Picking your brain

Inside the brain and spinal cord, billions of neurons fire electrical signals to send and receive information from every part of the body, controlling everything from breathing to sensory perception to movement and learning. How these cells function normally and what causes them to change how they operate is the landscape of study for neuroscientists.

In the Department of Neuroscience at the West Virginia University School of Medicine, part of the Rockefeller Neuroscience Institute, researchers are learning how the central nervous system is influenced by internal factors, such as genetics, and outside influences in our living environment. They’re looking at things like how working a night shift throws off the body’s natural rhythm, why what you eat can increase risk for dementia, and why some people recover from concussions while others develop additional health problems.

While WVU plays a central role in developing new technologies as part of a recently awarded National Science Foundation grant, research already underway is shedding light on the many roles the central nervous system plays in the body’s entire inner workings.

When night becomes day

What landed Randy Nelson, professor and inaugural chair of the Department of Neuroscience, in the neuroscience field was his interest in motivation, particularly in animals – why and when they eat, why and when they sleep or have a certain breeding season. He began studying how brain behaviors are regulated by a central clock, the nerve cell center located in the almond-sized hypothalamus at the base of the brain. His research has addressed seasonal biological rhythms such as seasonal affective disorder and, more recently, circadian rhythms.

“These are endogenous biological rhythms of about 24 hours and are a fundamental characteristic of life,” he said. “They are set to exactly 24 hours by exposure to bright light early in the day, especially short wavelength light, or blue light.”

When that cycle gets interrupted by bright lights at night, as it has been over the past 100-plus years, it disrupts the natural circadian rhythms. The result can be changes in physiological and behavioral patterns.

Nelson’s lab is studying these effects in several areas including immune function, metabolism, sleep, mood, pain response and neuroinflammation associated with stroke or cardiovascular events. Recently, some of the studies have translated from the lab to the hospital setting.

“In the case of stroke, patients are being directed to wear blue-light blocking glasses to see if that helps with recovery by reducing neuroinflammation,” Nelson said of the ongoing research.

Some people can’t help but disrupt their circadian system because they work at night instead of during daylight hours. In some of Nelson’s earlier studies, disrupted circadian rhythms by light at night was associated with several negative health conditions, including metabolic syndrome, cancer and depression.

In another ongoing study, researchers in Nelson’s lab are using circadian biology to help nurses cope with nightshift work. 

“This study provides a visor that emits blue-enriched light at the start of their shifts to reset their circadian rhythms so that nights become their days.  Our goal is to make night shifts less problematic,” Nelson said.

Close up the fast-food bag. Really.

Although age is the main instigator of Alzheimer’s disease and all dementias, not everyone who lives well past their prime develops it. For decades, researchers have explored various avenues to answer why.

So far, they know there are two varieties of Alzheimer’s disease – familial, meaning it’s genetic, and sporadic, which shows little genetic predisposition and therefore seems to come from something else. The familial type is less common with only 5-10% of all cases traced to a genetic mutation.

Bernard Schreurs, who’s among researchers who have spent decades seeking answers, is interested in the sporadic type. While he emphasizes none of his findings can be deemed a cause, he has uncovered some strong risk factors. As it turns out, most are lifestyle related, particularly conusming high fat and high sugar foods that lead to other diseases. That, he said, could spell big trouble for West Virginians.

His current and more recent work traces back to earlier studies with a colleague from another institution who was performing autopsies on people who had died from heart disease. When examining the brains of these people, the colleague found many of them had accumulation of beta amyloid, a protein that implicates Alzheimer’s disease.

“If the risk factors for Alzheimer's disease are cardiovascular in nature, then we have a serious problem in West Virginia because those risk factors are higher here than almost anywhere,” said Schreurs, professor of neuroscience. “In West Virginia, 38% of the people are obese and 71% are overweight. Diabetes and cardiovascular disease are highest or second highest in the nation.

“On top of that, the strongest risk factor for Alzheimer's and related dementias anywhere across all time is age. West Virginia has the third-to-fourth oldest population in the country, so combine that with higher risk factors than anywhere else in the country and that creates an almost perfect storm of at least potential cases.”

Schreurs, who also serves as director of the West Virginia Alzheimer's Disease Registry, said it is estimated that 39,000 people in the state have Alzheimer’s disease, but he believes that number to be much higher based on demographic studies from other parts of the country.

One of those demographics shows women have higher incidences of dementia. Schreurs said although they live longer than men, there’s more to the explanation than the obvious.

