Researchers show that memories reside in specific brain cells

by Cathryn Delude
An image of a transgenic mouse hippocampus. Image: Nikon Small World Gallery

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.

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 , and that simply activating a tiny fraction of brain cells can recall an entire — 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 Science Institute.

Related Stories

Neuroscientists identify a master controller of memory

Dec 22, 2011

When you experience a new event, your brain encodes a memory of it by altering the connections between neurons. This requires turning on many genes in those neurons. Now, MIT neuroscientists have identified ...

Scientists reveal molecular sculptor of memories

Sep 26, 2011

Researchers working with adult mice have discovered that learning and memory were profoundly affected when they altered the amounts of a certain protein in specific parts of the mammals’ brains.

Recommended for you

Emotional adjustment following traumatic brain injury

Oct 24, 2014

Life after a traumatic brain injury resulting from a car accident, a bad fall or a neurodegenerative disease changes a person forever. But the injury doesn't solely affect the survivor – the lives of their spouse or partner ...

New ALS associated gene identified using innovative strategy

Oct 22, 2014

Using an innovative exome sequencing strategy, a team of international scientists led by John Landers, PhD, at the University of Massachusetts Medical School has shown that TUBA4A, the gene encoding the Tubulin Alpha 4A protein, ...

User comments

Adjust slider to filter visible comments by rank

Display comments: newest first

vince_picariello
not rated yet Mar 23, 2012
While I am in every way scientific minded - I always find it disturbing how neuroscientists make such fundamental errors in inference on the nature of the mind after playing around with their cell mush.

"This experimental method is the ultimate way of demonstrating that mind, like memory recall, is based on changes in matter."

No, I'm afraid it is not. It is the ultimate way of demonstrating that: what is experienced by the mind is stored by the brain. Shocking. The statement is expressed in the same cocksure way that neuroscientists tout that brain structure definitely is what shapes thought; when time and time again, thought has been shown to shape brain structure.

You can infer absolutely nothing about the mind from your tests, much less that it is based on matter!
I can just as easily make the opposite statement asserting causation, using the same data:

"This experimental method is the ultimate way of demonstrating that brain, like memory recall, is based on changes in mind."
vince_picariello
not rated yet Mar 23, 2012
While I am scientific minded- I always find it disturbing how neuroscientists make such fundamental errors in inference on the nature of the mind after playing around with their cell mush.

"This experimental method is the ultimate way of demonstrating that mind, like memory recall, is based on changes in matter."

No, I'm afraid it is not. It is the ultimate way of demonstrating that: what is experienced by the mind is stored by the brain. Shocking. The statement is expressed in the same cocksure way neuroscientists tout that brain structure surely is what shapes thought; when time and time again, thought has been shown to shape brain structure.

You can infer absolutely nothing about the mind from your tests, much less that it is based on matter!
I can just as easily make the opposite statement asserting causation, using the same exact data:

"This experimental method is the ultimate way of demonstrating that the brain, like memory recall, is based on changes in mind."
Enakoa
not rated yet Mar 23, 2012
I agree. The experiment is wonderful but the basis that memory is just due to changes in matter is itself very unscientific. Knowledge is unlimited and history has taught us that rushing to make such statements as these will only be disproved in a matter of time. Is it not possible that the region of the brain which stores memory is actually linked with some unknown energy field which is probably part of a much bigger energy field which represents the human body. As long as science keep growing we are yet to discover more surprises. Anyway a very good experiment done.
nanotech_republika_pl
not rated yet Mar 23, 2012
Aren't those cells in hippocampus just like gate keepers of the information rather than storing all the information about the episode (engrams)? Most of the information is probably stored (when consolidated?) in neocortex cells that link to those hippocampus cells, isn't it?
d2xyz
not rated yet Mar 23, 2012
Thanks Vince. These researchers have a case of tunnel vision. Tell us where memory is stored after you can tell us the mechanism.
thomowen20
not rated yet Mar 23, 2012
Study does not consider hard problem of consciousness or qualia. The study only regards causation.
kochevnik
1 / 5 (1) Mar 23, 2012
The hippopotamus stores fast-trigger memories where there is no time for the prefrontal context to consciously process the stimulus. What the researchers triggered were reflexes, not memories wholesale. Repeat the experiment in a month and the fear might be attached to an entirely different memory, although the reflex response remains strong. The hippocampus is a generalized circuit, although it will invoke specific memories at any one particular time, like stills taken from a film.
pauljpease
not rated yet Mar 24, 2012
"You can infer absolutely nothing about the mind from your tests, much less that it is based on matter!
I can just as easily make the opposite statement asserting causation, using the same data"

