Brain Signals

Brain SignalsThe mysteries of the brain lead Tulane researchers down paths of discovery.

By Mary Ann Travis

The human brain is a mighty organ. It only weighs about three pounds but it controls all bodily functions—both voluntary and involuntary. It is through the brain that our senses perceive the world. And in the brain, we think, learn, plan, scheme, react—and remember. Our emotions are seated in the brain.

To understand the brain is to understand us, says Jill Daniel, professor of psychology and director of the Neuroscience Program at Tulane. "That’s why it's exciting to me to study the brain. It's who we are and what makes us human."

President Barack Obama announced the White House Brain Initiative (Brain Research Through Advancing Innovative Neurotechnologies) in April 2013. And in 2013-15, Tulane neuroscience faculty brought in over $21 million in external funding to support their research.

The Tulane Neuroscience Program encompasses 43 faculty re-searchers in the School of Science and Engineering, the School of Medicine and the National Primate Research Center. As part of a Brain Initiative at Tulane, they collaborate as they never have before to unravel the brain's mysteries, of which there are many.

The Tulane researchers operate in a matrix of postdoctoral fellows, PhD graduate students, master's students and undergraduates—all exploring the brain in one way or another.

"We have over 400 people in the Tulane community who are involved in the neuroscience endeavors," says Daniel.

The long-range goal is to create a Tulane Brain Institute. In the meantime, interdisciplinary work flourishes in four main areas of strength: hormones and the brain, cognition (learning, memory and attention), the autonomic nervous system and its disorders, and neurodegeneration.

Sex and The Brain

Daniel is a behavioral neuroscientist, meaning that she is interested in the relationship between the brain and behavior. For nearly two decades, she has studied the effects of sex on the brain and behavior. That's not amorous feelings and acts, but sex at the most basic biological level. That is, whether an animal or human is male or female. Because, says Daniel, "whether you are male or female has a profound effect on every organ of the body, including the brain."

Using rat models, Daniel has investigated the effects of hormones—estrogen, which is predominant in females, and androgens, most prevalent in males. Recently, she has looked at how androgens act in the brain to contribute to sex differences in impulsivity. And she's found that, yes, as parents of boys can probably attest, young males exhibit more impulsive behavior than their estrogen-laden counterparts.

At the other end of the lifespan, Daniel has explored estrogen and its effect on memory in aging females when estrogen drops off precipitously after menopause.

Both hormones—estrogen and androgen—affect the hippocampus area of the brain, an important site of memory making.

At the moment, Daniel has a National Institute on Aging grant to look at the effects of estrogen on the hippocampus. The long-term implication of her research is to figure out what is the optimum estrogen-replacement therapy for women in order to shore up memory functions.

She's not making clinical recommendations. She points out, "We're basic scientists." But she can say that indications are that good things happen in the relationship between plentiful estrogen and memory activity in the brain.

Stress and The Brain

Jeff Tasker, professor of cell and molecular biology, holds the Catherine and Hunter Pierson Chair in Neuroscience at Tulane. He, too, emphasizes the importance of basic research.

"Knowledge is gained through basic research," he says. The ultimate goal is human health and well-being, but scientists can't guarantee where their research is leading. Scientific inquiry might seem superfluous or even fantastical at times. But there's a necessary leap into the unknown to discover practical applications down the road. One can't always predict where lines of inquiry will go.

For more than 20 years, Tasker has studied neuroendocrine systems in the brain and the pituitary gland, which secretes hormones. Grants from the federal National Institutes of Health and National Science Foundation have funded his work.

Tasker concentrates on neurons—signaling cells that generate electrical impulses and transmit information to initiate behavior and control thought—in the hypothalamus.

The hypothalamus is an ancient part of the brain. It sits at the top of the brain stem and is essential to physiological homeostasis, the body's functional balance—all the things that happen in the body without our thinking about them.

Right next door to the hypothalamus is the amygdala—a part of the brain that controls anxiety. In the amygdala, "fear-memory" is expressed.

Stress—as might be expected—facilitates the expression of fear-memory.

It can be any kind of stress, says Tasker, "whether I'm about to be eaten by a lion or I've got a deadline, you produce this response that is a neuroendocrine response."

