A tantalizing mystery of neuroscience has been the precise location of memory engrams, the traces left by memories from which entire experiences can be conjured up. They reside in specific brain cells rather than in networks, concludes a study led by Susumu Tonegawa and published in the journal Nature.
“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,” reported Tonegawa, the study’s lead author and MIT’s Picower Professor of Biology and Neuroscience. “This is the rigorously designed 21st-century test of Canadian neurosurgeon Wilder Penfield’s early-1900s accidental observation suggesting that mind is based on matter.”
Penfield found success in treating epilepsy by cutting out parts of the brain. In an effort to isolate neurons implicated in seizures, Penfield used a probe to stimulate specific parts of the brain with jolts of electricity while patients under local anesthesia reported what they were experiencing. Penfield discovered that stimulating just a few neurons in the hippocampus caused patients to vividly recall entire events in full detail. The hippocampus is now accepted as the seat of episodic memories.
Despite extensive work on this phenomenon neuroscientists have never been able to prove that direct reactivation of the hippocampus alone was sufficient to trigger memories. Seven years ago optogenetics allowed the stimulation of mouse neurons genetically modified to express light-activated proteins, opening up the possibility for more precise location of memories.
Tonegawa began by identifying a specific set of cells in the hippocampus that were active only when a mouse was learning about a new environment. His group then identified the genes that were activated in those cells and coupled them with the gene for the light-activated protein channelrhodopsin-2 (ChR2).
Mice with this genetic couplet in the cells of the dentate gyrus of the hippocampus were subjected to pulses of light using tiny optical fibers. The light-activated protein would only be expressed in the neurons involved in experiential learning, allowing the pinpointing of the physical network of neurons associated with a specific memory engram for a specific experience.
After mice were allowed into a new environment, they were given a mild shock to the feet to condition a fear response to a particular environment. The brain cells activated during this conditioning became tagged with ChR2. Later, the mice were exposed to triggering pulses of light in a completely different environment. The neurons involved in the fear memory switched on and the mice froze into a defensive crouch.
This artificial reactivation of the memory of being shocked showed that the memory was located in specific brain cells.
“Our results show that memories really do reside in very specific brain cells,” Liu says, “and simply by reactivating these cells by physical means, such as light, an entire memory can be recalled.”
“René Descartes didn’t believe the mind can be studied as a natural science,” said Tonegawa, referring to the 17th-century French philosopher who wrote, “I think, therefore I am.” “He was wrong. This experimental method is the ultimate way of demonstrating that mind, like memory recall, is based on changes in matter.”
“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 co-author Steve Ramirez, a graduate student in Tonegawa’s lab.
This study was made possible by Karl Deisseroth of Stanford University, whose lab developed optogenetics, and Petti T. Pang, Corey B. Puryear and Arvind Govindarajan of the RIKEN-MIT Center for Neural Circuit Genetics at the Picower Institute for Learning and Memory at MIT. The study by Tonegawa’s group was funded by the National Institutes of Health and the RIKEN Brain Science Institute.
Susumu Tonegawa was born in Japan and attended Hibiya High School in Tokyo. He graduated from Kyoto University in 1963 and received a PhD in biology from UC San Diego in 1968. His postgraduate research included working at the Salk Institute in La Jolla under Nobel laureate Renato Dulbecco.
In 1971 Tonegawa accepted a research post in Basel, Switzerland where he made the immunological discovery that would lead to his 1987 Nobel prize in medicine for his seminal work on how hundreds of millions of human antibodies mobilize to react against infection. He began his tenure as professor of biology at the MIT Center for Cancer Research and Department of Biology in 1981. In 2007 Tonegawa and fellow researchers succeeded in reversing the symptoms of mental retardation and autism in mice.
On October 28, 2011 Tonegawa’s son Satto, a musically and academically gifted freshman a MIT, was found dead in his dorm room of an apparent suicide.
