What is the sound of one neuron firing?
"It's like a pop-pop-pop-pop," John Griffin says. "When they're nice and sharp they're really crisp and high-tone, and as they get sicker, the recording gets bad. The actual potential broadens. We call them thumpers, because they start going thump, thump, thump, and then they disappear."
Griffin studies how the brain's hypothalamus regulates body temperature. The procedure involved is simple, yet painstaking. A bit of tissue sliced from a rat or mouse hypothalamus is kept alive in a Petri dish so that Griffin, or one of his undergraduates, can insert a probe to record how the neuron reacts to changes in temperature. A properly seated probe will amplify the tiny electric signals of the neuron, generating the pops Griffin described, which degrade to thumps as the tissue begins to die.
Griffin is the director of William and Mary's interdisciplinary neuroscience program, presiding over a brain trust of 17 faculty members spread over five departments-Griffin himself is an associate professor in the biology department. In four years, neuroscience has grown to be among the most popular interdisciplinary major at the College and one of the most popular majors overall. The neuroscience major is as rewarding as it is demanding. Neuroscience grads find ready acceptance into programs at the nation's top medical schools and graduate programs. Griffin is careful to keep track of the program's graduates.
"So last year I knew that 21 percent were going to med school, about 8 percent to graduate school-this is out of 60-some students," he said. "Four of the graduates went to M.D./Ph.D. programs, and those are the ones that we are most proud of. I mean these are fully funded programs. They get their medical school and their graduate programs completely paid for. They get a stipend to live on through those seven to eight-plus years it takes them to complete both degrees. So when you think about how much that is, we're talking about a quarter million dollars a student."
Science . . . and Scientists
The program produces high-quality science in tandem with high-quality scientists. Griffin keeps track of current activity, too. Right now there are 98 William and Mary undergraduate students working in neuroscience faculty labs. The neuroscience faculty have produced 109 papers in research journals, many of which have William and Mary undergraduates as co-authors.
Such collaborative productivity is made possible only by the participation of what Christopher Del Negro calls "absolutely, absolutely, fantastic undergraduates." Del Negro is an assistant professor in the Department of Applied Science. Other neuroscience faculty come from the departments of biology, kinesiology, chemistry and psychology.
Del Negro's research concerns the neural mechanisms regulating breathing in mammals. The unconscious, seemingly simple, act of breathing is governed by a quite complex system in the brain.
"While it would be great to study a behavior like how do people give presentations or how do people think through complex problems, you can't really bring that kind of neuroscience problem into the laboratory," he said. "Whereas breathing really is just a fundamental rhythm which needs to be regulated to live."
He is part of a productive group, which includes undergraduates as well as graduate students in applied science. He and his group published four articles just this year detailing advancements in the understanding of the role in respiratory rhythm played by a group of brain cells in the preBötzinger Complex, a region of the lower brain stem. In addition to the four papers published by the group, two separate articles comment favorably on their work.
The lead author on the most recent article from Del Negro's lab is Erin Crowder, a member of the class of 2007. Erin's senior thesis ended up being good enough to be accepted into the prestigious, peer-reviewed Journal of Physiology. It makes a nice bookend to an undergraduate career that began the first semester of her freshman year.
"She came in and said 'I want to learn how to do research'," Del Negro said. "It also happened to be my first semester as a new faculty member and so Erin helped me build the lab. And she trained right from the get-go on how to do these experiments and she's worked with me every single semester and every single summer that she's been here. I would rate her as good as a third-year graduate student in any department."
Del Negro's methodology is similar to a degree to the one used in Griffin's lab. He and his colleagues manipulate brain tissue to retain the rudiments of behavior, essentially the motor rhythm that drives breathing movements. They use fluorescent marking to make the target respiratory neurons glow, so that they can record the neurons' activity at a number of levels.
