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Insulin induces long-term depression of ventral tegmental area dopamine neurons via endocannabinoids

Nature Neuroscience volume 16, pages 300–308 (2013)Cite this article

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Abstract

The prevalence of obesity has markedly increased over the past few decades. Exploration of how hunger and satiety signals influence the reward system can help us understand non-homeostatic feeding. Insulin may act in the ventral tegmental area (VTA), a critical site for reward-seeking behavior, to suppress feeding. However, the neural mechanisms underlying insulin effects in the VTA remain unknown. We demonstrate that insulin, a circulating catabolic peptide that inhibits feeding, can induce long-term depression (LTD) of mouse excitatory synapses onto VTA dopamine neurons. This effect requires endocannabinoid-mediated presynaptic inhibition of glutamate release. Furthermore, after a sweetened high-fat meal, which elevates endogenous insulin, insulin-induced LTD is occluded. Finally, insulin in the VTA reduces food anticipatory behavior in mice and conditioned place preference for food in rats. Taken together, these results suggest that insulin in the VTA suppresses excitatory synaptic transmission and reduces anticipatory activity and preference for food-related cues.

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Figure 1: Insulin depresses AMPAR-mediated synaptic transmission onto VTA dopamine neurons.
Figure 2: Insulin-induced LTD requires Akt and mTOR signaling.
Figure 3: Insulin-induced LTD in the VTA does not require endocytosis of AMPARs.
Figure 4: Insulin-induced LTD occurs presynaptically and requires CB1R activation.
Figure 5: Insulin-induced LTD is mediated by endocannabinoid retrograde signaling.
Figure 6: A SHF meal increases endocannabinoid tone and occludes insulin-induced LTD onto VTA dopamine neurons.
Figure 7: Insulin in the VTA decreases food anticipatory activity and conditioned place preference, but not effort.

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Change history

  • 04 February 2013

    In the version of this article initially published online, the y axis of Figure 1f was labeled AMPA EPSCs; the graph actually shows GABAA IPSCs. The error has been corrected for the print, PDF and HTML versions of this article.

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Acknowledgements

The authors would like to thank K. Lee for performing the insulin measurements and K. Haas, B. MacVicar and Y.T. Wang for suggestions on the manuscript. This research was supported by a Canadian Institute of Health Research operating grant (102617) and a Canadian Institute of Health Research new investigator award to S.L.B. G.L. was supported by a Swiss National Science Foundation postdoctoral fellowship. Behavioral experiments done in B.B.'s laboratory were supported by the Swiss National Science Foundation (31003A-133056).

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Author notes

  1. Gwenaël Labouèbe and Shuai Liu: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Anesthesiology, Pharmacology and Therapeutics, The University of British Columbia, Vancouver, British Columbia, Canada

    Gwenaël Labouèbe, Shuai Liu, Haiyan Zou, Jovi C Y Wong & Stephanie L Borgland

  2. Department of Psychiatry, Center for Psychiatric Neuroscience, Site de Cery, Lausanne University Hospital, Lausanne, Switzerland

    Gwenaël Labouèbe & Benjamin Boutrel

  3. State Key Laboratory of Medical Neurobiology, Shanghai Medical College, Fudan University, Shanghai, China

    Shuai Liu & Stephanie L Borgland

  4. Department of Psychiatry, The University of British Columbia, Vancouver, British Columbia, Canada

    Carine Dias & Anthony G Phillips

  5. Department of Cellular and Physiological Sciences, The University of British Columbia, Vancouver, British Columbia, Canada

    Subashini Karunakaran & Susanne M Clee

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  1. Gwenaël Labouèbe
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Contributions

G.L. and S.L. under supervision of S.L.B. conducted the electrophysiological experiments and wrote the first draft of the manuscript; C.D. and H.Z. under supervision of A.G.P. performed the CPP experiments. G.L. under supervision of B.B. performed the progressive ratio experiments. J.C.Y.W. under supervision of S.L.B. performed the anticipatory behavior experiments. S.K. under supervision of S.M.C. performed the insulin measurements. S.L.B. wrote the manuscript and supervised the experiments.

Corresponding author

Correspondence to Stephanie L Borgland.

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Labouèbe, G., Liu, S., Dias, C. et al. Insulin induces long-term depression of ventral tegmental area dopamine neurons via endocannabinoids. Nat Neurosci 16, 300–308 (2013). https://doi.org/10.1038/nn.3321

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