Recalibrating the Relevance of Adult

Neurogenesis Jason S. Snyder

Visit to download the full and correct content document:
https://ebookmass.com/product/recalibrating-the-relevance-of-adult-neurogenesis-jas
on-s-snyder/
 TINS 1479 1–15

Feature Review

Recalibrating the Relevance of Adult

Neurogenesis
Jason S. Snyder1,*,@

Conflicting reports about whether adult hippocampal neurogenesis occurs in Highlights

humans raise questions about its significance for human health and the rele- Animal work has revealed that imma-
ture neurons born in the adult dentate
vance of animal models. Drawing upon published data, I review species’
gyrus have key cellular and behavioral
neurogenesis rates across the lifespan and propose that accelerated neuro- functions.
developmental timing is consistent with lower rates of neurogenesis in adult
Recent reports are conflicted about
primates and humans. Nonetheless, protracted neurogenesis may produce whether adult neurogenesis occurs in
populations of neurons that retain plastic properties for long intervals, and humans.
have distinct functions depending on when in the lifespan they were born. With
Discrepancies could arise from spe-
some conceptual recalibration we may therefore be able to reconcile seemingly cies differences in neurodevelopmen-
disparate findings and continue to ask how adult neurogenesis, as studied in tal timing and differences in subject
ages.
animals, is relevant for human health.
Regardless of its extent, postnatally,
The Continuous Controversy of Adult Neurogenesis an extended period of neurogenesis
While broadly recognized today, the prospect of adult neurogenesis was essentially nonexis- may produce a heterogeneous popu-
tent until the 1960s when Joseph Altman reported that neurons continue to be produced lation of dentate gyrus neurons, due to
prolonged cellular maturation and dif-
throughout adulthood [1,2]. Despite its implications (or perhaps because of them), further ferences in the stage of the lifespan
research on adult neurogenesis stalled until the 1990s when advances in immunohistochem- when neurons are born.
istry and microscopy enabled the unambiguous identification of birthdated neurons [3]. Since
These developments warrant a recali-
then, there have been debates about methodological accuracy, the brain regions that harbor
bration of when and how dentate gyrus
adult neurogenesis, and the species that possess it [4–8], but the general consensus for the neurogenesis contributes to cognition
past decade has been that neurons are added, in adulthood, to at least one brain region in and mental health in humans.
humans and most mammals: the dentate gyrus (DG) subregion of the hippocampus [9–12].

A recent high profile report, arguing that hippocampal neurogenesis ends in childhood in
humans [13], has reignited the controversy [14–20]. However, a closer look reveals that this is
not the only study reporting that features of neurogenesis, whether stem cells, mitotic cells, or
immature neurons, decline to low or absent levels by childhood [21–25]. While methodological
factors may contribute to the discrepancies between studies that do and do not observe signs
of human adult neurogenesis [15], uncertainty may also stem from more general differences in
study design and interpretation [26]. For example, human studies that have included fetal and
infant subjects often conclude that neurogenesis ends in childhood, but note the occasional
sign of neurogenesis in older subjects [13,23–25]. Conversely, studies that have solely exam-
ined adults report ongoing DG neurogenesis, but at low rates [11,12]. Now that a reasonable 1
Department of Psychology, Djavad
amount of quantitative data exists for both humans and animals, I attempt here to objectively Mowafaghian Centre for Brain Health,
University of British Columbia, 2211
address the issue by comparing lifelong patterns of DG neurogenesis across rodents, nonhu- Wesbrook Mall, Vancouver, BC V6T
man primates, and humans. It is worth noting that adult neurogenesis in the subventricular 2B5 Canada
@
zone–olfactory bulb is well characterized [27], and new neurons have also been described in the Twitter: @jsnsndr

adult mammalian neocortex [28] and striatum [29], among other regions [8]. However, since too
*Correspondence:
few quantitative datasets exist for these regions for a comprehensive comparison, here I will jasonsnyder@psych.ubc.ca (J.S.
focus on the DG. Snyder).

