The Role of Dorsomedial Hypothalamic LepRb‐expressing Neurons in the Control of Respiratory Motor Output

Abstract

Previously we have demonstrated that leptin in the NTS activates leptin receptor (LepRb) and galanin-expressing neurons which directly increases phrenic motor output via a NALCN-dependent mechanism (Do et al, Cell Reports, 2020). We also reported that such NTS LepRb neurons are glutamatergic and project to the rostral ventral respiratory group (rVRG) and, interestingly, the dorsomedial hypothalamus (DMH). While the excitatory projections to the rVRG are consistent with the robust increase in integrated phrenic activity, projections to the DMH imply an integrative leptin-dependent circuit. The DMH includes a significant number of LepRb expressing neurons and our previous preliminary work suggests that optogenetic activation of DMH LepRb neurons increases phrenic nerve activity (Chang et al, FASEB Abstr. 2018). Here we report that selective optogenetic activation of LepRb DMH neurons induces a robust increase, on discrete timescales, in integrated phrenic activity and inspiratory activity in vagal motoneurons. These DMH LepRb neurons are dominantly GABAergic confirmed by the expression of VGAT with in situ hybridization. Lastly, viral tracing studies reveals DMH LepRb neurons project to the arcuate nucleus, periaqueductal gray (PAG), and parabrachial nucleus (PBN). Together, these findings highlight a leptin-dependent suprapontine circuit that, along with NTS LepRb neurons, is likely to participate in matching respiratory motor output to metabolism.