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Brain matters

Dr. Chris Anderson and his team are unlocking neurological mysteries that could one day lead to new treatments for head trauma, stroke and Alzheimer's disease

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Winnipeg Health Region
Wave, May / June 2014

If you want to take a look at how the brain operates on a cellular level, you are going to need a microscope. A powerful microscope.

As Director of the Neuroscience Research Program, Dr. Chris Anderson has just such a device. It is a two-photon microscope, which means it is capable of using infrared laser light and a series of mirrors and lenses to project images of functioning single cells about five one-thousandths of a millimetre across, deep beneath the brain surface, onto a computer screen.

Of course, even the most powerful microscope won't do you much good unless you have something to study. Anderson has that, too. He and his colleagues can examine cell function in isolated tissue and in live rodent brains to model human brain activity in intricate detail not possible in human subjects.

Place a slide of brain cells under the lens of the twophoton microscope, hook it up to a computer, and grab the popcorn. The microscope has a camera that can capture the inner workings of brain cells in real time video. As a result, scientists like Anderson are able to conduct experiments to see how brain cells interact with each other under different conditions.

Through these experiments, Anderson and his colleagues are able to gain new insights into the nature of neurodegenerative disorders such as head trauma, stroke, Alzheimer's, Parkinson's and amyotrophic lateral sclerosis, also known as ALS or Lou Gehrig's disease - and how they might be treated or even prevented. "On a broad level, our research involves exploring the mechanisms that underlie neurodegeneration," says Anderson, in reference to any affliction that undermines the brain's ability to function properly.

Launched in 2012, the Neuroscience Research Program - operated through a partnership between the University of Manitoba's Faculty of Medicine and the Kleysen Institute for Advanced Medicine at Health Sciences Centre Winnipeg - represents a timely investment in an important area of medical research. Currently, about one in three Canadians - 10 million people - are affected by neurological or psychiatric disease, disorder or injury at some point in their lives, according to a report by Brain Canada, a major research hub for neurological diseases.

In addition to the toll on the lives of sufferers and their families, Health Canada estimates the economic impact to be in the range of $23 billion annually, an expense that will continue to grow as the population ages, and Alzheimer's and other forms of dementia become more prevalent. And the forecast is dire, according to a 2010 report by the Alzheimer's Society of Canada. By 2038, Canadians suffering from dementia will more than double, resulting in a cumulative cost over the next three decades of more than $872 billion.

Undoubtedly, says Anderson, this will strain the health-care system's finite resources. "The incidence of Alzheimer's doubles every 10 years after the age of 65, and we have a lot more people who are 85 now - not to mention aging baby boomers living longer - so we will have a lot more people with these disorders."

Currently, the program is home to six principal investigators, including Anderson, and is looking to recruit two more. Each scientist specializes in complementary areas of neurological research, providing a complete team approach that may one day yield new advances for treating brain-related disorders.

Anderson, for example, is investigating the mechanisms that control blood flow in the brain. To understand why that is important, it helps to have a basic understanding of how the brain functions. When people think of the brain, they immediately picture a greyish red, sculpted mass of plasticinelike material that could fit in the palm of your hand.

The brain itself weighs approximately 1.4 kilograms (3.1 pounds) and is divided into two hemispheres and four regions. Each hemisphere and region is responsible for carrying out specific functions, such as sight, touch, movement and analytical thought. The brain is able to carry out these activities because it contains billions of tiny cells called neurons, which send signals to each other via chemicals called neurotransmitters to allow specific instructions (scratch your nose, turn your head) to be carried out. In order for the brain to carry out its work, it must have a steady supply of energy, which it gets from blood containing oxygen and glucose. And it is the flow of blood through the vast network of vessels in the brain that is at the heart of Anderson's work. As he explains, when the blood vessels leading to active brain areas are dilated, the blood flows as it should and your brain functions properly. But when the blood vessels leading to active brain areas become constricted, blood flow is decreased, and the brain's neurons can deteriorate and die over time.

So, what causes the blood vessels to expand or contract?

Potential answers to this question first started to emerge just over 10 years ago. At the time, Anderson was working at a lab at the New York Medical College in Valhalla, New York, as part of a team looking into the role played by tiny cells in the brain called astrocytes.

Although most people are aware of the importance of neurons, the astrocyte is a bit of an unknown. "Astrocytes outnumber neurons 10 to one in the human brain," says Anderson. "Up until about 25 years ago, people thought of them as just structural support for neurons."

The 1990s saw major advances in understanding that astrocytes, in fact, are critical contributors to the most basic of brain functions. Around 2003, the New York team and an Italian group were able to show that these cells, which derive their name from their star-like shape, have a major role in brain function because they are responsible for controlling the blood supply to the neurons in the brain.

