Defining roles for NTS Eya1 neurons in sickness and satiety - PROJECT SUMMARY/ABSTRACT Specialized neurons in the nucleus of the solitary tract (NTS) receive and integrate gastrointestinal signals of ingestion along with other relevant interoceptive parameters (e.g., gut irritants and infection) to restrain food intake. NTS neurons that respond to gut irritants or systemic infection promote nausea associated behaviors and sickness responses, and consequently reduce food intake; NTS neurons that track ingestion restrain food intake to promote satiety. It is important to understand the specific types of NTS neurons that respond to these distinct stimuli, and disentangle NTS neurons that promote satiety from those that promote nausea or sickness responses. The broad goal of this proposal is to understand how systemic infection and feeding converge on NTS neurons to reduce food intake. The previous integration of mouse NTS snRNA-seq with human GWAS body mass index (BMI) data predict that a novel NTS neuron population marked by expression of Eya1 (NTSEya1 neurons) plays crucial roles in the control of food intake and body weight. In silico data from others predict NTSEya1 neurons may promote sickness responses to lipopolysaccharide (LPS) administration, a model of systemic infection. To understand the function and mechanisms of action for these cells, we generated Eya1Cre mice with which to manipulate NTSEya1 neurons and test each in silico prediction. Our preliminary data suggest activating NTSEya1 neurons reduces food intake and body weight without promoting conditioned taste avoidance, a nausea associated behavior. Silencing NTSEya1 neurons leads to hyperphagic obesity. In addition, these neurons are activated in response to refeeding and LPS, suggesting that NTSEya1 neurons may restrain food intake in response to two distinct stimuli. This proposal will test overall hypothesis that NTSEya1 neurons reduce food intake and promote satiety without causing sickness responses. To discover the physiological, and potential pathophysiological roles of NTSEya1 neurons, we will: (1) Determine if activating NTSEya1 neurons are sufficient promote sickness responses, (2) determine if NTSEya1 neurons are necessary for the anorectic response to LPS, (3) define the structure of NTSEya1 neuron projections and (4) identify the downstream projections of NTSEya1 neuron important to promote satiation. At the conclusion of these studies, we will have defined the roles NTSEya1 neurons play in the control of food intake, energy balance, and sickness responses. Thus, we will contribute to the broader understanding of how brainstem systems integrate multiple interoceptive parameters to restrain feeding, potentially revealing novel targets for the therapy of obesity.
