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March 2011

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Astrocytes give humans an intellectual edge

By Robin Arnette
March 2011

Maiken Nedergaard, M.D., D.M.Sc.

Nedergaard is co-director of the Center for Translational Neuromedicine and professor of neurosurgery at the University of Rochester School of Medicine and Dentistry. She hopes her work will help scientists understand how humans process sensory information, make decisions, and store memory. (Photo courtesy of Steve McCaw)

David Miller, Ph.D.

Miller called Nedergaard a pioneer in the field of electrophysiology and imaging. Many of the techniques she discussed in the seminar were developed in her lab. (Photo courtesy of Steve McCaw)

from foreground, Rajendra S. Chhabra, Ph.D., Jean Harry, Ph.D., Annette Kirshner, and  Robert Langenbach, Ph.D.

The Nedergaard seminar drew numerous staff members with varying interests, including Toxicology Branch group leader Rajendra Chhabra, Ph.D., D.A.B.T. (foreground), Laboratory of Toxicology and Pharmacology (LTP) principal investigator Jean Harry, Ph.D., Division of Extramural Research and Training (DERT) Health Scientist Administrator Annette Kirshner, and LTP principal investigator Robert Langenbach, Ph.D(Photo courtesy of Steve McCaw)

Neuroscientist Maiken Nedergaard, M.D., gave the NIEHS Distinguished Lecture Feb. 8 and talked about brain cells known as astrocytes, which are important in learning and memory. Nedergaard has examined the differences between rodent and human brains, in regard to astrocyte form and function, and she relayed the remarkable findings during the seminar. Acting Scientific Director David Miller, Ph.D. hosted the event.

Nedergaard( Exit NIEHS explained that an astrocyte is a glial cell, a star-shaped supporting cell with fine fibril processes radiating from the center, which transmit information. She said that glial cells and neurons are the two major cell types in the brain, and that proportionally, humans have more glia than neurons, compared to roundworms or rodents. Nedergaard believes that researchers should keep this fact in mind when planning their brain studies. 

"If we're thinking about brain disorders in people, it may be inappropriate to base our studies on animal models, because any human brain disease would be more of a glial disease than it would be in rats," Nedergaard maintained. "However, it makes me wonder why we need more supportive cells in our brain."

Of mice and men

Nedergaard said that evolutionary pressures steadily increased both the number and structural complexity of astrocytes in animal species. As a result of these changes, she speculates that human astroctyes contribute to the cognitive functions in humans, including language, reasoning, and problem solving.

To tease out exactly what makes human astrocytes special, Nancy Ann Oberheim, a medical student in Nedergaard's lab, used immunohistochemistry to compare astrocytes in human and mouse brain. Nedergaard said that comparing both cell types under the microscope was the obvious place to start, but no one had looked at human astrocytes in detail since they were first described 150 years ago.

Oberheim found that human astrocytes were much larger than the rodent versions. In fact, the maximum cellular diameter of a human astrocyte was almost three times that of a mouse astrocyte, corresponding to a 20-fold increase in volume. The human astrocyte also had 40-50 major glial fibrillary acidic protein (GFAP+) processes, compared to approximately 3-5 GFAP+ processes in the mouse. Nedergaard said these differences meant that an individual astrocyte in the human brain had more synapses - a junction that allows a neuron to transmit electrical or chemical signals to another cell - and that one human astrocyte could integrate more information.

Boosting brain power

Nedergaard then wanted to know if the presence of human astrocytes in a mouse brain would alter the animal's behavior. To find out, two of Nedergaard's colleagues at the University of Rochester School of Medicine and Dentistry, Assistant Professor Xiaoning Han, M.D., and Professor Steven Goldman, M.D., Ph.D., implanted human astrocytes into the brains of young, immunosuppressed mice and waited at least one year. Using an antibody specific for human cell nuclei, Nedergaard saw that the human astrocytes differentiated as they would in human brain, creating chimeric mice.

To determine if these mice were smarter than normal mice, her team evaluated memory recognition in the chimeric mice. In collaboration with Professor Alcino Silva, Ph.D., at UCLA, the Nedergaard lab utilized a fear conditioning behavioral test that used an auditory tone. After several weeks of instruction, Nedergaard placed a normal and a chimeric mouse in separate cages and prepared to test her pupils.

"At first, both mice started exploring their surroundings as mice generally do, but when we used the tone, both mice froze," she said. "After a few seconds, the normal mouse started exploring again, while the chimeric mouse continued to stand still. This freeze can go on for several minutes."

Nedergaard said that her studies suggest human astrocytes differ from the astrocytes of other animals, and that these attributes impart greater learning capacity to humans. Her findings not only have implications for improving memory, but they may also lead to better treatments for brain disease.

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