Optogenetics uses light and genetics to manipulate and monitor the activities of defined cell populations, and this technique has transformed basic neuroscience research.
Optogenetic tools are genetically encoded proteins designed to manipulate and monitor neuronal circuits, and there are two types of proteins used: actuators (proteins that transduce light into neuronal signals for manipulation) and indicators (proteins that transduce neuronal signals into optical signals for monitoring).
An optogenetic approach involves light-based (optical) interventions and/or recordings of natural neural activity to elucidate the role of specified neuronal circuit elements in mammalian behaviour.
Numerous cognitive and emotional functions have already been studied using optogenetic approaches, including sensory perception, pain, decision-making, preference and avoidance, social interactions, and feeding behaviour; optogenetics has also been used in animal models of neuropsychiatric conditions.
Animal models for optogenetically induced disease states may facilitate the evaluation of drug candidates.
Optogenetics paves the way to novel therapeutic approaches in which chemistry is replaced by micro-optoelectronics and genetic modification of specific cells and in which modulation of specific neuronal circuits is the central mechanism of action.
Optogenetics — the use of light and genetics to manipulate and monitor the activities of defined cell populations — has already had a transformative impact on basic neuroscience research. Now, the conceptual and methodological advances associated with optogenetic approaches are providing fresh momentum to neuroscience drug discovery, particularly in areas that are stalled on the concept of 'fixing the brain chemistry'. Optogenetics is beginning to translate and transit into drug discovery in several key domains, including target discovery, high-throughput screening and novel therapeutic approaches to disease states. Here, we discuss the exciting potential of optogenetic technologies to transform neuroscience drug discovery.
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The authors acknowledge D. Nutt and P. M. Matthews and two anonymous expert reviewers for critically reading the manuscript and their many helpful suggestions. The authors also acknowledge the many other important contributions from the optogenetics community that, regrettably, could not be included in the present review owing to focus and space constraints.
The authors declare no competing financial interests.
- Neuronal circuits
Functional entities of interconnected neurons that typically include both excitatory and inhibitory neurons.
- Systems of circuits
The functional integration of local circuits; for example, sensory motor integration involves the system of sensory and motor circuitries.
- PET and functional MRI imaging
PET and functional MRI are imaging modalities that produce a three-dimensional image of functional processes in the body. PET uses a radioactive substance and functional MRI uses strong magnetic fields and radio waves.
- Forced swim test
The forced swim test is a rodent behavioural test used for the evaluation of endurance and motivation. This test is traditionally used to evaluate experimental manipulations that are aimed at rendering or preventing depressive-like states.
- Deep-brain stimulation
(DBS). A neurosurgical procedure involving the implantation of electrodes, to electrically stimulate specific parts of the brain for the treatment of movement and neuropsychiatric disorders.
- Locomotor sensitization
The locomotor response induced by acute drug administration, which is progressively augmented with repeated administration. This technique is used to evaluate addictive drug effects.
An enzyme that catalyses the recombination between two specific short DNA sequences (loxP sites in the case of the most widely used Cre recombinase), leading to excision or inversion of the intervening sequence. Genes that are artificially flanked with loxP sites are said to be 'floxed'. Recombination occurs if the cells both carry the floxed genes and express the recombinase. Expression of a recombinase in specific cell classes can be used to precisely target an optogenetic tool to these cells.
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Song, C., Knöpfel, T. Optogenetics enlightens neuroscience drug discovery. Nat Rev Drug Discov 15, 97–109 (2016). https://doi.org/10.1038/nrd.2015.15
Light-induced silencing of neural activity in Rosa26 knock-in and BAC transgenic mice conditionally expressing the microbial halorhodopsin eNpHR3
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