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 Research & Giving News Article  for PTSD, Alzheimer’s, Addiction The new research, published in late May in the online edition of the journal Nature Neuroscience, showed that mice genetically engineered to lack a single enzyme in their brains were more adept at learning than their normal “cousins,” and were quicker to figure out that their environment had changed. “It’s pretty rare that you make mice ‘smarter,’ so there are a lot of cognitive implications,” said James A. Bibb, M.D., assistant professor of psychiatry at UT Southwestern Medical Center, recipient of NARSAD’s Young Investigator award in 2003, and the study’s senior author. His collaborators included Craig M. Powell, M.D., Ph.D., assistant professor of neurology and also a NARSAD 2003 Young Investigator; and Donald Channing Cooper, Ph.D., assistant professor of psychiatry and a NARSAD 2006 Young Investigator.  “Everything is more meaningful to these mice," Dr. Bibb observed. “The increase in sensitivity to their surroundings seems to have made them smarter.” Specifically, the engineered mice were more adept at learning to navigate a water maze and remembering that being in a certain box involved a mild shock. Equally important, Dr. Bibb said, when a situation changed, such as the water maze being rearranged, the engineered mice were much faster to realize that things were different and work out the new route. Dr. Bibb cautioned that while the mice learn faster, studies on the long-term effects of deleting the enzyme, called Cdk5, from the brain are continuing. The research team is also beginning a search for drugs that might create the same effects without genetic manipulation, and is monitoring the animals’ health and behavior over time. Their findings ultimately may have applications in treating PTSD, in which getting a patient to learn that a once-threatening situation no longer poses a danger is a major goal. In addition, Cdk5 is heavily implicated in Alzheimer’s disease and addiction to drugs of abuse, so understanding how the enzyme affects the brain and behavior might aid in the development of new treatments for these and other conditions, Dr. Bibb said. The key in this study was being able to “knock out” the gene for Cdk5 only in the brain, and only at the point at which the laboratory mice had reached adulthood. This technique, only recently developed and called conditional knockout, allows much more sophisticated experiments than “traditional” knockout, which entirely eliminates the gene. “Being able to turn a gene off throughout a brain is a really advanced thing to do,” Dr. Bibb said. “It’s been shown that it can be done, but we put the system together and actually applied it.” Normally, Cdk5 works with another enzyme to break up a molecule called NR2B, which is found in nerve-cell membranes and stimulates the cell to fire when a nerve-cell-signaling molecule, or neurotransmitter, binds to it. NR2B previously has been implicated in the early stages of learning. The new research showed that when Cdk5 is removed from the brain, the levels of NR2B significantly increase, and the mice are primed to learn, Dr. Bibb said. “We made the animals ‘smarter,’ but in doing so and applying this technology, we also found biochemical targets that hold promise for future treatments of a variety of cognitive disorders,” he said. The researchers also recorded nerve-cell firings in the hippocampus, an area of the brain associated with learning. Hippocampus slices from the knock-out mice responded to an unusual degree to an electrical stimulation, supporting the finding that the mice were more prepared to learn. This story was adapted in part with permission of the University of Texas Southwestern Medical Center. |
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