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Deconstruction of a neural circuit for hunger

Abstract

Hunger is a complex behavioural state that elicits intense food seeking and consumption. These behaviours are rapidly recapitulated by activation of starvation-sensitive AGRP neurons, which present an entry point for reverse-engineering neural circuits for hunger. Here we mapped synaptic interactions of AGRP neurons with multiple cell populations in mice and probed the contribution of these distinct circuits to feeding behaviour using optogenetic and pharmacogenetic techniques. An inhibitory circuit with paraventricular hypothalamus (PVH) neurons substantially accounted for acute AGRP neuron-evoked eating, whereas two other prominent circuits were insufficient. Within the PVH, we found that AGRP neurons target and inhibit oxytocin neurons, a small population that is selectively lost in Prader–Willi syndrome, a condition involving insatiable hunger. By developing strategies for evaluating molecularly defined circuits, we show that AGRP neuron suppression of oxytocin neurons is critical for evoked feeding. These experiments reveal a new neural circuit that regulates hunger state and pathways associated with overeating disorders.

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Figure 1: ARC AGRP →ARC POMC is not required for evoked feeding.
Figure 2: Feeding is evoked by AGRP axon stimulation in the PVH but not the PBN.
Figure 3: Prolonged inhibition by ARC AGRP →PVH synapses.
Figure 4: PVH neuron inhibition recapitulates feeding from AGRP neuron activation.
Figure 5: ARC AGRP →PVH OXT circuit contributes to evoked food intake.
Figure 6: Pharmacological dissection of AGRP neuron-evoked feeding.

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Acknowledgements

This research was funded by the Howard Hughes Medical Institute. We thank J. Cox, A. Wardlaw, K. Morris for mouse breeding, genotyping, and viral injection support; S. Michael and A. Hu for histology support; M. Ramirez and B. Zemelman for rAAV production; H. Gainer for discussions about the oxytocin promoter; and E. Boyden for technical assistance.

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D.A., J.N.B. and S.M.S. designed the experiments and analysed data. D.A. and J.N.B. performed experiments. H.H.S. performed molecular cloning for viral constructs. S.M.S. and D.A. wrote the manuscript with comments from all of the authors.

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Correspondence to Scott M. Sternson.

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The authors declare no competing financial interests.

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Atasoy, D., Betley, J., Su, H. et al. Deconstruction of a neural circuit for hunger. Nature 488, 172–177 (2012). https://doi.org/10.1038/nature11270

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