NTS Neuron Populations that Mediate the Aversive and Non-Aversive Suppression of Food Intake - Abstract Early models of food intake control held that hypothalamic circuits integrate information about energy storage and utilization to regulate long-term energy balance, while the brainstem dorsal vagal complex (DVC) receives signals from the gut and inflammation (among other stimuli) to modulate only short-term parameters of food intake (e.g., meal size). We now understand that the DVC plays important roles in long-term energy balance, however. The nucleus of the solitary tract (NTS), a component of the DVC, integrates circulating and vagal sensory signals to modulate food intake. We and others have shown that activating Calcr/Prlh- or Lepr/Gcg-expressing NTS neurons non-aversively suppresses food intake, while activating NTS cells that express Cck or Adcyap1 promotes aversive responses. Unbiased clustering of single nucleus RNA- sequencing (snRNA-seq) data from DVC cells reveals that NTS Calcr/Prlh (CalcrNTS) neurons map to a single glutamatergic neuron population (GLU11); Gcg also marks a single NTS cell type (GLU14; GcgNTS cells). Furthermore, integrating these data with GWAS findings suggests that the CalcrNTS and GLU9 (marked by Eya1; Eya1NTS) neuron populations participate in the genetic determination of BMI. Indeed, we found that CalcrNTS neuron activity physiologically restrains body weight gain (but does not alter cardiovascular or respiratory parameters). In contrast, Cck and Adcyap1 each map to multiple snRNA-seq-defined NTS populations. GcgNTS cells express both markers but are non-aversive, so other NTS cell type(s) that express Cck and/or Adcyap1 must mediate aversive responses. The GLU1 population (marked by Rxfp1; Rxfp1NTS) expresses both Cck and Adcyap1; GLU5 (Gfral/vGlut3; vGlut3NTS) cells express Cck; and Eya1NTS cells express Adcyap1. Hence, the Rxfp1NTS, vGlut3NTS, and Eya1NTS populations represent candidate aversive cell types. Based upon our preliminary data, we hypothesize that CalcrNTS, GcgNTS, and Eya1NTS neurons each mediate the non-aversive suppression of food intake in response to specific signals and contribute to the long-term control of energy balance. We also hypothesize that Rxfp1NTS and vGlut3NTS neurons mediate aversive responses, but do not contribute to long-term energy balance. We have developed or obtained cre-recombinase mouse strains specific to CalcrNTS, GcgNTS, vGlut3NTS, Eya1NTS, and Rxfp1NTS neurons (collectively, “NTS populations”). We will use these lines together with a host of molecular genetic techniques to understand the regulation and function of each of these NTS populations. These studies should define NTS neuron populations that control food intake and body weight and distinguish neurons that mediate aversive versus non-aversive responses. Ultimately, these studies are expected to reveal potential targets for the therapy of obesity.
