Jabale Rahmat
Sophomore
School of Life Sciences
Independent University, Bangladesh
June 13th, 2018
“Tubelight”. We do not restrain ourselves from assigning our friends with this euphemistic word for dimwit. It indicates that their brain needs time to turn on and comprehend something. But lighting up the brain has a new and completely literal meaning today, and it is helping us address hitherto unanswerable questions about how the brain works.
The human brain is a labyrinth of neurons: thousands of nerve cells residing in a complex network. For decades, scientists have been working to elucidate how this labyrinth is compartmentalized to perform different functions and have made enormous strides in discovering which regions of the brain are involved in movement, sensation, memory, emotion, and other hallmarks of cognitive function. But it has been much harder until recently to get to the much finer resolution of the role of specific neurons in processes such as memory formation and retrieval.
Neurons in the brain work in synergistic or antagonistic ways for different processes that are occurring in the body. It is difficult to make associations between specific neuronal activity and cognitive functions. Classical ways to study neuron function include stimulating neurons with electrodes and identifying the effects of stimulation. But this is physically invasive, can lack specificity, and does not allow fine-scale control of neurons. To study the function of specific sets of neurons, one would ideally be able to turn them on and off at will and see how they affect different aspects of cognitive function.
To solve this problem, neuroscientists have developed a method known as optogenetics that uses light-sensitive proteins to turn neurons on and off. Before describing how optogenetics works let us work through the necessary background on how neurons work.
Light being shone onto the brain of a mouse. Britannica
Neurons carry electrical signals, much like electrical wires. These signals are transmitted through creating changes in the charge carried inside the membrane along the length of the neuron. Charge is manipulated by moving ions (which carry charge) in and out of neurons using molecular pumps and ion channel proteins that span the membrane and transport ions through it. Each kind of ion (sodium, potassium, chloride etc.) has its own specific channel protein.
When a neuron or part of a neuron is at a resting or inactive stage, the sodium-potassium pump maintains a constant resting charge inside the membrane relative to the outside due to the unbalanced share of ions inside and outside the neurons. The sodium-potassium pump transports three sodium ions out for every two potassium ions brought in, regardless of concentration or charge gradient. Both of these carry a single positive charge, so this makes the inside of the neurons less positive.
Upon receiving a sufficiently strong signal, for example from pressure receptors that are present under the skin, specific ion channels for sodium are activated, allowing sodium to flow down the concentration gradient into the region of the neuron that is closest to the signal, resulting in a positive charge inside the membrane. This sudden change activates sodium ion channels adjacent to the initial site of activation, and the signal is passed along neurons to be processed by the central nervous system. Once the stimulating signal is removed, activated regions are returned to their resting state via other ion channel proteins. When our brain responds to a stimulus, it activates a different set of neurons that carry signals to muscles and other effector organs. In a nutshell, neurons can be excited by activating specific ion channel proteins.
Optogenetics utilizes certain light-sensitive ion channel proteins isolated from microorganisms like unicellular algae and archaea that open in response to light. Channelrhodopsin-2, a blue light-sensitive channel protein from algae, allows the transport of positively charged ions into cells upon activation by blue light. Halorhodopsins, isolated from archaea, become activated by specific wavelengths of light to move negatively charged chloride ions into the cell, thereby making the inside of the membrane less positive and inhibiting neuronal activation.
But these proteins molecules are obviously not typically produced by the nerve cells of mammals. So how do we use them to turn neurons on and off? Well, specific neurons are genetically engineered to express the genes encoding the light-sensitive channel proteins. While we cannot experimentally manipulate humans in this manner, extensive research is being conducted in model organisms such as mice. One particularly interesting line of work using optogenetics has discovered that different neurons are involved in memory formation and recall. Picture one of the experiments conducted for this discovery: you turn off a set of neurons after teaching mice to be afraid of a stimulus. The mice no longer seem to remember the fear. But if you turn off those neurons while the fear is being taught, and later turn on the neurons and expose them to the stimulus, the mice do exhibit fear. This suggests that the memory had formed through a different pathway but could only be recalled upon activation of this specific set of neurons [1].
