Amylin Receptor Signalling in the Laterodorsal Tegmental Nucleus Controls Food Intake Through Projections to the Ventral Tegmental Area

ABSTRACT Background The role of amylin signalling in energy balance control has been understudied in calcitonin receptor (CTR) expressing nuclei such as the mesopontine laterodorsal tegmental nucleus (LDTg). Our lab has shown that LDTg amylin signalling reduces feeding and body weight, but the neuronal phenotype and downstream targets of LDTg CTR cells mediating these feeding effects remain unknown. Given that the LDTg has been established to modulate reward and motivated behaviours, we hypothesize that LDTg amylin signalling influences energy balance via direct modulation of VTA activity. Materials and Methods Here, we combine circuit tracing, immunohistochemical, fluorescent in situ hybridization, pharmacological, behavioural and chemogenic approaches to phenotype LDTg CTR neurons and explore LDTg CTR  → VTA neurons as a functional energy balance control pathway. Results LDTg CTR+ neurons are a heterogenous population composed of glutamatergic and GABAergic neurons that project to the VTA in both mice and rats. Our results show that chemogenetic activation of LDTg CTR neurons reduces c‐Fos expression in the VTA, suggesting a mechanism via which LDTg amylin signalling influences energy balance by modulation of downstream VTA signalling. In support of this, our experiments show that unilateral circuit specific (LDTg → VTA) Calcr knockdown was sufficient to attenuate the anorexigenic effects of peripherally delivered salmon calcitonin at 6‐ and 12 h post injection. Lastly, we demonstrate that projection‐specific chemogenetic excitation of this LDTg CTR  → VTA pathway is sufficient to reduce food intake and body weight in mice. Conslusion Altogether, these findings anatomically and functionally characterize a new amylin/CTR signalling pathway, further establishing the LDTg as a potential target for novel obesity pharmacotherapies.