Trends in Neurosciences, Month Year, Vol. xx, No. yy https://doi.org/10.1016/j.tins.2018.12.001 1

© 2018 Elsevier Ltd. All rights reserved.
 TINS 1479 1–15

Critical Periods and Functional Properties of Adult-Born Neurons

Before continuing, it is important to clarify exactly why we care about adult hippocampal
neurogenesis. A comprehensive review of its behavioral functions is beyond the scope of this
article, but suffice it to say that animal work has demonstrated that adult neurogenesis is
causally involved in many of the functions of the hippocampus. New neurons promote flexible
learning and adaptive behavioral and endocrine responses to cognitive and emotional chal-
lenges [30–32]. The potential relevance for mental health is also substantial since neurogenesis
may be involved in many disorders that are known to impact the hippocampus including
depression, anxiety, schizophrenia, addiction, epilepsy, age-related memory loss, and demen-
tia [33,34].

Behavioral functions of hippocampal neurogenesis have been identified almost exclusively from
rodent studies. One can also turn to cellular properties that speak to function, some of which I
will compare across human and animal models. Foundational studies in rodents, particularly
mice, have revealed that new neurons progress through discrete stages of maturation into
hippocampal circuits [35,36] (Figure 1). Particularly relevant for theories of memory, and
hearkening back to classic studies of developing systems, adult-born neurons have a critical
period for plasticity and excitability during their immature stages. From 2–6 weeks of age they
have a lower threshold for long-term potentiation (LTP) of their cortical inputs, due to the
presence of T-type Ca2+ channels, NR2B-containing NMDA receptors and reduced

MaturaƟon LPP H
L
F
MPP
I

Fast Slow GABA

GABAslow GABAdepol E
GABAfast G plasƟcity M ‘Mature’
A B C J

K
D DCX NeuN CA3
GABA
interneuron CA3
pyramid pyramid

Figure 1. Neuronal Maturation and Critical Period Properties. Many key maturational steps occur over the first weeks of neuronal life, when adult-born neurons
possess unique properties during a critical period. As identified in rodents, during the first few weeks (A) adult-born neurons first receive slow GABAergic signals [36],
then (B) depolarizing and trophic GABAergic inputs [44,151], and finally (C) fast GABAergic and glutamatergic synaptic inputs [36]. Over this interval they (D) lose
expression of the immature neuronal marker, DCX, and gain higher levels of NeuN expression [152]. Experience modulates (E) neuronal survival [153], (F) dendritic
remodeling [154], and (G) alters long-range GABAergic innervation [49]. At 4 weeks of age, new neurons (H) are more efficiently recruited by afferent inputs [155], (I)
they have enhanced afferent [40] and (J) efferent [41] synaptic plasticity, and (K) they drive feed-forward inhibition [156]. Immature adult-born neurons also (L) receive
inputs primarily from the lateral entorhinal cortex [139,140], (M) promote [157] or differentially contribute [43] to feedback/lateral inhibition in the DG, have different
functions in memory [158] and have distinct receptive fields during behavior [53] (not shown), although it remains unclear whether these properties are lost as cells
mature. It is generally believed that as they mature, adult-born neurons exit these critical periods and become functionally similar to the general population. However,
there is evidence that some unique properties persist beyond the traditional critical period, and depend on when in the lifespan a dentate granule neuron was born (see
Figure 4). Moreover, rodent studies have revealed that the timeframe of maturation is slowed dramatically with age [98,159]. The dial on the left highlights the fact that,
while little is known about maturation rates in other species, studies of adult-born neurons in primates and longer-lived mammals [160], and studies of DG growth in
humans [111,161], suggest the process is slower. In this way, later-born neurons might provide a substantial source of critical period plasticity for years after their
birthdate. Abbrevations: DG, dentate gyrus; LPP, lateral perforant path; MPP, medial perforant path.

2 Trends in Neurosciences, Month Year, Vol. xx, No. yy

 TINS 1479 1–15

GABAergic inhibition [37–40]. Adult-born neurons also display enhanced LTP at their efferent
synapses onto CA3 pyramidal neurons at 4 weeks of age, relative to 2 and 8 weeks [41].
Differential excitation–inhibition properties also cause immature neurons to uniquely respond
to, filter, and integrate synaptic inputs [42–45]. Structurally, learning and environmental enrich-
ment alter the survival and connectivity of adult-born neurons during defined windows of
immaturity [46–50]. These unique properties are likely to endow adult-born neurons with
distinct roles in sensory processing and memory [51–53]. Indeed, behavioral changes arise
within weeks after arresting neurogenesis, indicating that these immature neurons are func-
tionally important [54–56]. The transient nature of these critical periods, along with evidence
that adult-born neurons become broadly comparable to developmentally born neurons [57,58],
suggests that neurogenesis ultimately results in a homogeneous population of DG neurons.
Some have even proposed that, after a transient period of functional potency, DG neurons
become silent with age [59,60]. According to this perspective, an early decline in human
neurogenesis could imply that there would be no meaningful neurons remaining in adulthood.
After comparing neurogenesis rates across species, I therefore review emerging evidence that
questions the exclusive and privileged role of immature DG neurons and suggests that some
important functional properties are retained beyond the traditional critical window.

