幹細胞與前瞻

Reviews
1--------------------------------------------
Formation and integration of new

neurons in the adult hippocampus
Annina Denoth-Lippuner and Sebastian Jessberger ✉
Abstract | Neural stem cells (NSCs) generate new neurons throughout life in the mammalian brain.
Adult-born neurons shape brain function, and endogenous NSCs could potentially be harnessed
for brain repair. In this Review, focused on hippocampal neurogenesis in rodents, we highlight
recent advances in the field based on novel technologies (including single-cell RNA sequencing,
intravital imaging and functional observation of newborn cells in behaving mice) and characterize
the distinct developmental steps from stem cell activation to the integration of newborn neurons
into pre-existing circuits. Further, we review current knowledge of how levels of neurogenesis are
regulated, discuss findings regarding survival and maturation of adult-born cells and describe
how newborn neurons affect brain function. The evidence arguing for (and against) lifelong
neurogenesis in the human hippocampus is briefly summarized. Finally, we provide an outlook of
what is needed to improve our understanding of the mechanisms and functional consequences
of adult neurogenesis and how the field may move towards more translational relevance in the
context of acute and chronic neural injury and stem cell-based brain repair.
Granule cell layer The long-held belief that neurons are exclusively gene (GCL)3 (Fig. 1). Besides these two main neurogenic areas,
The granule cell layer consists rated during embryonic and early-postnatal develop- neurogenesis has been reported in the hypothalamus
mainly of excitatory granule ment was challenged in the 1960s by the discovery of and the brainstem, and might exist in the neocortex,
cells, the principal neurons of newborn neurons in the adult rat brain1. After decades striatum, amygdala and substantia nigra of rodents
the dentate gyrus.
of controversy that was overcome only by improved and other mammals; however, the existence of neuro-
methodology 2, adult neurogenesis has been since genesis in the latter regions, and also within the human
investigated from many different angles, including the brain, as outlined in Box 1, remains controversial10,13–15.
potential of neural stem cells (NSCs) to produce neurons Here we will focus on adult neurogenesis in the rodent
throughout life, the integration of newborn neurons, its hippocampal DG.
contribution to behavioural output and its potential role During the process of neurogenesis, cells undergo
in various diseases affecting the adult brain3,4. dramatic molecular and morphological changes. NSCs
Adult neurogenesis has been reported throughout divide and generate committed neuronal progenitors,
the animal kingdom, ranging from crustaceans to higher which then differentiate into immature neurons that
vertebrates, including birds, rodents, primates and integrate into the DG circuit, where they mature over the
humans2,5–10. In this Review, we focus mainly on adult course of several weeks in the rodent brain16–18. At each
neurogenesis in rodents, but the controversy regarding stage, cell-intrinsic signalling and inputs from the sur-
the evidence for human neurogenesis is summarized rounding niche regulate the transition to the next cellu-
(Box 1). Whereas the amount of widespread adult neuro lar state, leading to selection and successful integration
genesis decreases as we progress up the phylogenetic into the circuitry, or cell death. In the following sections,
tree, neurogenic areas also become more defined, argu- we decipher each step from NSC activation to functional
ing for an evolutionarily conserved plasticity in those integration of newborn neurons, summarize known reg-
Laboratory of Neural specific regions11. In rodents, adult neurogenesis is found ulators affecting NSC activity and neuronal survival, and
Plasticity, Brain Research mainly in two brain regions. The first is the subventricu- discuss open questions in the field.
Institute, Faculty of Medicine lar zone, which lines the lateral ventricles, where NSCs
and Faculty of Science, give rise to cells that tangentially migrate to the olfac- Stem cell identity and potential
University of Zurich, Zurich,
Switzerland.
tory bulb before they differentiate into different types The source of newborn hippocampal neurons is NSCs,
✉e-mail: jessberger@ of olfactory neurons4,12. The second main neurogenic also commonly referred to as neural stem or progen-
hifo.uzh.ch region is the subgranular zone of the hippocampal den- itor cells, owing to the still-controversial long-term
https://doi.org/10.1038/ tate gyrus (DG), where NSCs generate excitatory, gluta- self-renewal capacity and in vivo multipotency of
s41583-021-00433-z matergic neurons that integrate into the granule cell layer individual hippocampal precursors19–21. Isolated from
NATure RevieWS | NeuRoSCienCe volume 22 | April 2021 | 223
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Box 1 | Neurogenesis in the human hippocampus glial fibrillary acidic protein (GFAP)28–30. On the basis
of their morphology, glia-like cellular properties and
On the basis of thymidine analogue labelling, carbon dating and expression analyses gene expression profiles, hippocampal NSCs are often
of proteins expressed in neural stem cells and immature neurons, several studies have referred to as radial glia-like cells (R cells, or type 1 cells)
reported neurogenesis to occur throughout the lifespan in the human hippocampus5–8,14,53,54.
(Fig. 1).
However, others have questioned these findings using immunohistochemical detection
R cells in rodents are found mostly in a non-dividing,
of markers expressed in immature neurons, such as doublecortin (DCX)168. Not only the
presence of immature neurons (indicative of neurogenesis) is debated; there is also quiescent state and, once activated, they generate
controversy regarding the presence of neurogenic progenitor cells and a respective non-radial glia-like progenitor cells (NR cells, or type 2
niche in the human hippocampus. Whereas some groups have reported the presence cells) through cell divisions that divide again and sub-
of proliferating cells with characteristics similar to those of neurogenic cells found in the sequently differentiate into neurons31–33. The cellular
rodent brain, others have not found evidence for neurogenic cell divisions in the human behaviour of R cells — in particular, their mode of divi-
hippocampus8,53,54,168,169. Furthermore, labelling cells that express markers of ‘immaturity’ sion, process of lineage progression and differentiation
such as DCX may label cells that are not newborn but that retain such a molecular within the adult brain — has been assessed by various
(and potentially also a functionally immature) profile over extended periods — a cellular techniques (Table 1). New technologies, such as retro-
phenotype that has been described in a number of cortical areas in different species170,171.
viral labelling to characterize newborn granule cells
Together, these findings reignited discussions of whether neurogenesis is of relevance
in acute hippocampal slices, have enabled the field to
for human physiology and disease, similar to the controversy that existed when
neurogenesis in rodents and primates was at the centre of scientific discussions in gain novel insights18. However, each technique comes
the 1980s2,164,165,168,172,173. with advantages and disadvantages, leaving grounds for
One issue in addressing the controversy is the scarcity of healthy human tissues and speculations and interpretations (Table 1).
delays when fixing post-mortem samples for tissue analyses165. Furthermore, none of Lineage tracing using transgenic reporters to label
the techniques to detect and visualize newborn cells is perfect and free of experimental lineage-related cells has been used to determine the
error164,165,172. For example, one argument is that thymidine analogues may also cause output of activated R cells 19,21,34–37. However, these
low-frequency labelling of cells that are not newborn, although there is evidence that approaches led to ambiguous results for key questions
this may not cause substantial concern, at least in rodents174. in the field, such as the self-renewal potential of indi-
These are not unique problems for the field of neurogenesis; indeed, the direct
vidual NSCs: whereas some studies reported extended
translation of rodent-based experimental data to human brain function is by definition
self-renewal of R cells, including symmetric, duplicating
challenging and complex. The evidence for and against the birth of new neurons in the
human hippocampus has been extensively discussed recently2,164,165,172. Previous attempts R cell divisions and multipotency in terms of generat-
to use non-invasive imaging approaches to detect neurogenesis certainly require further ing neurons and astrocytes, others reported a relatively
validation162,163. Thus, novel technologies, including single-cell genomics48, are needed fast depletion of R cells, with these cells giving rise to
to evaluate the existence of neurogenic neural stem cells in the adult human brain and a few neurons before terminal differentiation19,21,35.
the potential mechanisms and roles of hippocampal neurogenesis in physiology The different outcomes might depend on the choice
and disease. of reporter lines, suggesting considerable heteroge-
neity of NSCs. The different reports may also depend
on whether lineages were studied on the level of indi-
the adult mouse brain and cultured in vitro with the vidual clones (in which case coexistence of R cells and
addition of mitogens such as fibroblast growth factor NR cells would imply self-renewal capacity) or whole
(FGF) and epidermal growth factor (EGF), NSCs can cohorts, where sufficient resolution may be lacking.
be propagated eternally22. On withdrawal of growth Static, post hoc analyses, which are the only possible
factors, cultivated NSCs can differentiate into neurons, analyses when histological sections are used for exam-
astrocytes or oligodendrocytes22,23, demonstrating the ple after Cre-mediated lineage tracing or genetic abla-
potential for unlimited self-renewal and multipotency tion of candidate genes, inherently miss cellular events
of in vitro NSCs derived from the adult mouse hip- before the final cellular outcome. Therefore, the ability
pocampus. However, growth factors might stimulate to longitudinally image NSCs in the living mouse brain
Thymidine analogues cellular behaviour that would rarely occur naturally using two-photon microscopy has allowed the analysis
Analogues of the DNA within the endogenous niche; for example, the addition of the neurogenic process over time within the endog-
component thymidine that can
of insulin-like growth factor 1 (IGF1) pushes adult NSCs enous niche31. Intravital imaging has revealed both
be injected in animals and are
integrated into replicating DNA to differentiate into oligodendrocytes24. asymmetric divisions and symmetric divisions of R cells;
strands and detected using
2--------------------------------------------
In vivo, the fate and potency of individual hip- however, when DG NSCs expressing the stem cell-
antibodies. pocampal NSCs remain controversial. With use of expressed Achaete–Scute homologue 1 gene (Ascl1) were
thymidine analogues (such as 5-bromo-2′-deoxyuridine followed in vivo using intravital imaging, most R cells
Vascular end-feet
Terminals of astrocytic
(BrdU)), transgenic labelling or viral labelling, NSCs were seen to terminally differentiate within 3 months
processes at the vascular have been identified in the subgranular zone underly- after activation31. Most commonly, R cells generated
surface that regulate vascular ing the GCL21,25. In the rodent DG, hippocampal NSCs NR cells that further amplified the pool of dividing
function. display certain astrocytic features, such as branched cells, revealing a high amount of asymmetric NR cell
morphology and vascular end-feet, as well as passive divisions, generating proliferative NR cells that went
Asymmetric divisions
Divisions generating daughter current characteristics that are comparable to those of through additional rounds of cell divisions and differen-
cells with different fates or astroglial cells25,26. Furthermore, hippocampal NSCs tiating neuroblasts. In addition, in vivo imaging revealed
properties. extend radial processes, reminiscent of those of radial that R cells can directly generate neurons through asym-
glial cells (which are neural progenitors in the embry- metric cell division31. Furthermore, intravital imaging of
Symmetric divisions
Divisions generating daughter
onic brain)27, that reach into the GCL and express a dis- R cells (genetically labelled by targeting neurogenic cells
cells with similar or identical tinct set of proteins that are also expressed in classical through the regulatory elements of the Gli1 promoter)
fates or properties. astrocytes, including the transcription factor SOX2 and identified long-term (more than 100 days) self-renewing
224 | April 2021 | volume 22 www.nature.com/nrn
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neurogenic cells in the adult mouse DG38. Together, notions regarding lineage relationships that were based
intravital imaging studies have identified previously on static lineage-tracing experiments.
unknown steps in the highly dynamic process of neuro- Therefore, numerous studies using various tech-
genesis but also confirmed some of the previously held niques such as thymidine analogue labelling, genetic
SVZ Ventricle
Dentate gyrus
RMS
OB
Ventricle
SVZ
Striatum
Dentate
gyrus
Activation
Maturation
Fate
choice
Proliferation
Integration
Quiescence
Differentiation
Quiescent R cell Active R cell NR cell