Optogenetics can also utilize light-emitting proteins to light up neurons engaged in specific activities. If you tie the expression of a light-emitting protein to genes that are turned on during learning, you can watch memories form by observing which parts of the brain glow while the organism is being exposed to novel stimuli.
Optogenetics can helps us answer central questions surrounding how the brain processes information. It holds great promise in understanding neurogenerative disorders such as Parkinson’s and Alzheimer’s through the study of the brains of model organisms. Although developed to study neurons, optogenetics is also being adapted to manipulate other cell types using light.
When a neuron or part of a neuron is at a resting or inactive stage, the sodium-potassium pump maintains a constant resting charge inside the membrane relative to the outside due to the unbalanced share of ions inside and outside the neurons. The sodium-potassium pump transports three sodium ions out for every two potassium ions brought in, regardless of concentration or charge gradient. Both of these carry a single positive charge, so this makes the inside of the neurons less positive.
Upon receiving a sufficiently strong signal, for example from pressure receptors that are present under the skin, specific ion channels for sodium are activated, allowing sodium to flow down the concentration gradient into the region of the neuron that is closest to the signal, resulting in a positive charge inside the membrane. This sudden change activates sodium ion channels adjacent to the initial site of activation, and the signal is passed along neurons to be processed by the central nervous system. Once the stimulating signal is removed, activated regions are returned to their resting state via other ion channel proteins. When our brain responds to a stimulus, it activates a different set of neurons that carry signals to muscles and other effector organs. In a nutshell, neurons can be excited by activating specific ion channel proteins.
Optogenetics utilizes certain light-sensitive ion channel proteins isolated from microorganisms like unicellular algae and archaea that open in response to light. Channelrhodopsin-2, a blue light-sensitive channel protein from algae, allows the transport of positively charged ions into cells upon activation by blue light. Halorhodopsins, isolated from archaea, become activated by specific wavelengths of light to move negatively charged chloride ions into the cell, thereby making the inside of the membrane less positive and inhibiting neuronal activation.
But these proteins molecules are obviously not typically produced by the nerve cells of mammals. So how do we use them to turn neurons on and off? Well, specific neurons are genetically engineered to express the genes encoding the light-sensitive channel proteins. While we cannot experimentally manipulate humans in this manner, extensive research is being conducted in model organisms such as mice. One particularly interesting line of work using optogenetics has discovered that different neurons are involved in memory formation and recall. Picture one of the experiments conducted for this discovery: you turn off a set of neurons after teaching mice to be afraid of a stimulus. The mice no longer seem to remember the fear. But if you turn off those neurons while the fear is being taught, and later turn on the neurons and expose them to the stimulus, the mice do exhibit fear. This suggests that the memory had formed through a different pathway but could only be recalled upon activation of this specific set of neurons [1].
Optogenetics can also utilize light-emitting proteins to light up neurons engaged in specific activities. If you tie the expression of a light-emitting protein to genes that are turned on during learning, you can watch memories form by observing which parts of the brain glow while the organism is being exposed to novel stimuli.
Optogenetics can helps us answer central questions surrounding how the brain processes information. It holds great promise in understanding neurogenerative disorders such as Parkinson’s and Alzheimer’s through the study of the brains of model organisms. Although developed to study neurons, optogenetics is also being adapted to manipulate other cell types using light.
Further Reading:
[1] D. S. Roy et al., “Distinct Neural Circuits for the Formation and Retrieval of Episodic Memories,” Cell, vol. 170, no. 5, pp. 1000-1012.e19, Aug. 2017.
Jabale is a Sophomore in the School of Life Sciences at IUB majoring in Biochemistry. He is a future scientist who is crazy about everything related to biology, especially genetics.
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