UAB Magazine Weekly - Features on Research
New Insights on DNA
UAB neurobiology chair David Sweatt’s own research has contributed greatly to the current understanding of the cellular events underlying neuroplasticity—discoveries that earned him the 2012 Fondation IPSEN neuronal plasticity prize, a prestigious international award. His lab continues to push the field forward, investigating the role of a newly discovered DNA base in learning and memory.
Three years ago, scientists discovered that, in addition to adenine (A), thymine (T), cytosine (C), and guanine (G) bases, mammalian DNA consists of additional bases, including 5-hydroxymethylcytosine (5-hmC). Embryonic stem cells and regions of the adult brain involved in learning and memory have very high levels of 5-hmC, Sweatt says. For embryonic stem cells, the base appears to play an important role in allowing them to develop into any kind of cell. In the brain, “our idea is that 5-hmC makes the neurons highly plastic and highly adaptable so that they can receive signals and trigger long-lasting functional changes,” Sweatt explains.
These basic science studies may eventually point the way to new treatments for a host of diseases, as well as medications that can improve healthy brains as well. “The question now is how far can we take some of these exciting new things?” Sweatt says.
Exercise and Neurogenesis
Perhaps the most dramatic form of neuroplasticity in the adult brain is the birth of new neurons, or neurogenesis—another phenomenon firmly believed to be impossible until the 1960s. Although scientists now generally acknowledge that neurogenesis occurs, the how and why of this process remain unclear. That is something that Linda Overstreet-Wadiche, Ph.D., an associate professor of neurobiology, aims to remedy.
Learning more about neurogenesis could provide new clues about treating many different diseases and shed light on the mysteries of learning and memory. People with epilepsy show increased neurogenesis, for example, while the process slows in the brains of patients with neurodegenerative diseases, Overstreet-Wadiche says.
Using special fluorescent dyes, researchers in her lab have tracked the development of stem cells into mature neurons in the dentate gyrus, a region of the brain involved in pattern separation. Overstreet-Wadiche explains pattern separation as the ability to identify small differences in the environment. “You need to discriminate things in order to learn something, so the dentate gyrus contributes to learning and memory,” she says.
Once the new cells mature, which can take months in the adult brain, they are identical to the neurons created during infancy and childhood. So what are these cells born to do? “One of the ideas proposed is that this process allows the whole system to respond to some cognitive demand,” Overstreet-Wadiche says. The cells that survive during enrichment may do so because they received input, “so maybe they’re primed to respond the next time they see it.”
In study published in 2011 in the journal Nature Neuroscience, Overstreet-Wadiche’s lab identified one specific type of cell, known as an interneuron, that appears to communicate with the developing neurons. “If activity in the network is being translated to the newborn cell through that cell type, then you might expect that in some diseases, or in situations where you have changes in neurogenesis, that maybe something happens with that interneuron first.”
Just about anything that alters neural activity in the dentate gyrus will affect neurogenesis, Overstreet-Wadiche adds. Studies have shown that exercise and environmental enrichment, such as learning a new language, enhance neurogenesis, while stress has been shown to reduce it.
In fact, “it’s unambiguous that environmental enrichment and exercise improve cognitive function,” Sweatt says. If you want to improve your brain, “you should go do that, right now.”
The Key to Manipulating Memories
UAB neurobiologist Farah Lubin, Ph.D., continues to remind scientists to keep an open mind about how the brain functions. She investigates the role of epigenetics—the regulation of genes by environmental factors, rather than by DNA—in the molecular events that lead to long-term memory formation and retrieval. “Epigenetics helps to bridge the two factors we know play a role in our behavior—our genetics and our environment,” Lubin says.
Like Taub, Lubin encountered resistance when she began her research. Scientists had accepted that epigenetic modification could occur during development, but the challenge for Lubin was to show that these mechanisms also occur in non-dividing, mature cells like neurons. Today, her groundbreaking research has convinced most investigators that epigenetics indeed influences the adult brain, allowing humans to adjust to and learn from new environmental situations. “Even in adulthood, you can still change,” Lubin says.