ID4 APOE GFAP ASCL1 CDK4 TBR2 Marker expression
SPOT14 HOPX NES MKI67 DCX
SOX2
• Glycolysis • Oxidative phosphorylation
• Fatty acid oxidation • De novo lipogenesis Metabolic changes
• Adhesion • Protein synthesis
• Lysosome • Proteasome
Asymmetric Symmetric Mode of cell division
Fig. 1 | Neurogenesis in the adult hippocampus. a | Schematized view of a sagittal section through the mouse brain
showing the two main neurogenic areas of the adult rodent brain. Neural stem cells (NSCs) reside in the subventricular zone
(SVZ) and give rise to newborn cells that migrate via the rostral migratory stream (RMS) towards the olfactory bulb (OB),
where newborn cells differentiate into different types of olfactory neurons. The focus of this Review is on neurogenesis in the
dentate gyrus (DG) of the hippocampus (boxed). The schematic on the right shows a coronal view of the human brain
highlighting areas where neurogenesis has been described in the human brain. For details regarding the controversial
evidence of neurogenesis in the human DG (and other brain areas such as the striatum), see Box 1. b | Over the course of
several weeks, NSC-derived newborn cells in the rodent DG mature into excitatory, glutamatergic granule cells and integrate
into pre-existing hippocampal circuits. NSCs in the DG have a triangular shape with a long radial process extending from the
apical part of the cells; thus, they are often referred to as radial glia-like cells (R cells). Most R cells are quiescent in the adult
hippocampus and express a distinct set of marker proteins (selected marker proteins are indicated). Owing to extrinsic or
intrinsic regulators, quiescent R cells become activated and make first fate decisions: they symmetrically duplicate, leading
to expansion of the R cell pool; asymmetrically divide to give rise to a self-renewed R cell and a non-radial glia-like progenitor
cell (NR cell) (by far the most common fate of R cells); generate two NR cells; directly give rise to neurons; or, rarely, generate
astrocytes31. R cell activation is accompanied by profound changes in gene expression and cellular metabolism, as
indicated32,42,166. Whether R cells exist in distinct states (for example, prone towards differentiation versus self-renewal) or
there are different R cell populations remains poorly understood but may be the case given the heterogeneous behaviour of
R cells in the adult DG19,21,31,38. APOE, apolipoprotein E; ASCL1, Achaete–Scute homologue 1; CDK4, cyclin-dependent kinase 4;
DCX, doublecortin; GFAP, glial fibrillary acidic protein; HOPX, homeodomain-only protein; ID4, inhibitor of DNA binding 4;
MKI67, marker of proliferation Ki-67; NES, nestin; SPOT14, thyroid hormone responsive protein; TBR2, T-box brain protein 2.
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Table 1 | Technical approaches to analysing adult neurogenesis

Approach Description Advantages Disadvantages Refs
Thymidine Incorporation of thymidine Easy method Potential toxicity of analogues 6,60
analogues or its analogues (tritiated

No special equipment Label is diluted by divisions
thymidine, BrdU, EdU, IdU
needed Visualizes only the nucleus (DNA)
or CldU) during S phase
Human tissue available
Antibody Detection of markers Easy method Markers may be species specific 25,33
labelling selectively expressed in

No special equipment Tissue fixation important
NSCs or their progeny
needed
(for example, nestin, DCX,
NEUROD1 or PSA-NCAM) Human tissue available
Retroviral Specific labelling of Fast method for tissue- Invasive method (stereotactic 18
labelling proliferating cells using specific manipulation injections of virus)

Moloney murine leukaemia of gene expression Labels only small cohorts of cells
retrovirus
Enables live analyses in
sections
Transgenic Transgenic expression Labels large cohorts Potential unspecificity of 75,161
markers of fluorescent label promoters used (for example

under control of cell GLAST and nestin)
type-selective promoters
Lineage Transgenic expression Can label large cohorts but Potential unspecificity of 21,36
tracing of recombinase (such as also trace clonal lineages promoters used (for example,
Cre) under control of cell GLAST and nestin)
type-selective promoters
scRNA-seq Cell type-selective isolation Provides extensive Morphological information is lost 42,46
and subsequent RNA molecular information Potential alteration in gene

expression analyses at the
Analyses of neurogenic expression due to single-cell
single-cell level
cells and niche possible isolation procedures
Possible in humans
Intravital Prolonged intravital Captures real-time Invasive method 31,154
imaging imaging using microscopy dynamics of the neurogenic Special equipment needed
process
Non-invasive Based on selective peaks May be used to measure Specificity remains controversial 5,14,162,163
imaging in magnetic resonance neurogenesis in living No broadly accepted approach

spectrum or changes in humans available
blood volume associated
with neurogenesis
Carbon Measures 14C content in Measures real age of Challenging method with limited 5,14
dating individual cell populations human brain cells or tissues availability (owing to dilution of
14
C in biosphere)
Advantages and disadvantages do not necessarily apply to all species analysed. For more detailed technical considerations in the
context of detecting neurogenesis, especially in the human hippocampus, see Box 1 (refs164,165). BrdU, 5-bromo-2′-deoxyuridine;
CldU, 5-chloro-2′-deoxyuridine; DCX, doublecortin; EdU, 5-ethynyl-2′-deoxyuridine; GLAST, excitatory amino acid transporter 1;
IdU, 5-iodo-2′-deoxyuridine; NEUROD1, neurogenic differentiation factor 1; NSC, neural stem cell; PSA-NCAM, polysialylated
neuronal cell adhesion molecule; scRNA-seq, single-cell RNA sequencing.
lineage tracing and intravital imaging have described context of NSC activation42. This trajectory revealed a
the generation of neurons and astrocytes from R cells change in expression of transcription factors associated
in the mouse DG. Furthermore, there is evidence that with NSC activation, confirming previously known
neurogenic cells in the DG are intrinsically able to gen- regulators but also identifying novel players in this step.
erate oligodendrocytes but under normal conditions are A molecular switch from active niche signalling and
prevented from doing so by microRNAs or the transcrip- glycolysis towards oxidative phosphorylation, ribosome
tion factor neurofibromatosis 1 (NF1)39–41. Thus, NSCs biogenesis and cell cycle progression was observed42.
in the adult DG possess bona fide multipotency, but may Furthermore, scRNA-seq may be useful to identify the
not use it to full capacity under physiologic conditions. molecular mechanisms underlying the heterogeneous
Single-c ell RNA sequencing (scRNA-s eq) has behaviour of neurogenic cells in the DG — for example,
recently provided novel insights as it not only pro- in the context of self-renewal19,21,38. Hence, several stud-
vides important information about the transcription ies using scRNA-seq have provided important insights
in individual cells but also enables the reconstruction into different cellular states during adult NSC activation
of developmental hierarchies by ‘lining up’ cells on the that are accompanied by changes in gene expression,
basis of their transcriptional similarity. One scRNA-seq translation and metabolism42–46.
study demonstrated that similarities in gene expression Similarly, a combination of single-nucleus RNA
profiles could be used to reconstitute trajectories in the sequencing and 5-ethynyl-2′-deoxyuridine labelling has
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shed light on NSC transcriptional dynamics, including partly in tissues from humans with, various neurolog-
a shift from the expression of genes involved in pro- ical and psychiatric disorders, including major depres-
liferation to neuronal differentiation and maturation sion, Alzheimer disease, Parkinson disease, ischaemic
between activated NSCs and newborn neurons within stroke and medial temporal lobe epilepsy8,53–56. Restoring
the hippocampus44,47. Thus, although scRNA-seq is a or normalizing levels of hippocampal neurogenesis
snapshot-based approach, it can be used to examine through pharmacological or environmental interven-
a dynamic process such as hippocampal neurogenesis, tions may be sufficient to partly prevent the onset of
even in the human brain48. or ameliorate symptoms in certain models of disease,
Although scRNA-seq-mediated lineage trajectories ranging from epilepsy to neurodegenerative diseases and
have shed light on different cellular states during this depression56–59. Thus, targeting changes in neurogene-
process and identified cell type-specific genes, they sis may potentially hold promise for novel therapeutic
inherently miss information on cellular behaviour approaches, as discussed later. Robust evidence across
within each state. A combination of lineage tracing or different species indicates a dramatic decrease of neu-
imaging and scRNA-seq will help us to better under- rogenesis with advancing age8,53,54,60,61 (Box 2). The stud-
stand the differentiation process from quiescent NSCs ies observing changes in neurogenesis, whether on the
to newborn neurons in the adult DG38. Furthermore, level of NSC proliferation, neuronal differentiation or
novel techniques enabling the investigation of epige- cell survival, suggest that adult neurogenesis is regulated
netic landscapes and single-cell proteomes will comple- at multiple levels, and that any disturbance of the balance
ment the insights gained by scRNA-seq49,50. Together, between activation and quiescence and between differ-
the approaches used thus far allow us to conclude that entiation and survival can have detrimental effects on
NSCs, although mostly found in a quiescent state, can outcome.
be activated to divide and to generate new neurons and Various factors that stimulate NSC proliferation and
astrocytes in the adult hippocampal niche. neurogenesis have been identified (Fig. 2). In rodents,
3———————————————— voluntary exercise increases NSC proliferation, and envi-
Regulation of neurogenesis ronmental enrichment enhances the survival of new-
Numerous different conditions, factors and genetic born cells, promoting both memory and learning62–64.
manipulations have been found to influence adult How increased NSC activation affects the long-term
neurogenesis (Fig. 2). Whether they affect NSCs intrin- maintenance of the stem cell pool remains only partly
sically or act through the hippocampal niche is often understood32. Quiescence is maintained by niche fac-
difficult to entangle3. Decreases in neurogenesis have tors, such as GABA released by parvalbumin-positive
been observed to be driven by diverse genetic aberra- interneurons, as well as intracellular factors, such as bone
tions as well as extrinsic factors such as drugs, stress morphogenetic proteins65–67 and the E3 ubiquitin ligase
and inflammation3,51,52. Furthermore, altered neurogen- HUWE1, which destabilizes the stem cell-associated
esis has been observed in animal models of, and also transcription factor ASCL1 (ref.20). Furthermore, other
Reduced neurogenesis Increased neurogenesis
Neurodegeneration Psychosocial stress Environmental

