Science - USA (2021-11-12)

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NEURODEVELOPMENT

Myelin: A gatekeeper of activity-dependent

circuit plasticity?

Giulia Bonetto, David Belin, Ragnhildur Thóra Káradóttir

BACKGROUND:Myelin, produced by oligoden-
drocytes, supports the rapid and synchronized
transfer of information across the central ner-
vous system (CNS). Earlier views of myelin as
inertandimmutablehavebeenreformedwith
the discovery that myelin changes throughout
the life span with experience or the acquisition
of new skills, adapting the function of neuronal
circuits like those underlying learn-
ing and memory. We discuss the
functional implications of myelin
changes, capitalizing on previous re-
views of mechanisms of myelin plas-
ticity to assess how such changes might
be linked to circuit function underly-
ing learning and memory.
In the CNS, there remains a sub-
stantial proportion of unmyelinated
or partially myelinated axons, which
can potentially become myelinated
duringthelifespan.Thisoffersady-
namic range for activity-dependent
structural plasticity, whereby newly
generated oligodendrocytes myeli-
nate these axons and axonal seg-
ments, or existing oligodendrocytes
alter myelin internodes in response
to neuronal activity. Neuronal activ-
ity seems to promote oligodendro-
cyte precursor cells (OPCs), evenly
distributed throughout the adult brain,
to differentiate into new myelinating
oligodendrocytes and to alter the
internodal length and thickness of
existing myelin, as well as increasing
lactate release from oligodendrocytes
via myelin to fuel conduction. Com-
putational models indicate that neu-
ronal activity–dependent myelin alterations
can promote neural phase synchronization,
which is needed for learning and memory.
Myelin plasticity therefore represents a mech-
anism by which experience and associated
learning may modify brain connections, pre-
sumably by shaping the computation of neu-
ronal circuits via alterations in the timing of
neuronal signal transmission.

ADVANCES:The few studies that have directly
investigated the role of myelin plasticity in
learning and memory have provided evidence
that brain plasticity in the form of de novo myelin

formation may play a role in the encoding

(learning) and storage (memory) of informa-

tion. Collectively these studies reveal that OPC

proliferation is fast, almost immediate, upon

initiation of training in a behavioral task,

driving change at a speed similar to that of

structural synaptic plasticity. However, new

oligodendrocytes and new myelin do not ap-

pear until days or weeks later. These dynamic

changes do not seem to be universal nor to

follow the ongoing constitutive myelination

program. Instead, they differ in brain regions

and timing depending on the task, the per-

formance of which relies on distinct and/or

interacting memory processes, including pre-

frontal cortex–dependent short-term/working

memory, hippocampus-dependent spatial mem-

ory, dorsal striatum–dependent procedural

memory, or amygdala-dependent Pavlovian

and emotional memory. As a result, it appears

that although the proliferation of oligoden-

drocytes seems nonspecific to the function and

underlying neural substrate that is being re-

cruited to the task, the pattern of myelination

is indeed memory system–dependent.

The functional role of OPC differentiation,

as these cells form new oligodendrocytes at

different times during learning and memory

formation, can be causally interrogated in

transgenic mouse models that use inducible

OPC-specific Cre lines to genetically delete

transcription factors needed for this process.

Preventing OPC differentiation into new mye-

linating oligodendrocytes affects memory across

an array of behavioral tasks, including prefrontal

cortex–and hippocampus-dependent spatial

navigation (in the Morris water maze), contex-

tual fear conditioning, and motor cortex/dorsal

striatum–dependent skill learning. Despite dif-

ferences in study designs that preclude direct

comparison, collectively the results of these

studies converge on one overarching picture:

The time at which the deficit emerges

after blockade of OPC differentiation

seems to coincide with the time when

multiple brain regions coordinate

functionally to mediate long-term

storage of a memory.

OUTLOOK:Various studies demonstrate

that suppression of adult oligodendro-

genesis differentially impairs memory

across memory/neural systems. Col-

lectively, they support the conclusion

that myelin plasticity could support

systems-wide memory consolidation,

a mechanism underlying long-term

memory. Together with the evidence

that dysfunctional myelin or altered

myelination during development im-

pairs learning and adaptive behavior,

this body of data suggests that even

small changes in myelin across the

lifespancanhaveanimpactoncircuit-

and systems-level mechanisms involved

in cognition and behavior. Myelin

might have a broader function than

previously assumed: Dysfunctional or

maladaptive myelination may con-

tribute to neurodegenerative and

neuropsychiatric disorders, which

have hitherto been considered to have

a neuronal basis. A deeper knowledge of the

functional role of myelin plasticity may unlock

alternative therapeutic approaches. Collect-

ively, this calls for further investigation of the

functional role of myelin plasticity.

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RESEARCH

838 12 NOVEMBER 2021•VOL 374 ISSUE 6569 sciencemag.org SCIENCE

The list of author affiliations is available in the full article online.

*Corresponding author. Email: [email protected] (R.T.K.);

[email protected] (D.B.)

Cite this article as G. Bonettoet al.,Science 374 , eaba6905

(2021). DOI: 10.1126/science.aba6905

READ THE FULL ARTICLE AT

https://doi.org/10.1126/science.aba6905

Myelin plasticity underpins learning and memory.Stylized diagram of

myelinating oligodendrocytes connecting different types of long-term

memory, including spatial memory, Pavlovian fear memory, and motor

skills, assessed in specific behavioral paradigms (clockwise from top left:

single-pellet forelimb reach, complex wheel, contextual fear, Morris water

maze) and underpinned by distinct neural systems, representing how

oligodendrocyte and myelin changes in the brain are involved in the

modification of circuit functions underlying learning and behavior.