Around 40% of the adult population in the United States is obese or overweight, underscoring the importance of studying the neural circuits controlling food intake and energy balance to develop novel pharmacotherapies treating obesity. Amylin signaling decreases food intake and gastric emptying in both humans and rats via activation of CNS amylin receptors (calcitonin receptor, CTR; heterodimerized with a receptor activating modified protein, RAMP1-3), without inducing malaise, making it a promising target of study in obesity pharmacotherapy. 

Despite the distributed nature of CNS amylin receptors, research on the role of amylin signaling in the control of energy balance has been largely focused on hypothalamic and hindbrain nuclei, leaving other nuclei with abundant CTR expression such as the mesopontine laterodorsal tegmental nucleus (LDTg) understudied. Recent work from our lab showed that LDTg CTR signaling reduces food intake. Additionally, in the absence of endogenous LDTg CTR signaling, rats show increased food intake and body weight gain. However, the mechanism by which CTR signaling in the LDTg modulates energy balance, as well as the downstream nuclei targeted by LDTg CTR expressing neurons have not been explored. 

The LDTg is known to modulate dopamine signaling to regulate motivated behavior via direct projections to the ventral tegmental area (VTA), and our data shows that several LDTg CTR neurons send monosynaptic projections to the VTA. Consequently, we performed immunohistochemistry (IHC) in the VTA for the immediate early gene c-Fos (a commonly established marker for cell activation) following pharmacological activation of LDTg CTR cells in a rat model to elucidate the mechanisms behind the functional role of LDTg CTR cells in feeding. Our results show increased neuronal activity in the VTA, suggesting that the LDTg CTR to VTA projection is excitatory. Moreover, rostral and medial VTA, as opposed to caudal VTA, were more strongly modulated by LDTg CTR signaling. Given that the most prevalent cell type in the rostral and medial VTA is dopaminergic neurons, the neurons that LDTg CTR cells modulate are likely dopaminergic. Overall, the increase of downstream VTA neuronal activity suggests that activation of LDTg CTR cells potentially activates dopaminergic neurons in medial-rostral VTA to influence the motivation to seek palatable food. Finally, to phenotype the neuronal components of the projection, we conducted fluorescence in situ hybridization (FISH) on LDTg CTR neurons, and identified approximately half to express a glutamatergic or GABAergic marker (the latter being a smaller population), with the remaining half unidentified. Under these preliminary results and the establishment of the drive of an excitatory input from the LDTg to VTA, LDTg CTR neurons are presumably primarily glutamatergic in nature, illuminating a functional mechanism in LDTg modulation of downstream VTA neurons. In sum, our results identify a promising avenue in the pursuit of obesity therapeutics: a novel mesopontine-limbic pathway with the potential to influence the rewarding value of food.