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 The painted brain: How our lives colour our minds By HANNAH HOAG, Special
to the Montreal GazetteJanuary 15, 2011 Maamar Bouchouka (from left), Josee
Prud'homme and Danielle Cecyre of the Brain Bank amid the hundreds of brains
in plastic containers at the Douglas Institute.Photograph by: Vincenzo
D'Alto, Montreal GazetteThe brain arrives shortly after lunch. 
It rests on the lab bench, in a Styrofoam box plastered with “Urgent
Delivery” and “Fragile” stickers, while two research assistants prepare the
dissection laboratory. One has tuned a small radio to a classical station.
The sounds of bassoons and strings waft into the room. The opus is an
allegro – upbeat and quick. 

The technicians glide around the room with practised coordination. They are
cloaked in knee-length blue plastic aprons, sleeves tucked into latex
gloves. They tape absorbent mats to the bench tops and lay out scalpels and
forceps. 
Josée Prud’homme adjusts her face mask and eye shield, and nods to her
colleague, Maâmar Bouchouka. 
Bouchouka lifts the red biohazard bag from the box and slices it open with a
scalpel.
“We’re starting. It’s 13:21,” he says. 
He pats the brain down with paper cloths and sets it on a white cutting
board. It slouches a bit. The tissue has started to break down. The brain is
pink and a little shiny. Dark red blood vessels snake through the deep
wrinkles and folds of the cerebral cortex, like rivers through weathered
canyons. 
It’s the brain of someone who took his life over the weekend, and was
donated to the Quebec Brain Bank shortly thereafter. 
“It’s very emotional, each time we receive a brain at the bank. We don’t get
used to death,” says Prud’homme.
For 90 minutes, Bouchouka and Prud’homme will remove and freeze the brain’s
key structures. They’ll separate the two hemispheres, preserving one in a
rectangular clear plastic container filled with a formaldehyde solution, and
cutting the other into one-centimetre-thick slices flash-frozen for storage
at minus 80 degrees Celsius. 
Now named S-252, this brain has become a critical resource for scientists
interested in the biological and environmental underpinnings of mental
illness.
* * * 
For scientists interested in the origins of disease, mental illnesses have
been difficult to untangle. Researchers have rummaged through the genome
looking for common genetic disruptions to explain the cause of these
overwhelming conditions. 
Some scientists assume they’ll find the genetic roots of mental illnesses
with more sophisticated technologies and approaches, and more powerful
computers, says Arturas Petronis, a senior scientist in the Krembil Family
Epigenetics Laboratory at the Centre for Addiction and Mental Health, and
the Tapscott Chair in Schizophrenia Studies at the University of Toronto. 
But genetics cannot explain all cases. Identical twins have nearly identical
DNA, but if one twin develops schizophrenia, the other has only a 50 per
cent chance of the same outcome.
“There’s another line of thinking that says, ‘There’s probably something
wrong with the paradigm,’ ” Petronis says. “Maybe we’ve been barking up the
wrong tree.” 
A growing cadre of scientists is finding that life experience can be
chemically “painted” onto DNA, creating a genetic on/off switch. This type
of genetic regulation is called epigenetics, “epi” meaning above. 
“Scientists have been studying epigenetics for years, but its application to
the study of behaviour is relatively recent,” says Barry Lester, a professor
of psychiatry and pediatrics at Brown University’s Center for the Study of
Children at Risk. 
The chemical traces of potent past experiences – such as famine or abuse –
can change the way the brain works, and may be a source of addictions,
depression and other mental illnesses. 
* * * 
In 2004, McGill University researchers Michael Meaney and Moshe Szyf showed
in a widely cited study that a mother rat’s nurturing could influence
whether her pups were frazzled or relaxed as adults. 
Meaney, a neurobiologist and clinical psychologist who splits his time
between the Douglas Mental Health University Institute at McGill and the
Singapore Institute for Clinical Sciences, has studied animal models of
maternal care using the Long-Evans rat, which sports a dark hood of fur over
its head and shoulders. Mother rats will nurse, lick and groom their
offspring during their first 21 days of life. Some are more attentive than
others, which can change how the rats turn out. 
