transporters, or other drug targets that could selectively manipulate their firin rates. Furthermore, the RMTg region lacks sharp boundaries on Nissl stains, and cannot be visualized without neural tracers or immediate early gene induction, methods often incompatible with other experimental paradigms. Hence, further progress in basic science and clinical studies of this region requires development of molecular tools and drug targets that selectively identify and manipulate these neurons. To meet these needs, we propose to examine RMTg gene expression by first using fluorescence activated cell sorting (FACS) to isolate these neurons from surrounding structures, followed by analysis on whole-genome expression arrays, and concluding with in situ hybridization to confirm expression patterns of candidate genes. We expect the results to fill in major gaps in our knowledge of this emerging brain structure, while also producing new tools for preclinical and clinical use. PUBLIC HEALTH RELEVANCE: In 2009, we and others identified a previously overlooked brain region, the rostromedial tegmental nucleus (RMTg), which provides dense GABA innervations of midbrain dopamine neurons, and plays key roles in aversive learning and behavior. Despite considerable interest, further research on this vital region is hampered by the lack of molecular and genetic tools specific to these neurons. By providing such tools, the proposed study could greatly accelerate pre-clinical and clinical studies of the RMTg.