Neurons in the hippocampus, a part of the brain crucial for memory. A new… (AFP/Getty Images )
In what could lead to a new group of targets for the treatment of memory loss disorders like Alzheimer's disease, scientists have identified a group of molecules that appear to be required for the transition from a short-term to a long-term memory.
The molecules, called nuclear receptors, belong to a class of proteins called transcription factors that play a central role in gene expression. The proteins bind to DNA and help regulate which genes are expressed at a given time. Previous research had suggested that nuclear receptors were somehow involved in memory formation, and the new study confirms that the loss of these proteins prevents long-term memories from forming.
People with memory loss from Alzheimer's disease tend to lose a particular form of memory called contextual memory-the association of a particular event with its larger context, like the location in which it occurred (a classic example is forgetting where you put your keys). This form of memory relies on a brain structure called the hippocampus.
In the new study, researchers at the University of Pennsylvania first sought to determine which of the 49 known types of nuclear receptors were involved in long-term memory formation. After teaching a mouse to connect a shock to a particular cage -- a typical approach to teaching a mouse a contextual memory called “fear conditioning” -- the scientists looked to see whether the amount of any of the nuclear receptors in the hippocampus went up. They found that a set of them did -- in particular, a class of nuclear receptors called Nr4a. This suggested that Nr4a proteins were somehow involved in consolidating a new contextual memory.
The researchers then created genetically altered mice in which they could selectively block Nr4a proteins in the hippocampus, and performed the shock-cage task on them as well. When they did this, they found that the mice had a less robust memory of where the shock took place. But other types of memories not dependent on the hippocampus-like the memory of an auditory tone paired with a shock, which is processed in another brain structure called the amygdala -- worked just fine. The mice also had normal short-term memory.
The results suggest that Nr4a nuclear receptors are essential for long-term memory formation, and that pharmaceutical approaches that boost the function of these proteins -- and the molecular machinery they set in motion -- could one day restore memory function in those who have lost it.
The study was published this week in the Journal of Clinical Investigation. You can read it online here.
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