NEUROSCIENCE
Adult neurogenesis in mammals
Neurogenesis in adulthood has implications for sense of self, memory, and disease
By Fred H. Gage
T
he first claim, in the early 1960s, that
neurons could be generated in the
postnatal mammalian brain was met
with considerable skepticism and con-
troversy (1). Over the next 20 years,
each subsequent study reporting adult
neurogenesis in the mammalian brain was
greeted similarly (2, 3). A dogma had been
established and accepted by the scientific
community: After birth, no new neurons
could be generated. Conceptually, it was
thought that the structural composition of
the neurons within the brain remained un-
changeable after birth. However, the detec-
tion of adult neurogenesis in certain regions
of the brain suggested that the adult brain
exhibits more plasticity than previously
thought, and this has implications for con-
cepts of self, memory, and the pathogenesis
of neurodegenerative diseases.
Neurogenesis occurs through the divi-
sion of neural stem cells and subsequent
maturation into neural progenitor cells;
these progenitors then migrate and mature
into neurons. This process was thought to
be restricted to embryonic development,
then ceasing postnatally, such that new
neurons could not be generated after birth.
Adult neurogenesis has unexpectedly been
detected to occur throughout the lifetime
of various mammals in certain areas of the
brain, particularly in the hippocampus, a
brain structure that is crucial for the acqui-
sition of new memories as well as the accu-
rate retrieval of older memories.
What were the arguments against adult
neurogenesis? The technical part of the
skeptics’ argument questioned how new
neurons could be generated from mature
neurons that were integrated into the exist-
ing mature brain network. The more con-
ceptual concern was that if new neurons
were being generated in the mature brain,
then memories and even the concept of
self would be unstable. The concerns were
countered by the discovery that adult ro-
dent brains contained neural stem and pro-
GRAPHIC: A. KITTERMAN/SCIENCE
genitor cells in the regions where postnatal
neurogenesis had been detected using fate-
mapping methods, such as bromodeoxyuri-
dine (BrdU) labeling of dividing cells and
Laboratory of Genetics, Salk Institute, La Jolla, CA 92037, USA.
Email: gage@salk.edu
SCIENCE sciencemag.org
genetic markers (4). Moreover, adult neuro-
genesis was shown to occur in limited areas
of the brain, and the number of new neu-
rons being generated was clearly small.
In the 1990s, adult neurogenesis was in-
vestigated in more species, including non-
human primates and humans (5). However,
attention was turning away from questioning
whether adult neurogenesis occurred, and to-
ward revealing the cell and molecular mech-
anisms for generating these new neurons in
a mature brain. This effort was particularly
Mammalian neurogenesis is regulated by many behavioral factors
Running potently induces neurogenesis, promoting the proliferation of neural progenitor cells. Enrichment
has a complementary effect by increasing the survival of neurons during their maturation. By contrast, stress
suppresses proliferation of neural progenitor cells. The effects of learning are more complex, suppressing
neurogenesis at some stages and increasing it at others.
Neurogenesis 3 days
1 week
Hippocampus
CA3
Dentate gyrus
Neural
Blood progenitor
vessel cells
Migration
Neural
stem cell Astrocyte
Proliferation Diferentiation
Learning
Running
Stress
interesting and challenging because of the
then-presumed lack of developmental signals
and structures present in the mature brain to
support neurogenesis. In addition, there was
substantial and growing interest in whether
adult neurogenesis had any consequences for
animal behavior. A twist in the adult neuro-
genesis story emerged with the finding that
environmental experiences such as learning,
exercise, enriched environmental stimulation
(enrichment), and stress could have marked
effects on various aspects of adult neuro-
Published by AAAS
genesis, including proliferation, maturation,
migration, differentiation, survival, and inte-
gration (6) (see the figure). Moreover, many
of these environmental experiences appeared
to have consequences for the behavior of ani-
mals, and they directly correlated with the
rate and extent of adult neurogenesis.
In the midst of this flourishing area of
research, technical concerns continued to
be expressed regarding the limitations of
the detection methods. In particular, ques-
tions were raised by a claim of adult neu-
Downloaded from http://science.sciencemag.org/ on May 31, 2019
2 weeks 3 weeks >4 weeks
to CA3
Survival
Enrichment
rogenesis in the neocortex of cynomolgus
monkeys (7). This claim was subsequently
revealed to be unlikely following the de-
velopment of a radiocarbon dating method
developed specifically for neurons in the
postmortem brains of humans exposed to
ionizing radiation during the atomic bomb
testing of the 1960s (8). Using this method,
adult neurogenesis was not detected in the
neocortex, cerebellum, and olfactory bulb of
humans. However, this method confirmed
that a consistent rate of neurogenesis oc-
31 MAY 2019 • VOL 364 ISSUE 6443 827
INSIGHTS | P E R S P E C T I V E S
curred in the human hippocampus well
into the ninth decade of life. These results
were supported by studies of postmortem
human brains that detected, by immunos-
taining techniques (whereby antibodies are
used to detect markers in tissue samples),
various markers of proliferation and early
neurogenesis in cells of the dentate gyrus,
a subregion of the hippocampus thought to
contribute to the formation of new memo-
ries, the exploration of new environments,
and other functions. The amounts of neuro-
genesis were found to be dependent on the
individual’s age or disease states, including
Alzheimer’s disease (AD) and depression.
However, no clear consensus was achieved
from these postmortem studies because of
technical challenges including differences
in postmortem delay prior to tissue fixation,
variation in life experience, and the use of
different antibodies in immunostaining.
During this period of the 1990s, researchers
were conducting experiments in which they
hoped to demonstrate causal and functional
roles for adult neurogenesis in the rodent hip-
pocampus by increasing the rate of neurogen-
esis or blocking it in a time-dependent,
regulated manner. Although the results