How Does Dentate Neurogenesis in Humans Align with Animals?

A number of considerations complicate the comparison of neurogenesis across species:
neurogenesis declines with age, subject ages vary across studies, and neurodevelopmental
timing differs between species. Accordingly, an objective comparison of neurogenesis levels
across the full lifespan may help elucidate differences and commonalities between species. To
this end, Figure 2 (Key Figure) displays neurogenesis rates from published studies of mice, rats,
primates, and humans, plotted alongside each other (see the supplemental information online
for details).

The general pattern of neurogenesis is similar across all species: early in life, neurogenesis
rapidly rises and falls, and then remains at lower levels for most of the lifespan. However, there
are notable species differences in the timing of neurogenesis, particularly with respect to birth.
In humans, neurogenesis peaks in the first half of gestation and the DG is mostly formed by
birth, consistent with qualitative reports [61]. In rodents, neurogenesis peaks later, around the
time of birth, and continues at moderate to high levels during the early postnatal period. The
picture in rhesus monkeys is intermediate, with 60% of neurons born prenatally and 25% in
the first three postnatal months [62] (in marmosets, a similar pre- vs postnatal pattern is
observed [63]). The timing of DG neurogenesis is therefore consistent with the broader
comparative pattern of neurodevelopment, where humans and nonhuman primates are born
with a mature nervous system (at least in terms of cell production) compared to that in rodents
[64,65]. Thus, defining birth as T0 can be misleading and gives the appearance that neuro-
genesis is conspicuously low in primates and humans compared to rodents (Figure 2B; y axis
still scaled to peak lifetime rates). In contrast, when aligning T0 to the date of conception
(Figure 2A), the postnatal differences seem reasonable given the amount of prenatal neuro-
genesis that occurs in primates and humans. Indeed, a comparative analysis found that
neurogenesis rates decline with absolute age and are not proportionally extended in lon-
ger-lived mammals [66]. Also, a recent modeling study has suggested that human and animal
DG neurogenesis rates are generally consistent with one another once species differences in
neurodevelopmental timing are accounted for [19].

DG neurogenesis is often labeled as developmental or adult but these distinctions are typically ill
defined (discussed in [67]). Since neurogenesis is continuous, it is reasonable to consider it as a

Trends in Neurosciences, Month Year, Vol. xx, No. yy 3

 TINS 1479 1–15

Key Figure
Comparison of Neurogenesis across the Lifespan

(A) Human Primate Mouse Rat

100
Full lifespan
neurogenesis (% max)

75
Dentate gyrus

Birth
Sexual maturity
50

25

0
ConcepƟon 0.01 0.1 1
Lifespan 2.2 y, 2 y,
25 y, 70 y

(B)
100 (C)
5
Aligned to birth 10%–100% lifespan
4
75
3
% max

% max

50
2
25
1

0 0
Birth P42, P37, 0.1 1
1.3 y, 3.5 y

Figure 2. (A) To objectively compare neurogenesis rates, published data of mitotic markers (3H-Thy, BrdU, and Ki67) were
used (and extracted from graphs with Plot Digitizer where necessary). Ranges of overlapping ages allowed different studies
to be normalized to one another, with peak neurogenesis set at 100%. For mice, studies by Angevine [162], Ben Abdallah
et al. [163], Mathews et al. [164], and Kronenberg et al. [165] span the full age range, from the onset of DG neurogenesis at
E10 to near the end of the lifespan, at 2 postnatal years. For rats, studies by Schlessinger et al. [119], Altman and Das [166],
and Kuhn et al. [167] span embryonic day 11 to 2.25 postnatal years. For primates (rhesus monkeys), studies by Jabes
et al. [62] and Ngwenya et al. [75] cover the end of the embryonic period (E140) through the majority of postnatal life (up to
25.5 years). There are no quantitative studies (to our knowledge) of prenatal DG development but Rakic and Nowakowski
[120] describe a highly neurogenic period from E45 to P32. Since cells that span the width of the granule cell layer are
generated from E60 to E120, E90 was designated as an approximate peak of primate DG neurogenesis. Timepoints
before (E45) and after (E140) were adjusted to produce a curve where 40% of DG neurons are generated postnatally in 7-
year-old monkeys [78]. For humans, studies by Yang et al. [168], Sorrells et al. [13], Seress et al. [23], and Dennis et al. [24]
have quantified Ki67 from gestational week 9 to 59 years. Since rates of decline varied, data points were averaged across
studies as follows. First, counts were converted to cells/mm3 based on the section thickness used in the study. Up to birth,

