“It seemed to be a very effective way of reversing these depres-
sion-related behaviors,” says Ramirez. In contrast, mice that expe-
rienced reactivation of a neutral or negative memory didn’t show
improvement of symptoms.
People with depression have difficulty recalling positive expe-
riences, Ramirez notes, but if there were some way to promote
those recollections, it might help. He wonders: “Could we almost
view memory as a drug?”
Memories lost and found
Everyone’s memories can naturally fade. Memory loss can also
be pathological, as in the case of Alzheimer’s disease or amnesia.
But when memories disappear, are they gone for good? Or has the
brain merely lost access to the trace?
At Columbia, Denny and colleagues tested whether they
could give mice better access to lost memories, jump-starting
the recollection with optogenetics. The researchers crossed mice
modeling Alzheimer’s disease (AD) with ones that would allow
them to label a memory trace in the dentate gyrus with chan-
nelrhodopsin. The team let the animals age until they started
to show deficits in memory tests at six months (the equivalent
of age around 30 in human years), then activated channelrho-
dopsin in the memory trace as the mice learned to anticipate a
shock in a particular chamber. Five days later, when the animals
were returned to that same chamber, the researchers stimulated
the channelrhodopsin-labeled trace cells with light. With their
memories reactivated, six-month-old AD mice froze as often as
non-AD animals, indicating that the memory was still there.^8
The effects wore off within a day of stimulation, though, sug-
gesting more stimulation would be necessary to produce ongo-
ing memory improvements.
Ryan and Tonegawa saw similar results in tests of mice with
amnesia.^9 With stimulation of a trace, “the memory comes back,”
Ryan says. “Even severe kinds of memory loss can be because the
memory is locked in your brain, not destroyed.” That matches the
tendency for most people with amnesia to recover.
Could such faded memories be restored in humans? Denny
thinks that somehow stimulating the dentate gyrus in people
with Alzheimer’s might help with memory loss. Of course,
that’s easier said than done. “We’re not going to be sticking
optic fibers into the human brain anytime soon,” says Ramirez.
Clinical applications will require different tools, such as medi-
cations or psychotherapy.
In some cases, it’s simpler to stimulate a memory in a per-
son than a mouse. Psychotherapists can bring up a past experi-
ence in conversation, or show a patient a picture. Just recalling
a memory makes it malleable, vulnerable to being overwrit-
ten with a different emotional load. In other words, “face your
fears,” says Johannes Gräff, a neuroscientist at the École Poly-
technique Fédérale de Lausanne in Switzerland. Researchers are
experimenting in clinical trials with drugs such as ketamine and
MDMA (dubbed “ecstasy” by recreational users) that may help
people change the emotional charge of certain memories as they
reflect upon those episodes.
But a person who has experienced trauma or forgetfulness in
a complex natural environment is hardly the same as a cloistered
lab mouse worried about a foot shock. “Life, in the real world, is
an accumulation of an almost infinite number of memories across
a lifetime,” says Cai. And complete memory traces are not limited
to the few thousand cells that scientists can access in a mouse
brain using an optic fiber.
As a result, researchers are moving toward more-realistic
interrogations of memory. Denny and Ramirez are building
whole-mouse-brain, 3-D memory maps. The pair and others are
investigating multiple memories, their interactions, and how the
system changes with age. Experiments of this variety will provide
deeper insights into the neuroscience of memory, which might
eventually support the clinical use of memory manipulation.
While direct manipulations of human memory traces are a
long way off, many neuroscientists remain in awe of what’s been
achieved in animals after just a decade of using optogenetics to
delete memories or implant false ones. “These crazy things we can
do in the lab are really important to back up our understanding
of what the brain is doing,” says Josselyn. Plus, she admits, “doing
the science-fiction type things is really fun.” gAmber Dance is a freelance science journalist living in the Los
Angeles area. Read her work or reach out at AmberLDance.com.References- G. Vetere et al., “Memory formation in the absence of experience,” Nat
Neurosci, 22:933–40, 2019. - J.-H. Han et al., “Selective erasure of a fear memory,” Science, 323:1492–96,
2009. - X. Liu et al., “Optogenetic stimulation of a hippocampal engram activates fear
memory recall,” Nature, 484:381–85, 2012. - C.A. Denny et al., “Hippocampal memory traces are differentially modulated
by experience, time, and adult neurogenesis,” Neuron, 83:189–201, 2014. - W. Zhao et al., “Inception of memories that guide vocal learning in the
songbird,” Science, 366:83–89, 2019. - B.K. Chen et al., “Artificially enhancing and suppressing hippocampus-
mediated memories,” Current Biology, 29:1885–94.e4, 2019. - S. Ramirez et al., “Activating positive memory engrams suppresses depression-
like behavior,” Nature, 522:335–39, 2015. - J.N. Perusini et al., “Optogenetic stimulation of dentate gyrus engrams restores
memory in Alzheimer’s disease mice,” Hippocampus, 27:1110–22, 2017. - T. J. Ryan et al., “Engram cells retain memory under retrograde amnesia,”
Science, 348:1007–13, 2015.
These crazy things we can do in the
lab are really important to back up our
understanding of what the brain is doing.
—Sheena Josselyn, Hospital for Sick Children
05.2020 | THE SCIENTIST 31