If the stress is not too severe, the fear-memory, in time, may be suppressed or extinguished.

What happens in anxiety and post-traumatic stress disorders is that the brain does not extinguish fear-memory. Debilitating unease remains.

Lately, at the cellular level in mice models, Tasker is looking at unextinguishable fear-memory triggered by stress.

"I'm passionate about our research," says Tasker.

And, he adds, research from the stress and stress disorder perspective is a good niche for Tulane. "We have distinct strengths in this area."

Attention and The Brain

Edward Golob, associate professor of psychology, is impressed with the mundane.

"I think that one indication of good brain engineering on the part of Mother Nature is when things happen without having to think about it," he says. "For example, speaking and listening to other people is a daily miracle."

Speech is a complicated series of sounds. Yet, we rapidly encode and decode these sounds to communicate ideas.

"Decades of work have gone into designing computers to do this," says Golob, "but the speech abilities of an average child develop naturally and are still much better."

Trained as a musician before he turned to psychology, Golob is also starting to explore how music operates in the brains of musicians.

"Music can tell us a lot about basic aspects of the brain," he says. "How do you hear? How do you move? How do you learn things?"

Musicians have to learn complicated musical parts. And their brains are demonstrably different from non-musicians' brains. "We can literally see that," says Golob.

Some of Golob's other research asks how the brain represents space. He is particularly interested in how auditory attention shifts, like a seesaw, over space when you are distracted. This research is a focus of Golob’s work that has support from both the National Institutes of Health and the National Science Foundation.

He uses human subjects to study the electrical activity—the neurons—in the brain, and track how attention is invested in different parts of space.

His exploration of how the auditory system is used for spatial attention is leading him to get interested in how attention and memory work together.

"Initially, people thought about long-term memory as being separate from attention and separate from perception but they actually may be much more interrelated," he says.

"The bigger picture here is that we carry around in our heads knowledge. It's being used on the fly every second of every day. And we want to understand how that knowledge sculpts your moment-to-moment experience in life. How does memory affect attention? How does it affect perception?"

In the end, the rationale for why Golob studies the brain is the same as Jill Daniel's reason: "It is about us—our brains are what make us tick," he says.

Plasticity in The Brain

Ricardo Mostany, assistant professor of pharmacology, is trying to understand how we learn, too. In the circuitry of the brain's cortex, he's looking into how we learn, remember and forget things.

He's doing his investigation with the most advanced imaging facilities in the region—in vivo two-photon laser scanning microscopy equipment that he built himself.

"We are putting Tulane in the vanguard of the South in terms of high-resolution imaging," says Mostany, who joined Tulane in 2012.

In a newly constructed lab in the School of Medicine building, Mostany is focusing on how the aged brain learns and stores information. With high-resolution imaging of living brains, he and his laboratory members can see the same cell, the same neuron, over days, weeks and months.

"We can study how this neuron is behaving normally and how this neuron behaves when the animal needs to learn how to do something," he says.

What Mostany is discovering is that in an old brain, the neurons make connections that are not stable. "So they change more often than it does in the young brain," he says.

That may be the reason why the aged brain is more forgetful, "because even being able to establish a connection between two cells, this connection is more temporary than in a young brain."

In younger brains, connections between neurons seem to stay longer.

"The brain circuits are plastic, are constantly changing at a certain degree," says Mostany. That's how we learn things. Plasticity in the brain is necessary for learning, for remembering.

"However, in the very old brain, those changes are more accelerated," says Mostany. "And, it’s the excessive plasticity that might be detrimental."

An old brain appears not to have good plasticity. "Plasticity somehow becomes exacerbated at a certain point that is not beneficial anymore."

The research line that Mostany is following is how to prevent neurons from making an elevated number of contacts. As the brain ages, it may need to make fewer contacts but more stable ones.

Mostany's work has significance for treating dementia and perhaps just remembering where we put our car keys. "There is a fine line between healthy aging and early stages of dementia," he says.

Cerebral Circulation

David Busija, Regents endowed professor and chair of pharmacology, is interested in how the brain is able to communicate with blood vessels that supply nutrients to the brain because "there's a need to match blood flow to metabolic demand," he says.

