The Switches That Can Turn Mental Illness On and Off

This story is about a tale of two rats. One rat got lots of attention from its mother when it was young; she licked its fur many times a day. The other rat had a different experience. Its mother hardly licked its fur at all. The two rats grew up and turned out to be very different. The neglected rat was easily startled by noises. It was reluctant to explore new places. When it experienced stress, it churned out lots of hormones. Meanwhile, the rat that had gotten more attention from its mother was not so easily startled, was more curious, and did not suffer surges of stress hormones.

The same basic tale has repeated itself hundreds of times in a number of labs. The experiences rats had when they were young altered their behavior as adults. We all intuit that this holds true for people, too, if you replace fur-licking with school, television, family troubles, and all the other experiences that children have. But there’s a major puzzle lurking underneath this seemingly obvious fact of life. Our brains develop according to a recipe encoded in our genes. Each of our brain cells contains the same set of genes we were born with and uses those genes to build proteins and other molecules throughout its life. The sequence of DNA in those genes is pretty much fixed. For experiences to produce long-term changes in how we behave, they must be somehow able to reach into our brains and alter how those genes work.

Neuroscientists are now mapping that mechanism. Our experiences don’t actually rewrite the genes in our brains, it seems, but they can do something almost as powerful. Glued to our DNA are thousands of molecules that shut some genes off and allow other genes to be active. Our experiences can physically rearrange the pattern of those switches and, in the process, change the way our brain cells work. This research has a truly exciting implication: It may be possible to rearrange that pattern ourselves and thereby relieve people of psychiatric disorders like severe anxiety and depression. In fact, scientists are already easing those symptoms in mice.

Two families of molecules perform that kind of genetic regulation. One family consists of methyl groups, molecular caps made of carbon and hydrogen. A string of methyl groups attached to a gene can prevent a cell from reading its DNA sequence. As a result, the cell can’t produce proteins or other molecules from that particular gene. The other family is made up of coiling proteins, molecules that wrap DNA into spools. By tightening the spools, these proteins can hide certain genes; by relaxing the spools, they can allow genes to become active.

Together the methyl groups and coiling proteins—what scientists call the epigenome—are essential for the brain to become a brain in the first place. An embryo starts out as a tiny clump of identical stem cells. As the cells divide, they all inherit the same genes but their epigenetic marks change. As division continues, the cells pass down not only their genes but their epigenetic marks on those genes. Each cell’s particular combination of active and silent genes helps determine what kind of tissue it will give rise to—liver, heart, brain, and so on. Epigenetic marks are remarkably durable, which is why you don’t wake up to find that your brain has started to turn into a pancreas.

Our experiences can rewrite the epigenetic code, however, and these experiences can start even before we’re born. In order to lay down the proper pattern of epigenetic marks, for example, embryos need to get the raw ingredients from their mothers. One crucial ingredient is a nutrient called folate, found in many foods. If mothers don’t get enough folate, their unborn children may lay down an impaired pattern of epigenetic marks that causes their genes to malfunction. These mistaken marks might lead to spina bifida, a disease in which the spinal column fails to form completely.

Other chemicals can interfere with epigenetic marks in embryos. Last year, Feng C. Zhou of Indiana University found that when pregnant lab rats consumed a lot of alcohol, the epigenetic marks on their embryos changed dramatically. As a result, genes in their brains switched on and off in an abnormal pattern. Zhou suspects that this rewriting of the epigenetic code is what causes the devastating symptoms of fetal alcohol syndrome, which is associated with low IQ and behavioral problems.

Even after birth the epigenetic marks in the brain can change. Over the past decade, Michael Meaney, a neurobiologist at McGill University, and his colleagues have been producing one of the most detailed studies of how experience can reprogram the brain’s genes. They are discovering the molecular basis for the tale of the two rats.

The differences between rats that got licked a lot and those that got licked only a little do not emerge from differences in their genes. Meaney found that out in an experiment involving newborn rat pups. He took pups whose mothers who didn’t lick much and placed them with foster mothers who licked a lot, and vice versa. The pups’ experience with their foster mothers—not the genes they inherited from their biological mothers—determined their personality as adults.

To figure out how licking had altered the rats, Meaney and his colleagues looked closely at the animals’ brains. They discovered major differences in the rats’ hippocampus, a part of the brain that helps organize memories. Neurons in the hippocampus regulate the response to stress hormones by making special receptors. When the receptors grab a hormone, the neurons respond by pumping out proteins that trigger a cascade of reactions. These reactions ripple through the brain and reach the adrenal glands, putting a brake on the production of stress hormones.