But that finding was just the start. Like most scientific discoveries, it only raised more questions. For example, if astrocytes control blood flow, how does this mechanism work? What are the conditions that cause it to promote or restrict blood supply?

Just over a decade later, Anderson and his team are part of the global effort to answer these questions. And progress is being made.

Two years ago, for example, Anderson and his team were the first in the world to identify that a cellular chemical called D-serine plays a critical role in the activation of astrocytes, in studies published in the Journal of Cerebral Blood Flow and Metabolism and Proceedings of the National Academy of Sciences. "The new information we've found shows that we are able to block the vascular effects by either chemically mopping up any D-serine that's released or by using a (genetically modified mouse) that's incapable of making D-serine," he says. "So we've identified that D-serine is a major contributor to the vascular effect of neurotransmission by astrocytes."

Anderson and his team are continuing to pursue this line of inquiry. While D-serine sheds new light on how astrocytes control blood flow, the discovery only partially explains the mechanisms that ensure an adequate blood supply to neurons in the brain.

"This is just one of the mechanisms we've found that might play a key role," he says. "What we know is D-serine activates a type of receptor called N-methyl-D-aspartate (NMDA) and we know this pathway is dependent on D-serine, but what we don't yet know is where these NMDA receptors are, because we know they are present in neurons, astrocytes and endothelial cells."

That is where the work of Adam Hogan-Cann, a member of Anderson's team, comes into play. The hypothesis is that the endothelial cells that make up the blood vessel walls of capillaries in the brain contain the NMDA receptors that are being activated by astrocytes, and, in turn, causing blood vessels to dilate.

"My job is to identify the NMDA receptors in the cells, and what their structure is," says Hogan-Cann, who is a graduate student in the Department of Pharmacology and Therapeutics at the University of Manitoba's Faculty of Medicine. "Once we have a better idea of their structure, then we can infer what their function might be."

Much of Hogan-Cann's work has involved studying the role of nitric oxide within the cells. What he's found is that nitric oxide is released by the endothelial cells in the blood vessel, which causes the smooth muscle in the blood vessel wall to relax and increase blood flow.

"We add agents that should activate the NMDA receptor and then we see increases in nitric oxide within these brain endothelial cells," he says in reference to experiments on brain cell samples in Petri dishes. "Then if you add a blocker that's going to prevent the receptor being activated, you don't get a nitric oxide response, or a significant reduction."

While the research team knows the receptors in the blood vessel cells are likely responsible, they still need to suss out where exactly the receptor is in the cell and then delineate its structure for concrete proof of the hypothesis.

Anderson says he is confident they are on the right track. With each new advancement in the field, including his own experiments, he becomes increasingly convinced that neurodegenerative illness - cognitive decline after stroke and brain trauma, Alzheimer's and other disorders - is caused at least partially by a long-term reduction in blood supply to the neurons that results in poor function and/or their death, and that malfunctioning astrocytes have an integral part in this process.

"There is a chronic starvation of neurons happening across a wide range of disorders. There is something at the very basic level going wrong, whether it's the result of an injury, genetics or other risk factors," he says. "If we can find these basic cellular defects in blood flow regulation, we might be able to apply them to several diseases and thus make a huge overall impact on human health."

In addition to astrocytes, Anderson is also looking into the role that a common neurotransmitter called glutamate plays in the death of neurons in the brain.

When blood flow is restricted, neurons lack the necessary energy supply to continue to function properly. As a result, much more than normal glutamate is released into the synapse, the chemical highway that allows neurons to communicate with each other. "There is a massive build-up of glutamate, leading to oxidative stress," he says. "Eventually you get neuron death, but one of the steps that comes before is the bioenergetic engines of the cell, called mitochondria, are destroyed."

Basically, the mitochondria become "leaky," releasing toxic chemicals into the neuron cell causing its death.

"What I've focused on more recently is how this increase in glutamate leads to mitochondrial dysfunction and permeability, causing neuron death. One pathway that we've latched onto that we think is important is an enzyme called PARP1," says Anderson. PARP1 is DNA's repair foreman, but massive doses of glutamate cause so much DNA damage that PARP1 is over-activated, and it uses up too much of a substance called nicotinamide adenine dinucleotide (NAD), an energy source for PARP1.

"What we've discovered recently is there is a specific mechanism by which NAD depletion leads to mitochondrial leakiness that then releases proteins that cause neuron damage."

Like his work with astrocytes, Anderson's work on the role of glutamate in neuron death represents an important line of inquiry in the search for cures to neurodegenerative conditions linked to head trauma, stroke and even ALS. It may also play a role in Alzheimer's disease.

Although new insights are being gained every day, Anderson says they represent baby steps in the journey toward discovery of drug treatments that can stabilize or reverse the restriction of blood flow in the brain that is at the centre of so many neurodegenerative disorders.