(Figure legend continued on the bottom of the next page.)

4 Trends in Neurosciences, Month Year, Vol. xx, No. yy

 TINS 1479 1–15

unitary, but protracted, phenomenon. The pattern of early DG neurogenesis is therefore likely to
impact neurogenesis later in life, potentially contributing to species differences. For example,
accelerated DG development in humans may lead to lower rates of neurogenesis in childhood
and adulthood if DG precursor cells undergo a finite number of divisions [68–70]. This is
suggested by Figure 2C, where postnatal neurogenesis rates are lower in humans until about
halfway through life, when in rodents the rates decline to comparable levels.

In contrast to the dynamic changes early in life, neurogenesis rates are more stable in the
second half of the lifespan and remain at 0.1–0.5% of maximum levels across all species
(Figure 2C). Middle- and old-aged rodents typically have hundreds of cells that are born per day
[71–73], and rhesus macaques have thousands (mid age) to hundreds (old age) of labeled cells
[74,75]. Assuming 600 000 DG granule neurons in mice [76], 2 400 000 in rats [77], and
7 000 000 in rhesus macaques [75,78], this translates to less than 0.1% of DG cells in middle
age and less than 0.01% in old age. This could be seen as reasonably on par with the
proportion of DCX+ cells in adult humans (0.005%, [79]) and the rate of daily turnover
estimated by 14C dating (0.004%, [10]). Commonly-used histological methods that only detect
new cells generated in a snapshot of time will therefore reveal only one new cell for every 10 000
+ DG neurons, which amounts to few or no cells per brain section. This may be high enough to
detect in controlled animal studies but too low to reliably detect in human samples.

The data in Figure 2 provide a semiquantitative starting point for reconciling DG neurogenesis in
humans and animals. Differences in developmental timing may explain why rodents have
greater neurogenesis than primates and humans, particularly in early postnatal life. While the
data cannot definitively address whether neurogenesis falls to zero in one species and not
another, it suggests that middle- to old-aged humans and animals are not so different from one
another in that few neurons (in proportion to the total number of DG neurons) are added, on a
daily basis, for much of the lifespan (see also [80]).

Age-Related Sampling Biases in Neurogenesis Studies

Why might negative human reports generate concern when new neurons are in fact fairly rare in
animals in later stages of the lifespan? One possibility is that the overwhelming focus on young
animals in neuroscience research [81] inflates the perceived magnitude of adult neurogenesis.
To explore this possibility, we examined subject ages in published studies of adult DG neuro-
genesis and found that neurogenesis tends to be examined at young ages in rodents, when
neurogenesis levels are high (median age of 90 days, 12% lifespan; Figure 3). In contrast, the
ages of human subjects span the full lifespan, and the majority are beyond the age when
neurogenesis has plateaued at low levels (median age 44 years; 63% lifespan). Rodent studies

time points and cell counts were grouped and averaged across studies if they fell within 3 weeks of the mean age of the
group. With age, the window expanded such that for the first year of life subject ages were grouped if within 1 month of one
another. Subjects aged 2–9 years were pooled and all other time points reflected averages for respective decades of life.
To be consistent with the animal data, which covered the entire lifespan, a data point was added for humans at 70 years
[average human lifespan, World Health Organization; calculated by averaging the three prior data points (since the curve
was asymptotic)]. The time scale on the x axis was normalized to postconception age (which approximates the species
lifespan – mice: 2 years, rats: 2.25 years, macaques: 25.5 years, humans: 70 years). Ages of birth and sexual maturity are
indicated by the circles that are embedded in the curves. They are merely meant to highlight, approximately, develop-
mental milestones, and are not data points with regards to neurogenesis. For sexual maturity ages, the following estimates
were used (postnatally): mice: 42 days, rats: 40 days, rhesus monkeys: 3.5 years, humans: 13 years. Data, calculations,
and detailed discussion of methodology are available as supplemental material. (B) Aligning the early postnatal period to
time of birth gives the impression that neurogenesis is greater in rodents than in humans and non-human primates. Graph
shows 5% of lifespan. (C) Enlargement of 10–100% lifespan suggests that neurogenesis rates can be seen as broadly
comparable across species later in life. Abbreviations: DG, dentate gyrus.

