Neuroscience Research Department: Research Annual Report 2003

The Neuroscience Research Department seeks to understand how the brain functions in mental illness and addictions. To do this, we study all levels of the brain, from the molecules through the cells and neurons to the whole brain.

To study these levels, we focus on certain areas of research. In one area, we look at the chemicals that transfer messages from one brain cell to another, the neurotransmitters. These include dopamine, serotonin, nor-adrenalin and glutamate. We look at the genetic code, the "blueprints," that the body uses to manufacture different brain proteins and chemical messages. If we see a genetic variant in a group of people who have a particular addiction or mental illness, then we can study why that genetic variation might create a change in brain function, which would, in turn, result in or influence the addiction or mental illness.

Another important theme in our research is the action of medications and drugs of abuse. Understanding the details of this action could help us develop novel medications, with better efficacy and reduced side-effects.

Recently, we have made some very interesting developments in our research methods. As you will see in the following pages, we have expanded the range of animal models available to study drug response and behaviour. By administering drugs, using learning paradigms and discovering or creating genetic alterations in the animals, our researchers are revealing mechanisms of action that relate to psychiatric conditions.

For example, building on a fascinating discovery by Dr. Marla Sokolowski at the University of Toronto, investigators in the Neurogenetics Section looked at a gene that controlled fruit fly behaviour. One variant of the gene created a "rover" fly, which wandered around extensively. Another variant of the same gene determined a "sitter" fly, which did not roam around as much. This fruit fly gene, PKR G1, controls a biochemical process that has a direct parallel in humans. We tested for genetic variations in the human PKR G1 gene in people with attention-deficit/hyperactivity disorder. While our initial results have not shown an effect of this fruit fly gene in human hyperactive behaviour, it nevertheless is a fascinating model for future investigation.

We continue to use the nematode C. elegans, introduced into the department by Dr. Van Tol, in our studies. This tiny worm, less than a quarter of an inch long, has a very simple brain that consists of a small number of neurons. Despite its brain simplicity, the worm can still learn, for example, to turn right instead of left to find a food source. The simplicity of this tiny animal is a great help in investigating how brain cells function and how they alter behaviour, illuminating processes that are relevant to humans.

Another exciting development is the use of microarray technology. This technology allows us to investigate the activity of up to 10,000 or more genes or proteins at a time in the brain.

An example of our use of microarray technology is the work done recently by Dr. Albert Wong and colleagues as a collaborative effort across the Molecular Neurobiology, Neurogenetics and Neuroimaging Sections. Dr. Wong treated a group of rats with the antipsychotic medication haloperidol. He then took portions of the brain tissue from the treated rats and compared these tissues with those from a group of untreated rats. From the comparison, he was able to create a mixture of all the message molecules from the rats' brain tissue affected by the haloperidol. He then poured the mixture over a series of microarrays -- small glass wafers with thousands of genetic probes printed on them. This process allowed us to see which genes were increased and which were decreased in the rat brain following treatment with the medication. In one experiment, more than 10,000 components of the brain could be investigated; from this Dr. Wong found about a dozen genes that were significantly changed by the action of the medication.

One of these genes, called 14- 3- 3, was then tested in a large group of people who had been diagnosed with schizophrenia; we found that certain variants of this gene occurred more often in the group of people who had schizophrenia than in a control group of people who did not have schizophrenia. Our Neuroscience Department researchers are now trying to understand better what this 14- 3- 3 molecule does in the brain and how it might play a role in schizophrenia.

The use of microarray technology immediately creates an enormous amount of information. A study of 10 drugs, for example, may involve microarrays for 20,000 genes and 30,000 proteins each. Multiplication of all these numbers leads to millions of potential interactions, any one of which might be involved in a mental illness. In this context, computers and information processing are central.

This field of information management, also called bioinformatics, is becoming more and more critical to our activities in neuroscience research. Powerful computers and vast amounts of information from microarray methods and the human genome databases can be combined with equally vast amounts of clinical information, including lists of symptoms and variable response to drugs, to create a massive database. Computers can then probe these enormous databases to try to find the metaphorical "needle in a haystack" -- a key part of the puzzle of how the brain functions in a psychiatric disorder.

We are submitting some of our discoveries for patent protection. Patent protection encourages private companies to invest in research toward new treatments or diagnostic tests. We are fortunate to have Dr. Klara Vichnevetski providing support and guidance to our researchers in the processes of patenting selected findings. This increasing collection of patents at CAMH also represents a potential source of significant financial return for our hospital, our researchers and our laboratories.

The Neuroscience Research Department continues to work closely with the Clinical Research Department. Dr. Leslie Atkinson is leading a large team of scientists to investigate the response of young children to stress; this project may help us understand how humans develop both adaptive and maladaptive responses to stress. We are also studying childhood-onset depression, attention-deficit/hyperactivity disorder, aggressive behaviour and autism.

We are beginning to investigate ways to bring neuroscience research results to a wider population; to do this, we are collaborating on education programs and joint research with the Social, Prevention and Health Policy Research Department. For example, we may conduct large-sample surveys that ask questions such as, "If we developed a blood test that could tell you if you were at risk for an addiction, how valuable would this be?"or "If a test could predict your risk for depression, would you ask your doctor for it?"

Meaningful discoveries in the molecules and mechanism of the brain can be used to develop new treatments for mental disorders and addictions. In the Neuroscience Research Department, one of our great strengths is that we are able to interact with clinical researchers. We expect that our discoveries at the laboratory bench will have applications in which predictive tests and new treatments can be evaluated at the bedside and the clinic. These evaluations will then be brought back to neuroscientists to help us refine our experiments, offering progressive improvements to psychiatric care.

Director: Dr. James L. Kennedy

Neuroscience Research Sections

Neuroscience Research Department: Research Annual Report 2003

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