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Alzheimer’s disease: Losing behavioural flexibility


Adapted from image by CNX OpenStax under Creative Commons Attribution 3.0 Unported license

On board game night, you embark on a night of fun, moving tiny figurines around a table, picking up various playing cards, and trying to outcompete your friends. This is a familiar setting. Every week the same friends join you to play the same three games you happen to own, each with rules you have learned by heart. That is until, a new player arrives. This novel companion claims to know these games you have been playing for years, but that they play by different rules. How well will you be able to compete under these circumstances? Will you be able to adapt your well learned strategies to accommodate the new rules? If this does not sound like a challenge to you, you probably have high behavioural flexibility. Behavioural flexibility is a function of the brain that allows an animal to learn rules of a game then switch their strategy for success when the rules change. If you find yourself struggling to accommodate new rules during board game night, you may be having a hard time switching strategies and this could be an indication of a problem in the brain.

Alzheimer’s disease (AD) is a neurodegenerative disease most commonly occurring in the elderly, with a brutal decline in cognitive ability over the course of decades. A new study published in the journal Brain Behaviour and Immunity by Alexander Levit, an MD/PhD Candidate working in Dr. Shawn Whitehead’s research laboratory at Western University, shows how impaired behavioural flexibility could be an indication of AD onset caused by particular changes in the brain’s immune system. To make this discovery, Dr. Whitehead’s group used a special breed of genetically modified rats, TgAPP21, that have the human version of an AD associated gene expressed in their brain. In fact, the mutations present in the AD associated gene that TgAPP21 rats express is only found in people who have AD onset extremely early; typically younger than 65. Whereas many studies have used rodent models with severe brain pathology and age-related memory decline to study AD, Dr. Whitehead’s group chose to use TgAPP21 rats at an age where these hallmarks of late stage AD are not present. Instead, these rats exhibit brain pathology and behaviour more reminiscent of early AD. Modeling early AD allows for understanding of a stage of AD where therapeutic intervention is more feasible compared to late stages in the disease where too much of the brain is already lost.

Two different tests of behavioural flexibility were done with the TgAPP21 rats. The first test involved training rats to press a lever only upon appearance of a light above it to receive a piece of food. This training continues until this rule is just as easy to remember for the rat as it is to remember doubles in the game Monopoly means roll again. Then, Dr. Whitehead’s group changed the rules. Now, the rats can only receive food by pressing the lever to one side, regardless of the light’s position. If rats are unable to adhere to this new rule, then this is an indication of a behavioural flexibility impairment.

A second paradigm for testing behavioural flexibility was also used in Dr. Whitehead’s rat study. Rats were taught to find an invisible escape platform in a tank of water using only spatial cues outside the pool, then the platform is removed on the last day to evaluate if the rat remembers the region where the escape platform used to be. Usually rats manage to swim to the correct region in a minute flat. But, given more time to explore, normal rats figure out that the platform is missing and begin to look elsewhere. Like in the game Clue where you must search for the murder location and rule out rooms by asking other players what they know, the rats rule out areas of the pool by feeling around for where the platform is not. By simply allowing rats to explore without the platform for additional time, Dr. Whitehead’s group were able to measure if they could learn that escape is no longer in the region where it used to be. No, it is not the billiards room, stop asking. If rats do not follow the new rule and increase exploration in the region where the escape platform used to be, then this indicates impaired behavioural flexibility.

Finally, Dr. Whitehead’s group sought to investigate the underpinnings of impaired behavioural flexibility in TgAPP21 rats and decided that brain inflammation was a good candidate because it has been shown to occur in the brain of AD patients. Just as a grazed knee becomes hot, red, and swollen, so does the brain when it is injured. This physiological response is called inflammation and it is mediated by immune cells. In the brain, microglia are the immune cells which are activated when certain regions are inflamed. To draw a connection between the two phenomena, behavioural inflexibility and brain inflammation, Dr. Whitehead’s group sought after evidence of inflammation in the brain of their TgAPP21 rats to see if there was a correlation with behavioural flexibility.

The results of Dr. Whitehead’s study demonstrate that TgAPP21 rats exhibit impaired behavioural flexibility in both methods used to test them, a clear similarity to the cognitive impairments of AD patients. Whether the rules changed were about lights and levers or a platform in a pool, TgAPP21 rats could not switch their strategy well. Just as cognitive impairments in AD patients generalize to many daily tasks, the deficits in TgAPP21 rats were generalized too. Furthermore, Dr. Whitehead’s group uncovered high levels of brain inflammation in TgAPP21 rats, quantified as level of activated microglia, that could significantly predict how impaired each rat’s behavioural flexibility was in the lever pressing task.

There are many reasons why one might want to stick to the classics and continue to play old games like Monopoly and Clue. But, if there is any way to help prevent AD patients from being unable to learn new rules to games and generally help prevent decline in cognitive abilities such as behavioural flexibility, then discovering the molecular underpinnings of AD is crucial. These findings from Dr. Whitehead’s lab demonstrate that brain inflammation occurs in a model of early stage AD and correlates well with impaired behavioural flexibility, which means that inflammation could be part of what triggers AD initially and warrants further investigation if preventative measures that reduce brain inflammation are to be discovered.

Original Research Article: Levit, A., Regis, A.M., Gibson, A., Hough, O.H., Maheshwari, S., Agca, Y., Agca, C., Hachinski, V., Allman, B.L., and Whitehead, S.N. (2019). Impaired behavioural flexibility related to white matter microgliosis in the TgAPP21 rat model of Alzheimer disease. Brain. Behav. Immun. 80, 25–34. https://doi.org/10.1016/j.bbi.2019.02.013

Author:::Ariel Frame