Optogenetics in Neuroscience

By Clarice Tse

Optogenetics is a photo-stimulation technique using light to control genetically modified neurons with high spatial and temporal resolution. Since its discovery, optogenetics was used widely in aiding the research in neuroscience to further the understanding of the neural circuits in the brain and how it contributes to brain function. It is also applied in clinical studies on Parkinson’s and Alzheimer’s and other neurodegenerative diseases, and has great prospects to become a treatment approach to chronic pain and blindness. 

The function of optogenetics is based on the rationale that neurons bioengineered with light-sensitive protein can be optionally stimulated or silenced upon light stimulation. Opsins are the light-sensitive proteins that control the action potential that would create neural firings. Therefore, through bioengineered neurons with opsins, scientists can trigger the nerve impulses or neural firings in specifically targeted neurons of a certain area of the brain, or a certain network of neural circuits,  to investigate brain function and behavior. 

Opsins with a shape in its resting stage will alter to its active state upon absorption of a certain wavelength of light. They convert light into electrochemical signals to modulate intracellular signalling cascades, which in turn opens pore channels or activate pumps. This induces a flux of ions that leads to  depolarization (activation) or hyperpolarisation (inhibition) of the membrane potential of the respective neuron, which leads to neural firings or the inhibition of nerve impulses (Seth, 2018).

There are two types of opsins: microbial and animal. Microbial opsins are most commonly used in optogenetic research as it is easier to genetically engineer cells to express microbial opsins and they are also quicker in terms of kinetics, when compared to animal opsins. Found in algae, eubacteria and other microbes, microbial opsins can be classified into light driven ion pumps, such as bacteriorhodopsins (BRs) and halorhodopsins (HRs), ion channels, such as channelrhodopsins (ChRs), and sensors, such as sensory rhodopsin I and II (SRI and SRII) (Joshi, Rubart and Zhu, 2020).

Channelrhodopsins are the most prevalently used opsin in investigating the neural systems. It is blue-light sensitive and exists in two forms- channelrhodopsin-1 and wild-type channelrhodopsin-2.  As a G-proteins-coupled receptor, this transmembrane protein passes through the membrane 7 times and contains a light izomerizable retinal (an aldehyde derivative of vitamin A). Unlike other G-proteins-coupled receptor which activates other ion channels of the membrane through the release of secondary messengers, channelrhodopsin forms its own ion channel. Upon blue light exposure, the retinal structure changes its conformation which induces a conformational change of the ion channel, opening its pore causing an influx of cations. Then it closes within milliseconds as the retinal returns to its original conformation. As channelrhodopsins form their own ion channels, cellular depolarisation is extremely fast, and therefore is why they are always applied in neuroscience research (Bamann, Kirsch, Nagel and Bamberg, 2008).

Many research findings in neuroscience involves the application of optogenetics. First would be the use of optogenetics to study the neural circuits of cognition and behaviour. Through genetically modifying targeted neurons, scientists stimulate or silence the neural activity through light to investigate on what role they play in altering behaviour and neural dynamics in animal models (Bernstein and Boyden, 2011).  For instance, the study on neural pathways connecting the basolateral amygdala of the brain, which is responsible for emotion related learning, and the nucleus accumbens which is responsible for motivated behaviour using optogenetics. Channelrhodopsin-2 which produce excitatory effects was injected into some mice while others were injected with inhibitory halorhodopsin in the basolateral amygdala. When light is delivered in an optical fibre implanted in the mice, neural synapases would either be excited or inhibited depending on which opsin expressed. At the end, it was found that mice with the stimulation of neural firings of neurons that connect the basolateral amygdala to nucleus accumbens serves as a rewarding stimulus. Meanwhile, mice with the silenced neural circuits has a reduced pursuit in reward. Thus, it was concluded that reward-seeking behaviour is directed by the synapse activation of neural circuits that connect from the basolateral amygdala to the brain (Stuber et al., 2011).

Another use would be in studying neurodegenerative diseases. One would be Parkinson’s disease which is characterized by the loss of neurons in the basal ganglia that are involved in motor control. Recently, it was found that optical activation and inhibition of two groups of neurons in the external globus pallidus of the basal ganglia restores movement in a mouse model of the disease; the effect lasted for hours. Therefore, new therapeutic applications may be developed from the finding. On the other hand, research findings made possible the treatment of Alzheimer’s with optogenetics. When neurons involved in learning are genetically modified to express excitatory opsins and were optogenetically activated, memories were able to be retrieved. From this scientists concluded that the memory problems during early stages of Alzheimer’s may be due to a deficit in retrieving information. The deficit can be corrected by stimulating a specific group of neurons (Seth, 2018). 

Recently, optogenetics was considered a possible treatment to chronic pain. After mice were bred with opsin expression in their pain-sensing neurons, they were implanted with wirelessly controlled devices that deliver light. Upon light stimulus, neural signalling was silenced by the opsin, which leads to pain relief (Seth, 2018). 

Until now, research using optogenetics are mainly done on animal models, and many treatment methods have yet been applied onto humans although human trials have established the promising potentials of using optogenetics as therapy for neurodegenerative diseases. This may be due to some limitations of optogenetics, such as the struggle to achieve a good expression of opsins in human brain, there may be a chance of opsin overexpression, tissue damage caused by repeated optical stimulation. In terms of ethical concerns, gene modification is an irreversible action, and optogenetics controls the behaviour of neurons of the brain and govern the behaviour and psychological actions of a human externally. Therefore, some may consider it as a third-party control over one’s brain and actions. However, even with such limitations, more research and development using optogenetics will further scientist’s understanding of the brain and expand the search for solutions to diseases using optogenetics. 

References:

Bamann, C., Kirsch, T., Nagel, G. and Bamberg, E., 2008. Spectral Characteristics of the Photocycle of Channelrhodopsin-2 and Its Implication for Channel Function. Journal of Molecular Biology, 375(3), pp.686-694.

Bernstein, J. and Boyden, E., 2011. Optogenetic tools for analyzing the neural circuits of behavior. Trends in Cognitive Sciences, 15(12), pp.592-600.

Joshi, J., Rubart, M. and Zhu, W., 2020. Optogenetics: Background, Methodological Advances and Potential Applications for Cardiovascular Research and Medicine. Frontiers in Bioengineering and Biotechnology, 7(466).

Seth, C., 2018. How To Treat Neurological Diseases By Optogenetics — Science Innovation Union. [online] Science Innovation Union. Available at: <http://science-union.org/articlelist/2018/4/17/how-to-treat-neurological-diseases-by-optogenetics&gt; [Accessed 11 October 2020].

Stuber, G., Sparta, D., Stamatakis, A., van Leeuwen, W., Hardjoprajitno, J., Cho, S., Tye, K., Kempadoo, K., Zhang, F., Deisseroth, K. and Bonci, A., 2011. Excitatory transmission from the amygdala to nucleus accumbens facilitates reward seeking. Nature, 475(7356), pp.377-380.

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