Exposure to new tasks in a social environment is extremely effective in reversing some of the behavioral and cognitive deficits associated with aging, epilepsy, and Alzheimer's disease.
Her lab now is looking for the exact epigenetic mechanisms that allow adults to retrieve old memories and make and store new ones. “Memory is basically who you are, and I think it’s very scary to people to think that they can lose their memory,” Lubin observes. Sometimes, though, the memory of a traumatic event is too much for a person to handle, and it can contribute to declines in physical and mental health. That is why Lubin also is investigating ways to manage epigenetics so that the process can suppress harmful memories.
While much of her research centers on pharmacological ways to manipulate memory, Lubin stresses that drugs are not the only—or necessarily the best—way to enhance neuroplasticity. According to research in her lab and others, mental enrichment, including exposure to new tasks in a social environment, is extremely effective in reversing some of the behavioral and cognitive deficits associated with aging, epilepsy, and Alzheimer’s disease. Unlike drugs, which often have side effects and target only one brain region or molecule, “enrichment seems to incorporate it all,” Lubin says. “I’m interested in this way that nature has given us to handle anything.”
Learn more about epigenetics in this UAB Magazine feature.
Stretching the Limits of Neuroplasticity
By Erin Thacker
Someday soon, we may be able to repair the brain damage from Alzheimer’s, erase traumatic memories, and access untapped reserves of potential in our minds. The key to altering our brains for the better is the insight—just a few decades old—that the brain constantly remodels itself.
Throughout our lives, from infancy to old age, our brains add connections over here, prune others over there, and ramp up production of certain genes while silencing others. As researchers tease out the intricacies of this process, however, they also are learning how to engineer it from the outside.
“Neural plasticity is perhaps the most powerful capacity your brain has,” says David Sweatt, Ph.D., chair of the UAB Department of Neurobiology, director of the Evelyn F. McKnight Brain Institute at UAB, and Evelyn F. McKnight Endowed Chair for Learning and Memory in Aging. “It’s a huge component of what makes us unique, and what makes us so flexible in our ability to adapt in both positive and negative ways to what’s going on around us.”
UAB already is recognized as a global leader in neuroplasticity research, Sweatt says. Now neuroplasticity is listed as a priority in the School of Medicine’s new strategic plan, which helps chart the future of research at UAB. “The brain, generally speaking, and plasticity of the nervous system, more specifically, is one of the last great frontiers in science and biomedicine,” Sweatt says.
Here is a sampling of the intriguing avenues UAB researchers are exploring now.
Desire Makes a Difference: Training the Brain to Repair Itself
In the 1990s, UAB stroke researcher Edward Taub, Ph.D., in collaboration with a group of German investigators, demonstrated that brain plasticity occurs in humans and can have a functional role in sensory experience and movement. He then provided the first concrete evidence that medical treatments can reshape the brain. Over several decades, and despite considerable early skepticism from colleagues, Taub developed constraint-induced movement therapy (CI therapy) to help patients after a stroke. By immobilizing a patient’s functional arm and encouraging the patient to complete tasks with the impaired limb, therapists have been able to produce dramatic results.
CI therapy, originally developed to treat patients after stroke, has been successfully adapted for a number of conditions, including multiple sclerosis.
Brain imaging techniques show that CI therapy leads to “a profuse increase in the gray matter of the brain in motor areas and in the hippocampus,” Taub says. Patients can benefit from CI therapy even if it begins decades after an injury. The therapy requires no surgery or drugs, and there are no side effects. There is one catch, though: Patients must actively participate in their rehabilitation to gain lasting benefits.
“Passive stimulation does not rewire the brain,” Taub says. “Most rehabilitation therapy is, in a sense, passive. People participate, and they move, but they move in response to what the therapist is telling them to do, and their responsibility ends there.”
