Summary: A new study suggests a lack of cognitive flexibility and ability to retain new information may be a result of the Arc protein not being fully switched off.
Source: University of Warwick.
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 co-led by the University of Warwick.
This new knowledge could enable us to better understand and combat neurological diseases which inhibit memory, such as Alzheimer’s.
Dr Mark Wall from Warwick’s School of Life Sciences, with researchers from the University of Bradford and Georgia State University, 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 behaviour, 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.
Dr Mark Wall, Director of Biomedical Science at the University of Warwick’s School of Life Sciences, commented:
“To give an analogy to explain our findings: Imagine you are staying at a hotel for a couple of weeks. After the first week, the manager changes your room but won’t tell you where your new room is located. To find your new room, you would have to test your key in each hotel room door until it opened your door. However, once found, the next time you returned to the hotel, you would be able to locate your room quickly using a series of spatial cues that could include which floor your room was on, how far your room was from the elevator, and whether it was located near a fire exit.
Dr Sonia A.L. Corrêa in the Faculty of Life Sciences at the University of Bradford continued:
“Now, imagine a situation where every time you returned to the hotel you had to test your key in every room door until you found your room. This inability to adjust your strategy to find the location of your new room is known as cognitive inflexibility and this what happens if the Arc protein is not switched off correctly. As we age, this altered behaviour occurs more frequently and more importantly, this type of behaviour is found in some forms of neurological conditions including Alzheimer’s disease.”
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 behaviourally normal but had specific defects in cognitive flexibility.
This study was led by Dr. Sonia A.L. Corrêa in the Faculty of Life Sciences at the University of Bradford and Dr Angela M. Mabb in the Neuroscience Institute at Georgia State University, in the United States in collaboration with Dr Mark Wall from the University of Warwick.
Researchers from the University of North Carolina-Chapel Hill, University of Utah, and Biogen were also involved in this study.
Source: Luke Walton – University of Warwick
Publisher: Organized by NeuroscienceNews.com.
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Original Research: Open access research for “The Temporal Dynamics of Arc Expression Regulate Cognitive Flexibility” by Mark J. Wall, Dawn R. Collins, Samantha L. Chery, Zachary D. Allen, Elissa D. Pastuzyn, Arlene J. George, Viktoriya D. Nikolova, Sheryl S. Moy, Benjamin D. Philpot, Jason D. Shepherd, Jürgen Müller, Michael D. Ehlers, Angela M. Mabb9,’Correspondence information about the author Angela M. MabbEmail the author Angela M. Mabb, and Sonia A.L. Corrêa in Neuron. Published May 31 2018.
The Temporal Dynamics of Arc Expression Regulate Cognitive Flexibility
•Mutation of Arc ubiquitination sites slows Arc degradation
•Arc knockin mice have enhanced mGluR-LTD
•The persistence of Arc reduces cognitive flexibility
Neuronal activity regulates the transcription and translation of the immediate-early gene Arc/Arg3.1, a key mediator of synaptic plasticity. Proteasome-dependent degradation of Arc tightly limits its temporal expression, yet the significance of this regulation remains unknown. We disrupted the temporal control of Arc degradation by creating an Arc knockin mouse (ArcKR) where the predominant Arc ubiquitination sites were mutated. ArcKR 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. These findings show that the abnormal persistence of Arc protein limits the dynamic range of Arc signaling pathways specifically during reversal learning. Our work illuminates how the precise temporal control of activity-dependent molecules, such as Arc, regulates synaptic plasticity and is crucial for cognition.