enrichment
Ageing Fear
Epilepsy (causing
Drugs of abuse Diet, hormones and aberrant cells)
e.g. alcohol neurotransmitters
Growth factors
Genetic background
Physical exercise
e.g. DBA e.g. C57BL/6
Ablation of apoptosis
Antidepressants
e.g. fluoxetine
Heterochronic
parabiosis
Fig. 2 | Systemic regulators of adult hippocampal neurogenesis. Shown are key regulators of hippocampal neurogenesis
that have been demonstrated to be associated with either an increase or a decrease of the levels of newborn neurons
in the adult dentate gyrus. Systemic regulators can affect the neurogenic process in the adult dentate gyrus at each step,
from activating quiescent neural stem cells, to enhancing or impairing the proliferation of radial glia-like cells (R cells) and
non-radial glia-like progenitor cells (NR cells), to altering the survival and integration of newborn granule cells.
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Box 2 | Age-dependent dynamics of neurogenesis to de novo lipogenesis and from glycolysis to oxidative
phosphorylation — all changes that are regulated by
The amount of neurogenesis decreases substantially with advancing age both in genetic and epigenetic factors42,74–78. Furthermore, there
rodents and in humans7,8,53,60,61. In rodents, the number of proliferating neural stem cells is evidence, mostly based on gene expression data, that
(NSCs) and newborn neurons decreases exponentially; however, the neurogenic output NSC quiescence may be a rather ‘active’ state, charac-
of NSCs then seems to reach a plateau at around 7–10 months of age, resulting in low
terized by many niche signalling interactions although
but detectable amounts of neurogenesis throughout life60,61. As the survival of newborn
cells seems to be largely independent of the age of the animal, the major contribution also by low protein translation capacity32,42. Recent data
to decreased neurogenesis seems to be the reduced proliferation of NSCs175. During from Drosophila melanogaster suggest that NSCs can
ageing, neurogenic niches in the dentate gyrus but also in the subventricular zone also rest in G2 during quiescence, rendering them more
undergo substantial changes, such as increased inflammation, transcriptional changes rapidly activated than cells in G0 (ref.79). Whether the
and changes in cellular composition, including infiltration of T cells in the subventricular same holds true in mammalian NSCs remains unclear.
zone176–178. Thus, various extrinsic factors that change with age, many of which might It seems plausible that there is heterogeneity among
affect NSC proliferation, can be modulated by dietary interventions and exercise179. different quiescent and activated stem cell states, with
Infusions of young blood plasma or heterochronic parabiosis is a systemic manipulation some NSCs more prone to rapidly divide and deplete
that can reverse or reduce the age-dependent decline in neurogenesis and enhance themselves and others more likely to divide slowly
synaptic plasticity and cognitive function in rodents180–184. Thus, studying the alterations
and even return to true, long-lasting quiescence32,38.
that lead to decreased neurogenesis is important to understand how the process is
regulated, and emerging manipulations that promote neurogenesis are of particular Whether these are different states of the same starting
interest, given the possibility of alleviating age-dependent decreases and the potential stem cells, or whether different pools of stem cells exist,
benefits for memory and learning185,186. remains an open question32,35. Genetic approaches such
On a cellular level, NSCs from aged animals show lysosomal defects and increased as intersectional genetics may enable the dissection of
amounts of aggregated proteins, concomitant with decreased levels of the chaperonin the exact lineage relationships of neurogenic cells in the
T-complex protein ring complex (TRIC; also known as chaperone-containing TCP1)187,188. adult DG. In addition, the fate and behaviour of indi-
Accordingly, activation of lysosomal activity by forced expression of transcription vidual NSCs may depend on their previous cellular
factor EB (TFEB), a master regulator of lysosome biogenesis and autophagy, enhances biography, such as previous cell division histories of
NSC proliferation in aged mice188. Furthermore, vimentin has a crucial role in recruiting mother cells4,80,81.
the proteasome and protein aggregates to the aggresome, leading to their asymmetric
segregation during NSC divisions189. 4————————————
Integration of newborn neurons
In aged NSCs, a weakened diffusion barrier leads to impaired asymmetric segregation
of damaged proteins190. Whereas the fidelity to segregate damaged proteins Survival and stability of newborn cells. The number
asymmetrically declines with age, it remains unclear whether in young animals such of cells generated via NSC divisions is delicately regu-
damaged proteins are inherited by the stem cell or the differentiating cell, whether lated by various extrinsic and intrinsic molecular cues.
they accumulate with increased numbers of divisions and what their consequences are However, the birth of new cells is just the first step in a
for the inheriting cell. Thus, the effect of age on neurogenesis, and NSCs in particular, process that will eventually lead to the stable addition of
is a field of emerging interest. newborn neurons into the adult DG circuitry.
Indeed, a substantial portion of newborn cells in
key pathways such as the forkhead box protein O the hippocampus of young adult rodents die within
(FOXO), Notch, sonic hedgehog (SHH) and canonical 3 weeks of their birth82–84. Cell death occurs in two dis-
WNT signalling pathways are critically involved in reg- tinct waves. On the basis of thymidine labelling and
ulating NSC activation and maintenance32. Decreased intravital imaging in rodents, a large number of cells
Notch and FOXO signalling was reported to enhance (approximately 60% of all cells undergoing cell death)
proliferation, leading to rapid stem cell exhaustion, were observed to die within the first 24–48 hours after
Heterochronic parabiosis whereas impaired signalling of these pathways eventually progenitor cell division31,83,85. The underlying cause for
Cross-circulation of humoral
factors via shared blood
leads to decreased neurogenesis68–70. In addition, other this early phase of cell death, which seems to be medi-
circulation, most commonly neurotransmitters besides GABA (such as serotonin), ated by BAX-dependent apoptosis, is unknown86,87.
used by connecting the hormones and growth factors affect the levels of Furthermore, it remains to be determined whether the
vasculature (and thus blood neurogenesis3,32,71,72. Indeed, some hormones, such as mode of mother cell division (for example, symmetric
circulation) of young and aged
corticosteroids, reduce proliferation and neurogenesis, versus asymmetric) may be predictive of subsequent cell
mice.
whereas others, such as oestrogens and male phero- death. Given the previously described high degree of
Vimentin mones, seem to stimulate neurogenesis. Other growth genetic mosaicism in the adult brain, and especially in the
A type III intermediate filament factors, such as EGF, FGF2, brain-derived growth factor DG, one hypothesis is that a subset of cells is removed
protein that is a cytoskeletal (BDNF), nerve growth factor (NGF), vascular endothe- due to deleterious or hazardous genetic alterations88,89.
component in various cell
types.
lial growth factor (VEGF) and transforming growth Future experiments isolating and molecularly character-
factor (TGF), have been associated with increased izing this population of dying cells will aim to address
Intersectional genetics neurogenesis3,73. this hypothesis.
Approaches that increase the Once activated, NSCs divide, differentiate and The early phase of cell death is followed by a second
accuracy of genetic access to
thereby deplete themselves, or return to an inactive wave approximately 12–16 days after the birth of the
cells by combining two or more
regulatory elements for a single phase, the so-called resting state, which might be a cells31,82,90. This wave of cell death coincides with the start
synthetic output. truly quiescent state (corresponding to G0) or a pro- of synaptic integration of newborn cells (see below), and
longed cell cycle phase (corresponding to G1)31,32. The previous work demonstrated that the successful survival
Genetic mosaicism transition from NSC quiescence to NSC activation is at this maturational stage is input dependent: newborn
The presence of different
genotypes in individual cells
accompanied by decreased intercellular interactions, neurons must receive NMDA receptor-dependent input
arising from a single zygote increased ribosomal biogenesis and switches from lyso- or they will be removed from the circuit90. Thus, new-
within an individual. somal to proteasomal activity, from fatty acid oxidation born cells have to pass through two distinct selection
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processes before they are stably integrated into the after cell birth, the first dendritic synapses are formed
DG circuit. and the cells thus receive extrasynaptic and synap-
Once newborn cells survive these early selection pro- tic GABAergic and glutamatergic inputs103,104 (Fig. 3).
cesses, they seem to become stable members of the DG Newborn granule cells receive synaptic inputs initially
circuitry82, indicating that once newborn cells survive, from local neurons (largely interneurons) before they
they last throughout the animal’s lifespan. However, receive synaptic inputs from long-range projection
the continuous birth of new neurons (and their stable neurons105–107 (Fig. 4a) . When the first synapses are
integration into the DG, albeit only at relatively low fre- formed onto newborn neurons in the molecular layer,
quency) predicts that either the DG should grow with these neurons also form axonal synaptic connections
advancing age or that embryonically or early postnatally with hilar cells and pyramidal cells in area CA399,108
generated cells should die to make space for adult-born (Fig. 4a) . Furthermore, newborn granule cells may
neurons. Indeed, the DG in a mouse brain grows directly connect monosynaptically with mature granule
in volume until approximately 6 months of age, and in cells to affect DG network activity (see later)109.
primates this growth period may be even longer11,91,92. A plethora of pathways and metabolic adaptations
Furthermore, a substantial fraction of early postnatally have been identified that are crucial for early migration,
generated granule cells have been shown to die even neurite extension and spine formation, including small
after reaching full maturity93. However, Cre-mediated Rho GTPases, shifts in mitochondrial metabolism and
population labelling with an extended chase of labelled the protein DISC1(disrupted in schizophrenia 1 pro-
adult hippocampal NSCs indicated that the fraction of tein)3,78,110–113. Furthermore, astrocytes in the DG have
labelled cells increases in the mouse DG within the first been shown to be important for the proper maturation
3 months after labelling but then reaches a plateau, sug- and integration of newborn granule cells114. Blockade
gesting that adult-born cells tend to replace adult-born of vesicular release specifically from astrocytes led to
sister cells36,37,94. Nevertheless, the generation of new decreased synaptic input to and spine density on new-
neurons in the DG beyond 9 months of age in the mouse born, but not mature, granule cells. However, most
brain is considerably reduced (Box 2), making it diffi- previous results were derived from static snapshot obser-
cult to measure increases in cell numbers experimen- vations following genetic or pharmacological manipu-
tally. Thus, whether adult-born cells replace each other lations. Thus, the exact involvement of certain genes or
(and thus represent a population with cellular turnover pathways in distinct developmental steps underlying
in itself), whether newborn neurons replace embryon- the dynamic processes of migration, neurite formation
ically or early postnatally generated cells, or whether and synaptic integration remains largely unknown.
there is true competition and stochastic replacement of Imaging-based approaches will help to gain further
embryonically but also adult-born cells remains incom- insights into previously observed phenotypes97,98.
pletely understood. In contrast to the olfactory bulb, Over the course of 6–8 weeks, a continuing matura-
where tissue deteriorates on depletion of adult NSCs tion process occurs, including extensive dendritic remod-
in the subventricular zone, the DG remains relatively elling, as observed by prolonged intravital imaging98.
unaffected in terms of size and neuron numbers after During this time, newborn neurons also dramatically
depletion of adult NSCs94,95. Longitudinal observations change their intrinsic properties: whereas young granule
using intravital imaging of individual cohorts of cells cells are characterized by inverted chloride potential due
labelled embryonically or early postnatally and also of to high expression of the Na+–K+–Cl− transporter NKCC1
cells generated in the adult DG within the same rodent (causing GABA to have initially a depolarizing effect
brain may be a suitable approach to understanding the on newborn neurons’ membrane potential), they even-
population dynamics of adult-born DG neurons. tually switch towards mature chloride gradients by
expression of KCC2 and subsequently lose their high
Morphological maturation and integration of newborn input resistance103,104,115–117. These changes do not occur
neurons. While experiencing the stages of selection and uniformly and gradually for all cells born at a similar
subsequent survival, newborn cells undergo dramatic time, but rather show heterogeneity among cells labelled
morphological changes (Fig. 3). Initially, newborn cells at the same time118. From approximately 8 weeks of age,
tangentially migrate away from their mother progenitor the electrophysiological properties and morphological
cells, guided at least partly by DG vasculature, before measures (such as dendritic complexity and spine den-
they stop tangential migration and move radially into the sity) of adult-born cells become highly similar to those of
GCL16,96. What causes the switch from tangential to radial cells that were born embryonically or early postnatally,
migration is largely unknown. Furthermore, the tempo- although adult-born granule cells continue to mature
ral stability and the dynamics underlying the extension over several months102,119,120.
Na+–K+–Cl– transporter of neurites growing from newborn cells remain relatively It is hypothesized that new neurons must compete for
NKCC1
unclear, although in vivo imaging data have started to synaptic inputs to enable their survival and integration.
A co-transporter that regulates
the transport of sodium, address that question97,98. This hypothesis is based on the observation that, early
potassium and chloride Newborn DG neurons undergo extensive neurite on, newborn granule cells largely contact axons in the
through cellular membranes. growth, during which their dendrites extend through molecular layer via multiple-synapse boutons, suggesting
the GCL and axons grow towards area CA3 of the that they preferentially contact axonal synapses that
Multiple-synapse boutons
Synapses with two or more
hippocampus16,17,99–101. During the early phase of mat- are already occupied by other neurons; by contrast, in
postsynaptic terminals on a uration, newborn cells receive largely extrasynaptic more mature stages, the most prevalent synaptic con-
single presynaptic terminal. GABAergic input 102–104. Approximately 12–14 days tact form is single-synapse boutons17,121 (Fig. 4a). Future
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Differentiation Maturation Early integration Late integration