Trends in Neurosciences, Month Year, Vol. xx, No. yy 5

 TINS 1479 1–15

Rodent Human
100 100
neurogenesis (% max)

Neurogenesis manipulaƟon studies

10 10
Dentate gyrus

Neurogenesis quanƟficaƟon studies

1 1
Rat
Mouse
0.1 0.1

0.01 0.01
0 100 200 300 400 500 600 700 800 900 0 10 20 30 40 50 60 70 80 90 100
Postnatal days Postnatal years

Figure 3. Subject Ages Differ in Rodent and Human Studies of Adult DG Neurogenesis. Subject ages in DG neurogenesis studies (horizontal scatterplots)
are plotted alongside lifetime neurogenesis curves. Subject-age data points do not have y-axis values, but are overlaid on neurogenesis curves to facilitate comparison
of the ages when subjects are sampled with the amount of neurogenesis at those ages. Filled symbols indicate subject ages when proliferation markers have been used
to quantify adult neurogenesis; open symbols (rodents only) indicate subject ages when neurogenesis was manipulated in studies of behavioral function; boxes and
whiskers indicate quartiles. In rodents, 75% of studies quantified neurogenesis rates at 4 months of age. At this age, the animals are considered young adults or
adolescents; they only recently have reached sexual maturity and neurogenesis has not yet substantially declined. By contrast, in humans, 75% of subjects are beyond
19 years of age, when neurogenesis rates have largely plateaued at low levels. Neurogenesis quantification: rodent studies were identified in Pubmed using the search
terms ‘dentate gyrus’ and ‘neurogenesis’, sorted according to date, and over 100 studies were randomly sampled with the exception that efforts were made to relatively
evenly sample the period of 1994 to 2018. Animal age was defined as the age when cell birth was assessed (time of BrdU injection, or age of euthanasia for Ki67). If
multiple BrdU injections were given, the average age was used. If multiple ages were examined, each age was included as a data point. Neurogenesis manipulation:
rodent manipulation–behavior studies were identified by including additional search terms such as ‘irradiation’, ‘tk’, ‘tmz’, ‘mam’, ‘arac’, ‘tamoxifen’, ‘chemogenetics’,
and ‘optogenetics’, in order to obtain a complete list of studies. Subject age was defined as the earliest age when neurogenesis manipulation began. Mice and rats are
pooled for the rodent subject age datasets. For humans, the individual ages of 375 subjects from 14 studies are shown. Human studies were excluded if they did not
provide individual subject ages and rodent studies were excluded if they did not define animal age. Since the intention was to compare rodent and human studies of
adult neurogenesis, studies were excluded if they focused entirely on the prenatal or early postnatal period. A list of studies and ages is provided as supplemental
material. Open and closed symbols that are embedded in the lifetime neurogenesis curves indicate birth and sexual maturity, respectively, as in Figure 1. Abbreviations:
DG, dentate gyrus.

that have manipulated neurogenesis do so at even younger ages (median 60 days). Thus,
neurogenesis is often studied soon after rodents reach sexual maturity (P40), which is
routinely used as a rough approximation of an adult-like stage of development. However,
compared to humans, not only does neurogenesis peak later in rodents but sexual maturity
occurs earlier (Figure 2A). Therefore, once ages and developmental differences are accounted
for, it is not surprising that young adult-like rodents have greater neurogenesis rates than the
middle-aged humans that comprise most studies.

Recalibrating According to Neurodevelopmental Timing

The data indicate that DG neurogenesis declines early in humans, raising the question of how it
might be relevant for health. Possibly, low rates may have substantial cumulative effects as has
been estimated for rats [82] and demonstrated in mice [83]. Spalding et al. estimated that only
0.004% of neurons are added each day in adult humans [10]. While this would appear negligible
under the microscope (1 cell in 25 000), it translates to 15% over a decade; a sizable fraction
that could reasonably be expected to offset hippocampus-based mental health disorders.

