Antidepressants, Exercise, Age, Even Food
Intake, Affect Generation Of New Brain Cells
ScienceDaily (Nov. 9, 2007) — Recent
research shows that the production of new brain cells may be crucial for
antidepressants to be effective and that the medication's effectiveness is
strongly influenced by age. What's more, meal frequency, type of food, and
physical exercise affect the brain's ability to manufacture these new cells.
For the first time in nonhuman primate models, scientists have documented the
cause-and-effect relationship between antidepressant drugs and neurogenesis. The
researchers found that the antidepressant drug fluoxetine improved the behavior
of macaque monkeys with depression-like symptoms.
They also discovered that administering the drugs to normally behaving
monkeys did not influence their behavior but did alter their brains by boosting
neurogenesis in the hippocampus, an area involved in memory and learning.
In one study with macaque monkeys, the stimulation of neurogenesis appeared
to be necessary for the treatment of depression, says Tarique Perera, MD, of
"Given the parallels between the monkey behavior model and human
clinical depression, and the structural similarities between the macaque and
human brains, we expect neurogenesis to play an equally important role in
antidepressant mechanisms in humans," he says.
The Columbia University scientists induced the monkeys' depression-like
behavior by repeatedly separating the animals from their social groups. In
addition, there was a control group of six monkeys that stayed in their social
groups. Perera administered the antidepressant fluoxetine to three of the
animals in the separated group and three animals in the control group. The
remaining separated and control animals were given a placebo.
The placebo-treated separated monkeys progressively lost interest in
pleasurable activities, and their social standing dropped. "These behaviors
parallel elements of depression in humans," Perera says. In contrast, the
control animals' behavior did not change. The scientists identified the reason
when they subsequently examined the animals' brain tissue.
In the hippocampus of the fluoxetine-treated monkeys in both the control and
separated animals, they found many new cells. However, despite the fact that the
rate of neurogenesis in their brains was higher than average, the behavior of
the treated control group stayed the same. In fact, it did not differ from the
behavior of the placebo-treated animals that remained in social groups.
The scientists next determined the impact of fluoxetine on brain and behavior
in the absence of neurogenesis. Four animals underwent two weeks of X-ray
radiation directed to the temporal lobe, a brain area that includes the
hippocampus. While the dose destroyed new cells, it was low enough to spare
The four separated, X-ray treated animals developed depression-like symptoms
despite the fact that they were being treated with fluoxetine. Subsequent
analysis of the animals' brain tissue showed that neurogenesis was not increased
in these animals despite treatments. The neurogenesis levels in the treated and
untreated animals did not differ.
In another animal study, conducted at the University Medical Center in
Regensburg, Germany, scientists determined that the action of antidepressant
therapy on neurogenesis is highly dependent on the age of the treated
individual. Their study suggests that the therapeutic effects of antidepressants
in elderly humans may not be mediated by neurogenesis.
The researchers studied mice in three different age groups: 100, 200, and
more than 400 days old. These ages correspond roughly to young adult, adult, and
elderly individuals in the human population, the scientists say.
"Paradoxically, the stimulatory activity of the antidepressant on
neurogenesis was more potent in youngest animals, even if their rate of
neurogenesis was already high as compared to the older mice," says
Sebastien Couillard-Despres, PhD.
Couillard-Despres and his team also showed that extended treatment with
fluoxetine enhanced neurogenesis only in the youngest animals. When the
scientists compared the treated and untreated animals in the two youngest age
groups, they found that although neurogenesis had occurred in all of these young
animals, more newly generated cells survived and developed into specialized
types of neurons in the rodents that had received fluoxetine.
To mimic the long-term antidepressant drug therapy that characterizes most
people with depression, the scientists treated the lab animals with fluoxetine
daily at a clinically relevant dosage over six weeks.
The scientists measured the rate of generation of new brain cells, the
survival rate of these cells over time, and the percentage of cells that became
mature. In addition to the fluoxetine-treated animals, the study included
control animals for every age group. The controls received only a placebo
Among the other factors that influence neurogenesis in the adult brain is the
amount of calories consumed in the diet, according to research of Sandrine
Thuret, PhD, at King's College in London.
Her laboratory also discovered that caloric intake affects learning and
memory and that, independent of calorie intake, meal frequency and food content
both play important roles in neurogenesis in the hippocampus. "Our cell
culture data show an impressive increase of 40 percent of adult hippocampal
neurogenesis upon addition of omega-3 fatty acids into the cell culture
dish," Thuret says.