“Menopause and the loss of estrogen is a loss of a protective factor and there’s a genetic risk that has to do with the way lipids, involving different versions of the protein apolipoprotein E Apoe, are transported,” he said. “That’s one of the only identified genetic risk that we have for sporadic Alzheimer's disease.”

Through current research, Schreurs’ lab has produced preliminary data that shows the loss of estrogen has cognitive consequences.

His team is also continuing work on the effects of high fat and high sugar in animal models to see how that affects cognition.

“We’re in the middle of those tests and there’s some indication that it may be detrimental,” he said. “That’s not just our research, that's research across the world.”

While there’s no cure for dementia, Schreurs suggests taking preventive steps to at least lower risk factors.  

How that diet affects the brain to cause dementia risk factor diseases is what Schreurs said is called a “question of mechanism,” where neuroscientists explore the molecular pathways.

“For example, sugar elevates blood glucose which is sensed by insulin receptors to secrete insulin to break down the sugars. The insulin receptors signal the brain. The brain’s reward centers say, ‘that’s good’ and the body says, ‘I don’t need it so I'm going to sequester it as fat in case we run out of food.’ The problem is, we don’t run out of food and we accumulate fat. The sad part is some of what we call empty calories don’t reach the brain and switch on signals of satisfaction.”

Turn up the volume on (sort of) selective hearing

Like dementia, hearing loss is a part of aging, causing the once crisp sounds to begin to fade.

In the Charles Anderson lab, researchers are using a new light-based, noninvasive technology to investigate how sound environments are represented in the brain.

“The more you use your ear, the more the cells responsible for detecting sound wear out,” said Anderson, assistant professor in the School of Medicine Departments of Neuroscience and Rockefeller Neuroscience Institute. “As we get older, we start to run out of cells, and you don't make more.”

One of the most challenging scenarios comes with what Anderson said is called the “cocktail party effect.” Imagine being in a restaurant or social gathering where a lot of people are talking and you’re trying to zero in on a personal conversation.

“What we’re trying to understand with our research is how do we subtract what we don’t want to hear and turn up the volume on what we do want to hear,” Anderson said.

To do this, researchers use genetically encoded calcium indicators, a tool that uses a fluorescent signal to show cell activity – in this case how the brain responds to sounds.

“We actually shine light on the brain,” Anderson said. “With a microscope we measure that light and we can track how bright it is, how long it is, and how different types of cells cooperate with each other based on the type of sounds we’re presenting.”

From those observations, researchers want to determine how two very similar sounds are distinguished from each other.

“If the subtle differences between words – like if I say ‘hat’ and ‘hot’ – are difficult to detect and big differences are easy to detect, how is this happening? Which cells, which circuits allow us to do those things?”

Once scientists have those answers, Anderson said findings could be applied to developing better hearing aids, designing more sophisticated sound distinguishing technology, and it could change the way hearing tests are administered.

A bump on the head could turn into more than just that

A lot of people get mild-to-moderate head injury, what most of us know as a concussion. They can occur from a low-speed car accident, a fall or during athletics.

Classic symptoms include dizziness, memory problems, headaches, trouble concentrating and sleep disturbance. About 80% of people recover in a week’s time without treatments such as physical and occupational therapy and medication. If they don’t get another head injury, all is well.

However, another group is more vulnerable, Zachary Weil, associate professor in the departments of neuroscience and RNI, said. Although these people experience the same type of injury as those who recover, their symptoms last months or, in some cases, the rest of their lives. Some even get better and then decline later.

“They have all kinds of health problems that you wouldn't necessarily predict from a head injury,” Weil said. “They can start to have problems with their kidneys, GI tract, cardiovascular disease and metabolic disease like diabetes and obesity. All these things that eventually kill people are occurring at a higher rate among patients with a history of traumatic head injury.”

It's these patients Weil and research colleagues hope to help through their current study. The team is looking at what type of treatment, if any, the patients receive at the time of the injury, what events occur right after the injury and whether the person has a pre-existing condition.

“We’re particularly interested in the blood supply to the brain because the brain is different than other organs and tissues in your body,” Weil said. “Most tissues in our body store energy in various forms. So, if there's an interruption or they need to get more energy out of storage, they have that capacity. For the most part, the brain doesn’t do that.

“For the brain, it’s like a supply chain where everything is brought in as it's needed. The only way that happens is by the blood flow.”

After a head injury, blood flow to the brain isn’t as plentiful and results in damage to small blood vessels in the organ. Weil and his team are trying to understand how that leads to long term neurological problems and damage to blood vessels in the whole body as well as peripheral tissues such as the heart. They’re also looking at whether blood flow is a predictor of disease risk factors.

