Studying the Brain with Light - Using Optics to Influence Neurons
The brain is one of the most complex organs in the human body and severe disability can result from even the slightest deviation from normal neural development and small areas of damage or neurodegeneration. The immense capacity of the brain to control a vast array of complex processes has fascinated scientists for centuries and barriers to studying it directly have only heightened the intrigue.
Unprecedented technological advances have greatly extended the capacity of brain research. Detailed images of the structure of the brain can be obtained with computed tomography (CT) and an insight into brain function has been achieved through the visualization of areas of the brain that are active using positron emission tomography (PET), functional magnetic resonance imaging (MRI) and magnetoencephalography (MEG) techniques. However, any conclusions have had to be based on observations and correlations rather than on direct evidence of causality.
Development of a completely new technology has made it possible to directly study the brain at neuron level in living animals. This has opened the door to gaining a much deeper understanding of how the brain functions (and malfunctions) by directly observing cause and effect in living animals. It enables brain function to be studied in an animal while it undertakes complex tasks, including social behavior and memory functions. Investigations into how the brain processes information can now be undertaken with a level of precision and control that was previously unimaginable. This breakthrough in neurological research is known as optogenetics.
Optogenetics is a technique that allows researchers to make individual neurons photosensitive using microbial opsin genes1. Opsin is a protein that is made light-sensitive by the binding of a chromophore. Unlike mammalian opsin, microbial opsin directly transduces photons into electrical current. Depending on the type of microbial opsin used, this can be in the form of either an excitatory signal or an inhibitory signal.
Using this technique, it is possible to make specific cells types in particular areas of the brain respond to light. This in turn enables neuroscientists to introduce information to the brain by using light to target specific cells. Thanks to recent advances in laser and fiber optic technology, this can be done extremely rapidly so the researcher can activate neural connections in a similar manner to normal brain activity.
Consequently, neural networks can be investigated whilst the brain is functioning under usual conditions. It is even possible to simultaneously study two distinct areas of the brain using dual-color optogenetics. The Andor Mosaic™ system has been successfully used to simultaneously activate and inhibit distinct regions of the brain2. Similarly, distinct populations of neurons expressing two different opsins could be simultaneously activated3.
Such optical stimulation of neurons has overcome many of the challenges faced when using electrical stimulation4. It is less invasive, not requiring the implantation of electrodes, and is not subject to electrical artefacts. Optical stimulation also allows more detailed exploration of the wider connectivity of neural networks since the stimulation is more selective and has a higher spatial resolution. Furthermore, optogenetics provides the means to turn neurons off as well as on.
Applications of optogenetics
Through optogenetic studies, it can be determined whether a particular pattern of cerebral activity occurring in a specific cell type is necessary or sufficient for a physiologic or behavioral response. Already, optogentics has provided a wealth of information. For example, optogenetic studies have identified specific cellular connections with a causal role in the loss of motivational behavior in depression5, and subsequently defined the circuitry underpinning anhedonia and revealed the importance of dopamine neuron recruitment in motivation6. Furthermore, anhedonic behavior was induced in rats by optogenetically elevating activity in the medial prefrontal cortex7.
The specificity of optogenetics has enabled investigation of adult neurogenesis in the olfactory bulb. Targeted stimulation of the neurons developed during adulthood was shown to uniquely influence olfactory function through a population of functionally unique GABAergic output synapses8. The Andor MOSAIC™9 was used to spatially restrict the light source so that only one or a few adult-born neurons were stimulated at a time. Sequential stimulation in this manner enabled the synaptic connectivity of adult-born neurons to be mapped.
Optogenetics has also proved to be a valuable tool in studies of neurodegeneration and neural regeneration in disease models for spinal cord injury, multiple sclerosis, Alzheimer’s disease and Parkinson’s disease10. Similarly, it has advanced understanding of the underlying pathology of epilepsy11.
Optogenetic advances have made it feasible to explore a virtually limitless range of ideas and hypotheses. In addition, ongoing increases in the capabilities of technologies used in conjunction with optogenetics are making it possible to study ever-larger networks of neurons. For example, the development of wide-field-of-view, high-sensitivity cameras, such as the ultrasensitive back-illuminated Andor Sona™, which has 95% quantum efficiency and a field of view 62% greater than was previously possible12. Over time, such optogenetic research projects will undoubtedly help unravel the causal and global neural circuit dynamics underlying numerous functions and behaviors. This in turn will inform a range of new therapeutic strategies.
Ongoing optogenetic research is likely to greatly further our understanding of how the brain interprets specific experiences under different circumstances and how this can go awry in psychiatric disorders. In turn, this depth of understanding may finally facilitate the development of novel treatments that will enable psychiatrists and neurologists to target a defect with precision to restore normal functioning, and relieve suffering, in their patients13. The use of optogenetics to treat blindness and Parkinson’s disease is already being explored.
As optogenetics continues to deepen our understanding of how the brain responds to daily experiences and how changes to these processes can manifest as a range of medical conditions, it surely holds the potential to improve well-being and optimize a host of patient outcomes.
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- Andor website. Available at https://andor.oxinst.com/products/photostimulation/mosaic#product-information-tabs
- Ordaz JD, et al. Neural Regen Res. 2017;12(8):1197–1209.
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