ATLANTA—An important breakthrough in understanding the mechanisms in the brain that control cognitive flexibility has been made by an international team of scientists.
Scientists from Georgia State University, the University of Bradford and the University of Warwick have found a protein known as Arc regulates this process. Their findings are published in the Cell Press journal Neuron.
Imagine the following scenario: You recently moved to a new home. However, you forget the new location of your home and inadvertently visit your old home day after day. This inability to learn how to find the location of your new home is known as cognitive inflexibility, and as we age, this altered behavior occurs more frequently. More important, this behavior is found in some forms of neurological conditions, including Alzheimer’s disease.
Previously, Arc was known to be critical for learning and memory, increasing during learning and then rapidly being switched off or removed thereafter. However, the significance of Arc removal was unknown. To understand the importance of this Arc “off-switch,” researchers generated a mouse that expresses a mutated form of Arc that does not get removed. They found that mice containing this mutation appeared normal but had specific defects in cognitive flexibility.
This study highlights the importance of Arc in learning and memory and shows that proteins not only need to be switched on, but also need to be removed at the correct times for proper learning. More important, these findings show for the first time that the dynamic expression of a single protein has profound implications in replacing a previously learned task with a new one.
This research project was led by Dr. Angela M. Mabb, assistant professor in the Neuroscience Institute at Georgia State, and Dr. Sonia A.L. Corrêain the Faculty of Life Sciences at the University of Bradford, in collaboration with Dr. Mark Wall from the University of Warwick in the United Kingdom. Former undergraduate Samantha Chery, graduate student Arlene George and researcher Zachary Allen in the Neuroscience Institute were co-authors on this study. Researchers from the University of North Carolina-Chapel Hill, University of Utah and Biogen were also involved in the study.
“It’s scary to think that the abnormal removal of one single protein [Arc] in the brain can cause this type of altered behavior,” said Mabb, who is also in the Center for Behavioral Neuroscience at Georgia State.“We are currently conducting new experiments in the lab to examine this more closely with the goal of identifying novel drug targets for neurological conditions, such as Alzheimer’s disease, which are known to have cognitive inflexibility.”
To read the study, visit https://www.cell.com/neuron/fulltext/S0896-6273(18)30384-2.
This image shows a dimensional perspective related to the changing rules of a room location. The successful completion of this task could be related to Arc actions on multiple forms of synaptic plasticity, which are known to be important for learning. In particular, the Arc “off-switch” controls a form of synaptic plasticity called metabotropic glutamate receptor long-term depression (mGluR-LTD) that, under normal induction, allows the mouse to efficiently find the doorway exit shrouded in a stairwell of dimensions. (Image was created by Fernanda Tallard, a Neuroscience B.S. graduate at Georgia State.)
Reference:
Wall MJ, Collins DR, Chery SL, Allen ZD, Pastuzyn ED, George AJ, Nikolova VD, Moy SS, Philpot BD, Shepherd JD, Müller J, Ehlers MD, Mabb AM, Corrêa SAL. (in press). The temporal dynamics of Arc expression regulate cognitive flexibility. Neuron.
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For more information on Dr. Mabb and the research being conducted in her laboratory, visit https://neuroscience.gsu.edu/profile/angela-mabb/.
For more information on the Neuroscience Institute, visit https://neuroscience.gsu.edu/.
For more information on the Center for Behavioral Neuroscience, visit https://www.cbn-atl.org/.
Featured Researcher
Dr. Angela Mabb
Assistant Professor
Neuroscience Institute, Center for Behavioral Neuroscience
Dr. Mabb’s lab is focused on understanding how disruptions in ubiquitin pathways in the nervous system lead to a multitude of neurological disorders. Her approach is to utilize and develop molecular biology methods and tools to explore ubiquitin pathways involved in nervous system function and disease. In her lab, there is a strong emphasis on in vitro neuron culture preparations, generation of transgenic mouse models, imaging and animal behavior.