People have long been fascinated with the brain. Writings on the body’s most mysterious organ date as far back as the 17th century BC. As Melissa R. Warden, Neurobiology and Behavior, puts it, her lab is addressing old questions using new technologies.

Specifically, Warden and her research team ask questions about the neural circuitry that mediates motivation and reward. Why, when in a challenging situation, do we sometimes give up and other times work really hard? How does dysfunction in motivation manifest as disease, like depression? The tools to answer such questions include an array of recently developed technologies, including optogenetics and imaging.

“These developments make it possible for us to ask really new and very interesting questions about brain function—questions that couldn’t be answered with classical techniques,” Warden says.

Before Optogenetics

Such older methods of study include electrical stimulation, in which electrical current is run through the brain to activate cells in a certain area, and pharmacology, for which researchers apply drugs to the brain to target specific receptors. Both approaches have been used widely to probe brain function and have resulted in many critical discoveries. Nonetheless, they do have limitations. Pharmacology operates on a very slow timescale in comparison to the brain’s millisecond-precision speed, and electrical stimulation affects many circuits, so it’s difficult to determine the specific functions of different types of neurons using this approach.

As a graduate student, Warden spent her time recording the electrical activity of neurons. She says that although the beauty of finding correlates of behavior in single cortical neurons blew her away, she became frustrated by the fact that she had no idea what kinds of neurons she was recording. She had no way of controlling what neurons to target in the brain. “I didn’t feel like we could actually understand a neural circuit until we started connecting this functional data with the underlying anatomy,” she says.

Toward the end of her PhD work, she spent a summer reading papers in the field. During this time, she stumbled upon the first optogenetics paper by Karl Deisseroth. “I read that paper and it was over. That was the direction I was going in,” she says. “It was very exciting because you got the sense that there was a lot of energy, there was a whole revolution sweeping the field.”

Optogenetics, a Revolutionary Technique

Optogenetics is a technique that uses light to control the activity of a genetically defined population of neurons in the brain on a millisecond timescale. Deisseroth’s lab discovered that you could insert “opsin” proteins into cells to make them responsive to certain types of light. The opsin reacts to light, absorbing a photon and changing. They specifically introduced channelrhodopsin-2, a protein from green algae, into mammalian neurons and found that they could turn neurons on and off with pulses of light. In 2010, optogenetics won the Nature Methods Method of the Year.

Warden went on to a postdoctoral fellowship in Deisseroth’s lab. There, she used optogenetics to stimulate brain cells responsible for motivation in rats. She found that the prefrontal cortex is crucial for motivated behavior in challenging situations. Optogenetically stimulating projections from the prefrontal cortex to the dorsal raphe nucleus (which is located in the midbrain and is the largest provider of serotonin to the brain) induced motivated behavior, while projections to the lateral habenula decreased motivation.

Optogenetics Help Answer Neurobehavioral Questions about Depression and Motivation

Now at Cornell, Warden’s lab is interested in using optogenetics to further probe communication between brain areas. In one project they are looking at serotonin neurons to see where they project in the brain. The goal is to better understand how specific serotonin projections are involved in depression symptoms such as melancholy, apathy, disturbed sleep and eating, and more. If they can identify the neural circuits that mediate specific components of depression, it might be possible to come up with very targeted therapeutics.

Optogenetics is a technique that uses light to target and control the activity of a single neuron in the brain, on a millisecond timescale.

Warden says that she is also interested in exploring more basic questions related to motivation in the brain. For example, how does one allocate energy and decide between staying where you are versus exploring new options? Which circuits are tied to being satisfied with a situation and which prompt a burst of energy to get out of it?

Warden received a $1.5 million grant in 2013 from the New York Stem Cell Foundation to pursue such research. She more recently received the NIH Director's New Innovator Award for $1.5 million, as well as the Sloan and Whitehall research fellowships.

Doing research at Cornell has been especially helpful in working toward answering these questions, Warden says. For example, she is actively pursuing several new imaging methods in order to get a fuller picture of the brain. To do this, she is collaborating with Chris Schaffer, Biomedical Engineering.

“Talking to people like Chris, who has a very deep expertise in imaging and a lot of on-the-ground knowledge, has been very helpful,” Warden explains.

She credits the university’s wide variety of research interests for helping her expand her own questions. “I have a lot of freedom to pursue different directions,” says Warden, and adds that the close proximity to other experts is a boon to her work. She says, “the engineering is spectacular here and given our focus is in using new technologies in the brain, I feel like this is a place where I have access to new developments in technology.”