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A Spotless Mind
Memories are difficult to pin down, in part because there is no
single kindthey can be fragmentary or interwoven, stable or
ephemeral, easily recalled or long dormant. Exploring how
learning and memory are encoded by changes in neuronal
structure is a pursuit that supplants the abstract with some-
thing tangible, a toehold for understanding one of the most
fundamental of experiences.
Seeking out where a specific memory is made and system-
atically erasing it by manipulating ensembles of synaptic
structures is the great achievement of recent work by Haya-
shi-Takagi et al. (2015). They cleverly create a probe that con-
tains a photoactivatable form of the small GTPase Rac1 (which
when active induces spine shrinkage) and link it to a deletion
mutant of PSD-95, which, together with a dendritic targeting
element (DTE), endows the probe with the property of accu-
mulating at activated synapses. With this combo of features,
the probe targets recently potentiated spines and upon photo-
stimulation will induce spine shrinkage. Using it, the authors
are able to see the extensive synaptic remodeling that occurs
in the motor cortex as mice learn a task involving balance and
motor coordination. When the probe is activated following
training, the mastery gained by the mice is lost, whereas
targeting spines activated by a different motor learning task
does not impact learning of the original one, despite the spatial
overlap of the assemblies of activated synapses.
The authors estimate that the erasure of the acquired motor
memory entails removal of 410,000 spines from 4,700 Visualizing neuronal spine potentiation. Image courtesy of A. Haya-
neurons, providing a glimpse of the complexity of neuronal shi-Takagi.
structural changes responsible for task-specific learning.
This raises interesting questions. How are these neurons vector to the frontal eye field, a region of the primate frontal
linked in circuits? And how equivalent are the contributions cortex that is part of the oculomotor system. The optogenetic
of individual spines to the acquired memory? Ultimately, it stimulation of channelrhodopsin-expressing axons that
will also be interesting to learn how this scale of structural project from this area to the superior colliculus triggers rapid
change compares to that which might be formed in other involuntary eye movements known as saccades, demon-
brain regions by exposure to objects and events. Might it strating the feasibility of pathway-selective optogenetic
be possible to accelerate learning with photoactivatable stimulation in primates. Casting our glance to the scientific
probes designed to augment the formation of these synaptic horizon, it seems that such studies bode well for translating
ensembles? Or perhaps to engineer proteins that wont the panoply of tools used in rodents to studies of behavior
require photostimulation for activation, but might instead in a wider range of models, particularly those amenable to
be triggered remotely? Studies have achieved remote control genetic modification (including macaques, Niu et al., 2014)
of channel proteins by radio waves using genetically en- or one day even to therapeutic applications in humans.
coded nanoparticles (Stanley et al., 2012; Stanley et al.,
2015). Such an approach, if possible, could target neurons REFERENCES
more spatially separated than the ensembles studied by
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mice with a reset switch for specific episodic memories?
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Controlling behavior in mice with optogenetic tools is being
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Cell 163, October 8, 2015 2015 Elsevier Inc. 265