When things are out of whack due to the metabolic syndrome (which includes hypertension, insulin resistance and diabetes), the long-term consequences can be dementia or stroke.

Busija has been at Tulane for five years after spending 20 years at Wake Forest University Medical School. The National Institutes of Health have provided continuous funding for his research since 1982.

He was among the first scientists to look at the cerebral circulation almost three decades ago. At that time, his research involved studying the large arteries on the brain surface through a cranial window as well as local blood flow using microspheres.

Recently, however, Ricardo Mostany has built new equipment for Busija that "allows us to look inside the brain and look at the blood flow in real time in a live rodent."

The new imaging capabilities have opened up exciting possibilities for exploring—and eventually treating—what happens in the 90 percent of strokes resulting from plugged up blood vessels.

Recent research by Ibolya Rutkai, a postdoctoral fellow in Busija's lab, has shown that after a stroke, mitochondria (energy-producing structures) of cells in cerebral arteries appear to be in fairly good shape.

Mitochondria produce ATP (adenosine triphosphate), which allows cells to repair, build proteins and transport nutrients.

"Therapies that target the mitochondria may improve outcome after a stroke," says Busija.

This is a hypothesis that needs more testing, he says. "It's like anything in science. You can have your hypotheses but until you do the experiment, you don't know what you're going to get."

"Studying the brain is very complex," he adds. "It took a long time to develop the methods to study the circulation of the brain because there are many arteries going to it, and many veins coming from it. And, until recently, it has been difficult to study small arteries inside the brain."

But the new equipment built by Mostany "gives us great imaging capacity," says Busija. "It's an exciting time."

Diabetes and The Brain

When diabetes strikes, the brain may not be the first thing that comes to mind.

But the brain is essential in the body's communication circuitry—and in diabetes something is "off" in that circuitry.

Andrea Zsombok, assistant professor of physiology, is investigating the brain’s role in regulating and maintaining glucose levels in the body.

"The brain has so much potential—and so many things we have no idea about," said Zsombok. "It's amazing."

Like many of the brain researchers, she's studying neurons. She's particularly looking at neurons that convey to the liver the need to store or release sugar.

Diabetes is a disease associated with high blood sugar levels. Sugar (or glucose) is blocked from proper use in the body because the pancreas does not release insulin or the body can't use its own insulin as well as it should. In addition, the liver, which also is responsible for storing and making glucose, plays an important role in the maintenance of sugar levels.

Zsombok studies brain activity in the hypothalamus, the site of control of all the autonomic functions of the body, such as body temperature and blood pressure—and glucose levels.

She's probing how neurons associated with the liver function normally. She then records what happens during diabetes when the neurons are not acting properly.

"We are interested in thinking about how we can prevent or reverse this change of the neuron during diabetes," says Zsombok.

Her work on how the brain controls glucose homeostasis is supported by the National Institutes of Health.

Her goal is to help people with diabetes and in the long run find a way to restore neurons gone awry in people suffering from the disease.

"Hopefully, we will succeed in that way," she says.

Stem Cell Therapy and The Brain

Bruce Bunnell is director of the Tulane Center for Stem Cell Research and Regenerative Medicine and a professor of pharmacology. His lab is in the J. Bennett Johnson Health and Environmental Research Building in downtown New Orleans.

Bunnell's recent emphasis is on using adult stem cells as potential avenues for treating neurodegenerative diseases, particularly multiple sclerosis, suffered by millions of people worldwide, and Krabbe's disease.

Through meticulous experimentation, Bunnell, PhD student Annie Bowles and others have collected "convincing" data, says Bunnell, that by giving stem cells to a mouse with fairly severe multiple sclerosis, the mouse's symptoms improve. The stem cells are derived from adipose tissue—fat cells retrieved from elective liposuction. Medical waste, really.

"Our data is good enough," says Bunnell, "that I would like to take it to human clinical trials as soon as I can."

Multiple sclerosis is an autoimmune disease in which the body starts attacking itself. What gets attacked is the myelin—the insulation of the nerves. "Think of myelin like the plastic coating of electrical wire, so that electricity flows down the wire," says Bunnell. "Myelin serves the same function for nerve conduction."

