CVM Researcher Uses Plasticity to Combat Neurodegenerative Diseases

Heraclitus, a Greek philosopher who predated Socrates, famously said, “Change is the only constant in life.” The truth of this paradox is found throughout the biological world. Organisms adapt to changes in their environment, or even differences between their various habitats.

Plasticity is the modern byword for this quality of being readily molded or changeable.

“Plasticity is when you’re exposed to something again and again, over time, you’re going to start to adapt to it; you’re going to develop plasticity,” says Nicole Nichols, PhD, a researcher and assistant professor in Biomedical Sciences at MU’s College of Veterinary Medicine (CVM).

“It’s like when you go to the gym for the first time,” Nichols explains. “You’re gung ho, you want to get in shape, but the next day you can hardly walk because you’re so sore. But then, two weeks later, you’re feeling pretty good, you’re getting into better shape. That’s an example of plasticity. Repeated over time, it will lead to a long-lasting change.”

Nichols is conducting research that focuses on plasticity as a way to influence interactions in the neural system to combat terrible diseases that can rob you of your ability to speak, eat, move, breathe, live.

Respiratory failure is often the cause of death in neuromuscular disorders and neurodegenerative diseases in which there is significant motor neuron loss. There are currently no treatment options that significantly and consistently improve ventilation in any of these disorders.

With help from a Missouri statewide funding mechanism called the Spinal Cord Injury and Disease Research Program (SCIDRP), Nichols’ lab is working to harness the central nervous system’s natural ability to develop respiratory plasticity in order to combat diseases that can rob people of the bodily functions necessary for life.

“They fund two different kinds of research: spinal cord injury that results in any kind of trauma to the spinal cord and diseases that occur in the spinal cord,” Nichols says. “There is a list of diseases that qualify, but it has to be in the spinal cord.

“Other things about the SCIDRP funding that stood out to me were the disease processes of the spinal cord, focused on motor neurons,” Nichols says. “We are utilizing our unique model of motor neuron death in the spinal cord, which has targeted respiratory motor neuron death to affect respiratory motor behavior, to determine the mechanisms that underlie plasticity in those motor neurons, in order to try to target a therapy. These are the goals of our SCIDRP-funded study.”

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The Nichols’ lab focuses on motor neuron death that occurs in diseases and disorders, which includes amyotrophic lateral sclerosis (ALS), a progressive neurodegenerative disease that affects nerve cells in the brain and the spinal cord. ALS was discovered in 1869 — almost 150 years ago — but, according to the ALS Association, the prognosis for anyone diagnosed with the disease is the same now as it was then — death in an average of two to five years.

Between 5 to 10 percent of ALS cases are hereditary; the rest occur for unknown reasons. Smoking, being male, white and older than 60 are the most closely associated risk factors for the general population. For some reason, military veterans — regardless of service branch, theater, conflict or peacetime service — have a 60 percent higher risk of developing ALS than the general population.

ALS is also known as Lou Gehrig’s disease, after a renowned New York Yankees slugger and first baseman whose diagnosis introduced America to the disease in 1939. The robust baseball star died less than two years later at age 37.

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“Most people who are diagnosed with ALS die of respiratory failure,” Nichols says. “But, they don’t have just respiratory failure. They may have problems walking or problems swallowing — there are a myriad of problems going on, not just issues with breathing. During my postdoctoral work at the University of Wisconsin, I wanted to look only at breathing and determine if we could improve it in an ALS genetic rodent model. However, when you are giving a systemic therapy to the genetic rodent model of ALS, there is no way to know if you are targeting just one region, in other words, you don’t know if just breathing is affected or if locomotor activity is affected, for example.

“That’s why I developed the model we’re working with here at Mizzou, which was the basis of my first National Institutes of Health funding,” Nichols continues. “I was funded by a K99/R00 Pathway to Independence Award the first three years I was here. The basis of that funding was to develop this inducible model and start to figure out if it is similar to other rodent models of neurodegenerative disease or not. In general, we ask if our inducible model induces motor neuron death, and is it targeted and specific, so that we can develop targeted therapeutics?