Griffin and Del Negro, both cellular guys, collaborate a lot and have complementary skills. For instance Griffin relies on Del Negro's expertise when it comes to injecting dye into cell nuclei, while Del Negro acknowledges "John is a better microscopist than I am."
Neuroscience at the cellular level will get a big boost from the establishment of a new microscopy facility in William and Mary's Integrated Science Center, now under construction between Rogers and Millington halls. The ISC will be the permanent home of the neuroscience program's new confocal microscopy facility. The instrument itself, which Del Negro calls "the best thing we can possibly get, the best microscope around," arrived in April and has been set up temporarily in Millington.
If the brain is to work well, it needs a steady supply of oxygen-bearing blood. A problem in the blood supply leads to a problem with the brain.
"Many brain disorders are actually vascular disorders," Robin Looft-Wilson points out. "Many dementias are caused by vascular disease in the brain. Stroke is a vascular disease, it's not a brain disease."
Looft-Wilson is an assistant professor in the kinesiology department at William and Mary and insists that she's "a physiologist and not exactly a neuroscientist." Nevertheless, she is presiding over important work in the neuroscience program regarding the understanding of how blood vessels work and how their workings contribute to the health of the brain. One of the projects she is working on concerns a condition known as hyperhomocysteinemia, the excess of a certain amino acid in the bloodstream.
"Hyperhomocysteinemia is a very common cardiovascular risk factor in the population," Looft-Wilson said. "It's an independent risk factor like high cholesterol and everybody's heard about cholesterol. And hyperhomocysteinemia is typically the result of low B vitamins in the diet, which is actually very common."
Hyperhomocysteinemia, she explained, tends to increase oxidative stress--that biological imbalance we try to counter by consuming foods rich in antioxidants. Oxidative stress is involved in the physical manifestations of the aging process, as well as a number of disease states, notably Alzheimer's and atherosclerosis--hardening of the arteries.
"High oxidative stress makes blood vessels not function properly. It interferes with lots of chemical reactions," she said. A healthy blood vessel, she explains, produces plenty of that critical and versatile biological messenger, nitric oxide. Looft-Wilson knew that hyperhomocysteinemia reduces nitric oxide availability, but how?
She and a group of students working in her lab ("They are all neuroscience majors.") recently concluded a study that shows hyperhomocysteinemia alters the regulation of endothelial nitric oxide synthase (eNOS), an enzyme that triggers production of nitric acid. They wrote up their findings in a paper--with four undergraduate co-authors--for a journal and also presented at a physiology conference in Washington, D.C., that attracts thousands of scientists, of whom only a hundred or so are undergraduates.
Learning and Memory
Pamela Hunt studies learning and memory--which, from her point of view, are intertwined. She is associate director of the neuroscience program and an associate professor in William and Mary's Department of Psychology--and says that developmental psychology and neuroscience are intertwined, too.
"How do we get this brain? How does it develop? How does it grow? What are the processes involved? That's a really big area of neuroscience," she says. "So developmental psychology, where there's an interest in how psychological processes develop--behavior, learning, memory, eating behaviors, attachments, whatever--must correspond to the development of the body, and the brain in particular."
One of Hunt's major areas of research concerns a problem she characterizes as "a terrible condition, 100 percent preventable"--fetal alcohol syndrome. She notes that while the cause and effects of fetal alcohol syndrome are well documented, the number of cases continues to rise. Education hasn't seemed to help, she said.
"There are more and more kids that are diagnosed with fetal alcohol syndrome and some related disorders that are the result of prenatal exposure to alcohol," Hunt said. "So, rather than devoting all of our time and energy into prevention, which so far has not seemed to work, now the trend is to try to focus on the afflicted individual--the baby."
Hunt's lab uses a technique known as "fear conditioning" to study behavior. Fear conditioning, she explains, draws on the primitive defensive response to the threat of predation. It's a tool by which researchers can understand acquisition in a simple learning process--what Hunt calls the neuromechanisms of learning. The behaviors are similar for mice and men.