CI therapy, by contrast, makes patients the key agent in regaining lost motor function by requiring that they continue extensive use of the impaired arm in everyday tasks when they are outside the clinic. “The patients are thereby immersed in a therapeutic environment for a substantial portion of the day,” Taub says. Over the past decade, stroke patients around the world have benefited from the therapy. Taub and his colleagues have successfully rehabilitated patients with traumatic brain injuries and children with cerebral palsy as well.
Now Taub is working with Victor Mark, M.D., an associate professor in the UAB Department of Physical Medicine and Rehabilitation, and Gitendra Uswatte, Ph.D., associate professor in the Department of Psychology, to demonstrate the power of CI therapy in patients with multiple sclerosis (MS).
Unlike stroke or traumatic brain injury, MS is a progressive, degenerative neurological disorder, and at first, Taub and his colleagues weren’t positive that CI therapy would provide any benefit. To their delight, however, MS patients can regain some of their lost function immediately after starting CI therapy, and this improvement persists over time, Taub says.
“If anything, we get a better result with MS than we do with stroke, and for the motor functions we train it has prevented the progress of the motor deficit which normally occurs,” Taub explains. “We seem to be getting the same change in gray matter that we do after stroke as well.” The improvements remain up to five years after treatment—the longest observation that researchers have made so far.
Taub, in collaboration with Margaret Johnson, Ph.D., of the University of Montevallo and Jamie Wade and Leslie Harper of the UAB Department of Rehabilitation’s Speech and Hearing Program, also is seeing benefits in patients with aphasia, a language disorder that can result from brain injury. In the few patients treated so far at UAB, CI therapy seems to be very effective at improving the ability to speak. And in work with psychology graduate student Michelle Haddad, Taub has shown that the therapy increases gray matter in language areas of the brain.
Computer Scientist Uses Language to Fight Crime
By Matt Windsor
olice detectives track criminals using fingerprints.
UAB computer scientist Thamar Solorio, Ph.D., wants to do the same with words. Her research team is bringing artificial intelligence technology to bear on the field of stylometry, which aims to figure out who wrote a piece of text by analyzing word choice and other idiosyncrasies.
“Our goal is to see if we can generate a ‘writeprint’ to identify a document with its author,” Solorio says. The UAB group is developing algorithms that can sift through tiny snippets of style from Twitter updates, Facebook posts, and chat transcripts to discover common elements. Several other research teams are working on automated “authorship attribution,” Solorio notes, but her lab is one of the first to tackle social media.
Solorio’s work, funded by the National Science Foundation and the United States Office of Naval Research, among others, could help identify the authors of terrorist plots from conversations in Internet chatrooms. The same algorithms could also be used to combat cyberbullying among schoolkids and provide valuable information in many other applications, Solorio says. She and fellow UAB researcher Ragib Hasan, Ph.D., are now investigating ways to use authorship attribution techniques to combat a major problem facing Wikipedia—namely, the altering, or defacing, of pages on controversial topics by partisans supporting different sides.
The Clue’s in the Comma
Solorio’s research group, the Computational Representation and Analysis of Language (CoRAL) lab, specializes in natural language processing. This branch of artificial intelligence drives everything from Google’s sorting of search queries to the speech-recognition software used by your bank.
Whether you’re aiming to teach a computer to recognize customers’ voices or a cyberbully’s threats, “you’re trying to design a program that can generalize beyond the examples that you give it so that it can make accurate predictions about new data,” Solorio explains.
The trick is to generate useful predictions when you have only a handful of characters to study—such as the dozen or so words in a typical Twitter post. To succeed, “you need to move beyond word choice and frequency,” Solorio says. “You need to look at syntax, what kinds of word classes are being used, and the length of the sentences, for example. On the Web, you can look at emoticon use and capitalization, too.” Punctuation marks can also hold clues, Solorio says—“there are definite patterns in how people use semicolons, for instance.”