“The focus of my current research program is to understand underlying mechanisms of plasticity following motor neuron death to ultimately preserve or restore breathing and swallowing function,” Nichols continues. “In our SCIDRP-funded study, our goal is to understand if harnessing an underlying pathway required for plasticity, in combination with exposure to daily acute intermittent hypoxia (therapeutic bouts of intermittent oxygen deficiency), preserves or restores respiratory motor output and overall breathing in a novel model of respiratory motor neuron death,” says Nichols, a 2016-2017 participant in MU’s Faculty Scholars Program. Nichols also received the American Physiological Society’s prestigious Giles F. Filley Memorial Award for Excellence in Respiratory Physiology and Medicine in 2015, and was a Parker B. Francis Fellowship in pulmonary research recipient, 2011-2014.

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“When I was in high school, I had a grandmother who developed COPD — Chronic Obstructive Pulmonary Disease — so I started to become really interested in how that happens, how you control that, and what it is that goes wrong,” Nichols says. “I just didn’t know much about it, so I was really interested in working on that for my PhD. Wright State had a biomedical sciences PhD program, which allows one to get broadly trained while also specializing in different things. Neuroscience was one of those things. That appealed to me, so that’s the path I took.

“In the work we did there, not only did we characterize the part in the brain stem that has a role in controlling breathing, but we also started to look at how adaptations to certain things can change the neurons that are responsible for sensing changes to help us breathe,” Nichols says.

“During my PhD work, I exposed our lab animals to a simulation of what you would see at high altitude,” Nichols says. “What we saw was that the individual neurons started to develop plasticity in response to that exposure. I didn’t really know much about plasticity, so I started to get excited about that and wanted to learn more about it — and not just how it works, but how it changes in disease states.

“High altitude is more like a physiological response, but I was also interested in what the pathophysiological response is. That’s when I decided to do my postdoctoral training at the University of Wisconsin, to learn more about plasticity in the face of disease,” Nichols says.

Pathophysiology is a convergence of pathology — conditions observed during a disease state — with physiology, the processes or mechanisms operating within an organism. Pathology describes the abnormal or undesired condition, whereas pathophysiology seeks to explain the functional changes that are occurring within an individual due to a disease or pathologic state.

Nichols moved to Madison to begin postdoctoral work with Gordon S. Mitchell, PhD. Mitchell is a prolific researcher, studying the importance of neuroplasticity in respiratory motor control. In his 33 years at Wisconsin, Mitchell became the Steenbock Professor of Behavioral and Neural Science and chair of the Department of Comparative Biosciences.

“It just so happened that the professor I went to work with, Gordon Mitchell, is a world-renowned researcher in spinal cord plasticity, specifically how it pertains to breathing,” Nichols recalls. “He had just started a collaboration with a colleague, Dr. Clive Svendsen, who was interested in using stem-cell biology to improve breathing in ALS. Specifically, they wanted to look at the question of how does respiratory motor behavior change in combination with stem-cell biology in a genetic rodent model of ALS.

“I got naturally hooked into that project because I was interested in studying different aspects of the disease,” Nichols says. “That was my first project as a postdoc, and looking at how this spinal-delivered stem-cell application affected the respiratory motor behavior. We found that it was beneficial, and did increase respiratory motor output. At about the same time, I had also started a project using acute intermittent hypoxia to induce plasticity. Basically, we give hypoxia three times, each separated by going back to baseline, or normoxia. What will happen over time is that motor output will begin to ramp up or, in other words, exhibit plasticity.”

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Military service can come with a veritable smorgasbord of risks: combat, terrorist threats, head trauma, intense exertion, or exposure to climate extremes, certain chemicals or metals.

But, the fact that military veterans have a 60 percent greater chance of developing — and dying from — ALS than non-veterans has the attention of the U.S. Department of Defense (DOD). Nichols plans to continue and expand her research by applying for a two-year, DOD grant known as the ALS Research Program Therapeutic Idea Award. These awards are designed to promote new ideas aimed at drugs or treatments that are still in the early stages of discovery. Emphasizing innovation and impact, the awards are to support research that may lead to potential therapeutics for ALS.