"To some, what we do might seem a little far removed from patient-oriented health research - that we're mucking around with these molecules in the brain. But some of this work will lead to breakthroughs in human therapies for neurological and mental health disorders, and if you look at the history of drug development, it is discoveries like these that have been able to get us to that point."

Joel Schlesinger is a Winnipeg writer.

 

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Unravelling the mysteries of the brain

Researchers break new ground in effort to combat neurological disorders

Established in 2012, the Neuroscience Research Program within the University of Manitoba's Faculty of Medicine is home to some of Canada's top neuroscientists. Based in the Kleysen Institute for Advanced Medicine on the campus of Health Sciences Centre Winnipeg, the program currently has six principal investigators conducting research into neurological disease, with plans to appoint two more in the near future. The following is a brief overview of the researchers and their work.

Dr. Tiina Kauppinen
Inflammation and cell death in the brain

Recruited from University of California San Francisco (UCSF), Dr. Tiina Kauppinen started at the Neuroscience Research Program in 2012, bringing a strong research background in a number of areas, including stroke, Alzheimer's disease, multiple sclerosis and traumatic brain injury.

"My speciality is neuro-inflammation, which is one of the pathological mechanisms involved in brain injuries and disorders," says Kauppinen, an assistant professor in the Department of Pharmacology and Therapeutics at the University of Manitoba's Faculty of Medicine. Kauppinen's expertise in this area is an important addition to the unit because inflammation is both a major symptom and one of the possible main causes of most brain disease.

Kauppinen's research involves investigating the response of different brain cells to stress and the inflammation that results, but they are particularly focused on a cell called microglia. These cells make up the brain's own immune system and are considered to have a key role as a driver of neuro-inflammation. "They are the first cells to respond to even the smallest change in the brain, and microglial activation is a hallmark of any brain injury and disorder."

When the brain is injured, microglial cells are activated to protect the brain. "Microglia have a dual role in an injured brain," she says. "They have an important role in protecting the brain from pathogens and supporting neuronal circuitry."

But over-activation of these cells is also thought to contribute to cell death and neuro-degeneration. "I am trying to understand how their functions affect other brain cells and, in turn, how we can regulate or modulate microglial functions so that when someone experiences a brain injury, for example, we can prevent microglial cells' actions that contribute to neuronal damage while promoting their beneficial actions that support neuronal survival and recovery."

Dr. Fiona Parkinson
Chemical clues to mental illness

It's widely understood that depression and other mental illnesses are likely caused in part by chemical imbalances in the brain. For decades, neuroscientists have been examining different chemicals - called neurotransmitters - to better understand how too much or too little of these molecules can cause neuropsychiatric disorders.

The role of neurotransmitters in mental illness is also the focus of Dr. Fiona Parkinson's research team. They are studying the role of one neurotransmitter called adenosine, which also plays a role in the functioning of the lungs and heart.

In the brain, adenosine is a very potent inhibitory transmitter, thought to have an important role in promoting sleep and dampening arousal. "Too much adenosine is linked to depression and too little is linked to seizures, anxiety and insomnia," says Parkinson, a professor in the Department of Pharmacology and Therapeutics at the University of Manitoba's Faculty of Medicine. "Our research addresses when, where and how adenosine is produced, with the twin goals of first, understanding adenosine's role in various brain disorders, and second, identifying drugs acting through this pathway to treat these conditions."

One challenge Parkinson faces is finding a technique to accurately measure rapid changes in adenosine levels that occur in response to drug treatments or environmental conditions.

Parkinson's team is developing two techniques to address this problem. One leverages positron emission tomography (PET) to image adenosine levels in anesthetized rats' brains. The other technique uses bio-sensors designed to measure rapid changes in adenosine that are produced in tissue samples.

"Coupling these techniques for measuring adenosine to animal models of disease will bring us closer to novel treatments for brain disorders with a high impact on human health and quality of life," says Parkinson.

Dr. Michael F. Jackson
Calcium's role in the brain

Calcium isn't just important for the health of our bones, according to Dr. Michael F. Jackson. It also plays a pivotal role in the function of cells.

An assistant professor in the Department of Pharmacology and Therapeutics at the University of Manitoba's Faculty of Medicine, Jackson and his research team are investigating the role calcium plays in neuronal death in the brain.

Neurons require just the right amount of calcium in order to function properly, but under stress from injury or persistent adverse conditions, this balance is upset and leads to a cascade of chemical events inside the cell that causes its death.

"Using advanced multidisciplinary approaches, including electrophysiological, biochemical and cellular imaging techniques, we are seeking to understand how these channels become activated under conditions intended to mimic those occurring during stroke and Alzheimer's," Jackson says. "The central premise of these studies is that calcium permeation is an important contributor to calcium dysregulation underlying neuronal injury and neurodegeneration."

