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MOUSE HELPS RESEARCHERS DISTINGUISH PAIN AND MEMORY PATHWAYS IN THE BRAIN
Reporting in the issue of Nature Neuroscience, the researchers demonstrate that mice need a substance called calcium-calmodulin-dependent protein kinase IV in order to associate painful events with the activities and environment where they occurred. This so-called “fear memory” allows animals and people to be extra careful in situations where they might get hurt. For example, a child who touches a hot skillet and sustains a mild burn probably will avoid touching the skillet in the future. “We found that in pain-related memory tests, mice who can’t make CaMKIV don’t have very good memories about painful events, but they respond normally to pain,” says principal investigator Min Zhuo, Ph.D., professor of anesthesiology and of anatomy and neurobiology. “Because we were able to separate pain from memory, I believe it may be possible to design drugs that could block a pain response without inhibiting higher brain function.” Zhuo and colleagues compared normal mice with genetic knockout mice completely lacking CaMKIV. The knockout mice were developed by co-investigator Talal A. Chatilla, M.D., associate professor of pediatrics. Post-doctoral fellow Feng Wei, Ph.D., is the study’s first author. The researchers played a particular tone or placed the mice in a specific environment prior to exposing them to a mild foot shock. Not only did the normal mice respond to painful stimuli, they also, after several trials, froze in apparent fear when they heard the tone or were placed in the environment associated with pain. Like Pavlov’s famous dogs salivating at the sound of a dinner bell, the mice reacted strongly to the environmental cues that preceded certain events. Mice lacking CaMKIV also reacted normally to painful events. However, unlike normal nice, they did not learn to react to the environmental cues. The team also studied activity at the cellular level in brain structures like the hippocampus and the amygdala, known to be involved in fear, memory and pain sensation. In particular, they looked for changes in the activity of a protein called cyclic AMP-responsive element binding protein, which is involved in creating new memories. Brain slices taken from mice that could not make CaMKIV had severely lower levels of CREB activity triggered either by fear conditioning or neuronal activity than those from normal mice. In past studies, Zhuo has learned that brain processes like long-term potentiation and long-term depression are involved not only in so-called higher brain functions like learning and memory, but also might influence things like how individuals react to painful events. For example, LTP and LTD sometimes are involved in the reaction of sensory neurons in the spinal cord to painful events. “For many years, we thought that pain was only in the periphery or in the spinal cord,” he explains. “Most everybody thought of pain as a spinal cord phenomenon. But when you look at all of these studies together, they suggest that the brain plays a very important role in the interpretation of noxious information.” In addition to the CREB pathway, Zhuo is studying other brain events to learn how pain sensation and higher brain function are connected and to figure out ways to separate them. “The findings show that genetic and molecular activity upstream of CREB might provide a key to selectively suppressing pain without interfering with memory and other higher brain function,” Zhuo says.
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