DCX NEUN
Marker expression
PSA-NCAM NEUROD1 Calretinin Calbindin
PROX1
Dendrites/axons Spines Maturation
Tangential Radial Migration
Cell death
GABA input, tonic
GABA input, dendritic
Glutamate input, spine
Glutamate output, hilus
Glutamate output, CA3
GABA input, soma
Fig. 3 | Maturation of adult-born neurons in the hippocampus. New neurons are either generated via symmetric or
asymmetric divisions of non-radial glia-like progenitor cells (NR cells) or through direct neurogenesis from radial glia-like
cells (R cells). Directly after birth, new neurons tangentially migrate from their mother cells, start to extend neurites, and
radially migrate into the granule cell layer, form dendritic spines and synapses, and extend functionally connected
axons17,18,96–98,108. However, the exact dynamics of each of those maturational steps on a single-cell level remain partly
unknown given the lack of long-term in vivo observations of individual maturing neurons over extended time periods.
During each developmental stage, newborn neurons express a set of marker proteins (a selection is shown) and go
through distinct phases of physiological maturation, receiving different types of inputs and generating different types
of outputs, as indicated33,102–104,109,150. DCX, doublecortin; NEUN, neuronal nuclei; NEUROD1, neurogenic differentiation
factor 1; PROX1, prospero homeobox protein 1; PSA-NCAM, polysialylated neuronal cell adhesion molecule.
experiments that follow the extension and maturation behaviour was largely based on correlative data: increased
of single dendritic spines or axonal boutons in vivo may neurogenesis seemed to be associated with improved
address the dynamics of how newborn granule cells hippocampus-dependent behaviour (for example, in the
establish synaptic input and output connections. Morris water maze), whereas reduced neurogenesis was
5———————————————— associated with impairments in hippocampus-dependent
Functional role of adult-born neurons learning tasks62,63,122. However, more mechanistic or
Functional importance of newborn neurons for causal experimental approaches that selectively dis-
DG-dependent behaviour. The findings that new neurons rupted neurogenesis without affecting other neural
are added to the adult mammalian DG prompts an structures were technically challenging. Most, if not all,
obvious question: what are they good for? What is the con- strategies to impair NSC function, to reduce neuronal
Morris water maze tribution of hippocampal neurogenesis to hippocampal output or to kill newborn neurons (for example, by using
A behavioural, spatial
navigational task, mostly used
function? pharmacological, transgenic, viral or irradiation-based
in laboratory rodents, to study Early experimental evidence of the functional rel- approaches) showed potential off-target effects, such as
spatial learning and memory. evance of neurogenesis for hippocampus-dependent non-specific targeting of proliferating cells outside the
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DG or the brain, non-specific inflammation or the sheer experiments have suggested that the activation of
presence of dead or dying cells within the DG95,123–127. adult-born granule cells approximately 4–6 weeks after
Thus, numerous studies were published showing their birth overall inhibits DG network activity, although
consistent effects but also some opposing effects on this effect seems to be input dependent and a highly
hippocampus-dependent tasks, including contextual complex process152,153.
fear conditioning and spatial learning128. Over the past few years, the field has moved towards
Similarly, probing for the functional relevance of adult using more dynamic approaches, such as functional
hippocampal neurogenesis continued to produce partly in vivo imaging of newborn neurons while animals
controversial findings when the field moved towards learn a task or express a memory, to examine how new
behavioural tasks that may challenge the function of the neurons affect DG connectivity and network activity154.
DG more specifically. Previous experimental work and Both head-fixed approaches using two-photon imag-
computational modelling data indicated that the DG is ing and gradient-index lens-based approaches in freely
involved in behavioural pattern separation, the distinct behaving animals have been used109,154,155. Initial evi-
encoding of highly similar experiences or inputs129,130 dence gathered with use of these technologies suggests
(Fig. 4b) , not only in rodents but also in humans 131. that new neurons show distinct responsiveness to certain
Indeed, work from different laboratories using vari- cues. Specifically, increasing neurogenesis (by delet-
ous tasks to probe for behavioural pattern separation, ing the proapoptotic gene Bax from adult NSCs) inhibits
and using both gain-of-function and loss-of-function the ventral DG, reduces the activity of stress-responsive
approaches, identified a critical role for newborn cells and thereby seems to promote stress resilience
granule cells in DG-d ependent pattern separation in mice52,155. Furthermore, distinct effects of newborn
in mice86,132,133. However, others could not confirm these granule cell activation via the lateral entorhinal cortex
findings134,135. In addition, there is evidence that new (preferentially mediating contextual information) ver-
neurons may be important for hippocampus-dependent sus the medial entorhinal cortex (preferentially mediating
Behavioural flexibility
behavioural flexibility (for example, when a mouse is spatial information) have been described. Activation of
Adaptive changes in the
behaviour of an animal in required to learn a novel position in the Morris water the lateral entorhinal cortex causes adult-born granule
response to changes of the maze)44,136. Notably, new neurons seem to be impor- cells to monosynaptically inhibit mature granule cells,
external or internal tant not only for encoding novel experiences but whereas stimulation of the medial entorhinal cortex
environment.
also for forgetting previously learned experiences and instead leads to the excitation of mature neurons by
Memory traces memory traces137,138. newborn granule cells109 (Fig. 4a). Future work will need
Units of cognitive information Importantly, the DG, and therefore hippocam- to analyse how this diverse responsiveness and trans-
in the brain that may cause pal neurogenesis, is crucial not only for learning and mission of incoming inputs of new granule cells affects
structural or biochemical memory but also for various other behaviours, such as activity and the encoding of information in downstream
alterations allowing the storage
of memory.
addiction, reward-related behaviour, social behaviour hippocampal structures such as CA3 during natural
and emotional control139–141. Ventral parts of the DG (that is, behavioural) activation156. Understanding how
Homosynaptic long-term are engaged in mood control, and previous work has neurogenesis affects local DG circuits at different mat-
potentiation linked mood, stress resilience and the efficacy of certain urational stages and affects the activity of DG networks
Changes in synaptic strength
antidepressants to the birth and integration of newborn connecting to pyramidal cells in the main output area of
that are specific for
postsynaptic targets that are
granule cells in rodents142,52,59. Clearly, not all functions CA3 — for example, by dynamic imaging approaches —
specifically stimulated by of antidepressants rely on hippocampal neurogenesis143. will help to further elucidate the functional relevance of
presynaptic cells. Nevertheless, experimentally enhanced neurogenesis adult-born granule cells in the context of hippocampal
has certain antidepressant effects in mice treated with connectivity and function.
Heterosynaptic long-term
depression
corticosterone or experiencing chronic social defeat
A reduction in synaptic stress (models of depression), such as reducing signs Conclusions and perspectives
strength at unactivated of anxiety in an elevated plus maze or forced swim The finding that new neurons are born throughout life
synaptic connections that are test144,145. in the mammalian hippocampus has had a profound
input nonspecific.
How do new neurons exert their function on these fea- impact on previously held concepts regarding plas-
Gradient-index lens tures of hippocampus-dependent behaviour? As outlined tic changes and dynamic adaptations in response to
A lens that makes use of a earlier, newborn granule cells show high excitability and experience in the adult brain. However, the translation
gradient of the refractive index a low threshold to induce plasticity-inducing potentia- of experimental data obtained largely in mice to the
of a material, allowing a lens tion such as long-term potentiation 4–6 weeks after their human brain has been complicated, given the difficulty
with a flat surface or that does
not have aberrations of
birth115–117. At this maturational stage, new granule cells in accessing healthy human hippocampal tissues and
traditional spherical lenses. show a gradual increase in levels of homosynaptic long- the continuing lack of robustly validated approaches to
term potentiation and heterosynaptic long-term depression146. detect neurogenesis in live human brains (Box 1). Thus,
Lateral entorhinal cortex Furthermore, newborn granule cells also display the extent of lifelong neurogenesis in humans and any
Part of the medial temporal
an increasing molecular responsiveness to stimula- roles or changes it may show in human disease remain
lobe; it projects via the lateral
perforant path into the dentate
tion with increasing maturation147–149. Weak afferent controversial. Irrespective of a potential translational
gyrus. activity is sufficient to activate newborn cells during relevance, the finding that new neurons are born and
this maturational stage, albeit with relatively low input can integrate successfully into mature neuronal net-
Medial entorhinal cortex specificity150,151. However, when cells mature beyond works, as doubtlessly occurs in the rodent hippocam-
Part of the medial temporal
lobe; it projects via the medial
6 weeks of age, their threshold for activation increases pus, represents a unique entry point to analyse and
perforant path into the dentate and their input responses become more specific. Specific eventually understand all the required steps, from stem
gyrus. manipulations in slices and using in vivo optogenetic cell division to cell selection and neuronal maturation
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a
CA1
pyramidal
neuron
Entorhinal
cortex
Newborn
granule cell LEC
MEC
Mature
granule cell
Mossy Basket cell
cell
CA3
pyramidal Areas of competition
neuron
b Context A Context B
Overlap of activation of mature