In laboratory animals, Thuret found that meal frequency is more important
than calorie intake in regulating adult hippocampal neurogenesis. "Indeed,
adult female mice fed a calorie-restricted diet of 10 percent less than
normal-fed mice did have a higher level of newborn cells in the
hippocampus," she says. But few of these new cells were neurons. In mice
fed every other day-which led to a similar decrease of 10 percent of calories
over two days-neurogenesis and learning abilities increased.
"Remarkably, we also showed that diet has an influence on the level of
expression of genes in the brain," Thuret says. These genes, which are
critical for cognition, are not the same genes that are regulated by
Additional research on these genes may help identify the cellular and
molecular mechanisms underlying the influence of food intake on neurogenesis in
the adult brain and in learning and memory.
The search for neurobiological mechanisms that link nutrition, adult
neurogenesis, and behavior is a new emphasis in biomedical research, prompted in
part by recent findings from laboratory rodent studies indicating that a reduced
calorie diet promotes healthy aging.
"It is well recognized that dietary restriction increases life span,
reduces neuronal damage, enhances learning abilities, and improves behavioral
outcome in experimental animal models of neurodegenerative disorders,"
But not well recognized is how these effects are achieved. In her search for
the answers, Thuret and her colleagues selected mice as a lab model, since
previous research had associated neurogenesis in the hippocampus with improved
memory and learning abilities in rodents.
Each of the three groups of mice in the study included 20 adult females, half
of which were used for histology and gene expression data. The remainder were
used for behavior research. For three months, one group ate at will, the second
group ate every other day, and the third were fed a diet in which calories were
restricted by 10 percent every day.
The behavioral tests included the Morris water maze (in which scientists
measure animals' ability to learn and use visual cues to find a hidden platform)
and object recognition tests (in which the ability of the mice to remember their
encounter with different objects over time is measured).
"We studied their ability to learn and remember, and we looked at the
amount of newborn neurons in their brain upon different diets," Thuret
says. "Then we correlated the changes with the regulation of the expression
of their genes."
"There is much to learn about the effects of food intake-for example,
how much, how often, what, and when-on the cellular and molecular biology of the
nervous system and its functional capabilities, reflecting cognitive performance
in both normal and ill circumstances," Thuret says.
"This area of investigation needs attention because a better
understanding of the neurological mechanisms by which nutrition affects health
may lead to novel approaches for disease prevention and treatment."
In another study, frequent physical exercise on activity wheels, which are
the rodents' equivalent of a treadmill, was found to stimulate the birth of new
brain cells in young laboratory rats with brain damage resembling the prenatal
effects of binge drinking by pregnant human females.
William Greenough, PhD, of the University of Illinois at Urbana-Champaign,
reports that new brain cells, including neurons as well as supportive glial
cells, were generated at much higher rates in the physically active rats than in
the rodents whose cages were not connected with activity wheels. "These
findings in animals are expected to lead to treatments for humans with brain
damage caused by their mother's alcohol consumption," Greenough says.
In the study, newborn rats, 4 to 9 days old, were given alcohol in amounts
reflecting prenatal exposure to alcohol caused by human mothers binge drinking
while pregnant. At this age, a newborn rat's brain is developing rapidly. In
human development, a comparable brain growth spurt occurs during the third
trimester of pregnancy.
Twenty days after the young rats were first exposed to alcohol, half of the
now adolescent animals were allowed to exercise on activity wheels whenever they
wished over a period of 12 days. The home cages of the other half of the rats
were not attached to wheels.
In previous studies by this team of researchers, motor skills training helped
rats overcome some deficits resulting from alcohol exposure during sensitive
periods of brain growth.
"Developmental exposure to alcohol is known to affect coordination and
synchronization of paw movements," Greenough says. But after three weeks of
daily training on a demanding obstacle course, the rats performed much better
than did the untrained, normal rats in the study. The alcohol-exposed, trained
rats had learned to maneuver effectively. In addition, as a result of the
physical activity, more connections had developed between the neurons in the
animals' cerebellum, a brain structure likely to be involved in their improved
Prenatal exposure to alcohol resulting from maternal drinking is the most
common preventable cause of developmental disability. According to detailed
studies of brain structure, heavy prenatal alcohol exposure can destroy cells in
many brain regions including the hippocampus, which is crucial to learning,
memory, cognition, and emotion.
"Severe impairments in learning and cognition and in emotional
regulation are frequently present during development and typically persist into
adulthood," Greenough says.
Adapted from materials provided by Society
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