EB2013 ASPET Blogging: Flexible Brains! Cognitive Flexibility and the GABAA Receptor

Figure 1: Layers of nesting dolls. Source

You've seen Russian nesting dolls, right? The kind that hide inside each other and every time you think you've gotten to the smallest one you realize there is one still smaller inside? Scientific research is a lot like that. Often, just when we think we have something figured out we realize there is another layer of complexity beneath. When it comes to the body and the brain, often the little things make a big difference.

We’d all like to think we’re flexible but when it comes to the brain, flexibility isn’t like yoga and putting your feet behind your head. Cognitive flexibility is the ability to switch between tasks smoothly. An example of how to test cognitive flexibility in humans is the Stroop Test. In this test, there is a list of words in different colors. But the words are colors… for example, the word “blue” in red print. So: blue. The subjects are asked to read the color of the word and NOT the word. Then they’re asked to read the word and NOT the color that it is. You can try it here. Being able to easily switch between the two tasks is an example of cognitive flexibility. It’s harder than it seems. I kind of suck at it. I don’t know if I want to know what that means.

In real life situations, an example of cognitive flexibility is being able to get used to a change in plans at the last minute. Maybe you had a meeting scheduled for 3:00 pm but the meeting was canceled at 2:45 pm and you’ve been asked to give a tour of your place of work instead. In autism spectrum disorder, patients have a difficult time switching their thinking like this. It’s often called rigidity of thought or rigidity of behavior.

Back to the nesting dolls, we’re going 6 layers deep in this nest. Here we go. Behavior is brain-based; we have to think of something and process it in order to do it. So layer 1 is the brain. One area of the brain that is important in cognition is the hippocampus: that’s layer 2. Within the hippocampus is layer 3: an area called the dentate gyrus which is involved in specific types of cognition such as separating patterns.

Figure 2: Brain showing the hippocampus,outlined 

in yellow, and the dentate gyrus in blue. Source

There are cells in the dentate gyrus, called interneurons, which inhibit the signals in other cells, called granule cells (layer 4). The inhibition is produced by a release of chemicals that bind to receptors (layer 5) on the granule cells. These receptors are made up of several subunits (layer 6). We made it! Whew. Here’s your cheat sheet.

Brain > hippocampus > dentate gyrus > cells  > receptors > receptor subunits

Figure 3: GABA_A receptor showing subunits.Source

In Dr. Uwe Rudolph’s lab at McLean Hospital and Harvard Medical School, they study the GABA_A receptor and its involvement in cognitive flexibility in mice.  Dr. Elif Engin, an Instructor and researcher, is interested in how a subunit of the GABA_A receptor mediates this behavior. GABA_A receptors can be made of several types of subunits (Fig 3) but the one Dr. Engin is interested in is called alpha 5 (α5).

The dentate gyrus has a high level of tonic inhibition, which means that it takes a large stimulus to activate the granule cells. Once activated, the granule cells send signals to other cells to activate them. This allows for sparse activation - so small groups of cells are activated with each stimulus rather than every cell being activated with each stimulus. GABA_A receptors that contain an α5 subunit are partly responsible for tonic inhibition in the dentate gyrus.

In this study, they used mice lacking the α5 subunit of the GABA_A receptor ONLY in the granule cells of the dentate gyrus. Everywhere else in the brain the α5 subunit was right where it should be and functioning great. What they found when they got rid of it in the dentate gyrus was pretty neat. The animals learned simple behavioral tasks as good as or better than normal animals but whenever a test depended on the ability to switch tasks, the mice did poorly when compared with the normal mice.

For example, in a test where the mice were placed in a tub of water and had to swim to find a submerged platform, the mice lacking the α5 subunit learned how to find the platform just as well as the normal mice. After learning the task, the researchers made it a little more difficult: they moved the platform to another location and plopped the mice back in the water. This time, the mice lacking the α5 subunit in the dentate gyrus did poorly when compared with the normal mice. They kept swimming around the area where the platform had previously been. Their little brains insisted the platform must be there somewhere and they couldn’t fathom that it would be elsewhere. Even after several more days of swimming around in the tub, they still hadn’t learned how to find the platform easily.

Dr. Rudolph and Dr. Engin’s research is interesting because others have shown that blocking the α5 subunit can actually enhance learning and memory… but only in simple behavioral tasks. No one has ever studied the α5 subunit and cognitive flexibility until now. It seems that while blocking the α5 subunit could help with simple tasks, it is a different story as the tasks get harder.

The research is relevant to real world situations and many psychiatric disorders. Dr. Engin said the most obvious disorder is autism in which the patients have a very difficult time transitioning between activities or thinking. She said, “People with autism are sometimes very good at certain cognitive tasks like memorizing long strings of words. However, switching between tasks is very difficult for them.” An example of a high functioning autist is Sheldon Cooper from the Big Bang Theory. No, they don’t come right out and say he’s autistic on the show but many of his behaviors are similar to those with autism spectrum disorder. Despite the fact that Sheldon has the ability understand very complex concepts that are difficult for most of us, he has a hard time with some daily situations because of his rigid thinking patterns and strong desire to keep a repetitive daily routine.

Dr. Engin’s research suggests that some of our ability to switch tasks could be due to the changes in the GABAA receptor and the α5 subunit. While autism spectrum disorders have a complex origin, involving a multitude of genetic and environmental influences, understanding how the α5 subunit is involved in cognitive symptoms can help us understand such disorders better and how they work.