Home Issue 1, Volume 1 • Alzheimer’s disease: Losing behavioural flexibility

Alzheimer’s disease: Losing behavioural flexibility

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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, these rats’ brains have the same abnormal gene 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 this particular breed of 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.

A test of behavioural flexibility wasdone with the genetically modified rats. This test involved training rats to press a lever only upon appearance of a light above it to receive a sugar reward. 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 a reward 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.

The results of Dr. Whitehead’s study demonstrated that this specific breed of genetically modified rats exhibit impaired behavioural flexibility – these rats could not switch their strategy well. This has a clear similarity to the cognitive impairments of AD patients. Just as cognitive impairments in AD patients generalize to many daily tasks, the deficits shown by these rats were generalized to other measures of behavioural flexibility.

Finally, Dr. Whitehead’s group sought to investigate the underpinnings of behavioural flexibility impairments 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 genetically modified rats to see if there was a correlation with behavioural flexibility. Dr. Whitehead’s group uncovered high levels of brain inflammation in these 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