“We spent eight hours a day watching these rats lick and groom their pups,”
says Meaney. “It’s the ideal activity for long Canadian winters; it keeps
your graduate students and post-docs off the streets.”
Meaney’s team found they could divide the young rats into two groups: the
well licked developed into calm, even-tempered critters; the others were
bundles of nerves that performed poorly on stress tests. 
To figure out why, the team measured the expression of a protein called the
glucocorticoid receptor in the hippocampus, one of the brain structures
involved in storing long-term memories, anxiety and depression, and placing
events in place and time. 
The hippocampi of the nurtured pups were awash with glucocorticoid
receptors. When the stress hormone cortisol activates the receptor, it
dampens the stress response. More receptors mean a more modest response to
stress. 
Could maternal care change gene expression? Meaney turned to Szyf, a
molecular biologist and cancer researcher who had long been interested in
epigenetics, specifically in a process called DNA methylation. Painting
methyl groups (a carbon atom and three hydrogens) onto specific parts of DNA
silences nearby genes. 
The group looked at the methylation patterns in the hippocampus and found
the nurtured rats had lightly painted glucocorticoid receptor genes, whereas
the others were slathered with the epigenetic mark. Because the cell’s
protein-making machinery could more easily read the unadorned gene, it
pumped out glucocorticoid receptors, muting the stress response. 
What Meaney and Szyf had uncovered was most unorthodox. They had evidence
that life experiences alter DNA, not by changing its sequence, but by
painting it and changing nearby gene expression.
* * * 
Rats are good animal models for studying human neurobiology, but eventually
one must study the real thing.
Gustavo Turecki, a psychiatrist, neuroscientist and the director of the
McGill Group for Suicide Studies, approached Meaney after hearing him speak
at a meeting. 
“I said, ‘Michael, we have to do this in humans. We have everything we
need,’ ” says Turecki, who is also the director of the Réseau Québécois de
recherche sur le suicide and co-director of the Quebec Suicide Brain Bank (a
division of the Quebec Brain Bank). The two worked a floor apart, but had
never collaborated on a research project. 
Turecki had seen many patients who had experienced early traumatic events –
neglect and abuse – that seemed to have triggered the onset of mental
illness. 
Patrick McGowan, a post-doctoral fellow in Meaney’s lab, turned to the
Quebec Suicide Brain Bank to translate the research from rats to humans. He
withdrew 36 brain samples: 12 from men who had been abused as children and
later died by suicide, 12 from men who had no history of abuse but committed
suicide, and for the control group, 12 samples of healthy brains from men
who died of other causes.
The epigenetic marks on the glucocorticoid receptor gene in the human
hippocampus closely matched what they’d seen in the rodents. The
glucocorticoid receptor gene of those who had been abused was rich with
methyl groups.
The results couldn’t explain everything about abuse and suicide – but they
offered a proof of concept.
“What we did was pretty cool,” Meaney says. “It might take us somewhere that
lets us understand why the genome operates differently in one individual vs.
another, and why environmental events might explain that.”
In psychiatry, adaptation and vulnerability are linked, says Meaney. Someone
who grows up in a “toxic environment,” such as an abusive one, and adapts in
the short term is vulnerable to developing a mental illness in the long
term.
Methylation allows the genome to adapt – it’s a molecular coping strategy.
“For abused children, it sends the message that the world is harsh,” Szyf
says. “If you’re raised in a highly adverse environment, being super-anxious
and super-stressed is probably protective.” 
* * * 
Many groups are now studying epigenetics, the brain and behaviour. At a
meeting in Boston in October, scientists showed how epigenetics affects
learning, memory, drug addiction, schizophrenia and other psychiatric
disorders. 
“There was a time when this idea – that an environmental signal could alter
the methylation of a gene – wasn’t accepted,” Meaney says. Yet by showing
methylation changes at specific spots in the genome in response to fear
conditioning, drug use or other scenarios, these groups are supporting this
hypothesis. 