granule cells without
neurogenesis/low pattern
separation
No neurogenesis
Reduced but more precise

activation of mature granule
cells due to indirect inhibition of
the DG via newborn granule
cells/high pattern separation
With neurogenesis
Granule cell activated in Granule cell activated in Newborn granule cell activated
Silent granule cell
context A or context B context A and context B in context A or context B
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◀ Fig. 4 | Circuit function of newborn granule cells in the adult hippocampus. cells — for example, in the context of neurodegenera-
a | Newborn granule cells in the dentate gyrus (DG) receive stronger input from the lateral tion. For example, what is required for the functional
entorhinal cortex (LEC) than from axons arising from the medial entorhinal cortex (MEC). and meaningful integration of new neurons into mature
Immature granule cells may affect DG circuit activity by directly exciting mature granule brain networks? And how can we activate endogenous
cells or by indirectly inhibiting them via activation of inhibitory interneurons (such as
neurogenic precursors to enhance regeneration?
parvalbumin-positive basket cells) or hilar mossy cells. With maturation, granule cells
receive strong perisomatic inhibition and form large boutons onto CA3 pyramidal The neurogenic hippocampal niche may hold the
cells, thus modulating output onto area CA3 and area CA1, from where information flows answer to those questions, and substantial progress has
back to the entorhinal cortex and other association cortices. The exact effects of newborn been made to understand these processes on a molec-
neurons at distinct maturational stages on activity and information flow of the DG circuit ular and cellular level. However, to make a true impact
and its output into area CA3 will need to be further analysed by in vitro and in vivo on the causes and eventual therapeutic amelioration of
imaging and electrophysiological recordings. Blue shaded areas indicate sites where acute and chronic neuropsychiatric disease, the field
new neurons may have to compete with pre-existing cells for presynaptic and postsynaptic will have to push towards a better understanding of
partners. b | Newborn granule cells seem to contribute to DG-dependent behavioural exactly how neurogenesis affects functional connectiv-
pattern separation, which is the distinct encoding of highly similar inputs or experiences, ity and hippocampus-dependent behaviour. Novel ideas
in rodents. Without neurogenesis (upper row), activation of mature granule cells (blue) may
are needed to translate findings obtained in rodents to
activate overlapping cells owing to the similarity of the experience of being in context A
and the experience of being in context B (illustrated by a highly similar object arrangement neurogenesis that might occur in human tissues — for
in an arena), and thus the output to CA3 may overlap for similar inputs (reactivating cells example, using human cellular models of hippocampal
are labelled in light blue with a blue outline). When neurogenesis is present (lower row), development and maturation, or ideally by improving
newborn granule cells (purple) are more easily activated than existing granule cells, but current approaches of working directly with human
overall reduce the activity of the DG, possibly by inhibiting the activity of mature granule hippocampal tissues. In addition, novel technologies
cells (blue). Thus, coding becomes sparser, and the overlap of activated mature granule cells with high cellular or single-cell resolution, such as
is reduced, enabling enhanced behavioural pattern separation of highly similar inputs. single-cell genomics and epigenomics, proteomics and
Additional considerations of how new neurons contribute to and influence DG coding spatial transcriptomics, will soon be used to define the
are more extensively discussed elsewhere142,167. molecular mechanisms that underlie neurogenesis in
the adult brain48,157–160. Furthering our knowledge of life-
Spatial transcriptomics and integration. Understanding these steps may not long neurogenesis in health and disease may open novel
The characterization of mRNA only be instructive for future attempts to harness the avenues to understand and treat brain diseases affecting
composition in individual cells
while maintaining information
regenerative potential of endogenous neurogenesis for the hippocampal formation.
regarding their spatial position brain repair but may also guide therapeutic interven-
within complex tissues. tions that are based on the transplantation of exogenous Published online 25 February 2021
1. Altman, J. & Das, G. D. Post-natal origin of 14. Ernst, A. et al. Neurogenesis in the striatum of the shows electrophysiological and morphological
microneurons in the rat brain. Nature 207, 953–956 adult human brain. Cell 156, 1072–1083 (2014). characteristics of astrocytes. Mol. Cell. Neurosci. 23,
(1965). 15. Bergmann, O. et al. The age of olfactory bulb neurons 373–382 (2003).
Seminal study suggesting the postnatal birth in humans. Neuron 74, 634–639 (2012). 27. Malatesta, P. et al. Neuronal or glial progeny: regional
of neurons in the mammalian brain. 16. Zhao, C., Teng, E. M., Summers, R. G. Jr., Ming, G. L. differences in radial glia fate. Neuron 37, 751–764
2. Kuhn, H. G., Toda, T. & Gage, F. H. Adult hippocampal & Gage, F. H. Distinct morphological stages of dentate (2003).
neurogenesis: a coming-of-age story. J. Neurosci. 38, granule neuron maturation in the adult mouse 28. Moss, J. et al. Fine processes of nestin-GFP-positive
10401–10410 (2018). hippocampus. J. Neurosci. 26, 3–11 (2006). radial glia-like stem cells in the adult dentate gyrus
3. Goncalves, J. T., Schafer, S. T. & Gage, F. H. 17. Toni, N. et al. Synapse formation on neurons born in ensheathe local synapses and vasculature. Proc. Natl
Adult neurogenesis in the hippocampus: from stem the adult hippocampus. Nat. Neurosci. 10, 727–734 Acad. Sci. USA 113, E2536–E2545 (2016).
cells to behavior. Cell 167, 897–914 (2016). (2007). 29. DeCarolis, N. A. et al. In vivo contribution of nestin-
4. Obernier, K. & Alvarez-Buylla, A. Neural stem cells: 18. van Praag, H. et al. Functional neurogenesis in the and GLAST-lineage cells to adult hippocampal
origin, heterogeneity and regulation in the adult adult hippocampus. Nature 415, 1030–1034 (2002). neurogenesis. Hippocampus 23, 708–719 (2013).
mammalian brain. Development 146, dev.156059 19. Encinas, J. M. et al. Division-coupled astrocytic 30. Lugert, S. et al. Quiescent and active hippocampal
(2019). differentiation and age-related depletion of neural neural stem cells with distinct morphologies respond
5. Spalding, K. L. et al. Dynamics of hippocampal stem cells in the adult hippocampus. Cell Stem Cell 8, selectively to physiological and pathological stimuli
neurogenesis in adult humans. Cell 153, 1219–1227 566–579 (2011). and aging. Cell Stem Cell 6, 445–456 (2010).
(2013). 20. Urban, N. et al. Return to quiescence of mouse neural 31. Pilz, G. A. et al. Live imaging of neurogenesis in the
6. Eriksson, P. S. et al. Neurogenesis in the adult human stem cells by degradation of a proactivation protein. adult mouse hippocampus. Science 359, 658–662
hippocampus. Nat. Med. 4, 1313–1317 (1998). Science 353, 292–295 (2016). (2018).
The first study suggesting the birth of neurons 21. Bonaguidi, M. A. et al. In vivo clonal analysis reveals First study to use in vivo imaging to follow single
in the human adult hippocampus. self-renewing and multipotent adult neural stem cell NSCs and their daughter cells over months.
7. Knoth, R. et al. Murine features of neurogenesis in the characteristics. Cell 145, 1142–1155 (2011). 32. Urban, N., Blomfield, I. M. & Guillemot, F. Quiescence
human hippocampus across the lifespan from 0 to Seminal study that analyses the fate and potency of adult mammalian neural stem cells: a highly
100 years. PLoS ONE 5, e8809 (2010). of adult hippocampal NSCs on a clonal level. regulated rest. Neuron 104, 834–848 (2019).
8. Moreno-Jimenez, E. P. et al. Adult hippocampal 22. Reynolds, B. A. & Weiss, S. Generation of neurons and 33. Kempermann, G., Jessberger, S., Steiner, B. &
neurogenesis is abundant in neurologically healthy astrocytes from isolated cells of the adult mammalian Kronenberg, G. Milestones of neuronal development
subjects and drops sharply in patients with central nervous system. Science 255, 1707–1710 in the adult hippocampus. Trends Neurosci. 27,
Alzheimer’s disease. Nat. Med. 25, 554–560 (2019). (1992). 447–452 (2004).
9. Charvet, C. J. & Finlay, B. L. Comparing adult 23. Ray, J., Raymon, H. K. & Gage, F. H. Generation and 34. Imayoshi, I., Ohtsuka, T., Metzger, D., Chambon, P. &
hippocampal neurogenesis across species: translating culturing of precursor cells and neuroblasts from Kageyama, R. Temporal regulation of Cre recombinase
time to predict the tempo in humans. Front. Neurosci. embryonic and adult central nervous system. Methods activity in neural stem cells. Genesis 44, 233–238
12, 706 (2018). Enzymol. 254, 20–37 (1995). (2006).
10. Amrein, I. Adult hippocampal neurogenesis in natural 24. Hsieh, J. et al. IGF-I instructs multipotent adult neural 35. Berg, D. A. et al. A common embryonic origin of stem
populations of mammals. Cold Spring Harbor progenitor cells to become oligodendrocytes. J. Cell cells drives developmental and adult neurogenesis.
Perspect. Biol. 7, a021295 (2015). Biol. 164, 111–122 (2004). Cell 177, 654–668 e615 (2019).