The effect of the adult fat stem cell therapy is to quiet the inflammation associated with multiple sclerosis. An inherent property of fat cells is that they are "potently anti-inflammatory," says Bunnell.

"What we're focused on," he says, "is what is the mechanism by which the brain and the spinal cord get better?"

"In my heart of hearts, I feel that if we can get these cells to MS patients, they will benefit."

Bunnell says that basic science researchers such as Jill Daniel and Jeff Tasker on the uptown campus do "very good neuroscience. They help us understand how the brain works, and why it works the way it does."

"Then we're on the other end of the spectrum, saying we want to treat disease."

The push for interconnectivity between basic neuroscience researchers and researchers exploring treatments is welcomed by Bunnell. "There's a lot we could learn from each other."

He anticipates that the Brain Initiative and increased uptown/downtown/primate center collaborations will lead to better understanding of disease processes, which can result in tailored therapeutic treatments, whether gene therapy, stem cells or a pharmacological approach.

"If you understand what goes wrong, fixing then becomes a little bit easier," says Bunnell.

"The brain is so complex. And we still understand so little about how the brain works that it’s going to be challenging. But with good basic neuroscience from the people we have uptown, within the next few years, we'll understand a lot more than we do now."

Hope for Alzheimer's

The fact that so much is unknown about Alzheimer's and other neurodegenerative diseases has hit home in a personal and sad way to uptown researcher Anne Robinson.

Robinson, who came to Tulane three years ago, holds the Catherine and Henry Boh Chair of Engineering, and she is chair of the Department of Chemical and Biomolecular Engineering.

More than eight years ago, Robinson's mother was diagnosed with a neurodegenerative disease, and within a year she died.

In her mother's case, as in more than 90 percent of Alzheimer's cases, there was no family history of the disease.

"What I became aware of, because of the personal aspect, was the feeling of helplessness for those impacted," says Robinson. "At that time, talking to doctors, there were no therapies offered and nothing that would even slow down the progression of the disease."

What amazed Robinson as she learned more about the disease is the huge impact it has on our society, with more than 5 million Americans suffering from Alzheimer's in 2014.

While Robinson had long looked at stress-response pathways in cells, she had not studied neurodegeneration.

But with her mother's death in 2007, the focus of Robinson’s research shifted. She set out to learn as much as she could about tau protein in the brain. Tau tangles, like amyloid beta plaques, are associated with Alzheimer's.

And Robinson's mother’s brain had many tau tangles.

Tau protein forms structure for neurons—the communicating cells—by wrapping around microtubules in the brain and spinal cord to stabilize them.

But, "when tau gets messed up," says Robinson, "it doesn't function like it should, and the microtubules fall apart. That's part of why the neurons start to die."

A result is a decrease in the size of the entire brain in Alzheimer's. That's why memory goes, and Alzheimer's patients start to not connect with people, even people they've known for years.

"The one thing that's correlated with a decreased risk of Alzheimer's is exercise," says Robinson.

Exercise brings more oxygen to the brain. And more oxygen may lead to healthier regeneration of cells.

In her lab now, Robinson is looking at what happens when oxygen is deprived in the brain cells of rodents. "If the loss of oxygen is the problem," she says, "can we reproduce that effect by depriving the cells of oxygen? Then we look to see whether the affected pathways in the brain mimic neurodegeneration."

She'd like to find out if there is a way of using chemicals to reoxygenate the cells—and if such a therapy would help.

It's too early to say exactly where Robinson's research will lead.

But her personal experience motivates her to try to find ways to disrupt the neuro-degenerative pathways involved in Alzheimer's so that, at the least, the progress of the disease can be slowed.

"If we can offer a potential therapy to slow down progression, then that would be significant," she says.

Like other Tulane brain researchers, she's optimistic. "I hope that in the next few years that we'll have something like that, or another option to help people.

"There's nothing I can do anymore for my mother, right? But to help have an impact on other people who might be facing something similar, I feel like that has some meaning."

And another mystery of the brain will be untangled. — M.A.T.

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