05.2020 | THE SCIENTIST 27RAMIREZ LAB, BOSTON UNIVERSITY
allel technique can make a mouse forget. Christine Ann Denny,
a neuroscientist at Columbia University Irving Medical Center,
and colleagues bred mice to produce archaerhodopsin, a pro-
tein that pumps protons out of the cell in response to yellow
light, silencing neurons. The researchers manipulated a group
of hippocampal neurons that linked a lemon-scented chamber
to a foot shock. When they silenced those neurons with yellow
light, the mice forgot their fear.^4False memories
Perhaps the ultimate test for scientists’ understanding of mem-
ory is to make one, from scratch, as Frankland, Josselyn, and
colleagues did last year. To succeed, they needed to do two
things: First, fake some cue—the neural equivalent to the real-
life sensation, such as a tone, that mice are normally exposed
to in conditioning experiments. And second, falsify the mouse’s
associated expectations—the good or bad outcome that the ani-
mal would anticipate when it sensed that cue.
For the cue, the team chose smell because the neurons in
the olfactory system are understood in detail. Olfactory neurons
with a receptor called M72 are activated by orange-scented ace-
tophenone. Using mice that produce channelrhodopsin in every
M72 sensory neuron, the team could shine blue light in this part
of the brain to trigger the sensation of a whiff of orange.
To set the animals’ expectations, the researchers tapped into
one of two known pathways into the midbrain’s ventral tegmen-
tal area, which is involved in behavior reinforcement. One of the
pathways is linked to reward, the other to aversion. By pairing
the optogenetic stimulation of one of those pathways with opto-
genetic stimulation of M72, the team could link the scent cue to
a good or bad “memory.”
Control mice didn’t particularly prefer one side or the other
of the striped and dotted box, despite the different wallpaper
and scents. But mice that had been optogenetically trained to
associate M72 activation with a reward spent more time near
the end smelling like oranges. If they were conditioned to link
the orange smell with an unpleasant sensation, they avoided
it. The mice showed no preference for or aversion to carvone,
the control scent.
It was exactly as the team predicted, demonstrating that the
researchers understood the rudiments of the underlying mem-
ory systems. When the scientists examined the neurons activated
in the animals’ brains, there was significant overlap between the
memory traces of mice with the artificial aversion memory and
those of mice that had actually experienced a foot shock while
smelling acetophenone, further validating the results.
“This shows that we are beginning to have a much deeper
understanding of how memories are made,” says Josselyn, “so
much so that we can mimic the process and create an artificial
memory using only optogenetics.”
Most neuroscientists in this field work in rodents and study
episodic memories—memories of experiences that an animal has
lived through. In contrast, University of Texas Southwestern Medi-cal Center neuroscientist Todd Roberts has successfully implanted
procedural memories, which encode how to do something, in the
brains of birds. Young male songbirds must learn their father’s song
in order to woo mates when they grow up. For zebra finches, Rob-
erts says, just a few seconds of dad’s tune—a repetition of three
to six unique elements, about 100 milliseconds each—is enough
to seed the young bird’s memory. Male chicks then spend months
practicing until their songs match the melodies they remember.
“They will develop a perfect copy,” says Roberts.
In 2014, Roberts and then-graduate student Wenchan Zhao
set out to do something much simpler than implant a memory:
they wanted to disrupt the song-learning circuit in the bird’s
nidopallium, a brain region that serves similar top-level func-
tions to those of the mammalian cortex. They assumed that if
they did so while the bird was listening to an adult’s song, the
memory of the song would be scrambled. But a control experi-
ment yielded unexpected results. Zhao used channelrhodopsin
to stimulate the learning circuit of a young bird raised without
a father figure, before the animal was transferred to the com-
pany of an adult male tutor. Zhao expected that when the baby
interacted with the male tutor, it would learn that male’s song.
It didn’t. “This bird, when it grew up, had a really weird song,”REMEMBER WHEN: In a slice of hippocampus from a mouse brain, green
fluorescent protein is present in the neurons associated with a fear memory of
mild foot shocks (top) or a positive memory of a male-female social interaction
(bottom). (Blue and red are counterstains for all the cells in the area.)