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Optogenetic investigation of neural circuits underlying brain disease in animal models

Nature Reviews Neuroscience volume 13, pages 251–266 (2012)Cite this article

Subjects

Key Points

  • 'Optogenetic' approaches (the use of light-sensitive genetically encodable tools to manipulate cellular activity) in neuroscience have matured beyond the proof-of-principle phase and have grown into a widely used set of techniques for dissecting the circuits underlying behaviour.

  • Recent technological advances include the integration of optogenetics with established techniques in electrophysiology and pharmacology, as well as the expansion of the optogenetic toolbox to include new opsin variants and new transgenic rodent lines.

  • Optogenetic approaches provide new advantages such as precise cellular targeting and greater temporal control, but also bring new limitations that are important to consider, such as heating artefacts and problems with light delivery and overexpression toxicity.

  • Optogenetic approaches have led to the dissection of microcircuits in the amygdala underlying fear and anxiety and to the discovery of unexpectedly broad temporal regimes in which the hippocampus is involved in recalling remote memories.

  • The use of optogenetics to target a specific projection or specific cell type in transgenic Cre recombinase rodents has advanced our understanding of the circuits underlying reward-related learning relevant to addiction.

  • Manipulating parvalbumin neurons, rhythmic oscillations and the balance of excitation and inhibition in neocortex using optogenetic tools has advanced our understanding of schizophrenia- and autism-related phenomena.

  • The use of optogenetic methods has advanced our understanding of neurological disorders and treatments, clarifying our understanding of deep brain stimulation and striatal circuits in the context of Parkinson's disease.

Abstract

Optogenetic tools have provided a new way to establish causal relationships between brain activity and behaviour in health and disease. Although no animal model captures human disease precisely, behaviours that recapitulate disease symptoms may be elicited and modulated by optogenetic methods, including behaviours that are relevant to anxiety, fear, depression, addiction, autism and parkinsonism. The rapid proliferation of optogenetic reagents together with the swift advancement of strategies for implementation has created new opportunities for causal and precise dissection of the circuits underlying brain diseases in animal models.

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Figure 1: Optogenetic tools.
Figure 2: Targeting strategies with optogenetic tools in vivo.
Figure 3: Functional dissection of amygdala microcircuitry using an integrated approach involving optogenetic tools.
Figure 4: Optogenetic dissection of limbic circuits in the context of reward-seeking behaviour.
Figure 5: Functional mapping of basal ganglia circuitry using optogenetics in the context of Parkinson's disease.

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Acknowledgements

We would like to acknowledge E. E. Steinberg, P. H. Janak, S.-Y. Kim, L. D. Tye, O. Yizhar, A. Kreitzer, A. Kravitz and L. E. Fenno for helpful comments and discussion. We thank the Deisseroth laboratory for intellectual and scientific support. K.M.T. is supported by the US National Institute of Mental Health (NIMH) (1F32MH088010-01), the Picower Institute of Learning and Memory and the Picower Institute Innovation Funds (PIIF). K.D. is supported by the NIMH, the US National Institute on Drug Abuse, the US National Institute of Neurological Disorders and Stroke, the Howard Hughes Medical Institute, the Defense Advanced Research Projects Agency Reorganization and Plasticity to Accelerate Injury Recovery Program, the Keck Foundation, the Wiegers Family Gift Fund and the Gatsby Charitable Foundation. Full funding support is described at http://www.optogenetics.org/funding. Stanford University has filed for patent protection on technologies invented by K.M.T. and K.D., and K.D. is one of the founders of a company (Circuit Therapeutics) focused on drug screening and optogenetic therapies for bladder dysfunction. K.D. and K.M.T. have no more than 5% interest in any company and receive no research funding, royalties or consultant fees from any company. All optogenetic tools and methods are distributed and supported freely from the laboratory (http://www.optogenetics.org).

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Authors and Affiliations

  1. Department of Bioengineering, Stanford University, 318 Campus Drive, Clark Center, Stanford, 94305-5444, California, USA

    Kay M. Tye & Karl Deisseroth

  2. Department of Brain and Cognitive Sciences, Picower Institute of Learning and Memory, Massachusetts Institute of Technology, Cambridge, 02139-4307, Massachusetts, USA

    Kay M. Tye

  3. Department of Psychiatry, Stanford University, 401 Quarry Road, Stanford, 94305-5717, California, USA

    Karl Deisseroth

  4. CNC Program, Stanford University, Stanford, 94305, California, USA

    Karl Deisseroth

  5. Howard Hughes Medical Institute, Stanford University Medical School, Stanford, 94305-5323, California, USA

    Karl Deisseroth

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Glossary

Opsins

Membrane-bound proteins that can incorporate small organic 'retinal' molecules to become a light receptor.

fMRI

(Functional magnetic resonance imaging). This method can use detection of blood oxygen levels as a proxy for neural activity, and offers a non-invasive method to globally assay brain activity in humans.

BOLD

(Blood oxygen level dependent). The BOLD signal is one kind of signal that fMRI can use to assess neural activity.

Channelrhodopsin

A light-driven cation channel, found in algae, that can be used to depolarize cell membranes.

Halorhodopsin

A light-driven chloride ion pump found in phylogenetically ancient archaea, known as halobacteria, that can be used to hyperpolarize cell membranes.

UP states

Sub-threshold membrane depolarization states that have been observed to spontaneously occur in vivo in some neurons and that may serve to increase the intrinsic excitability of the neuron.

Cre recombinase

DNA recombinase that excises DNA sequences flanked by loxP sequences with the same orientation, or inverts sequences flanked by loxP sites with opposite orientation. It is effective in mammalian cells in vitro and in vivo.

Vectors

Vehicles used to transfer genetic material to a target cell.

Conditioned place preference

(CPP). A behavioural test in which an unconditioned stimulus is paired with one distinctive context and a neutral event is paired with a different context. Preference is determined by allowing the animal to move between the two contexts and measuring the amount of time spent in each context.

Duty cycle

The time that a machine, system or light source spends in an active state as a fraction of the total time under consideration.

Conditioned fear responses

A fear-associated stimulus (such as a shock-predictive tone) that may evoke conditioned responses such as freezing, fear-potentiated startle or increases in blood pressure, perspiration or heart rate.

Deep brain stimulation

(DBS). Continuous therapeutic electric stimulation of subcortical areas at high frequencies (∼ 130 Hz) using chronically implanted electrodes.

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Tye, K., Deisseroth, K. Optogenetic investigation of neural circuits underlying brain disease in animal models. Nat Rev Neurosci 13, 251–266 (2012). https://doi.org/10.1038/nrn3171

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