Integration of light-controlled neuronal firing and fast circuit imaging

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For understanding normal and pathological circuit function, capitalizing on the full potential of recent advances in fast optical neural circuit control will depend crucially on fast, intact-circuit readout technology. First, millisecond-scale optical control will be best leveraged with simultaneous millisecond-scale optical imaging. Second, both fast circuit control and imaging should be adaptable to intact-circuit preparations from normal and diseased subjects. Here we illustrate integration of fast optical circuit control and fast circuit imaging, review recent work demonstrating utility of applying fast imaging to quantifying activity flow in disease models, and discuss integration of diverse optogenetic and chemical genetic tools that have been developed to precisely control the activity of genetically specified neural populations. Together these neuroengineering advances raise the exciting prospect of determining the role-specific cell types play in modulating neural activity flow in neuropsychiatric disease.

Section snippets

Genetically targeted circuit control technologies

Several technologies recently have been developed to control the activity of genetically specified neural populations. Chemically triggered genetic silencing technologies include MISTs [1••], AlstR [2••], GluClαβ [3••], and modified GABA-A receptors [4]; all of these allow for inducible and reversible ‘knock out’ of genetically specified cell populations from neural circuits after application or washout of appropriate small molecule drugs. This chemical-genetic strategy (reviewed in this issue

Integrating fast optical control with fast optical imaging of activity flow

The chemical and optogenetic tools described above in principle allow characterization of the contribution of genetically defined cell types to neural activity flow through intact circuits. Complementing these control strategies, recent advances in high-speed optical imaging now allow for quantification of activity flow through intact neural circuits with high spatiotemporal resolution. Activity imaging presents clear advantages over alternative techniques in quantifying whole-circuit activity

Preclinical disease models

Could this kind of method also be applied to quantifying-altered circuit dynamics in neuropsychiatric disease models? For the slice preparation method to be effective, stable changes in the circuit of interest would have to be involved in the pathophysiology of the neuropsychiatric phenotype. A strategy for quantitative delineation of the changes to neural circuitry underlying neuropsychiatric disease would entail (Figure 3): first, identification of a validated animal model and target brain

Conclusions

By driving expression of optogenetic probes (or their chemical counterparts) in specific cell types, circuit elements can be controlled to determine their role in behavior. With high-speed imaging, activity propagation can be quantified both in normal circuits and in animal models of neuropsychiatric disease. When these two classes of fast optical technology are combined (Figure 1, Figure 2), a high-speed experimental platform results that may further our quantitative understanding of

References and recommended reading

Papers of particular interest have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

We thank the entire Deisseroth Lab for helpful discussions. This work was supported by NIDA, NIMH, and the NIH Director's Pioneer Award, as well as by NARSAD, APIRE, and the Snyder, Culpeper, Coulter, Klingenstein, Whitehall, McKnight, Kinetics, and Albert Yu and Mary Bechmann Foundations (KD) and the Stanford Medical Scientist Training Program (RDA).

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