MIT Triggers Total Fear Recall in Mice

Be afraid, be very afraid. An optogenetic technique that uses light to target specific populations of neurons in the brain has been used to make mice recall fear memories and respond by freezing in a defensive, immobile crouch.

Using optogenetics, researchers at MIT sought to learn whether memory traces, known as memory engrams, are conceptual or if they are a physical network of neurons in the brain. The technique enabled them to show that memories reside in specific brain cells, and that activating a small fraction of brain cells can recall an entire memory.

“We demonstrate that behavior based on high-level cognition, such as the expression of a specific memory, can be generated in a mammal by highly specific physical activation of a specific small subpopulation of brain cells – in this case, by light,” said Susumu Tonegawa, the Picower professor of biology and neuroscience at MIT and lead author of the study.

“We wanted to artificially activate a memory without the usual required sensory experience, which provides experimental evidence that even ephemeral phenomena, such as personal memories, reside in the physical machinery of the brain,” said Steve Ramirez, co-author and a graduate student in Tonegawa’s lab.

The scientists first identified a specific set of brain cells in the hippocampus that were active only when a mouse was learning about a new environment. They determined which genes were activated in those cells and coupled them with the gene for channelrhodopsin-2 (ChR2), a light-activated protein used in optogenetics.

They studied the mice with this genetic couplet in the cells of the dentate gyrus of the hippocampus using tiny optical fibers that delivered light pulses to the neurons. They observed that the light-activated protein was expressed only in the neurons involved in experiential learning. This allowed for labeling of the physical network of neurons associated with a specific memory engram for a specific experience.

Lastly, the scientists put the mice into an environment to explore. After a few minutes, the mice received a mild foot shock, learning to fear the particular environment in which the shock occurred. The brain cells activated during this fear conditioning became tagged with ChR2. Later, when exposed to triggering pulses of light in a completely different environment, the neurons involved in the fear memory switched on — and the mice quickly entered into a defensive, immobile crouch position.

The light-induced freezing suggested that the animals were actually recalling the memory of being shocked. The mice perceived this replay of a fearful memory — but the memory was artificially reactivated.

“Our results show that memories really do reside in very specific brain cells and [that] simply by reactivating these cells by physical means, such as light, an entire memory can be recalled,” said Xu Liu, a doctoral student in Tonegawa’s lab.

The method also may have applications in the study of neurodegenerative and neuropsychiatric disorders.

“The more we know about the moving pieces that make up our brains, the better equipped we are to figure out what happens when brain pieces break down,” Ramirez said.

The work, which was supported by the National Institutes of Health and the Riken Brain Science Institute, appeared in Nature.

For more information, visit: www.mit.edu