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 Columbia University.
"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 mature neurons.
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 treatment.
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 intermittent fasting.
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," Thuret says.
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 motor skill.
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.
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