A protein "switch off" controls cognitive flexibility

A protein "switch off" controls cognitive flexibility

Memory, learning and cognitive flexibility depend on a protein 'off-switch' in the brain, according to a breakthrough discovery made by an international research collaboration.

Researchers have found that the Arc protein - which increases in the brain during learning - needs to be rapidly switched off and removed shortly after we have received new information, in order for us to remember and retain it.

The significance of Arc in regulating the brain's memory and learning process was already known - but the vital importance of its 'off-switch' and removal remained hidden until now.

Cognitive flexibility allows us to learn and adapt to the world around us, picking up and remembering new pieces of information such as visual and audio clues to inform how we act and react to changing situations.

In people living with neurological conditions, such as Alzheimer's disease, cognitive flexibility is reduced - causing altered behavior, confusion, and an inability to learn and retain new information, such as the location of a building or a person's name.

The research suggests that this lack of cognitive flexibility and inability to learn and remember new information could result from Arc protein not being fully switched off and thus persisting in the brain.

Clinical researchers could use this key discovery to better comprehend and treat diseases like Alzheimer's by targeting the 'off-switch', and finding out what causes it to malfunction.

To make their discovery, the researchers generated a mouse with a mutated form of the Arc protein that did not get switched off or removed. They found that mice containing this mutation were behaviorally normal but had specific defects in cognitive flexibility.

Mechanistically, Arc knock in mice had intact spatial learning but showed specific deficits in selecting an optimal strategy during reversal learning. This cognitive inflexibility was coupled to changes in Arc mRNA and protein expression resulting in a reduced threshold to induce mGluR-LTD and enhanced mGluR-LTD amplitude.