How Do We Learn and Remember?

The protein Arc helps our brains form memories, but new research from Gladstone gives it an intriguing new role.
By GARY C. HOWARD, PhD
Roll Over Image
Neuron
This image shows a single neuron and all of the branches that extend from it. These branches, known as axons and dendrites, form the "highways" along which information gets communicated from one neuron to the next. This information gets transferred at "intersections" known as synapses, an essential process for forming new memories. The neuronal cell body contains the nucleus, which is where new protein synthesis begins. These proteins travel along axons and dendrites to get to synapses, where they influence synaptic function. [Neuron imaging: Anna Lisa Lucido]
June 9, 2013: How do we learn and remember? Somehow the things we see, feel, and hear are translated into electrical impulses and chemical connections in our brains, and we can call up those memories for years and even generations later. In Alzheimer’s diseases, we lose those memories. How memories are formed and sometimes lost is one of the great problems in biology.
Meet Dr. Finkbeiner
Steve Finkbeiner
Steve Finkbeiner, MD, PhD, is associate director and senior investigator at the Gladstone Institute of Neurological Disease, professor of neurology and physiology at the University of California, San Francisco. He also directs the Taube-Koret Center for Neurodegenerative Disease Research, the Hellman Family Foundation Alzheimer’s Disease Research Program, and is an investigator with the Roddenberry Center for Stem Cell Biology and Medicine.

 

Where did you go to school?
I went to college at Wheaton College in Illinois, and then, I went to Yale University for my MD and PhD degrees. I then completed a residency in neurology at UCSF and a research fellowship at Harvard where I briefly started my first faculty job before being recruited back to UCSF and Gladstone.

What brought you to Gladstone?
I came to Gladstone because I knew that I would be able to do cutting-edge research here in a stimulating and productive environment. I have not been disappointed.

How do you select students and postdoctoral fellows for your laboratory?
Gladstone is affiliated with UCSF, and so, we can recruit new students through them. I believe the chemistry between lab members is a key part of our success, so I ask every applicant to interview with all of the current members of our lab. It’s a pretty grueling day for applicants. At the end, the lab votes on the applicant. This system has worked extremely well for me.

Rumor has it that you don’t sleep much. You send emails at all hours of the day and night. Is that true?
I have to plead the 5th on this one. But I do confess to being passionate about our work. It is exciting to me, and as a practicing physician, I also never forget that we are working to improve the lives of real patients. That realization gives me an extra sense of urgency.

What about the candy at Halloween?
That is a fun tradition that we have. Each year I decorate the lab, usually with the help of my own children. And I put out lots of candy for everyone. It’s a fun time for everyone.

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.

Steve Finkbeiner talks about the role of Arc in learning and memory [~5min.]

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.”