11. Kempermann, G. New neurons for ‘survival of the 25. Seri, B., Garcia-Verdugo, J. M., McEwen, B. S. & 36. Lagace, D. C. et al. Dynamic contribution of nestin-
fittest’. Nat. Rev. Neurosci. 13, 727–736 (2012). Alvarez-Buylla, A. Astrocytes give rise to new neurons expressing stem cells to adult neurogenesis.
12. Doetsch, F., Caille, I., Lim, D. A., Garcia-Verdugo, J. M. in the adult mammalian hippocampus. J. Neurosci. J. Neurosci. 27, 12623–12629 (2007).
& Alvarez-Buylla, A. Subventricular zone astrocytes 21, 7153–7160 (2001). 37. Ninkovic, J., Mori, T. & Gotz, M. Distinct modes
are neural stem cells in the adult mammalian brain. Key study indicating the identity of adult NSCs and of neuron addition in adult mouse neurogenesis.
Cell 97, 703–716 (1999). showing that cells with astroglial properties give rise J. Neurosci. 27, 10906–10911 (2007).
13. Gould, E. How widespread is adult neurogenesis to new neurons in the adult rodent hippocampus. 38. Bottes, S. et al. Long-term self-renewing stem cells in
in mammals? Nat. Rev. Neurosci. 8, 481–488 26. Filippov, V. et al. Subpopulation of nestin-expressing the adult mouse hippocampus identified by intravital
(2007). progenitor cells in the adult murine hippocampus imaging. Nat. Neurosci. 24, 225–233 (2020).
0123456789();:
Reviews
39. Rolando, C. et al. Multipotency of adult hippocampal 63. Van Praag, H., Kempermann, G. & Gage, F. H. 89. McConnell, M. J. et al. Mosaic copy number variation
NSCs in vivo is restricted by Drosha/NFIB. Cell Stem Running increases cell proliferation and neurogenesis in human neurons. Science 342, 632–637 (2013).
Cell 19, 653–662 (2016). in the adult mouse dentate gyrus. Nat. Neurosci. 2, 90. Tashiro, A., Sandler, V. M., Toni, N., Zhao, C.
40. Sun, G. J. et al. Latent tri-lineage potential of adult 266–270 (1999). & Gage, F. H. NMDA-receptor-mediated, cell-specific
hippocampal neural stem cells revealed by Nf1 64. Olson, A. K., Eadie, B. D., Ernst, C. & Christie, B. R. integration of new neurons in adult dentate gyrus.
inactivation. Nat. Neurosci. 18, 1722–1724 (2015). Environmental enrichment and voluntary exercise Nature 442, 929–933 (2006).
41. Jessberger, S., Toni, N., Clemenson, G. D. Jr., Ray, J. massively increase neurogenesis in the adult 91. Bayer, S. A., Yackel, J. W. & Puri, P. S. Neurons in the
& Gage, F. H. Directed differentiation of hippocampal hippocampus via dissociable pathways. Hippocampus rat dentate gyrus granular layer substantially increase
stem/progenitor cells in the adult brain. Nat. Neurosci. 16, 250–260 (2006). during juvenile and adult life. Science 216, 890–892
11, 888–893 (2008). 65. Song, J. et al. Parvalbumin interneurons mediate (1982).
42. Shin, J. et al. Single-cell RNA-seq with waterfall reveals neuronal circuitry-neurogenesis coupling in the 92. Ngwenya, L. B., Heyworth, N. C., Shwe, Y., Moore, T. L.
molecular cascades underlying adult neurogenesis. adult hippocampus. Nat. Neurosci. 16, 1728–1730 & Rosene, D. L. Age-related changes in dentate
Cell Stem Cell 17, 360–372 (2015). (2013). gyrus cell numbers, neurogenesis, and associations
43. Artegiani, B. et al. A single-cell RNA sequencing 66. Song, J. et al. Neuronal circuitry mechanism with cognitive impairments in the rhesus monkey.
study reveals cellular and molecular dynamics regulating adult quiescent neural stem-cell fate Front. Syst. Neurosci. 9, 102 (2015).
of the hippocampal neurogenic niche. Cell Rep. 21, decision. Nature 489, 150–154 (2012). 93. Cahill, S. P., Yu, R. Q., Green, D., Todorova, E. V.
3271–3284 (2017). 67. Mira, H. et al. Signaling through BMPR-IA regulates & Snyder, J. S. Early survival and delayed death
44. Bowers, M. et al. FASN-dependent lipid metabolism quiescence and long-term activity of neural stem cells of developmentally-born dentate gyrus neurons.
links neurogenic stem/progenitor cell activity to in the adult hippocampus. Cell Stem Cell 7, 78–89 Hippocampus 27, 1155–1167 (2017).
learning and memory deficits. Cell Stem Cell 27, (2010). 94. Imayoshi, I. et al. Roles of continuous neurogenesis
98–109 e111 (2020). 68. Ables, J. L., Breunig, J. J., Eisch, A. J. & Rakic, P. in the structural and functional integrity of the adult
45. Llorens-Bobadilla, E. et al. Single-cell transcriptomics Not(ch) just development: Notch signalling in the forebrain. Nat. Neurosci. 11, 1153–1161 (2008).
reveals a population of dormant neural stem cells that adult brain. Nat. Rev. Neurosci. 12, 269–283 95. Saxe, M. D. et al. Ablation of hippocampal
become activated upon brain injury. Cell Stem Cell 17, (2011). neurogenesis impairs contextual fear conditioning
329–340 (2015). 69. Kannangara, T. S. & Lagace, D. C. The multi-pronged and synaptic plasticity in the dentate gyrus. Proc. Natl
46. Hochgerner, H., Zeisel, A., Lonnerberg, P. regulation of adult neurogenesis by Forkhead Box Acad. Sci. USA 103, 17501–17506 (2006).
& Linnarsson, S. Conserved properties of dentate O family members. Neuron 99, 1099–1101 (2018). 96. Sun, G. J. et al. Tangential migration of neuronal
gyrus neurogenesis across postnatal development 70. Schaffner, I. et al. FoxO function is essential for precursors of glutamatergic neurons in the adult
revealed by single-cell RNA sequencing. Nat. Neurosci. maintenance of autophagic flux and neuronal mammalian brain. Proc. Natl Acad. Sci. USA 112,
21, 290–299 (2018). morphogenesis in adult neurogenesis. Neuron 99, 9484–9489 (2015).
47. Habib, N. et al. Div-Seq: single-nucleus RNA-Seq 1188–1203 e1186 (2018). 97. Wang, J. et al. Lateral dispersion is required for circuit
reveals dynamics of rare adult newborn neurons. 71. Cameron, H. A. & Gould, E. Adult neurogenesis is integration of newly generated dentate granule cells.
Science 353, 925–928 (2016). regulated by adrenal steroids in the dentate gyrus. Nat. Commun. 10, 3324 (2019).
48. Zhong, S. et al. Decoding the development of the Neuroscience 61, 203–209 (1994). 98. Goncalves, J. T. et al. In vivo imaging of dendritic
human hippocampus. Nature 577, 531–536 (2020). 72. Brezun, J. M. & Daszuta, A. Depletion in serotonin pruning in dentate granule cells. Nat. Neurosci. 19,
49. Swaminathan, J. et al. Highly parallel single-molecule decreases neurogenesis in the dentate gyrus and the 788–791 (2016).
identification of proteins in zeptomole-scale mixtures. subventricular zone of adult rats. Neuroscience 89, 99. Faulkner, R. L. et al. Development of hippocampal
Nature Biotechnol. 36, 1076–1082 (2018). 999–1002 (1999). mossy fiber synaptic outputs by new neurons in the
50. Clark, S. J., Lee, H. J., Smallwood, S. A., Kelsey, G. 73. Aimone, J. B. et al. Regulation and function of adult adult brain. Proc. Natl Acad. Sci. USA 105,
& Reik, W. Single-cell epigenomics: powerful new neurogenesis: from genes to cognition. Physiol. Rev. 14157–14162 (2008).
methods for understanding gene regulation and cell 94, 991–1026 (2014). 100. Sun, G. J. et al. Seamless reconstruction of intact
identity. Genome Biol. 17, 72 (2016). 74. Hsieh, J. & Zhao, X. Genetics and epigenetics in adult adult-born neurons by serial end-block imaging
51. Morris, S. A., Eaves, D. W., Smith, A. R. & Nixon, K. neurogenesis. Cold Spring Harbor Perspect. Biol. 8, reveals complex axonal guidance and development
Alcohol inhibition of neurogenesis: a mechanism of a018911 (2016). in the adult hippocampus. J. Neurosci. 33,
hippocampal neurodegeneration in an adolescent 75. Knobloch, M. et al. Metabolic control of adult neural 11400–11411 (2013).
alcohol abuse model. Hippocampus 20, 596–607 stem cell activity by Fasn-dependent lipogenesis. 101. Markakis, E. A. & Gage, F. H. Adult-generated
(2010). Nature 493, 226–230 (2013). neurons in the dentate gyrus send axonal projections
52. Snyder, J. S., Soumier, A., Brewer, M., Pickel, J. 76. Knobloch, M. et al. A fatty acid oxidation-dependent to field CA3 and are surrounded by synaptic vesicles.
& Cameron, H. A. Adult hippocampal neurogenesis metabolic shift regulates adult neural stem cell J. Comp. Neurol. 406, 449–460 (1999).
buffers stress responses and depressive behaviour. activity. Cell Rep. 20, 2144–2155 (2017). 102. Laplagne, D. A. et al. Functional convergence
Nature 476, 458–461 (2011). 77. Stoll, E. A. et al. Neural stem cells in the adult of neurons generated in the developing and adult
53. Tobin, M. K. et al. Human hippocampal neurogenesis subventricular zone oxidize fatty acids to produce hippocampus. PLoS Biol. 4, e409 (2006).
persists in aged adults and Alzheimer’s disease energy and support neurogenic activity. Stem Cell 33, 103. Ge, S. et al. GABA regulates synaptic integration
patients. Cell Stem Cell 24, 974–982 e973 (2019). 2306–2319 (2015). of newly generated neurons in the adult brain. Nature
54. Boldrini, M. et al. Human hippocampal neurogenesis 78. Beckervordersandforth, R. et al. Role of mitochondrial 439, 589–593 (2006).
persists throughout aging. Cell Stem Cell 22, metabolism in the control of early lineage progression Seminal study that shows how the cellular
589–599 e585 (2018). and aging phenotypes in adult hippocampal environment affects neurogenesis in the adult
55. Parent, J. M. et al. Dentate granule cell neurogenesis neurogenesis. Neuron 93, 560–573.e6 (2017). rodent hippocampus.
is increased by seizures and contributes to aberrant 79. Otsuki, L. & Brand, A. H. Cell cycle heterogeneity 104. Markwardt, S. J., Wadiche, J. I. &
network reorganization in the adult rat hippocampus. directs the timing of neural stem cell activation from Overstreet-Wadiche, L. S. Input-specific GABAergic
J. Neurosci. 17, 3727–3738 (1997). quiescence. Science 360, 99–102 (2018). signaling to newborn neurons in adult dentate gyrus.