"How do we avoid predation? Well, one way that we do that is to exhibit a variety of behaviors that allow us to protect ourselves," she said. A mouse, for instance will freeze at a shadow that might be a hawk, an evolved response that helps the mouse avoid detection. "They stop moving, their heart rate decreases and they increase their attention and their vigilance to the environment."
Children born with fetal alcohol syndrome (FAS) often, but not always, look different from other kids. Alcohol also is detrimental to the development of the brain and Hunt's concern is with how learning and memory are affected in FAS.
"I have become very interested in ways that we might be able to take an individual who has problems as a result of alcohol in the memory domain and try to improve that, try to overcome that," she said. "Maybe if we train the individual using a different technique, they could learn. We might be able to give them a drug treatment that would be able to facilitate their memory and help them perform better in school."
Hunt has received funding from the National Institute on Alcohol Abuse and Alcoholism, one of the National Institutes of Health, to investigate such possibilities in animal models. One of the most promising ways to improve memory/learning, she says, is through choline supplementation.
"We found that the animals that are given alcohol exposure for a model of fetal alcohol syndrome are deficient in some kind of fear conditioning," she said. "And then we give the animal extra choline, which is just basically like giving you extra broccoli when you were a kid or a vitamin supplement. Given extra choline, they actually perform much more normally later on in that particular type of memory task."
The neuroscience program at William and Mary brings together "perfect storm" conditions for undergraduates looking forward to medical school or neuroscience graduate programs--particularly the elite M.D./Ph.D. programs at major research universities.
"Out of about 60 graduates in 2006, we had four who went on to M.D./Ph.D. programs," said John Griffin, director of William and Mary's neuroscience program. "They get their medical school and their graduate programs completely paid for. They get a stipend to live on through those seven- to eight-plus years it takes them to complete both degrees and so when you think about how much that is, that's about a quarter million dollars a student."
Griffin likes to keep track of where his neuroscience grads end up; he posts updated stats on the program's web page. Many waver between medical school and graduate programs and Griffin asks indecisive students a simple question.
"My question to them is: Do they ever want to see patients? Do they want to be on the clinical side?," he said. "With an M.D., you can be a clinician or you can be a research scientist. With a Ph.D., obviously there's no clinical side of that."
The interdisciplinary nature of William and Mary's neuroscience program provides a high degree of versatility, and graduates have taken a variety of paths. Once the basics are covered, a neuroscience major can pick a number of directions.
"So Student A can say, 'I really like neuroscience, I've been exposed to it and I have the basic science background but I really like behavior," Griffin said. "That kind of student is going to take behavioral courses and maybe apply to a behavioral neuroscience graduate program. Student B says, 'I really like cell-molecular...' They're going to take more cell-molecular courses and apply to a cellular-molecular-based neuroscience program."
One of the program's goals is to get as many neuroscience students into the lab as possible. Griffin says a third of the papers published by faculty in the program have undergraduate co-authors. Papers in important journals with undergraduates as first authors are not unknown.
Research requires dedication and tenacity from the students. In turn they bring the usual virtures of youth-not least of which are the fine motor skills necessary for some of the neurological lab work. Christopher Del Negro says a pair of "pretty decent hands" are necessarily for fine neural work and that young people are able to get the knack more often than not.
"I mean I've worked with students who have been practicing neonatal medicine for years and years who just cannot learn this dissection that we do in the lab," he said. "But most 19-year-olds can learn it in about a week." Students unable to perform the fine dissections need not give up on neuroscience, he said-there are other opportunities, such as microscopy and mathematical modeling. It comes back to the interdisciplinary nature of the program, Griffin said.
"I think our program is different in that we really try to create a well-rounded scientist who has had exposure to all these different disciplines, who's had exposure to all the different aspects of neuroscience," he said. "I think that's what makes our students so sellable when they graduate. That's why they are getting snapped up, by professional programs-med schools, pharmacy schools, veterinary schools-as well as by the top graduate programs."