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Dopamine neurons modulate neural encoding and expression of depression-related behaviour

Abstract

Major depression is characterized by diverse debilitating symptoms that include hopelessness and anhedonia1. Dopamine neurons involved in reward and motivation2,3,4,5,6,7,8,9 are among many neural populations that have been hypothesized to be relevant10, and certain antidepressant treatments, including medications and brain stimulation therapies, can influence the complex dopamine system. Until now it has not been possible to test this hypothesis directly, even in animal models, as existing therapeutic interventions are unable to specifically target dopamine neurons. Here we investigated directly the causal contributions of defined dopamine neurons to multidimensional depression-like phenotypes induced by chronic mild stress, by integrating behavioural, pharmacological, optogenetic and electrophysiological methods in freely moving rodents. We found that bidirectional control (inhibition or excitation) of specified midbrain dopamine neurons immediately and bidirectionally modulates (induces or relieves) multiple independent depression symptoms caused by chronic stress. By probing the circuit implementation of these effects, we observed that optogenetic recruitment of these dopamine neurons potently alters the neural encoding of depression-related behaviours in the downstream nucleus accumbens of freely moving rodents, suggesting that processes affecting depression symptoms may involve alterations in the neural encoding of action in limbic circuitry.

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Figure 1: Selective inhibition of VTA dopamine neurons induces a depression-like phenotype.
Figure 2: Temporally sparse phasic photoactivation of VTA dopamine neurons rescues stress-induced depression-like phenotype.
Figure 3: Phasic activation of VTA dopamine neurons modulates escape-related behaviour in TH::Cre rats.
Figure 4: Phasic activation of VTA dopamine neurons modulates NAc encoding of escape-related behaviour.

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Acknowledgements

We thank T. Davidson, S. Pak, C. Ramakrishnan, L. Grosenick, Z. Chen and the members of the Deisseroth Laboratory for support. I.B.W. was supported by the Helen Hay Whitney Foundation; K.M.T was supported by NRSA fellowship F32 MH880102 and the JPB Foundation; K.R.T., M.R.W. and K.D. are NARSAD grant awardees. K.D. was supported by the Wiegers Family Fund and by the NIMH, the NIDA, the DARPA REPAIR Program, the Keck Foundation, the McKnight Foundation, the Gatsby Charitable Foundation, the Snyder Foundation, the Woo Foundation and the Albert Yu and Mary Bechman Foundation. All tools and methods described are distributed and supported freely (http://www.optogenetics.org).

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Author Contributions K.M.T., J.J.M., M.R.W., H.-C.T. and K.D. contributed to study design. K.M.T., J.J.M., M.R.W., H.-C.T., J.F., S-Y.K., E.A.F., A.A., K.R.T., L.A.G., I.B.W. and K.D. contributed to data collection or interpretation. K.M.T. coordinated all experiments, M.R.W. led development of the induction-coil FST and the FST electrophysiology; K.M.T., J.J.M., M.R.W. and A.S.A. contributed to data analysis, and K.D. supervised the project. K.M.T. and K.D. wrote the paper.

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Correspondence to Kay M. Tye or Karl Deisseroth.

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Competing interests

K.M.T., M.R.W. and K.D. have disclosed these findings to the Stanford Office of Technology Licensing, which has filed a patent application for the possible use of the findings and methods in identifying new treatments for depression. All materials, methods and reagents remain freely available for academic and non-profit research in perpetuity through the Deisseroth optogenetics website (http://www.optogenetics.org).

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Tye, K., Mirzabekov, J., Warden, M. et al. Dopamine neurons modulate neural encoding and expression of depression-related behaviour. Nature 493, 537–541 (2013). https://doi.org/10.1038/nature11740

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