Eric Nestler, a psychiatrist at Mount Sinai School of Medicine in New York
City, has spent 25 years studying why stress and drug use lead some to
develop depression and addiction, but not others.
Nestler has pinpointed epigenetic changes in the brain’s reward centre – the
nucleus accumbens – following recurrent drug use. His studies in rats show
that chronic cocaine use strengthens the connections between brain cells,
heightening the rush when the drug is taken again. It also launches a
cascade of events, altering methylation patterns and gene expression, and
ultimately increasing the animal’s stress response and depression. 
Several animal studies, including those done by Nestler and Szyf, have found
that some chemicals can alter the epigenetic marks, suggesting that, at
least in theory, treatments that target these brush strokes could be
developed. 
Epigenetics – far better than genetics or environment alone – can help
explain why the intensity of some diseases fluctuates, says Petronis. “Think
about bipolar disorder, multiple sclerosis or psoriasis. There are periods
when the affected individuals are perfectly normal, and then three months
later they’re very sick,” he says. Because methylation is reversible, a
gene’s on/off switch can be altered over time. 
“I trained as a geneticist. When I realized that there was this whole new
world that we had basically been ignoring, I changed my religion. I started
believing in epigenetics,” Petronis says. In a 2008 pilot project on the
epigenomics of major psychiatric disease, Petronis identified epigenetic
marks on the brains of people with schizophrenia. 
* * * 
Meaney, meanwhile, is deep into another study to understand the
gene-environment collaboration. 
The Maternal Adversity, Vulnerability and Neurodevelopment (MAVAN) project
is tracking 500 women and their children to learn why some children stay
healthy though they have impoverished and stressful childhoods. 
Generally, kids who are cuddled less and have a weaker emotional bond with
their mothers have a greater risk of developing learning difficulties or
behavioural problems, and are more sensitive to stressful events. Seven
years ago, Meaney’s team began recruiting pregnant women living in Montreal
and Hamilton, some of whom suffered from depression or lived in poverty.
Part of the project uses puzzles to test the kids’ confidence and
self-assurance. Some are easy; others are rigged and impossible to complete.
After each test, the child is asked how well he thought he did, how well he
thinks he’ll do on the next puzzle, and how he feels about doing the next
puzzle. 
Confidence tends to drop following failure. But whether it plummets or dips
depends on two factors: genetics and maternal care. 
A child with the short version of the gene that makes the serotonin
transporter, a protein linked to emotion, is at greater risk for depression.
But the short gene can’t predict which children will be most upset by their
performance. This also depends on the child’s attachment to his mother.
Those with the shorter gene generally avoid the emotional crash if they
received nurturing care. 
“It’s only through the two – genes and environment – that you can understand
it,” Meaney says. “There are two points to this: one is the interdependence
of gene and environment, and the other is that your genes don’t make you
sick. They make us more or less susceptible to environmental influences.
It’s a much more sophisticated way of thinking of what genes do.” 
* * * 
Meaney’s office is down the hall from the brain bank, where it’s been a busy
day. While working on S-252, the team received a telephone call. Another
brain might soon be on its way. 
The donor is still alive. But Danielle Cécyre, the brain bank’s coordinator,
has been told that death is imminent. 
In this case, the man decided nearly a decade ago to donate his brain at
death. All the forms are signed and the copies are in the right places. 
“The people who donate are people with hope. They hope that what we do here
at the brain bank will change things,” says Cécyre. 
Hannah Hoag received a Canadian Institutes of Health Research Journalism
Award to support her research on the epigenetics of mental health.
© Copyright (c) The Montreal Gazette PreviousNext Maamar Bouchouka (from
left), Josee Prud'homme and Danielle Cecyre of the Brain Bank amid the
hundreds of brains in plastic containers at the Douglas Institute.Photograph
by: Vincenzo D'Alto, Montreal Gazette

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