But by your criteria, no experiment whatsoever could challenge your preconceived notion of what the mind is. You can always say, "yes, your experiment explains every single detail of what is experienced by a mind in terms of brain cells, and nothing 'extra' is needed, but I believe there IS something extra and you can't disprove there isn't anything extra, so your experiment doesn't really tell us anything about my conception of what mind really is." Do you see that you are putting "mind" in the same category as "god", that is, something that can never be proven or disproven and will always remain a matter of belief?
C_elegans
not rated yet Mar 24, 2012
I think there's a bit of confusion going on here. There is much debate in the field as to what "is" a memory. Many scientists believe that memories are formed by strengthening of synapses. "Neurons that fire together wire together". Thus neurons that are synchronized will contain molecules that strengthen the synapses within this network. No one has been able to demonstrate however that this molecular strengthening is actually a memory, until now. The researchers argue that the 'learning' genes, which are coexpressed with the optogenetic channelrhodopsin, occured in the maze fear network. They then reactivated that fear network using the channelrhodopsin that was expressed in neurons that experienced learning.

It's a nature publication. You guys might want to consider a lil background knowledge of the field before spouting your gut feelings about how brains work.
Tausch
1 / 5 (3) Mar 25, 2012
you can 'relight' - 'reanimate' any memory...

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.


The humans 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 WORDS (SOUNDS), an entire memory can be recalled.


By the way feel free to label associations any way this suits neuroscience and you best... ..."engrams".

There. Do you feel better now? Neuropsychology/psychiatry will accommodate and cater to your every label and whim.

Many paths lead to the same memory/experience.

Tausch
1 / 5 (3) Mar 25, 2012
The 'there-is-always-something-extra' are the hidden associations every brain creates uniquely - to which even the subjects (of experimentation) themselves has no cognitive access to:

The light-activated protein would only be expressed in the neurons involved in experiential learning an ingenious way...


to dupe readers into believing every neuron was monitored that harbored the potential to be involved in the experiential learning.

Kudos. Duping successful.
HenisDov
1 / 5 (4) Mar 31, 2012
A Milestone,
Rediscovered Pavlov And That Genes Are Organisms,
RNA Nucleotides Genes Organisms Complying With Pavlov

From
http://strokereve...e-in-spe
Showing that the reactivation of those nerve cells that were active during learning can reproduce the learned behavior is surely a milestone.

Dov Henis (comments from 22nd century)
http://universe-l...enetics/
Tausch
1 / 5 (2) Apr 04, 2012
From
http://strokereve...e-in-spe
Our results show that memories really do reside in very specific brain cells, says says co-author Xu Liu, a postdoc in Tonegawas lab, and simply by reactivating these cells by physical means, such as light, an entire memory can be recalled.

Oh. Alright. Hint:
..."very specific brain cells"...

SPECIFIC to the event/experience are to be found everywhere (scattered) throughout the brain.
You have no idea which "of ANY nerve cells" are "active" during "learning". If you manage to find them all, the hypothesis of localization for a learned behavior will be abandoned.

Susumu Tonegawa, I have patience. You will abandoned this nonsense. Do not retract the paper. Nature will never do this - their reputation/selling is at sake - clever on your part.