Janelia Farm Research Campus
Dr. Karpova is a group leader at the Janelia Farm Research Campus.
Neural Circuits Underlying Reward-Dependent Behavior and Their Perturbation in Diseases of Perseveration
Alla Karpova's lab is interested in the neural circuits underlying action selection in the context of voluntary choice and their dysregulation in neurological disorders. Her lab employs quantitative decision-making behavior in rats and mice; specific perturbation of neural circuit function, using molecular tools; and sophisticated electrophysiological and optical techniques to find neural correlates of the interesting aspects of the behavioral tasks.
Alla Karpova says she became a biologist "by accident." Born and raised in St. Petersburg, Russia, by parents who were scientists, Karpova recalls that she "first fell in love with chemistry in high school and took a lot of chemistry courses. My school wasn't strong in biology, so I didn't learn biology until I was in college."
When she came to the United States, she had a feeling that applying chemistry to biology might be more interesting. "When I went to the University of Chicago, I naïvely assumed that biochemistry was just a biological aspect of chemistry," she says. "So, I thought, 'Great! I'm going to major in biochemistry.' That was the notion I came to college with, and that was my first real exposure to biology. I just fell in love with it. The elegance of it completely captivated me and still does."
Karpova's intellect shone at the University of Chicago, where she was named a Selz Scholar, an honor awarded to the woman who completes her freshman year with the highest grade point average. She moved to Harvard University for graduate studies in molecular cancer biology with Peter M. Howley and was named a Howard Hughes Medical Institute predoctoral fellow.
Karpova, a lab head at the Janelia Farm Research Campus, is now drawing on her interests in chemistry, biology, and biochemistry to develop a suite of powerful tools that selectively switch off neurons. The tools have been built around a chemical technique for inducible crosslinking of proteins and are called MISTs, which is an acronym for molecular systems for inactivation of synaptic transmission. She developed the approach during her postdoctoral fellowship in the Cold Spring Harbor Laboratory of HHMI investigator Karel Svoboda, who is also a Janelia lab head.
MISTs allow researchers to silence communication between neurons by injecting a drug that induces the linking, or dimerization, of molecules critical for transmission of nerve impulses from neuron to neuron across a synapse. The beauty of MISTs, says Karpova, is that the silencing is rapid, specific, and reversible.
"Older methods of silencing neurons inactivate synapses by inducing transcription of toxins, such as tetanus toxin," she explains. "They can take several days, whereas MISTs work on the scale of minutes or hours. So, you can block neurotransmission and study the neural and behavioral effects quite readily."
There are rapid approaches to silencing synapses that are based on inactivating ion channels. "But those approaches inactivate all of a neuron's connections. And many types of neurons send axonal connections to many different areas of the brain, so if you shut down an entire neuron, it is difficult to figure out which particular connection is important for the circuit you are studying," she says. MISTs act locally at a specific synaptic terminal and therefore have the potential to allow scientists to test if the observed effects—for example, in behavior—are a direct consequence of silencing that particular terminal.
Karpova became acutely aware of the importance of this method while probing the role of the reward system in the mouse brain. "While I was developing this tool to alter synaptic transmission, I became interested in how a neurotransmitter called dopamine, which is widely believed to be central to the processing of reward, affects a part of the brain called the cortex. I discovered that while a mouse is growing up, the development of the neuronal circuitry in a particular part of the cortex is strongly dependent on dopamine. But I realized I wouldn't be able to probe the role of different parts of the reward system without tools such as MISTs; it just wasn't possible to manipulate parts of the system precisely and specifically."
Karpova plans to use MISTs, in combination with other neuronal silencing techniques, to characterize and trace the neural circuitry of the reward system. "I hope to be able to use these methods, in combination with other tools, to better understand how rats and mice perform what comes naturally to all animals: learning and relearning the link between events and pleasurable outcomes." She will use MISTs to produce targeted perturbations of components of this reward circuitry, so she can determine which of those components are important for the reward circuit's function.
Although she will continue to develop new tools such as MISTs for the research community and apply them to basic studies, Karpova's research philosophy also emphasizes applying those tools to help in understanding mental disease. "I really want my work to have a tangible link to disease, because it is more fulfilling to me personally to contribute to understanding disease and helping people," she says.
Karpova's studies of the reward circuitry, for example, will aim at understanding how that system goes awry in disorders such as drug addiction and obsessive-compulsive disorder. "I hope the animal studies of this system will help us understand such diseases of perseveration, in which people continue to do something despite a detrimental outcome," she says.
Karpova says MISTs themselves may ultimately have clinical application. They might be used in therapy for disorders such as epilepsy and Parkinson's disease that are caused by neuronal hyperactivity in regions of the brain. MISTs could be used to selectively silence that hyperactivity, she says. For example, clinicians could use the reversible technique to temporarily shut off specific neural circuits to pinpoint the focus of epileptic seizures or Parkinson's symptoms. Such information could be used as a diagnostic to guide surgical or other therapeutic interventions.
In Karpova's opinion, the major strengths of Janelia are its collaborative atmosphere and the freedom to do research. "Having the major administrative responsibilities taken off your shoulders gives you the time to devote to research and mentoring people," she says. "I really enjoy doing science, and I highly value good mentoring. Throughout the early stages of my career, there have been several established scientists, sometimes even outside of my institutions, who have been so generous with their time in helping me learn and evolve my ideas and in giving me valuable advice on career development. I would have never been where I am right now without their support."
"Janelia affords an incredible opportunity both to do excellent science in a wonderfully open and collaborative environment and to mentor young scientists. So, as a lab head, I hope to contribute not only my scientific skills, but my efforts at mentoring people in my lab as well as others," says Karpova.