Saturday, September 7, 2024
9/7/2024
PROJECT SUMMARY More than 40% of adults in the United States are obese, and that number is expected to rise to over 50% by 2030. Obesity is a critical health concern as it is associated with several leading causes of death including diabetes, heart disease, stroke, and cancer. Ingestion of a meal can elicit both positive and negative feelings. However, the pathways underling these different valences are not well understood, but maladaptive changes could have broad implications for both overeating and emotional disorders. Drugs that inhibit food intake (FI) also often lead to aversive side-effects like nausea. Understanding what mediates the positive or negative feelings associated with satiety is therefore critical to help drive the development of treatments for obesity without aversive side-effects. Recent work has identified a population of cholecystokinin (CCK) expressing neurons in the nucleus of the solitary tract (NTS). Stimulation of these neurons leads to a decrease in FI, but stimulation of terminals in the paraventricular hypothalamus (PVH) is rewarding, while stimulation of terminals in the parabrachial nucleus (PBN) is aversive. However, it remains unclear what drives these divergent projections physiologically and how terminals activate neurons in the PVH and PBN. To investigate this, I first characterized what types of vagal afferents innervate NTS-CCK neurons and what currents they express. My results suggest that there are two subpopulations of neurons: one that is downstream of both CCK and serotonin (5-HT) sensitive afferents and another that is downstream of only CCK sensitive afferents. Information carried by 5-HT sensitive afferents is thought to be aversive, while information carried by CCK sensitive afferents is thought to be rewarding. Thus, I hypothesize that NTS-CCK neurons projecting to the PVH are driven primarily by CCK sensitive afferents, while PBN projecting neurons receive inputs from both CCK and 5-HT sensitive afferents. Further, I posit that release of fast transmitters and peptides will have different effects on downstream cells in the PVH and PBN. These studies will provide valuable information regarding the cellular mechanisms underlying previously reported behavioral findings. They will also help guide future studies aiming to develop more selective and less aversive therapies for the treatment and prevention of obesity. To accomplish the proposed experiments in the F99 phase, I will need to learn stereotaxic injections as well as in-slice photostimulation techniques. My sponsor, Dr. Suzy Appleyard, and co-sponsor, Dr. Shane Hentges, have expertise in all proposed techniques as well as established mentoring records. During the K00 phase, I plan to build on the skills learned during the F99 phase by identifying a supportive and knowledgeable postdoctoral mentor. Specifically, I will receive training on in-vivo opto and chemogenetic stimulation, in-vivo neuronal recording techniques, and computational models for behavioral analysis. The cellular techniques learned in the F99 phase, combined with the behavioral techniques learned in the K00 phase will optimally position me to interrogate feeding circuitry from behavior to cellular mechanisms as an independent investigator.
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