An early start for the thinking brain

Lacking an enzyme linked to diabetes and obesity, mice stay slim on a high-carb diet

Et cetera

Smoking and nicotine receptors

Testosterone vs. nerve cells

Yale scientists have identified the first neurons (the golden area in the image) in the embryonic human cerebral cortex, which appear only 31 days after fertilization. This is much earlier than previously thought, and the discovery of these predecessor cells in the part of the brain responsible for such human attributes as memory, language and intellect may provide insights into mental illness.

An early start for the thinking brain

Yale scientists discover predecessor cells that pave the way for the cerebral cortex.

The cerebral cortex, a layer of cells just a few millimeters thick on the outermost surface of the brain, is largely what makes humans noble in reason and infinite in faculties. New research from the School of Medicine shows that developing embryos, in their haste to become quintessentially human, generate the first neurons of the cortex only 31 days after fertilization—much earlier than previously thought.

The cerebral cortex is an evolutionary marvel. Its distinctive convoluted shape arose because the size of the cortex expanded disproportionately in relation to the rest of the brain during evolution. The 20 billion neurons packed within the cortex’s smooth gray folds account for about 40 percent of the brain’s weight, and the connections among them are largely responsible for the functions considered unique to humans, such as memory, thought, perceptual awareness, language, intellect and consciousness.

Using precise cellular markers, Pasko Rakic, M.D., Ph.D., the Dorys McConnell Duberg Professor of Neurobiology and professor of neurology, and chair of neurobiology and colleagues have discovered “predecessor” neurons that first appear in human embryos before the neural tube, the precursor of the central nervous system, has completely closed and before eyes, arms and legs begin to bud. According to Rakic, these predecessors could well be one type of neural stem cell of the “thinking brain.”

Until recently, researchers thought that all cortical neurons arose within a rudimentary cortical nexus and then migrated radially, like spokes jutting out from an axle, into place. However, Rakic’s findings show that the predecessor neurons arise from basal layers within the developing brain and then travel through inner cell layers to reach the cortex. The precocious cells generate long extensions that pull them to different locations as the brain develops. These extensions may also act as scaffolds to guide late-blooming cortical neurons to their proper locations.

In the July issue of Nature Neuroscience, the researchers wrote that studying how predecessor cells help to wire the billions of neurons of the adult human cortex may provide new insights into how humans differ from more primitive species and may shed light on the causes of mental illness. “Unraveling the early development of this complex structure,” the team wrote, “might provide the key to understanding both the mechanisms underlying its expansion during evolution and the pathogenesis of many cognitive disorders.” Rakic added, “If we want to repair the human brain, we have to know how the human cortex develops; we have to know the timing, the sequence and the type of cells involved.”

Rakic said that the next goal is to determine which genes are switched on in predecessor cells to control early cortex development. If the predecessors are indeed neural stem cells, identifying the genes responsible for early cortex formation could provide insight into ways to generate new cortical neurons to repair brain injury. The team also plans to identify the source of predecessor cells by performing experiments in nonhuman primates that will enable them to visualize neuron migration using modern microscopy techniques.

These findings will bring researchers one step closer to understanding the developmental mechanisms responsible for creating the thinking brain. “I am fascinated with the idea that I use my cortex to look at the cortex itself to determine what makes it possible for me to think,” said Rakic.

The project, supported by the Kavli Institute for Neuroscience at Yale, involves collaborations with societies in England and Russia.

—Kara A. Nyberg

Lacking an enzyme linked to diabetes and obesity, mice stay slim on a high-carb diet

Even on a “supersize” diet, mice bred to lack a certain enzyme remained more svelte than mice with the enzyme, according to a study by Yale scientists in the July 2006 issue of the journal Cell Metabolism. Moreover, in a finding that surprised the research team, the mice’s blood sugar levels remained under control.

The study’s senior author cautioned against premature talk of an elixir that prevents diabetes or does away with the need for exercise. “The long-term goal, I think, would be to figure out how this enzyme is working under normal circumstances,” said Anton M. Bennett, Ph.D., associate professor of pharmacology. “But I think we’re a long ways away from this as an obesity target.”

Bennett’s laboratory studies mitogen-activated protein kinase phosphatases (MKPs), important players that have been implicated in numerous cellular functions such as cell growth and cell survival. For a better understanding of these enzymes, mice were bred to lack one of them, MKP-1. “There was no preconceived hypothesis that it would necessarily be involved in regulating body mass,” Bennett explained.

At first there appeared to be no obvious differences between the mice lacking MKP-1 and the control mice. “If you looked in the cage and had the mice side by side, they would be indistinguishable,” Bennett said. Both groups ate a typical chow diet—“the equivalent of three squares a day.” Soon, the knockout mice showed that they were less likely to put on the ounces.

“Then we put them on a McDonald’s ‘supersize’ equivalent, where 55 percent of the calories was from carbohydrates,” he continued. “The differences in weight were extremely pronounced.” The mice without the enzyme were, on average, 15 to 20 percent leaner than the control group. “The enzyme seems to act as a brake on how fast you burn energy. When you remove that enzyme, energy expenditure seems to go up dramatically.”

The mice without the enzyme were also better able to control their glucose levels. Because they were leaner, they also should have exhibited signs of increased insulin sensitivity. “But it was normal,” Bennett said. “That was somewhat of an unexpected result.” The knockout mice also were less likely to show signs of metabolic syndrome, a constellation of risk factors for heart disease and diabetes. One of the hallmarks of metabolic syndrome is a fatty liver, and the mice without the enzyme were resistant to that symptom.

While the study shows that MKP-1 “may contribute to obesity and diabetes,” it is far from certain whether turning it off will prevent or ameliorate those conditions. There is also concern about the overall effect of turning off the enzyme in the body. Bennett said studies have found knockout mice to be more susceptible to infection. “That’s not a good thing,” he said. “Everything is connected.”

—John Dillon

et cetera

Smoking and nicotine receptors

Smokers may have a hard time quitting because their brains have significantly more nicotine receptors than those of nonsmokers, according to a study by Yale researchers published in August in the Journal of Neuroscience. The study, funded by the National Institute of Drug Abuse, is believed to be the first to offer direct evidence in living smokers that the numbers of the most common nicotine brain receptors are higher during early abstinence from smoking.

“Nicotine craving is an important factor associated with relapse,” said Julie K. Staley, Ph.D., associate professor of psychiatry and diagnostic radiology and lead author of the study. “This study paves the way for determining whether medications normalize the number of receptors and why some smokers, such as women and those with neuropsychiatric disorders, have more difficulty quitting smoking.”

Staley said the team used SPECT imaging to see how the nicotine receptors adapt in response to the repeated stimulation of smoking a cigarette.

—John Curtis

Testosterone vs. nerve cells

A study by Yale scientists has shown that a high level of testosterone—such as that caused by the use of steroids—can lead to the death of brain cells. “Next time a muscle-bound guy in a sports car cuts you off on the highway,” said senior author Barbara E. Ehrlich, Ph.D., professor of pharmacology and cellular and molecular physiology, “don’t get mad, just take a deep breath and realize that it might not be his fault.”

Previous studies have shown that large doses of steroids can cause hyperexcitability, an aggressive nature and suicidal tendencies, which could mean alterations in neuronal function caused by the steroids. “In the present study we have demonstrated for the first time that the treatment of neuroblastoma cells with elevated concentrations of testosterone for relatively short periods, six to 12 hours, induces a decrease in cell viability by activation of a cell death program,” said Ehrlich, whose study appeared in the Journal of Biological Chemistry in September.

—J.C.