Connectivity of melanocortin 3 receptor (MC3R) neurons and their role in stress-related responses

Stress is a common trigger for inappropriate eating behaviors within modern society and it could lead to a disrupted energy homeostasis. Our focus has been on the role of melanocortin-3 receptor (MC3R) neurons and their role in regulating energy balance. Recent studies showed that MC3R knockout mice develop anxiety like behavior, and exhibit more dominant effects upon different stressors. The MC3R has been shown to have a robust expression in the paraventricular nucleus of the thalamus (PVT). However, how the MC3R neurons in the PVT are exerting effects on food intake and behavior is still poorly understood. One potential candidate region playing a role in this response is the central amygdala (CeA), as one major efferent target of PVT. Here we hypothesize that the MC3R neurons send projections from the PVT to the amygdala, and this neuronal projection is involved in regulating feeding behavior under stress conditions. To test the hypothesis, this project consists of two aspects: a neuroanatomical study and whole animal behavioral tests. We first checked innervation of the MC3R neurons to amygdala using a genetically modified mouse model and retrograde viral tracing. Through these methods, we identified the PVT to be the main nucleus of input into the CeA. We studied the role of MC3R modulation in feeding behavior under stress using a chemogenetic mouse model both in the whole body and specifically in the PVT MC3R neurons using a virus-mediated expression. A nutritional stress (16 hour overnight fasting) and a social stress (an adapted social defeat test) were applied in this model. From the fasting experiment, we determined that activation of MC3R cells during fasting can consequentially change feeding behavior. From the social defeat test, we observed that activation of whole body MC3R cells protected the animals from stress-induced body weight loss by inducing more food intake. Assessment of the neuronal activity marker c-Fos, demonstrates a sex difference with females showing a more profound pattern of neuronal activation in response to chemogenetic-mediated activation of MC3R cells. However, PVT-MC3R modulations did not exhibit this phenotype. In conclusion, we confirmed a connection between PVT and amygdala. Furthermore, MC3R cells were involved in mediating feeding behavior under stress exposure. However, PVT-MC3R neurons alone could not affect feeding and the role of the PVT-CeA connection remain as an open area of research.