An image of a transgenic mouse hippocampus. Image: Nikon Small World Gallery
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.
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.
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.”
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.
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
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.
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.
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.
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.
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.
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.”
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.”
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.”
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.”
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.