“Hypertension, obesity, low grade diabetes, those kinds of metabolic risk factors, all share a reduction in blood flow to the brain,” Weil said.

They’re finding these preexisting conditions might be responsible for a viscous cycle when a traumatic brain injury occurs. Not only is recovery less effective, but patients often experience other conditions such as tiny strokes and heart damage.

Mikayla Oldham, an undergraduate assistant in Weil’s lab, said she hopes the research enhances health care providers’ understanding of traumatic brain injuries.

“This can be through increasing the knowledge of how TBIs impact the patients both physically and cognitively as well as the structural/functional changes that occur within the brain itself,” said Oldham, an exercise physiology major from Morgantown.

Immune cells to the rescue not always a good thing

When a person is injured or disease invades their system, immune cells naturally go to battle. They can be either a help or a hindrance. The same holds true when the brain encounters disruption, only with a few more yet-to-be-understood variables.

At the intersection of neuroscience and immunology is the study of neuroimmunology, the focus of Aminata Coulibaly’s lab.

“We try to better understand how the interaction between the immune system and the nervous system affects brain function,” said Coulibaly, assistant professor in both the Department of Neuroscience and Rockefeller Neuroscience Institute.

Specifically, Coulibaly and her team are interested in the most abundant type of white blood cells, called neutrophils, and how their activity affects recovery of the brain after stroke and whether they worsen Alzheimer's disease or decrease its progression.

While the NIH-funded study is still in its early stages, researchers have so far learned that neutrophils’ role in stroke recovery differs between the sexes. Coulibaly is examining the effects of the immune cells in female mice with strokes, while earlier work at other institutions has involved only male mice.

“It’s been documented that if you get rid of neutrophils in males, they do much better with recovery. What we’re finding in our lab is that if you remove the cells from the female mice, their cognition gets worse,” Coulibaly said. “So, we have evidence that in female mice, these cells may play a role in maintaining their brain function after the injury. This is important because the impact of stroke in women is different than men. Therefore, understanding the role of these cells in the female system can help devise targeted therapies.”

It is well established that Alzheimer’s disease is more prevalent in females. Dr. Coulibaly’s work is showing that changing the activity of neutrophils in mice models with Alzheimer’s disease also produces differing results in males and females. When the immune cell is overactive, females’ conditions improve, while males tend to succumb.

“This is interesting because it shows we can manipulate the disease outcome by changing this one cell,” Coulibaly said. “With the results we’re getting, we need to ask more probing questions. We need to ask whether this is the pathway that is important for the changes we are seeing. If it is not, what other pathways are there that we can look at specifically and will those then become things that are targetable?”

Coulibaly hopes that gaining a better understanding of how neutrophils affect brain function will someday lead to new treatment for stroke victims and people who experience Alzheimer’s disease.

The future has arrived

To augment the ever-growing field and position the Mountain State as an epicenter of neuroscience research, WVU will play a pivotal role in a $20 million, National Science Foundation-funded project. Nelson is co-leading the West Virginia Network for Functional Neuroscience and Transcriptomics, a collaboration of neuroscientists and bioinformaticists who aim to expand and diversify the neuroscience and data science workforce in the state through implementing education and development activities for students, especially those who are rural, first-generation college students, and from other underrepresented groups.

“A big part of this grant is workforce development in West Virginia which we share with Marshall University, West Virginia State University and Shepherd University,” Nelson said. “We have an industry advisory board and we’re looking at ways that kids can find jobs or internships in West Virginia so they can go out into the workforce and be competitive.”

Among the top research goals, according to Nelson, is studying synaptic and circuit plasticity, which involve changes in neurons and the connections between them as the result of developmental or environmental changes.

In the future, Nelson expects to see – literally – major advancements in brain imaging, with both general and real-time activity.

“With transcriptomics, for example, we’ll see what the brain is doing, what gene is activated at the same time that there's neural activation happening,” he said. “With that, you can understand the molecular mechanisms underlying things like memory structure or failure of memory and how you learn something. The goal of these projects is to provide foundational neuroscience knowledge that can be applied by our clinical colleagues in the RNI to improve treatments and outcomes of patients.”

Using what’s called computational neuroscience, researchers will attach a small scope to the head to allow them to watch whether functional connections in the brain form or fail after damage such as a stroke.

“Neural transcriptomics and connectomics is the next big area we’re going to investigate,” he said. “It’s pretty dramatic.”