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Pathological circuit function underlying addiction and anxiety disorders

Nature Neuroscience volume 17, pages 1635–1643 (2014)Cite this article

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Abstract

Current models of addiction and anxiety stem from the idea that aberrant function and remodeling of neural circuits cause the pathological behaviors. According to this hypothesis, a disease-defining experience (for example, drug reward or stress) would trigger specific forms of synaptic plasticity, which in susceptible subjects would become persistent and lead to the disease. While the notion of synaptic diseases has received much attention, no candidate disorder has been sufficiently investigated to yield new, rational therapies that could be tested in the clinic. Here we review the arguments in favor of abnormal neuronal plasticity underlying addiction and anxiety disorders, with a focus on the functional diversity of neurons that make up the circuits involved. We argue that future research must strive to obtain a comprehensive description of the relevant functional anatomy. This will allow identification of molecular mechanisms that govern the induction and expression of disease-relevant plasticity in identified neurons. To establish causality, one will have to test whether normalization of function can reverse pathological behavior. With these elements in hand, it will be possible to propose blueprints for manipulations to be tested in translational studies. The challenge is daunting, but new techniques, above all optogenetics, may enable decisive advances.

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Figure 1: Long-range circuits involved in fear and reward perception.
Figure 2: Emerging cell type–specific anatomy of the amygdala and the VTA.
Figure 3: Schematics of proposed model.

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Acknowledgements

We thank the many colleagues who have, with discussions and suggestions on the manuscript, helped us improve this review. A.L. and C.L. are supported by grants from the Swiss National Science Foundation and the Swiss national competence center for research on synaptic basis of disease (Synapsy). C.L. is an European Research Council advanced grant holder.

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  1. Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland

    Andreas Lüthi

  2. Department of Basic Neurosciences, Medical Faculty, University of Geneva, Geneva, Switzerland

    Christian Lüscher

  3. Department of Clinical Neurosciences, Clinic of Neurology, Geneva University Hospital, Geneva, Switzerland.,

    Christian Lüscher

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Lüthi, A., Lüscher, C. Pathological circuit function underlying addiction and anxiety disorders. Nat Neurosci 17, 1635–1643 (2014). https://doi.org/10.1038/nn.3849

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