Energy balance is maintained by an extended circuitry in the central nervous system that carefully balances food intake with energy expenditure. We have recently shown that the brainstem’s dorsal raphe nucleus (DRN) is an important component of this extended circuit, capable of potently regulating both energy intake and expenditure, and ultimately body weight. Despite its important role in energy homeostasis, the DRN is markedly heterogenous, consequently hindering our ability to manipulate and record from its distinct cell subtypes. Towards this end, we have recently performed nuclear tagging of large classes of DRN neurons, enabling us to molecularly profile these cells at both ensemble and single-cell resolutions. Using this approach, we have found that even among a priori defined major cell types within the DRN - for example, those marked by the vesicular glutamate and GABA transporters - there is a marked degree of molecular heterogeneity. Despite this significant molecular heterogeneity, some subclasses of DRN neurons are hierarchically differentiable, leading to the identification of molecularly dissociable ‘clades.’ These clades have unique molecular handles; these handles are now enabling us to record from and perturb the activity of distinct DRN subpopulations, which were previously genetically inaccessible. Together, this work represents an important conceptual and technical advance, enabling us to classify DRN neurons with new resolution, as well as to genetically access them to establish their cell subtype-specific function.
American Diabetes Association (1-18-ACE-49)