biology
Shedding Light on the Mysteries of the Brain and Behavior By Neil Mehta interviewing Dr. Andrew Leifer Designed by Jessie Liu and Erica Tsai
Ever wonder how our brains are able to grasp complex activities, such as playing an instrument or driving a car? How about riding a bike or turning a doorknob? Such everyday activities, called “motor-sequence behaviors,” are a fascination to neuroscientists around the world because they require a precise coordination between many different groups of brain cells, or neurons, and muscles. Here at Princeton, Dr. Andrew Leifer of the Lewis-Sigler Institute for Integrative Genomics is studying this very phenomenon. His work attempts to understand how different connections between neurons are responsible for such coordinated behaviors and habits in organisms. “Currently, we know how individual neurons function, and how large areas in the brain are related to behavior,” explains Dr. Leifer. “But what we don’t know is how small neural circuits can play a role in behavior. How are small, individual neural circuits relevant to behavior? How can they affect stuff like motor memory and addiction, etc?” Dr. Leifer’s goal is to understand how different combinations of neurons can result in this coordination of complex movements so fluidly in everyday life. He approaches this research by using what biologists call “model organisms,” specifically the worm C. elegans. These worms are useful because scientists have fully mapped out the genome of the worm, and know how every single cell in this worm is 16
created and dies, and how all 302 neurons of this worm are connected, and therefore there is a large knowledge basis that can be used for researchers to take advantage. Dr. Leifer activates or inactivates individual neurons in the worms to see how that affects motor sequence behaviors, such as turning around when the worm bumps into an object. But how is it possible to activate or deactivate one or two specific neurons in an organism? How is it possible to understand how all the neurons in C. elegans interact with its approximately 100 muscle cells, both directly, and indirectly, to coordinate various motor-sequence behaviors? Dr. Leifer and other neuroscientists have ingeniously implemented a novel technique in neuroscience, called optogenetics, to aid in their research. In optogenetics, scientists force neurons to express special proteins. These proteins, depending on which ones the researchers use, can either activate or inactivate the neuron or group of neurons, when hit with a specific color of light. For example, the protein channelrhodopsin-2 activates neurons that express it when those neurons are hit with blue light, and the protein halorhodopsin inactivates neurons that express it when those neurons are hit with yellow light. In this way, neuroscientists can specifically ask how changing one neuron can affect the behavior of an entire organism! For example, in the worm C. elegans, optogenetic
activation of the worms’ sensory neurons causes the worm to back up, turn around, and continue to move in a random direction different than before. This reaction is the exact same as the worm’s reaction to bumping into an obstacle. Expressing halorhodopsin in the worms’ sensory neurons and shining yellow light on the worms, however, prevents this behavioral response when the worms swim into an obstacle! In
Researchers can use complex genetic engineering to get these proteins expressed in any neuron of their choosing. some cases, the results are very surprising, and scientists have concluded that some specific neurons are essential for some very important behaviors of model organisms. Furthermore, researchers can use complex genetic engineering to get these proteins expressed in any neuron of their choosing, hence the name optogenetics (opto → light, genetics → controlling protein expression). Optogenetics is widely used in model organisms, such as rats and mice, to control neural circuits, and in turn study the function these neurons have in behavior in these organisms. Because the anatomy and genetics of the worm C. elegans are so well known, and because these worms are optically trans-