56. Toda, T., Parylak, S. L., Linker, S. B. & Gage, F. H. 80. Harris, L. et al. Progressive changes in hippocampal J. Neurosci. 29, 15063–15072 (2009).
The role of adult hippocampal neurogenesis in brain stem cell properties ensure lifelong neurogenesis. 105. Bergami, M. et al. A critical period for experience-
health and disease. Mol. Psychiatry 24, 67–87 bioRxiv https://doi.org/10.1101/2020.03.12.987107 dependent remodeling of adult-born neuron
(2019). (2020). connectivity. Neuron 85, 710–717 (2015).
57. Li, Y. et al. MDM2 inhibition rescues neurogenic 81. Denoth-Lippuner, A. et al. Visualization of individual 106. Deshpande, A. et al. Retrograde monosynaptic
and cognitive deficits in a mouse model of fragile cell division history in complex tissues. bioRxiv https:// tracing reveals the temporal evolution of inputs onto
X syndrome. Sci. Transl Med. 8, 336ra361 (2016). doi.org/10.1101/2020.08.26.266171 (2020). new neurons in the adult dentate gyrus and olfactory
58. Cho, K. O. et al. Aberrant hippocampal neurogenesis 82. Kempermann, G., Gast, D., Kronenberg, G., bulb. Proc. Natl Acad. Sci. USA 110, E1152–E1161
contributes to epilepsy and associated cognitive Yamaguchi, M. & Gage, F. H. Early determination and (2013).
decline. Nat. Commun. 6, 6606 (2015). long-term persistence of adult-generated new neurons 107. Vivar, C. et al. Monosynaptic inputs to new neurons in
59. Santarelli, L. et al. Requirement of hippocampal in the hippocampus of mice. Development 130, the dentate gyrus. Nat. Commun. 3, 1107 (2012).
neurogenesis for the behavioral effects of 391–399 (2003). 108. Toni, N. et al. Neurons born in the adult dentate
antidepressants. Science 301, 805–809 (2003). 83. Sierra, A. et al. Microglia shape adult hippocampal gyrus form functional synapses with target cells.
Seminal study that functionally links adult neurogenesis through apoptosis-coupled phagocytosis. Nat. Neurosci. 11, 901–907 (2008).
hippocampal neurogenesis to the efficacy of certain Cell Stem Cell 7, 483–495 (2010). 109. Luna, V. M. et al. Adult-born hippocampal neurons
antidepressants in rodents. 84. Snyder, J. S. et al. Adult-born hippocampal neurons bidirectionally modulate entorhinal inputs into the
60. Kuhn, H. G., Dickinson-Anson, H. & Gage, F. H. are more numerous, faster maturing, and more dentate gyrus. Science 364, 578–583 (2019).
Neurogenesis in the dentate gyrus of the adult rat: involved in behavior in rats than in mice. J. Neurosci. Pioneering study that shows how adult-born
age-related decrease of neuronal progenitor 29, 14484–14495 (2009). hippocampal granule cells can shape the behaviour
proliferation. J. Neurosci. 16, 2027–2033 (1996). 85. Lu, Z. et al. Phagocytic activity of neuronal progenitors and activity of the rodent DG circuit in vivo.
61. Ben Abdallah, N. M., Slomianka, L., Vyssotski, A. L. regulates adult neurogenesis. Nat. Cell Biol. 13, 110. Steib, K., Schaffner, I., Jagasia, R., Ebert, B. & Lie, D. C.
& Lipp, H. P. Early age-related changes in adult 1076–1083 (2011). Mitochondria modify exercise-induced development
hippocampal neurogenesis in C57 mice. Neurobiol. 86. Sahay, A. et al. Increasing adult hippocampal of stem cell-derived neurons in the adult brain.
Aging 31, 151–161 (2010). neurogenesis is sufficient to improve pattern J. Neurosci. 34, 6624–6633 (2014).
62. Kempermann, G., Kuhn, H. G. & Gage, F. H. separation. Nature 472, 466–470 (2011). 111. Duan, X. et al. Disrupted-in-schizophrenia 1 regulates
More hippocampal neurons in adult mice living 87. Dupret, D. et al. Spatial learning depends on both the integration of newly generated neurons in the adult
in an enriched environment. Nature 386, 493–495 addition and removal of new hippocampal neurons. brain. Cell 130, 1146–1158 (2007).
(1997). PLoS Biol. 5, e214 (2007). 112. Vadodaria, K. C., Brakebusch, C., Suter, U.
Pioneering study that shows dynamic regulation 88. Lodato, M. A. et al. Aging and neurodegeneration are & Jessberger, S. Stage-specific functions of the small
of hippocampal neurogenesis with environmental associated with increased mutations in single human Rho GTPases Cdc42 and Rac1 for adult hippocampal
enrichment in rodents. neurons. Science 359, 555–559 (2018). neurogenesis. J. Neurosci. 33, 1179–1189 (2013).
0123456789();:
Reviews
113. Karalay, O. et al. Prospero-related homeobox 1 138. Gao, A. et al. Elevation of hippocampal neurogenesis 164. Duque, A. & Spector, R. A balanced evaluation
gene (Prox1) is regulated by canonical Wnt signaling induces a temporally graded pattern of forgetting of the evidence for adult neurogenesis in humans:
and has a stage-specific role in adult hippocampal of contextual fear memories. J. Neurosci. 38, implication for neuropsychiatric disorders. Brain
neurogenesis. Proc. Natl Acad. Sci. USA 108, 3190–3198 (2018). Struct. Funct. 224, 2281–2295 (2019).
5807–5812 (2011). 139. Noonan, M. A., Bulin, S. E., Fuller, D. C. & Eisch, A. J. 165. Kempermann, G. et al. Human adult neurogenesis:
114. Sultan, S. et al. Synaptic integration of adult-born Reduction of adult hippocampal neurogenesis confers evidence and remaining questions. Cell Stem Cell 23,
hippocampal neurons is locally controlled by vulnerability in an animal model of cocaine addiction. 25–30 (2018).
astrocytes. Neuron 88, 957–972 (2015). J. Neurosci. 30, 304–315 (2010). 166. Knobloch, M. & Jessberger, S. Metabolism and
115. Wang, S., Scott, B. W. & Wojtowicz, J. M. 140. Seib, D. R., Espinueva, D. F., Floresco, S. B. neurogenesis. Curr. Opin. Neurobiol. 42, 45–52
Heterogenous properties of dentate granule neurons & Snyder, J. S. A role for neurogenesis in probabilistic (2017).
in the adult rat. J. Neurobiol. 42, 248–257 (2000). reward learning. Behav. Neurosci. 134, 283–295 167. Miller, S. M. & Sahay, A. Functions of adult-born
116. Ge, S., Yang, C. H., Hsu, K. S., Ming, G. L. & Song, H. (2020). neurons in hippocampal memory interference
A critical period for enhanced synaptic plasticity in 141. Malberg, J. E., Eisch, A. J., Nestler, E. J. & Duman, R. S. and indexing. Nat. Neurosci. 22, 1565–1575
newly generated neurons of the adult brain. Neuron Chronic antidepressant treatment increases neuro (2019).
54, 559–566 (2007). genesis in adult rat hippocampus. J. Neurosci. 20, 168. Sorrells, S. F. et al. Human hippocampal neurogenesis
117. Schmidt-Hieber, C., Jonas, P. & Bischofberger, J. 9104–9110 (2000). drops sharply in children to undetectable levels in
Enhanced synaptic plasticity in newly generated 142. Anacker, C. & Hen, R. Adult hippocampal adults. Nature 555, 377–381 (2018).
granule cells of the adult hippocampus. Nature 429, neurogenesis and cognitive flexibility - linking memory 169. Cipriani, S. et al. Hippocampal radial glial subtypes
184–187 (2004). and mood. Nat. Rev. Neurosci. 18, 335–346 (2017). and their neurogenic potential in human fetuses and
118. Brunner, J. et al. Adult-born granule cells mature 143. David, D. J. et al. Neurogenesis-dependent and healthy and Alzheimer’s disease adults. Cereb. Cortex
through two functionally distinct states. eLife 3, -independent effects of fluoxetine in an animal model 28, 2458–2478 (2018).
e03104 (2014). of anxiety/depression. Neuron 62, 479–493 (2009). 170. Nacher, J., Crespo, C. & McEwen, B. S. Doublecortin
119. Beining, M. et al. Adult-born dentate granule cells 144. Hill, A. S., Sahay, A. & Hen, R. Increasing expression in the adult rat telencephalon. Eur. J.
show a critical period of dendritic reorganization adult hippocampal neurogenesis is sufficient Neurosci. 14, 629–644 (2001).
and are distinct from developmentally born cells. to reduce anxiety and depression-like behaviors. 171. La Rosa, C. et al. Phylogenetic variation in cortical
Brain Struct. Funct. 222, 1427–1446 (2017). Neuropsychopharmacology 40, 2368–2378 (2015). layer II immature neuron reservoir of mammals. eLife
120. Cole, J. D. et al. Adult-born hippocampal 145. Yun, S. et al. Stimulation of entorhinal cortex-dentate 9, e55456 (2020).
neurons undergo extended development and are gyrus circuitry is antidepressive. Nat. Med. 24, 172. Paredes, M. F. et al. Does adult neurogenesis persist
morphologically distinct from neonatally-born 658–666 (2018). in the human hippocampus? Cell Stem Cell 23,
neurons. J. Neurosci. 40, 5740–5756 (2020). 146. Jungenitz, T. et al. Structural homo- and heterosynaptic 780–781 (2018).
121. Toni, N. & Schinder, A. F. Maturation and functional plasticity in mature and adult newborn rat hippocampal 173. Dennis, C. V., Suh, L. S., Rodriguez, M. L., Kril, J. J.
integration of new granule cells into the adult granule cells. Proc. Natl Acad. Sci. USA 115, & Sutherland, G. T. Human adult neurogenesis
hippocampus. Cold Spring Harb. Perspect. Biol. 8, E4670–E4679 (2018). across the ages: an immunohistochemical study.
a018903 (2015). 147. Kee, N., Teixeira, C. M., Wang, A. H. & Frankland, P. W. Neuropathol. Appl. Neurobiol. 42, 621–638 (2016).
122. Drapeau, E. et al. Spatial memory performances Preferential incorporation of adult-generated granule 174. Bauer, S. & Patterson, P. H. The cell cycle–apoptosis
of aged rats in the water maze predict levels of cells into spatial memory networks in the dentate connection revisited in the adult brain. J. Cell Biol.
hippocampal neurogenesis. Proc. Natl Acad. Sci. USA gyrus. Nat. Neurosci. 10, 355–362 (2007). 171, 641–650 (2005).
100, 14385–14390 (2003). 148. Jessberger, S. & Kempermann, G. Adult-born 175. Martin-Suarez, S., Valero, J., Muro-Garcia, T.
123. Gu, Y. et al. Optical controlling reveals time-dependent hippocampal neurons mature into activity-dependent & Encinas, J. M. Phenotypical and functional
