MODIFIED FROM ©ISTOCK.COM, RETROROCKETRoberts says. Zhao’s brief pulse of light had set the bird’s song
memory, implanting an artificial sense of how the tune should
sound. The bird then spent its youth striving to measure up to
that fake memory.
Intrigued, Zhao experimented by exposing young, untutored
birds with channelrhodopsin-carrying neurons in their learning
circuit to the blue light for different periods of time, then raising
them without tutors. If Zhao flashed the light for 50 milliseconds,
the chicks grew up to sing songs with shorter-than-normal ele-
ments, producing a melody more like the quick trills of a canary. If
she lit up the brain for 300 milliseconds, the sound elements were
too long.^5 “It sounds like they’re just yelling one pulse,” says Rob-
erts. “It’s really quite bizarre.”Good memories, bad memories
Many memories aren’t neutral, but are charged with emotion.
Ramirez recalls enduring a breakup that took place over a large
iced coffee at Crema Café in Harvard Square in 2012 when he wasin graduate school. “In the immediate aftermath, going past Crema
was a painful reminder... an emotional kick to the gut,” he recalls.
The cafe became linked to the unpleasant memory, he says.
But with time, as Ramirez came to terms with the breakup and
continued to frequent Harvard Square, that emotional tinge faded.
He says he could visit the cafe for his favorite peanut butter–banana
sandwich without distress by the time Crema closed last year, seven
years later. His experience illustrates the theory behind exposure
therapy for negative memories, which involves re-experiencing the
real situation linked to trauma or anxiety, or an imagined version
or virtual reality simulation. For example, therapists have used vir-
tual reality scenes featuring jungles and helicopters to treat PTSD
in Vietnam veterans. The hypothesis holds that repeated exposure
to a memory can drain it of emotional power.
Ramirez wondered if he could do the same thing, optogeneti-
cally, in mice—if repeatedly activating the memory of something
scary could diminish the associated freezing behavior.
His team focused their attention, and light beams, on the top
of the dentate gyrus, where contextual information such as place
and time is recorded. (See “Memories of Time” on page 32.) They
trained mice to associate a particular chamber with a shock, and
tagged the corresponding memory trace in the dentate gyrus with
channelrhodopsin. Then they reactivated that trace with light for
10 minutes, twice daily for five days, forcing the mice to recall
the experience while in a novel, shock-free zone. Mice that were
returned to the original, shock-linked chamber were less likely to
freeze than mice who had not been subject to memory reactiva-
tion. In the treated mice, fewer neurons from the original trace
were active the second time in the chamber.^6 “We think, in this
case, it’s that particular fearful memory that we were able to turn
the volume down on,” says Ramirez.
The researchers discovered that the location of the stimula-
tion mattered. When they reactivated neurons from the same
trace, but in the bottom of the dentate gyrus—associated with
responses to stress and anxiety—they got the opposite results.
Mice activated more of the neurons associated with the original
fear memory when returned to the original enclosure, and the
animals were more likely to freeze, as if the volume of their fear-
ful memory had been turned up.
In other experiments, Ramirez has examined the power of
positive memories to alleviate depression-like symptoms in
mice. To create that positive memory, the researchers let the
mice spend time with a mouse of the opposite sex, while label-
ing active trace neurons in the dentate gyrus with channelrho-
dopsin. Then, they stressed the mice by immobilizing them in
a cone-shaped device to produce a depression-like state. When
the animals were then lifted by their tails, these mice spent less
time struggling than non-stressed mice, and they showed lit-
tle preference for sugar water, normally a desirable treat. But
when the team stimulated the recollection of the earlier roman-
tic interlude, the mice immediately acted like they felt better,
choosing sugar water over plain water and spending more time
trying to escape when dangled.^730 THE SCIENTIST | the-scientist.com