Exploring the building blocks of memory

October 28, 2015
By J. David Sweatt
J. David Sweatt, Ph.D., an international expert in the molecular mechanisms underlying learning and memory, explains exciting breakthroughs in the field, including his own lab's work on ways to block, erase and enhance memories.

J. David Sweatt, Ph.D., an international expert in the field of learning and memory, is Evelyn F. McKnight Chair of the UAB Department of Neurobiology and director of the McKnight Brain Institute and Civitan International Research Center at UAB. In this story and video, he explains how fundamental discoveries in his lab are pointing toward new treatments for learning and memory disorders.

When I was a graduate student, getting close to finishing up and getting my Ph.D., I realized I was probably going to spend the rest of my life working on one single thing. So I asked myself the question: What’s the most interesting thing in the world? And to me, that is how memories are formed and stored. I’ve been fortunate to be able to spend the last 25 years of my career exploring that question.

One of the major breakthroughs in the learning and memory field in the past two decades or so was the discovery that active changes in gene readout in the brain are necessary for anyone to make a long-term memory. If you remember something tomorrow that you experienced today, it will be in part because you had a change in gene readout in parts of the brain that are critically important for memory formation. My lab wants to understand how that works.

A hidden layer between nature and nurture

It turns out there’s a layer of mechanisms, known as epigenetic mechanisms, that sit above the level of the genes and all the cells in your body, including in your brain. These mechanisms were discovered only fairly recently, and they’re really pretty amazing — a previously hidden layer that acts as an interface between environmental stimuli and the genes that make up the DNA coding system in your cells.

Epigenetic mechanisms were originally discovered as a basic information storage mechanism in all the cells in your body. We all basically started out as a ball of embryonic stem cells, and some of those cells got a signal to turn into nerve cells and liver cells and muscle cells and so on and so forth. And those nerve cells and liver cells have stayed nerve cells and liver cells for your entire lifespan.

That tells you right on its face that there has to be some lifelong information storage mechanism in cells that allows them to stay the kind of cell that they’re supposed to be. So we got interested in the epigenetic mechanisms that underlie that information storage, and hypothesized that maybe some of those same mechanisms are used when we have experiences and store acquired information in our brain. And it turns out that is the case. My lab discovered — about 10 years ago — that everyday experiences tap into these epigenetic mechanisms. The events we experience drive changes in epigenetic mechanisms, and that’s critically important for long-term memory formation and the stable storage of long-term memory. It’s quite exciting.

What that means in biochemical terms is that when you have an experience that causes a long-term memory to be formed, that experience actually changes the three-dimensional and chemical structure of the DNA in your brain.

Blocking, erasing and enhancing memories

We’ve discovered in the lab that these basic mechanisms might give us some really important tools that we can try to use to treat learning and memory disorders. In animal studies, very talented postdoctoral fellows and graduate students who work in my lab have discovered that, by manipulating the epigenome with targeted drugs, we can block memory formation. We can actually erase a pre-existing memory by manipulating the three-dimensional structure and chemical structure of DNA in the brain, and most importantly — really in terms of thinking about drug development — we can enhance memory formation by boosting up some of these epigenetic mechanisms.

That is in normal animals, but really more important is what we have been able to do in animal models of things like Alzheimer’s disease and learning disabilities. In laboratory experiments with genetically engineered mouse models, we can use these epigenetic regulating drugs to restore normal learning and memory capacity back to these animals.

You can’t fix something that’s broken, completely, until you understand how the process works normally. Basic research allows us to understand how things work normally so we can restore a disrupted process in diseases such as Alzheimer’s or intellectual disabilities. We can restore that broken mind back to normal function by understanding what normal function really is.