Genetic identification of a neural circuit that suppresses appetite - PubMed (original) (raw)

Genetic identification of a neural circuit that suppresses appetite

Matthew E Carter et al. Nature. 2013.

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 nucleus, 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 cholecystokinin, as well as by lithium chloride and lipopolysaccharide, compounds that mimic the effects of toxic foods and bacterial infections, respectively. Hyperactivity of the parabrachial nucleus is also thought to cause starvation after ablation of orexigenic agouti-related peptide neurons in adult mice. 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, optogenetic and pharmacogenetic 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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Figures

Figure 1

Figure 1. Co-localization of PBelo CGRP neurons with Fos following conditions that reduce food intake

a, AAV carrying a Cre-dependent mCherry reporter injected into the PBN. Grey triangles and black triangles represent loxP and lox2722 sites, respectively. b, mCherry expression in the PBelo. scp, superior cerebellar peduncle; scale bar, 500 μm. c-j, Representative histological examples and quantification of coincidence of mCherry and Fos expression. k, Degree to which various conditions reduce food intake. l, Appetite suppression correlates with the percentage of PBelo CGRP neurons expressing Fos. Dashed lines represent 95% confidence intervals. See Supplementary Information for statistical analysis.

Figure 2

Figure 2. Stimulation of PBelo CGRP neurons reduces food intake and causes starvation

a, Placement of fiber optic implant in the PBN in a CalcaCre/+ animal injected with AAV DIO ChR2-mCherry. b, c, Photostimulation of CGRP neurons reversibly inhibits food intake in both baseline (b) and fasted (c) conditions. d, Top, diagram showing AAV DIO hM3Dq-mCherry transgene unilaterally injected into the PBN; bottom, timeline of experiments in (e-f). e, f, Pharmacogenetic stimulation of CGRP neurons inhibits food intake in both baseline (e) and fasted (f) conditions. g, h, Chronic administration of CNO (every 12 h for 4 d) suppresses food intake (g) and reduces body weight (h). *P<0.05, **P<0.01, ***P<0.001; See Supplementary Information for statistical analyses.

Figure 3

Figure 3. Inhibition of PBelo CGRP neurons increases food intake during conditions that suppress appetite

a, AAV DIO hM4Di-mCherry transgene bilaterally injected into the PBN. b, Pharmacogenetic inhibition of CGRP neurons increases food intake after administration of anorexigenic compounds. c, d, Chronic administration of CNO (every 12 h for 8 d) increases food intake (c) and prevents starvation (d) in AgrpDTR/+ mice after two injections of diphtheria toxin. The mCherry animals were sacrificed on day 8 due to extreme weight loss. *P<0.05, **P<0.01, ***P<0.001; see Supplementary Information for statistical analyses.

Figure 4

Figure 4. Efferent projections from PBelo CGRP neurons to the CeAlc mediate appetite suppression

a, Left and middle, mCherry-expressing fibers from the PBelo to the CeAlc; scale bar, 500 μm. Right, PBelo fibers expressing mCherry, Synaptophysin-GFP, and CGRP. b, EPSC from a CeAlc neuron upon photostimulation of PBelo-to-CeAlc fibers before (black) and after (red) bath application of CNQX and APV. c, AAV DIO ChR2-mCherry with fiber optic implant above the CeAlc. d, Photostimulation of PBelo fibers in the CeAlc reversibly inhibits food intake. e, Injection of CAV2 Cre into the CeAlc and AAV DIO hM4Di-mCherry into the PBN. f, Inhibition of retrogradely-targeted PBelo neurons increases food intake. *P<0.05, **P<0.01; See Supplementary Information for statistical analyses.

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