In order to make the hormone receptors, though, the hippocampus must first receive signals. Those signals switch on a series of genes, which finally cause neurons in the hippocampus to build the receptors. Meaney and his colleagues discovered something unusual in one of these genes, known as the glucocorticoid receptor gene: The stretch of DNA that serves as the switch for this gene was different in the rats that got a lot of licks, compared with the ones that did not. In the rats without much licking, the switch for the glucocorticoid receptor gene was capped by methyl groups, and the neurons in the underlicked rats did not produce as many receptors. The hippocampus neurons therefore were less sensitive to stress hormones and were less able to tamp down the animal’s stress response. As a result, the underlicked rats were permanently stressed out.

These studies hint at how experiences in youth can rewrite the epigenetic marks in our brains, altering our behavior as adults. Meaney and his colleagues cannot test this hypothesis by running similar experiments on humans, of course, but last year they published a study that came pretty close.

Meaney’s team examined 36 human brains taken from cadavers. Twelve of the brains came from people who had committed suicide and had a history of abuse as children. Another 12 had committed suicide without any such history. The final 12 had died of natural causes. The scientists zeroed in on the cells from the hippocampi of the cadavers, examining the switch for the stress hormone gene they had studied in rats. Meaney and his colleagues found that the brains of people who had experienced child abuse had relatively more methyl groups capping the switch, just as the researchers had seen in rats that had not been licked much as pups. And just as those rats produced fewer receptors for stress hormones, the neurons of the people who had suffered child abuse had fewer receptors as well.

Child abuse may leave a mark on its victims in much the same way that parental neglect affects rat pups. Abuse seems to have altered the epigenetic marks in their hippocampi. As a result, they made fewer stress receptors on their neurons, which left them unable to regulate their stress hormones, leading to a life of anxiety. That extra stress may have played a part in their committing suicide.

The hippocampus is probably not the only place where experiences rewrite epigenetic marks in the brain. An international group of researchers recently compared the brains of 44 people who had committed suicide with those of 33 people who died of natural causes. The scientists looked at a gene that produces the protein BDNF, which promotes hormone receptors, in a part of the brain called the Wernicke area. That area, located behind the left ear in most people, helps us interpret the meanings of words. In March the researchers reported that the BDNF switch had more methyl groups attached to it in the Wernicke area of suicide victims than in other people.

And the influence of environment doesn’t end with childhood. Recent work indicates that adult experiences can also rearrange epigenetic marks in the brain and thereby change our behavior. Depression, for example, may be in many ways an epigenetic disease. Several groups of scientists have mimicked human depression in mice by pitting the animals against each other. If a mouse loses a series of fights against dominant rivals, its personality shifts. It shies away from contact with other mice and moves around less. When the mice are given access to a machine that lets them administer cocaine to themselves, the defeated mice take more of it.

Eric Nestler, a neuroscientist at Mount Sinai School of Medicine in New York City, wondered what the brains of these depressed mice looked like. Last fall he reported discovering an important difference in a region of the brain called the nucleus accumbens. It was probably no coincidence that depression altered this region, since the nucleus accumbens plays an important role in the brain’s reward system, helping to set the value we put on things and the pleasure we get from them.

The change Nestler and his colleagues discovered in the nucleus accumbens was epigenetic: Some of the DNA in the neurons in that region became more tightly or less tightly wound in depressed mice. Such an epigenetic change might permanently alter which genes are active in the brains of those mice. The same may hold true for humans. Nestler’s team looked at cadaver brains from people who had been diagnosed with depression in life. They discovered the same epigenetic changes in the human nucleus accumbens.

If scientists can pinpoint the epigenetic changes that our experiences impart, it may be possible to reverse those changes. Nestler and his colleagues pumped drugs known as HDAC inhibitors into the nucleus accumbens of their depressed mice. These drugs can loosen tight spools of DNA, making it possible for cells to gain access to genes again. Ten days after treatment, the mice were more willing to approach other mice. The drug also erased many other symptoms of depression in the animals.

The possibility that we can rewrite the epigenetic code in our brains may be exciting, but it is also daunting. Modifying epigenetic markers is not easy—and that’s a good thing. After all, if our methyl groups and coiling proteins were constantly shifting, depression would be the least of our problems. Nothing ruins your day like finding that your brain has turned into a pancreas.

(By: Carl Zimmer, Courtesy: Discover)

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