Jackson's work aims to prove that ion channels (active chemical pathways) in the cells are over-activated, which leads to a massive increase in calcium in the neurons that "ultimately kills them. In stroke, the damage is acute, so pathways are over-activated, causing cellular destruction that can be measured in minutes. With degenerative diseases, like Alzheimer's, the activation is much more gradual, causing a slower but progressive effect.

Jackson is one of the world's leading basic scientists in this field, says Dr. Chris Anderson, Director of the Neuroscience Research Program. Having joined the team last year, recruited from Western University in London, Ontario, he brings a unique set of skills to the program as an electro-physiologist, Anderson adds. "He's a world-class scientist who can do things that not a lot of other scientists can do, so he can really give us a new area that we can work in together," he says. "By collaborating with him, I have access to a technical approach that I don't have and nobody else here has."

Dr. Jun-Feng Wang
Oxidative stress and mental health

Oxidative stress is a culprit in many diseases, from cancer to cardiovascular disease. Dr. Jun-Feng Wang's area of investigation aims to determine whether oxidative stress also plays a critical role in mental illness.

"I am interested in understanding the role played by oxidative stress in the pathophysiology of neuropsychiatric disorders, particularly in bipolar disorder but also how it may work in schizophrenia and others," he says. "While oxidative stress-induced neuronal damage has been consistently found in neurodegenerative disorders such as Alzheimer's disease, my lab was the first to find that oxidative stress is present in bipolar disorder, and that it can be inhibited by mood-stabilizing drugs."

The consequences of oxidative stress in bipolar disorder are still by no means clear.

"In contrast to neurodegenerative disorders, onset of bipolar disorder typically occurs in late adolescence or early adulthood, when no significant neuronal loss has been observed," says Wang, an associate professor in the Department of Pharmacology and Therapeutics at the University of Manitoba's Faculty of Medicine.

Although the level of oxidative stress in bipolar disorder appears to be insufficient to cause brain cell death, Wang's lab hypothesizes that it may modify the brain chemistry to affect synaptic proteins and enzymes that play a critical role in how neurons communicate with each other. As a result, these changes have an impact on mood regulation, which is impaired in patients with bipolar disorder.

"We are able to treat bipolar disorder pharmacologically with some success, but the mechanisms of action of current treatments are still unclear," he says. "My lab focuses on identifying specific oxidative stress-modified proteins in bipolar disorder and analyzing their potentials for future pharmacological treatment."

Wang says the research also holds promise for understanding Alzheimer's. "Recognizing that there is considerable co-morbidity between Alzheimer's and neuropsychiatric disorders, our research also works to understand the different roles played by oxidative stress in the pathophysiology of bipolar disorder and Alzheimer's disease as we continue to illuminate the mechanisms of oxidative stress in neuropsychiatric disorders in general."

Dr. Donald Miller
Understanding the blood-brain barrier

The brain is a blood-thirsty organ.

In fact, the brain is so densely packed with blood vessels that, viewed all together with high-tech imaging techniques, they look like a ball of steel wool. This is important because the brain needs the energy provided by glucose and oxygen contained in blood in order to do its job. And in order for that to happen, the blood must travel through a membrane called the blood-brain barrier.

Just how the blood-brain barrier works - and how it can be negatively affected by disease and toxins that ultimately cause disease - is the subject of study by Dr. Donald Miller, a professor in the Department of Pharmacology and Therapeutics at the University of Manitoba's Faculty of Medicine.

The blood-brain barrier is responsible for allowing the nutrients, hormones, and growth factors required for optimal brain function to enter into the brain while restricting the access to potential toxins and compounds in the bloodstream that would interfere with brain function," says Miller. "My area of research is focused on the brain micro-vessel endothelial cells that form the blood-brain barrier."

While brain cells called neurons are responsible for transmitting chemical signals into electrical impulses, the brain capillary endothelial cells of the blood-brain barrier help keep the neurons functioning properly.

"I am interested in the function of the brain endothelial cells under normal conditions and following various neurological disorders such as brain tumor or acute trauma," Miller says. "As many neurological disorders involve diminished blood-brain barrier function, identifying ways to protect and enhance the barrier properties is important to understanding and treating the disease."

Although ensuring this permeable membrane functions properly to let in nutrients and hormones while keeping out the toxins is one major avenue of research, Miller's team is also studying how it can be manipulated to allow new drugs and other therapies to be absorbed by the brain's cells.

"Unfortunately, many of the drugs being developed to treat neurological disorders do not have sufficient blood-brain barrier permeability to reach therapeutic levels in the brain," he says. "So, my laboratory is interested in how various transport proteins in the blood-brain barrier can be used to increase the brain penetration of drugs."

Miller's lab is also researching how nanoparticles - manmade microscopic carriers of drugs - could enhance drug delivery from the blood through the membrane to the brain's cells.

 

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