• An image of a transgenic mouse hippocampus.

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Researchers show that memories reside in specific brain cells

Simply activating a tiny number of neurons can conjure an entire memory.


Our fond or fearful memories — that first kiss or a bump in the night — leave memory traces that we may conjure up in the remembrance of things past, complete with time, place and all the sensations of the experience. Neuroscientists call these traces memory engrams.

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But are engrams conceptual, or are they a physical network of neurons in the brain? In a new MIT study, researchers used optogenetics to show that memories really do reside in very specific brain cells, and that simply activating a tiny fraction of brain cells can recall an entire memory — explaining, for example, how Marcel Proust could recapitulate his childhood from the aroma of a once-beloved madeleine cookie.

“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,” says Susumu Tonegawa, the Picower Professor of Biology and Neuroscience at MIT and lead author of the study reported online today in the journal Nature. “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.”

In that famous surgery, Penfield treated epilepsy patients by scooping out parts of the brain where seizures originated. To ensure that he destroyed only the problematic neurons, Penfield stimulated the brain with tiny jolts of electricity while patients, who were under local anesthesia, reported what they were experiencing. Remarkably, some vividly recalled entire complex events when Penfield stimulated just a few neurons in the hippocampus, a region now considered essential to the formation and recall of episodic memories.

Scientists have continued to explore that phenomenon but, until now, it has never been proven that the direct reactivation of the hippocampus was sufficient to cause memory recall.

Shedding light on the matter

Fast forward to the introduction, seven years ago, of optogenetics, which can stimulate neurons that are genetically modified to express light-activated proteins. “We thought we could use this new technology to directly test the hypothesis about memory encoding and storage in a mimicry experiment,” says co-author Xu Liu, a postdoc in Tonegawa’s lab.

“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,” adds co-author Steve Ramirez, a graduate student in Tonegawa’s lab.

The researchers 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.

Next, they studied mice with this genetic couplet in the cells of the dentate gyrus of the hippocampus, using tiny optical fibers to deliver pulses of light to the neurons. The light-activated protein would only be expressed in the neurons involved in experiential learning — an ingenious way to allow for labeling of the physical network of neurons associated with a specific memory engram for a specific experience.

Finally, the mice entered an environment and, after a few minutes of exploration, 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 a defensive, immobile crouch.

False memory

This light-induced freezing suggested that the animals were actually recalling the memory of being shocked. The mice apparently 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,” Liu says, “and simply by reactivating these cells by physical means, such as light, an entire memory can be recalled.”

Referring to the 17th-century French philosopher who wrote, “I think, therefore I am,” Tonegawa says, “René Descartes didn’t believe the mind can be studied as a natural science. He was wrong. This experimental method is the ultimate way of demonstrating that mind, like memory recall, is based on changes in matter.”

“This remarkable work exhibits the power of combining the latest technologies to attack one of neurobiology’s central problems,” says Charles Stevens, a professor in the 
Molecular Neurobiology Laboratory at the Salk Institute who was not involved in this research. “Showing that the reactivation of those nerve cells that were active during learning can reproduce the learned behavior is surely a milestone.”

The method may also have applications in the study of neurodegenerative and neuropsychiatric disorders. “The more we know about the moving pieces that make up our brains,” Ramirez says, “the better equipped we are to figure out what happens when brain pieces break down.”

Other contributors to this study were 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 work was supported by the National Institutes of Health and the RIKEN Brain Science Institute.


Topics: Brain and cognitive sciences, Memory, Neuroscience, Optogenetics, Picower Institute for Learning and Memory, Research

Comments

Am very happy to know this information... thank you
“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.” It is one thing to say "mind is based on matter," it's quite another to say that memories are located in the brain. Suppose I shine a light on some brain cells, and the subject says, "I just remembered a terrible car accident I was in," but, in fact, he was in no such accident. Did he "remember it?" A necessary condition of remembering X is the subject being familiar with X as in X having happened to the subject. Whether X did, in fact, happen to the subject is not a question that can be answered by looking into the subject's brain. By the same token, a particular brain state is neither a necessary, nor a sufficient condition of someone's having a memory of something. Granted, we can't think if we don't have brains. But that doesn't mean our memories, reasons, emotions, etc., are located in our brains.
What exactly is being recalled? A purely emotional feeling like fear or a real memory that triggers the fear. This could be one way environmental stress factors influence genetic change through DNA.
I reject the conjecture: "mind is based on matter." To use simile: imagine the mind IS like a computer. Stimulating a RAM quanta may recall the memory contained within the particular RAM site. The conjecture still does not follow. Consider the conjecture that the brain is a physical firmware for the mind, it would follow that changes to this firmware would change the experienced qualia of the mind. However, the mind or consciousness itself need not be limited or contained within the paradigm. Simile again: light passing through a prism- you alter the crystalline characteristics of the prism you alter the color spectrum perceived by the sense organ (the eye). But- the light has NOT been changed. To say the spectrum = the light is false. The brain is a filter for consciousness- not its creator. This allows validity for both these memorial effects and for the separateness of a priori consciousness and brain function. Science should not presume to function as an override for philosophy.
A mouse going into a defensive crouch shows that whole memories are being experienced by the mouse? How so?
Mr. Greg Hill isn't sure that our memories, reasons, emotions, etc. are located in our brains. So, Greg, then where do you think these things ARE located? There is nothing belittling about humans as organisms made of matter, using energy to perform life functions such as thinking. If the Creator made it that way, can you be comfortable with the plan? Mind and spirit may be separate, but only mind can be studied scientifically. That's what MIT is doing and I applaud this effort.
I suspect that the simple memory of being shocked could be represented by one or very few neurons in mice. This article seems to infer that much more complex memories in humans may also be encoded by a single neuron. This seems unlikely, to say the least. IMO, it's much more likely that if the activation of a single neuron can trigger the recollection of a specific complex memory it's because many other neurons, perhaps in a specific combination, sequence and/or configuration, are also activated during the recollection process.
The article states "The brain cells activated during this fear conditioning became tagged with ChR2. " How are the cells tagged? Earlier in the article it was mentioned that the identified cells were "coupled" with the gene for ChR2, but no indication of how this was accomplished.
So abraxas, I just was curious about who or what those posters who seem somewhat offended by this study believe is a more correct interpretation of what is going on. Your consciousness is spiritual? Or a philosophical conundrum? This seems an interesting finding; that memories are stored in the brain in specific cells OR maybe gateway cells that set of a series of connections. I will tell you that watching a parent whose brain cells are being destroyed by Alzheimer's is very much like watching the essense of that individual disappear. THAT is a very physical reality.
Greg, I suspect that researchers have checked on the correctness of at least some of the retrieved memories. If someone recalled there house burning down -- that person and their family might remember such an event free of light stimulation. And your last point is... odd. Do you believe that if an accident rendered your brain hamburger--you would still have your memory functions, emotional responses and intelligent reason in tact somewhere else? In your Hallmark Card heart? Your big toe? Where do you propose we look?
If I knew exactly where I'd be quite famous.. Consider though that there could be whole aspects of the universe that we don't know about - just like people in the 10th century had no idea about electromagnetism. molecular biology or quantum physics. Since we don't understand the mechanisms behind how the brain/mind works, imho it's quite a leap of faith to believe that nothing else is involved with consciousness.
I knew it. There were a few theories circulating that perhaps memories were stored in an electro magnetic field outside the brain & head.
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