How Do We Learn and Remember?
For many years, this question has fascinated former graduate student Erica Korb. In fact, she decided to study it for her PhD thesis research at Gladstone and UCSF. Her work recently culminated in a significant paper in the journal Nature Neuroscience that sheds new light on this problem.
“I always wondered how our brains learn,” said Dr. Korb. “I used to play the violin. I was often amazed at how a piece that initially seemed impossible to play would become easier and easier as I practiced it again and again until eventually I knew it by heart. I wondered how the brain could practice into memories.”
Her research supervisor Steven Finkbeiner, a senior investigator at Gladstone, agrees that playing the violin is a great example of learning and memory. “As Erica played, her brain quickly strengthened connections between specific brain cells and makes new proteins to secure the memory. That process is fairly well understood. However, those signals have to be controlled, and that is what we found in this latest paper with a protein called Arc.”
How Does the Brain Form Memories?
The brain is a complex biological machine made up of many different types of cells. Neurons are the cells responsible for processing and transmitting the information necessary for us to learn and remember. Neurons do this by forming highly specialized structures called synapses. Synapses between neurons form a complex network, and our memories reside in those neurons and connections.
The second task is much less well understood. The brain has to allow the first step to proceed, but it can’t let it spin out of control. For example, a certain set of notes will stimulate synapses to get stronger, but the brain has to keep the overall excitability of each neuron within an acceptable range. This prevents epilepsy, in which the brain becomes completely overstimulated, and preserves the system’s capacity to form new memories.
A New Role for Arc
In the new paper, Drs. Korb and Finkbeiner show how the protein Arc modulates the process of learning and memory. Arc was originally discovered as a gene that is turned on during epileptic attacks, but it is also involved in learning and memory. Mice in which the Arc gene is genetically disrupted can learn new tasks, but if they are re-tested a day later, they have forgotten the learned behavior. Thus, they can learn, but they cannot remember. Arc has a role in making memories more permanent, and that activity seemed to take place at the synapses.
At least that is what everyone thought. But the new study included a surprise. After Arc protein is made and appears at synapses, it moves to the nucleus where the genes reside. In fact, eventually, most of the Arc ends up in the nucleus.
What Does It All Mean?
How does Arc get there, and what could it be doing there? Dr. Korb found that it contained three regions that direct its localization. One gets it into the nucleus. A second keeps it there. A third exports it from the nucleus. This complex control system suggests that the location of Arc is important for its function.
Dr. Korb genetically changed each of these regions of the protein and determined how the changes affected the protein’s function. Changing Arc also changed its nuclear localization and affected synapse strength by preventing over-excitement.
“This was a big surprise,” said Dr. Korb. “Neuroscientists have focused almost exclusively on what Arc does at synapses. But we found that it functions in the nucleus to control neuronal signaling by turning on or off genes that regulate synaptic connections.”
Dr. Korb is continuing her studies as a postdoctoral fellow at The Rockefeller University in New York, and Dr. Finkbeiner is continuing his studies of Arc.
“We were looking at how we learn and remember and not specifically at neurological disease,” said Dr. Finkbeiner.
“Nevertheless, our results have implications for diseases, such as autism, schizophrenia, Alzheimer’s disease and others, and that makes us very excited about our findings.”