How neurons spark flexible decisions

15 July 2019

Dr Alex Kwan (Croucher Fellowship 2009) didn’t originally plan to become a neuroscientist. Growing up, he dreamed of a career as a computer programmer.

Kwan, whose family emigrated from Hong Kong to Vancouver, Canada, when he was 12 years old, recalled: “I took biology classes in high school, but I thought it was very boring.” So after school, he went on to pursue a BASc in Engineering Physics from Simon Fraser University before embarking on a PhD in Applied Physics at Cornell University.

Kwan’s initial graduate rotations were in labs studying condensed matter physics, but he ended up joining a biophysics lab, where he tinkered with microscopes and developed optical methods to visualise biological samples. He still remembers the moment that sparked his interest in neuroscience.

“I was slicing a mouse brain using a vibratome, and I was struck by the beauty of the organisation of the cortex and the hippocampus,” he recalled. “The anatomy of the structures is very striking. I thought, there must be something to this.”

After finishing his PhD, Kwan joined the University of California, Berkeley, as a postdoctoral researcher, supported by a Croucher Fellowship. He credited the fellowship with giving him the freedom to choose what he wanted to study. The lab had previously focused on the visual cortex, but Kwan was one of the first in the team to move to study the prefrontal cortex.

Kwan joined the Psychiatry Department at Yale University in 2013, where he is currently an associate professor. His lab studies how the prefrontal cortex contributes to flexibility when making decisions in an ever-changing environment.

He explained flexible decision-making with an example: “When you’re crossing the street, you might first look left or right, depending on the context, that is, if you are in the United States or Hong Kong. The nervous system can be flexible in choosing these actions based on context and prior experiences.”

The lab mainly uses optical microscopy to generate images of neuronal activity, and manipulates neural circuits using optogenetics. Kwan’s background in physics has been useful for this line of research, as his lab often builds the team’s own instruments and constructs computational models to interpret animal behaviour data.

In a study published in Nature Neuroscience, Kwan’s team recorded the activity from large groups of neurons in the mouse prefrontal cortex. To investigate flexible decision-making, the researchers used an auditory cue to signal the mice to lick the left or right port of a water reservoir. Licking the correct port rewarded them with a drink of water.

However, the rules for which auditory cue indicated left or right changed over time. The mice had to notice the change and adapt their responses accordingly.

Kwan’s group found that if they imaged a large enough ensemble of neurons in the prefrontal cortex they could use the pattern of activity to identify the current rule. In addition, the rule-related signal would sometimes change in the brain, even before the mouse changed its behaviour. This suggests that the prefrontal cortex has a leading role in driving rule-changing behaviour.

More recently, Kwan has developed an interest in psychiatric drugs. “Many people are taking drugs for mental illnesses, but not much is known about what the drugs do to neural circuits and brain activity,” he explained.

His latest research, available on the preprint server BioRxiv, investigated the action of ketamine, the primary ingredient for an intranasal antidepressant that was recently approved by the Food and Drug Administration in the United States. Kwan’s team administered ketamine to mice and imaged individual dendritic spines (the part of a neuron that can receive a signal input) within the prefrontal cortex.

They found that ketamine causes increased flow of calcium into the dendritic spines in prefrontal cortex pyramidal neurons. This was unexpected, since ketamine is known to inhibit the N-methyl-D-aspartate (NMDA) receptor, which normally opens to allow calcium to enter a cell.

Imaging the flow of calcium ions in single dendritic spines. Still frames from a time-lapse movie taken in the prefrontal cortex of an awake mouse using a laser-scanning microscope. The concentration of calcium ions is visualized using a fluorescent calcium indicator. Sometimes, calcium is seen in all or parts of the dendritic branch, indicative of a widespread electrical event. Other times, calcium influx is highly localized to the dendritic spines. Image credit: Farhan Ali, Alex Kwan (Yale University).

Upon further investigation, the team realised that ketamine was also acting on NMDA receptors for another neuronal subtype, GABAergic interneurons (named because of their release of gamma-aminobutyric acid). These interneurons play a vital role in neural circuitry and activity by inhibiting pyramidal neurons. But by inhibiting the interneurons, ketamine disinhibits the pyramidal neurons, resulting in increased calcium intake.

Kwan believes that this process could contribute to increased plasticity in the prefrontal cortex, which may mediate ketamine’s antidepressant effects. He is hopeful that by better understanding ketamine’s mechanisms, his research can be useful for developing better alternatives, with fewer side effects.

His own flexible decision-making, in his career and research interests, could now have long-term benefits for the treatment of mental health problems.

Dr Alex Kwan received a BASc in Engineering Physics from Simon Fraser University and a PhD in Applied Physics from Cornell University. At Cornell, he developed nonlinear optical microscopy methods in the laboratory of Watt Webb. In 2009, as a Croucher Fellow, he went to the University of California, Berkeley, to work in the laboratory of Yang Dan, where he studied cortical GABAergic interneurons. He joined the Yale School of Medicine in 2013. Research in the Kwan lab focuses on the mouse prefrontal cortex. The lab is interested in how circuit mechanisms enable flexible decision-making, and how dendritic dysfunctions underlie neuropsychiatric disorders. The lab’s expertise lies in developing and applying optical methods to record and control neural activity in behaving mice. Kwan received a Croucher Fellowship in 2009.

To view Dr Kwan’s Croucher profile, please click here