increasingly indicated that adult neu- “Adult neurogenesis has unexpectedly
rogenesis in rodents was required for been detected to occur throughout
some forms of learning and memory,
the interpretations of the results and the lifetime of various mammals…”
the theoretical (computational) frame-
work for understanding the role of adult neu-
rogenesis in hippocampal function continued
to be points of contention. Nonetheless, these
studies defined a number of diverse poten-
tial functions of the new neurons, including
enhancing resilience against stress (affective
resilience) (9), regulating the ability to dis-
criminate among similar experiences (pat-
tern separation) (10), incorporating time
into episodic memories, and enabling the
forgetting of old memories (11). Theoretical
models continue to aid investigators to rec-
oncile different interpretations based on the
behavioral task used and on when the task
was administered in experiments compared
to the experiences the rodents had prior to
and after performance of the task (12). There
is now more consensus than contention re-
garding the existence of a functional role of
adult hippocampal neurogenesis in the mam-
malian brain, but more research is needed to
establish a common language to describe the
role(s) of adult hippocampal neurogenesis in
the behavior of the adult organism.
However, the debate continues, as two
recent studies have reported contradictory
findings of undetectable levels of hippocam-
pal neurogenesis in adult human brains (13)
versus persistent human hippocampal neu-
rogenesis throughout aging (14). Both stud-
ies were based on the same premise that if
828 31 MAY 2019 • VOL 364 ISSUE 6443
neurogenesis occurs in humans, specific
markers of neural stem and progenitor cells
should be expressed in the dentate gyrus.
The anatomical and molecular features of
the neural stem and progenitor cells in the
dentate gyrus had been defined in the adult
mouse hippocampus. Both studies used a
variety of similar antibodies to immunostain
for markers of neural stem and progenitor
cells, proliferating cells, migrating neural
progenitors, and markers expressed at vari-
ous stages of neuron maturation. The un-
derlying thesis for both studies was that if
neurogenesis is occurring in the hippocam-
pus, then some combination of these mark-
ers and cells should be present there. Both
studies detected marker-positive cells in the
adult human hippocampus, but they used
different criteria for concluding that the
immunostaining was adequate, relevant, or
accurate to define the cells as neurogenic. It
is clear that there are a variety of technical
and methodological issues that can add to
the variability in immunostaining between
samples in these postmortem human stud-
ies. These issues include postmortem delay,
tissue fixation, and the physical and psycho-
logical state of the subject before death, add-
ing to the difficulty of establishing invariant
criteria for calling an immunostained cell a
neural stem or progenitor cell (15).
Currently, the argument that adult neuro-
genesis persists in the human hippocampus
is more convincing because of evidence us-
ing fate markers such as BrdU and carbon
dating, as well as the more rigorously con-
trolled studies with shorter postmortem
times and extensive information about the
individual, well-characterized fixation pro-
tocols, and accepted cell-counting methods
(16). But how can the conditions for studying
adult neurogenesis in humans be improved
to resolve the debate? Ideally, more work
should be done to validate and extend the
methods that have already been used to de-
tect indirect indicators of neurogenesis, such
as functional magnetic resonance imaging
in living humans. More direct measures of
adult neurogenesis using, for example, pro-
ton magnetic resonance spectroscopy or
probes could be developed for positron emis-
sion tomography brain imaging. In addition,
single-cell RNA sequencing studies from
postmortem brains are now under way and
should add valuable information for more
sophisticated understanding of the cellular
components in neurogenic regions.
Published by AAAS
A more universal approach to consider is
the creation of open-access brain banks with
tissues more ideally suited to these types of
studies. Such brain banks would have clear,
consistent, and reliable record-keeping for
postmortem brain tissue, and the tissue
would be stored in optimal conditions for
preservation in standardized locations so
that multiple researchers from different in-
stitutions could use their unique staining
methods and antibodies on the same tissues.
One reason why it is important to es-
tablish reliable and consistent methods is
highlighted by the recent finding that adult
neurogenesis persists into the ninth decade
of life in the human hippocampus and that
there is a significant decline in neurogenesis
in patients with AD (16). The hippocampus
and its functions, such as learning, memory,
and emotional resilience, have been consis-
tently implicated as a brain area that is af-
Downloaded from http://science.sciencemag.org/ on May 31, 2019
fected early in the pathogenesis of AD. This
study is notable for using short postmortem
delay, clinically characterized subjects, well-
tested tissue fixation protocols, and state-
of-the-art quantitative methods.
Neural stem and progenitor cells per-
sist in the adult mammalian brain and
can faithfully integrate into the adult
brain circuitry; this constitutes the
most robust form of adult structural
plasticity at the cellular level. Brain
plasticity, in this context, refers to the
anatomical and functional changes that can
occur in brain cells in response to environ-
mental stimulation. Even more extraordinary
is that the fate and functions of adult-born
neural stem and progenitor cells and their
progeny are regulated by an individual or-
ganism’s internal and external environmental
experiences. Contradictions and controversy
generally drive science to develop better and
more reliable methods and procedures; this
process is already under way in this remark-
able field. These new tools will help to further
our knowledge of the mechanisms and func-
tion of adult mammalian neurogenesis. j
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10.1126/science.aav6885
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Adult neurogenesis in mammals
Fred H. Gage

Science 364 (6443), 827-828.

DOI: 10.1126/science.aav6885

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