roles for adult-born dentate granule cells. Nat. responsiveness. Eur. J. Neurosci. 18, 2707–2712 heterogeneity of neural stem cells in the aged
Neurosci. 15, 1700–1706 (2012). (2003). hippocampus. Aging Cell 18, e12958 (2019).
124. Shors, T. J. et al. Neurogenesis in the adult is involved 149. Jungenitz, T., Radic, T., Jedlicka, P. & 176. Hafezi-Moghadam, A., Thomas, K. L. & Wagner, D. D.
in the formation of trace memories. Nature 410, Schwarzacher, S. W. High-frequency stimulation ApoE deficiency leads to a progressive age-dependent
372–376 (2001). induces gradual immediate early gene expression in blood-brain barrier leakage. Am. J. Physiol. Cell
125. Dupret, D. et al. Spatial relational memory requires maturing adult-generated hippocampal granule cells. Physiol. 292, C1256–C1262 (2007).
hippocampal adult neurogenesis. PLoS ONE 3, e1959 Cereb. Cortex 24, 1845–1857 (2014). 177. Verbitsky, M. et al. Altered hippocampal transcript
(2008). 150. Marin-Burgin, A., Mongiat, L. A., Pardi, M. B. profile accompanies an age-related spatial memory
126. Jessberger, S. et al. Dentate gyrus-specific knockdown & Schinder, A. F. Unique processing during a period deficit in mice. Learn. Mem. 11, 253–260 (2004).
of adult neurogenesis impairs spatial and object of high excitation/inhibition balance in adult-born 178. Dulken, B. W. et al. Single-cell analysis reveals T cell
recognition memory in adult rats. Learn. Mem. 16, neurons. Science 335, 1238–1242 (2012). infiltration in old neurogenic niches. Nature 571,
147–154 (2009). 151. Dieni, C. V., Nietz, A. K., Panichi, R., Wadiche, J. I. 205–210 (2019).
127. Zhang, C. L., Zou, Y., He, W., Gage, F. H. & Evans, R. M. & Overstreet-Wadiche, L. Distinct determinants of 179. Navarro Negredo, P., Yeo, R. W. & Brunet, A. Aging
A role for adult TLX-positive neural stem cells in sparse activation during granule cell maturation. and rejuvenation of neural stem cells and their niches.
learning and behaviour. Nature 451, 1004–1007 J. Neurosci. 33, 19131–19142 (2013). Cell Stem Cell 27, 202–223 (2020).
(2008). 152. Drew, L. J. et al. Activation of local inhibitory circuits in 180. Fan, X., Wheatley, E. G. & Villeda, S. A. Mechanisms
128. Cameron, H. A. & Glover, L. R. Adult neurogenesis: the dentate gyrus by adult-born neurons. Hippocampus of hippocampal aging and the potential for
beyond learning and memory. Annu. Rev. Psychol. 66, 26, 763–778 (2016). rejuvenation. Annu. Rev. Neurosci. 40, 251–272
53–81 (2015). 153. Adlaf, E. W. et al. Adult-born neurons modify (2017).
129. Deng, W., Aimone, J. B. & Gage, F. H. New neurons excitatory synaptic transmission to existing neurons. 181. Horowitz, A. M. et al. Blood factors transfer
and new memories: how does adult hippocampal eLife 6, e19886 (2017). beneficial effects of exercise on neurogenesis and
neurogenesis affect learning and memory? Nat. Rev. 154. Danielson, N. B. et al. Distinct contribution of adult- cognition to the aged brain. Science 369, 167–173
Neurosci. 11, 339–350 (2010). born hippocampal granule cells to context encoding. (2020).
130. Leutgeb, J. K., Leutgeb, S., Moser, M. B. & Moser, E. I. Neuron 90, 101–12 (2016). 182. Villeda, S. A. et al. The ageing systemic milieu
Pattern separation in the dentate gyrus and CA3 of 155. Anacker, C. et al. Hippocampal neurogenesis confers negatively regulates neurogenesis and cognitive
the hippocampus. Science 315, 961–966 (2007). stress resilience by inhibiting the ventral dentate function. Nature 477, 90–94 (2011).
131. Bakker, A., Kirwan, C. B., Miller, M. & Stark, C. E. gyrus. Nature 559, 98–102 (2018). Pioneering study that links humoral factors to
Pattern separation in the human hippocampal 156. Hainmueller, T. & Bartos, M. Parallel emergence reduced neurogenesis in the aged brain.
CA3 and dentate gyrus. Science 319, 1640–1642 of stable and dynamic memory engrams in the 183. Katsimpardi, L. et al. Vascular and neurogenic
(2008). hippocampus. Nature 558, 292–296 (2018). rejuvenation of the aging mouse brain by young
132. Clelland, C. D. et al. A functional role for adult 157. Stahl, P. L. et al. Visualization and analysis of gene systemic factors. Science 344, 630–634 (2014).
hippocampal neurogenesis in spatial pattern expression in tissue sections by spatial 184. Ozek, C., Krolewski, R. C., Buchanan, S. M.
separation. Science 325, 210–213 (2009). transcriptomics. Science 353, 78–82 (2016). & Rubin, L. L. Growth differentiation factor 11
133. Nakashiba, T. et al. Young dentate granule cells 158. Budnik, B., Levy, E., Harmange, G. & Slavov, N. treatment leads to neuronal and vascular
mediate pattern separation, whereas old granule cells SCoPE-MS: mass spectrometry of single mammalian improvements in the hippocampus of aged mice.
facilitate pattern completion. Cell 149,188–201 cells quantifies proteome heterogeneity during cell Sci. Rep. 8, 17293 (2018).
(2012). differentiation. Genome Biol. 19, 161 (2018). 185. McAvoy, K. M. et al. Modulating neuronal
134. Swan, A. A. et al. Characterization of the role of adult 159. Cusanovich, D. A. et al. Multiplex single cell profiling competition dynamics in the dentate gyrus to
neurogenesis in touch-screen discrimination learning. of chromatin accessibility by combinatorial cellular rejuvenate aging memory circuits. Neuron 91,
Hippocampus 24, 1581–1591 (2014). indexing. Science 348, 910–914 (2015). 1356–1373 (2016).
135. Whoolery, C. W. et al. Multi-domain cognitive 160. Jackson, H. W. et al. The single-cell pathology landscape 186. Berdugo-Vega, G. et al. Increasing neurogenesis
assessment of male mice shows space radiation is not of breast cancer. Nature 578, 615–620 (2020). refines hippocampal activity rejuvenating navigational
harmful to high-level cognition and actually improves 161. Sawamoto, K. et al. Direct isolation of committed learning strategies and contextual memory
pattern separation. Sci. Rep. 10, 2737 (2020). neuronal progenitor cells from transgenic mice throughout life. Nat. Commun. 11, 135 (2020).
136. Garthe, A., Behr, J. & Kempermann, G. Adult- coexpressing spectrally distinct fluorescent proteins 187. Vonk, W. I. M. et al. Differentiation drives widespread
generated hippocampal neurons allow the flexible use regulated by stage-specific neural promoters. rewiring of the neural stem cell chaperone network.
of spatially precise learning strategies. PLoS ONE 4, J. Neurosci. Res. 65, 220–227 (2001). Mol. Cell 78, 329–345 e329 (2020).
e5464 (2009). 162. Pereira, A. C. et al. An in vivo correlate of exercise- 188. Leeman, D. S. et al. Lysosome activation clears
137. Akers, K. G. et al. Hippocampal neurogenesis induced neurogenesis in the adult dentate gyrus. aggregates and enhances quiescent neural stem cell
regulates forgetting during adulthood and infancy. Proc. Natl Acad. Sci. USA 104, 5638–5643 (2007). activation during aging. Science 359, 1277–1283
Science 344, 598–602 (2014). 163. Manganas, L. N. et al. Magnetic resonance (2018).
First study that links forgetting to hippocampal spectroscopy identifies neural progenitor cells in the 189. Morrow, C. S. et al. Vimentin coordinates protein
neurogenesis. live human brain. Science 318, 980–985 (2007). turnover at the aggresome during neural stem cell
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quiescence exit. Cell Stem Cell 26, 558–568.e9 (BSCGI0_157859 and 310030_196869 to S.J.), the Novartis Peer review information
(2020). Foundation (to A.D.-L . and S.J.), the Helmut Horten Nature Reviews Neuroscience thanks L. Bonfanti, who
190. Moore, D. L., Pilz, G. A., Arauzo-Bravo, M. J., Barral, Y. Foundation (to S.J.), the Betty & David Koetser Foundation (to co-reviewed with C. La Rosa; S. Schwarzacher; and the other,
& Jessberger, S. A mechanism for the segregation of S.J.), a Forschungskredit of the University of Zurich (to A.D.-L.) anonymous, reviewer(s) for their contribution to the peer
age in mammalian neural stem cells. Science 349, and the Zurich Neuroscience Center (to S.J.). review of this work.
1334–1338 (2015).
Author contributions Publisher’s note
Acknowledgements The authors contributed equally to all aspects of the article. Springer Nature remains neutral with regard to jurisdictional
The authors thank D. C. Lie for comments. The authors’ lab- claims in published maps and institutional affiliations.
oratory is supported by the European Research Council Competing interests
(STEMBAR to S.J.), the Swiss National Science Foundation The authors declare no competing interests. © Springer Nature Limited 2021
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Formation and integration of new

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Quiescent R cell Active R cell NR cell

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Table 1 | Technical approaches to analysing adult neurogenesis

analogues or its analogues (tritiated

labelling selectively expressed in

labelling proliferating cells using specific manipulation injections of virus)

markers of fluorescent label promoters used (for example

and subsequent RNA molecular information Potential alteration in gene

imaging in magnetic resonance neurogenesis in living No broadly accepted approach

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Reduced neurogenesis Increased neurogenesis

Neurodegeneration Psychosocial stress Environmental

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Diﬀerentiation Maturation Early integration Late integration

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Overlap of activation of mature

Reduced but more precise

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