The Brain Wave: Studying brain mysteries with algae

Before the advent of modern neuroscience, the brain was viewed as an impenetrable box.

Given the rudimentary techniques available, it was impossible to investigate the physical events that underlie the human mind and behavior. Thus, classical behaviorists avoided the human brain, depending entirely upon easily observable behavioral characteristics to investigate the human mind.

Since then, scientific technology has grown immensely. Advances in microscopy have allowed for an impressive view of neuronal anatomy and structure. Sophisticated electrophysiology and calcium-based imaging have enabled recording of neuronal activity in single neurons as well as large neuronal populations without sacrificing resolution. We can now even use rabies virus to elucidate the extracellular communication of neurons. These technological breakthroughs have significantly accelerated research progress in the exploration of brain science.

Arguably, however, one experimental technique stands out. Perhaps the greatest scientific invention of 21st century neuroscience, it is a technique that has allowed neuroscientists to biologically probe neurons in ways that provide unprecedented understandings of circuit mechanism underlying brain function. Termed optogenetics, the tool is a fascinating story of how algae can be used to shed light on mysteries of the brain.

Nearly 100 years ago, the Spanish pathologist Ramon y Cajal discovered that neurons are the fundamental unit of the nervous system. By releasing chemicals called neurotransmitters, neurons can communicate with each other within circuits to modulate all aspects of our everyday life, from sensory perception to emotions and creativity. Thus, the overarching view of contemporary neuroscience posits that brain function is a reflection of neuronal networks.

Experimentally speaking, however, investigating how networks influence behavior is a major technological conundrum. Neuroscientists require a method to selectively activate or silence neural circuits that would be similar to the molecular tools available to geneticists for studying the functional significance of genes.

By observing what function is enhanced or lost after a specific circuit is deactivated or activated, neuroscientists can gain a better understanding of how different circuits are responsible for various types of brain function. However, such loss and gain of function studies have been challenging to realize owing to the difficulty of functionally probing the activity of certain neurons without disrupting others. In addition to this specificity problem, neuronal activity occurs on the scale of microseconds. How can we recapitulate this precise temporal solution on the lab bench?

Optogenetics is the solution to these problems. It allows specific control over neural activity with high temporal resolution.

The story of optogenetics began with photosynthetic green algae. Since green algae make their food from photosynthesis, they will tend to move toward areas of brighter light. This movement from low intensity to high intensity light is controlled by light-sensitive ion channels known as rhodopsin. Expressed on the cell membranes of algae, rhodopsins open in response to light to allow ions to pass through, leading to a cascade of intracellular reactions that guide algal movement towards areas of brighter light.

Control of neuronal activity operates in very similar ways. Depending on the ion that floods inside the cell membrane through an ion channel, the neuron can either be turned on or off. The channels that exist on neuronal membranes usually open in response to binding of a neurotransmitter or electrical energy.

By genetically engineering desired neurons to express light-sensitive algal rhodopsins on their membranes, scientists can cause ions to flow inside a neuron by shining a light. Depending on the type of rhodopsin expressed on the membrane (which dictates what ion flows through), the neuron can be functionally excited or silenced. In other words, neuronal activity can be manipulated by the switch of a light.

As soon as the light is turned on, the rhodopsin channels open to allow for modulation of activity through ion movement. As soon as the light is turned off, the rhodopsin channels close, and the ion flow ceases. Therefore, combining the temporal resolution of using light (opto-) with the specificity of genetic tools (-genetics), optogenetics emerges as a powerful tool dissecting neural circuits.

Since its first experimental application in 2005 by the Karl Deisseroth lab at Stanford University, optogenetics has been widely used for neuroscience research throughout the world. For instance, the profound utility of optogenetics cannot be understated within the realm of psychiatric illnesses. Last year, two studies published in Science provided the first-ever direct proof of a specific neuronal pathway responsible for obsessive-compulsive disorder (OCD).

For a long time, the organic basis for psychological disorders has evaded clinicians and scientists. Unlike disorders of the heart or the liver, diseases that affect the brain radiate an aura of great mystery. The lack of insight into the pathogenesis of psychiatric illnesses has resulted in ineffective treatments. Given the ubiquity of brain disorders and their significant impact on society, newer and more efficacious treatments are in desperate need.

For the first time ever, optogenetics is beginning to unveil neuronal circuits responsible for brain dysfunction, setting the groundwork for development of better therapeutics. By helping scientists better understand the circuit mechanism of neuronal function, optogenetics is moving us towards a future free of depression, schizophrenia and other brain disorders that devastate individuals, families and society.

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