In a remarkable new study, scientists at The Scripps Research Institute have unlocked one of the secrets of how memory is formed. Working with a unique breed of transgenic mice, the new study has shown for the first time that the same neurons activated during fear conditioning are, in fact, reactivated during memory retrievalThe findings could potentially be used to uncover precisely how drugs such as antidepressants work in the brain, allowing clinicians to more accurately evaluate various treatment options.
"Our study provides the answers to some basic questions," said Mark Mayford, whose laboratory conducted the groundbreaking study. "We show that when you learn, and when you recall what you've learned, you reactivate the same neurons used during the original experience. While some studies have shown which region of the brain is active during learning and recall, we've now shown this at the level of individual neurons."
The new results suggest that the affected neurons evolved stable synaptic changes, giving them a capacity for reactivation by conditioned stimulus for at least three days. The study concluded that the reactivated neurons were likely a component of a stable engram or memory trace for conditioned fear.
Memories are presumably stored in subgroups of neurons that are activated in response to various sensory experiences, the study said. Previously, some encoding of memories in complex neuronal networks had been identified with electrophysiological recordings, and similar approaches have identified neurons with firing properties temporally linked to various aspects of learned task performance.
But, Mayford noted, this is like knowing only that a computer is turned on. The new study shows precisely which circuits are active during a specific memory formation.
"We found neurons in the basolateral amygdala that were activated during fear conditioning and were reactivated during memory retrieval," Mayford said. "The number of reactivated neurons correlated with the behavioral expression of that fear memory in the mice themselves, which indicates a stable correlation between these neurons and memory."
The basolateral amygdala is the part of the brain believed to be responsible for memories involving emotional arousal.
An innovative mouse
The new study utilized a unique transgenic mouse (TetTag mouse) that enabled scientists to genetically tag individual neurons activated during a given time frame. The tag can be used for the direct comparison of neuronal activity at two distinct and widely spaced points in time.
(The name TetTag comes from the technology itself; it combines elements of the tetracycline-transactivator system. Gene expression is controlled in these transgenic mice through exposure to tetracycline or derivatives such as doxycycline.)
This novel technology can be used with free roaming mice, enabling the scientists to record and measure the correlation between neuronal activity and any behavioral expression of a specific memory. Moreover, the study noted, the technology requires only basic laboratory equipment, which is generally available to most researchers.
"The TetTag mouse allows us to put genes into neurons that have been activated by an environmental stimulus," Mayford said. "Basically, we can put any gene we want into those neurons activated by fear, and this gives us genetic control over very specific circuits in the brain."
The reason fear and anxiety were used as the activating experience, Mayford said, is because fear is an ancient and fundamental emotion" "We know that mice feel fear; we don't know if they feel joy. In the wild, you can survive without joy, but you don't live very long without fear."
The ability to genetically manipulate these activated neurons should allow a better and more precise understanding of the underlying molecular mechanisms of memory encoding within a particular neuronal network.
This might one day translate into a clinical advantage for treating patients suffering from disorders such as depression, Mayford said.
"Antidepressants don't work the same in every individual," he said, "so our genetic tagging technique could potentially help clinicians evaluate treatment by showing how an individual's brain works at two different times during treatment-where and how the drug is affecting specific neurons."
The new study was published in the August 31, 2007, edition of the journal Science. Other authors of the Science study, "Localization of a Stable Neural Correlate of Associative Memory," were Leon G. Reijmers, Brian L. Perkins, and Naoki Matsuo of The Scripps Research Institute.
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