Optogenetics has revolutionized brain research in recent years. Using light, Marie Carlén and her colleagues can turn selected neurons on and off and see the direct effect on behavior. This enables the team to piece together the brain’s networks with its activities, knowledge shedding light on the cause of mental illness, among other things. In future it is hoped that this will lead to more effective drugs to combat schizophrenia, for example.
Associate professor in neuroscience
Wallenberg Academy Fellow/Wallenberg Scholar
Linking animal behavior with various brain functions using optogenetics to study cognition and the causes of mental diseases.
As a Wallenberg Academy Fellow, brain researcher Marie Carlén is working to improve our knowledge of the role played by the brain in mental illness. The aim is to understand cognition better – brain functions such as attention, memory, social skills and emotions.
For instance, a person diagnosed with schizophrenia displays cognitive impairment, which may hinder the performance of day-to-day tasks, such as showing up to work or the ability to make decisions. The challenge is to understand how the brain performs cognitive processes in the first place, and how this is changed in psychiatric disorders.
“If we succeed, we will not only learn about mechanisms underlying mental illness; we can also provide guidance in the development of new and improved medicines,” Marie explains.
And now there is a technology that enables the researchers to control brain activity. Karl Deisseroth at Stanford University paved the way for the new field of optogenetics in 2005. The method involves modifying selected neurons in the brains of laboratory animals with a gene that produces a light-sensitive protein. The cells that have been modified can then be turned on and off like a switch with the help of light from a laser or an LED.
Marie heard about the new method during her time as a postdoc at MIT in Boston. At the time her main field of research was stem cells, and she had come to a dead end.
“I had given up and didn’t know what area of research to turn to next, when I heard about optogenetics. It struck me that it ought to be possible to use the technology to try to change brain activity in mice to try to mimic the processes occurring in mental illness.”
If the laboratory animals displayed the same deviant behavior as that seen in patients, this would clearly indicate which neurons in the brain are involved in mental illness. The first study was published in 2009 in collaboration with Deisseroth’s research team, and the findings whetted researchers’ appetites.
“I see it as recognition that many eminent researchers believe in what I am doing. It is very gratifying that other people have faith and are willing to invest in me as a researcher. The funding also allows me to adopt a bolder approach. Now I will be able to carry out the projects that I would otherwise only have been able to think about doing.”
Neurons controlling information
Marie is now continuing her research back in Sweden at Karolinska Institutet by studying numerous cell types in different regions of the brain. Particular attention is paid to neurons called parvalbumin, PV, interneurons. These inhibit other neurons, thereby determining when other neurons can be active.
“PV interneurons play a central part in the way the brain processes information. They dictate which neurons are active, and when, thereby creating patterns and networks of activity, which can be likened to a code. I want to crack that code and understand it, since it underlies cognitive thought processes, for example.”
It is also possible to measure electrical activity in the brain and thereby see that PV interneurons affect rhythmic signals in the brain called gamma oscillations. Brainwaves are normally synchronized when we perform various cognitive thought processes, e.g. when we concentrate on a task. But synchronization of brainwaves is disrupted in those suffering from schizophrenia, a phenomenon that may be caused by changes in the activity or function of PV interneurons.
“We used optogenetics in mice to show that PV interneurons can generate gamma oscillations all on their own. The theory had existed for more than forty years, but we were the first to demonstrate it in a living brain. By manipulating the activity of PV interneurons using optogenetics in mice, the team has also been able to show how this results in deviations in the animals’ attentiveness and memory– direct evidence of the central role played by neurons of this kind and by inhibition in cognitive thought processes.”
Complex mental diseases
Marie is at pains to stress that mental illness is a complex subject. It is not possible to study hallucinations and delusions in rodents. But it is possible to select cognitive problems, certain fundamental thought processes, and identify a strong link to humans.
“It is not meaningful or realistic to model an entire disease like schizophrenia, but using this approach we can study fundamental aspects of the disease for the first time. Our type of research also shows that mental illness does not mean “being crazy”; it is a state in which the brain does not function normally.”
Marie speaks in almost philosophical terms, and traces of her Ångermanland accent remain, reflecting her childhood years growing up in the High Coast region of northern Sweden. She has not taken the direct route; she began by studying medicine, but dropped out to take a four-year sabbatical before studying biology at Stockholm University. But idea-driven research has ended up being her great passion.
“Anyone can be a researcher. You don’t need to have attended special schools or have parents who are researchers or doctors. But researchers need to be bold – it is the only way to succeed, whether or not money is available. If you have the interest and the will, there is no limit to how far you can go.”
Text Nils Johan Tjärnlund
Translation Maxwell Arding
Photo Magnus Bergström