Genetic identification of a neural circuit that suppresses appetite

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Abstract

Appetite suppression occurs after a meal and in conditions when it is unfavourable to eat, such as during illness or exposure to toxins. A brain region proposed to play a role in appetite suppression is the parabrachial nucleus1,2,3, a heterogeneous population of neurons surrounding the superior cerebellar peduncle in the brainstem. The parabrachial nucleus is thought to mediate the suppression of appetite induced by the anorectic hormones amylin and cholecystokinin2, as well as by lithium chloride and lipopolysaccharide, compounds that mimic the effects of toxic foods and bacterial infections, respectively4,5,6. Hyperactivity of the parabrachial nucleus is also thought to cause starvation after ablation of orexigenic agouti-related peptide neurons in adult mice1,7. However, the identities of neurons in the parabrachial nucleus that regulate feeding are unknown, as are the functionally relevant downstream projections. Here we identify calcitonin gene-related peptide-expressing neurons in the outer external lateral subdivision of the parabrachial nucleus that project to the laterocapsular division of the central nucleus of the amygdala as forming a functionally important circuit for suppressing appetite. Using genetically encoded anatomical, optogenetic8 and pharmacogenetic9 tools, we demonstrate that activation of these neurons projecting to the central nucleus of the amygdala suppresses appetite. In contrast, inhibition of these neurons increases food intake in circumstances when mice do not normally eat and prevents starvation in adult mice whose agouti-related peptide neurons are ablated. Taken together, our data demonstrate that this neural circuit from the parabrachial nucleus to the central nucleus of the amygdala mediates appetite suppression in conditions when it is unfavourable to eat. This neural circuit may provide targets for therapeutic intervention to overcome or promote appetite.

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Figure 1: Co-localization of PBelo CGRP neurons with Fos following conditions that reduce food intake.
Figure 2: Stimulation of PBelo CGRP neurons reduces food intake and causes starvation.
Figure 3: Inhibition of PBelo CGRP neurons increases food intake during conditions that suppress appetite.
Figure 4: Efferent projections from PBelo CGRP neurons to the CeAlc mediate appetite suppression.

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Acknowledgements

We thank B. Roth for hM3Dq–mCherry and hM4Di–mCherry constructs, and K. Deisseroth for mCherry and ChR2–mCherry constructs. E. Allen, J. Resnick, M. Soleiman and S. Padilla assisted with histology, E. Allen and A. Rainwater assisted with animal husbandry, and J. Shulkin provided suggestions and advice. We thank members of the Palmiter and Zweifel laboratories for feedback on the manuscript. M.E.C. is financed by a fellowship from the Hilda and Preston Davis Foundation. L.S.Z. is financed by a grant from the National Institutes of Health (R01MH094536). R.D.P is supported in part by grants from the National Institutes of Health (R01DA024908) and the Klarman Family Foundation.

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M.E.C. and R.D.P. conceived and designed the study. M.E.C. performed and analysed histological and behavioural experiments, M.E.S. performed electrophysiology experiments and R.D.P. generated CalcaCre knock-in mice. L.S.Z. and R.D.P. provided equipment, reagents and expertise. M.E.C. wrote the manuscript in collaboration with the other authors.

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Correspondence to Richard D. Palmiter.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-17 and Supplementary Statistical Analyses. (PDF 8023 kb)

Stimulation of PBelo CGRP neurons with ChR2 during consumption of palatable food

This video is representative of data from a single trial in Figure 2b. Left (near) lickometer port contains palatable liquid diet; right (far) lickometer port contains water. Video filmed 5 minutes after start of the active period. (MOV 3696 kb)

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Carter, M., Soden, M., Zweifel, L. et al. Genetic identification of a neural circuit that suppresses appetite. Nature 503, 111–114 (2013). https://doi.org/10.1038/nature12596

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