Alternatively, if human neurogenesis ends in childhood, or if rates are too low to produce a
meaningfully-sized population of highly-plastic neurons, it becomes important to recalibrate
predictions about when in the lifespan DG neurogenesis is most relevant. Indeed, the high rates
of neurogenesis in early postnatal mice may be relevant for understanding infantile amnesia
[84]. Adult neurogenesis, as commonly studied in (young) animals, may be a more accurate
model of childhood neurogenesis in humans, and may make less of a contribution to

6 Trends in Neurosciences, Month Year, Vol. xx, No. yy

 TINS 1479 1–15

Aβ vulnerable In vivo firing Semilunar

Earlier born

(A) (B) (C)

Axon plasƟcity Spine rich Late death

(D) (E) (F)

Dendrite plasƟcity IEG response Precursor diversity

Later born

(G) (H) (I)

Figure 4. Ontogeny-Based Cellular Heterogeneity. DG neurons born at different stages of the lifespan acquire distinct properties, many of which persist
throughout the lifespan of the cell. (A) Early-born, superficially-located neurons undergo atrophy in a mouse model of Alzheimer’s disease [149]. (B) Mature-
appearing, highly branched neurons are more likely to fire during spatial navigation [129]. (C) Semilunar granule neurons are born on E14 in mice [126,127]. (D) A
subset of DG neurons have elaborate mossy fiber extensions [136] and (E) higher than usual spine density [108,109,135], although the age of these cells and their
ontogenetic origins, if any, remain to be determined. (F) Neurons born in early postnatal rat development die at old (neuronal) ages [133,134]. (G) Old adult-born
neurons display experience-dependent plasticity [100] and (H) unique patterns of IEG expression compared to early-born neurons [130,169] and depending on
when in adulthood they were born [131]. (I) Heterogeneity in the DG precursor cell population may also contribute to neuronal diversity [170–172]. Abbreviations:
DG, dentate gyrus; IEG, immediate-early gene.

hippocampal function and disorders later in life. As indicated in Figure 3, few have tested this
hypothesis. However, blocking neurogenesis in 1-month-old mice has greater behavioral
effects than in 3–4-month-old mice [85]. Additionally, one study found that new neuron
functions in object recognition were absent in young irradiated mice and mice that have aged
to 7 months, suggesting that neurogenesis rates are too low by early-middle age to have a
behavioral impact [56]. Collectively, these data highlight the need to study older animals that

Trends in Neurosciences, Month Year, Vol. xx, No. yy 7

 TINS 1479 1–15

can better model adult humans, and they provide a fresh impetus for identifying strategies to
enhance neurogenesis in older age.

While neurogenesis may decline early, this does not render irrelevant the large body of work that
has identified important roles for new neurons in cognition and mental health. It is becoming
increasingly clear that many mental health disorders, including those that involve the hippo-
campus, emerge prior to adulthood while the human brain continues to develop during
childhood and adolescence [86–89]. Of all mental illnesses, DG neurogenesis has most
consistently been linked to depression in animal models [90]. In humans, depression is often
precipitated by early life adversity and can emerge in adolescence [89,91,92]. Similarly, DG
neurogenesis is also implicated in anxiety, addiction, and schizophrenia [34,90,93], all of which
are influenced by early life events and can arise prior to adulthood [94–96]. Thus, functions of
neurogenesis, as identified in adult animals, remain relevant for understanding human disor-
ders. However, given the timecourse of neurogenesis and the developmental trajectory of
mental illness, greater emphasis on the relevance for younger humans is warranted.

Neuronal Development and Plasticity: Questioning the Critical Period

Immature DG neurons have distinct properties that could endow them with important behav-
ioral functions. What happens as the cells mature? One possibility is that, upon reaching a
certain age, DG neurons become comparable to the larger, older population. While mature
adult-born neurons do share properties with mature developmentally-born neurons, there is
emerging evidence that adult-born neurons have unique properties that extend beyond the
traditional 4–6-week critical period.

The first line of evidence comes from studies of the maturation of neurons born at different
stages of life in rodents. DG neurons born in adulthood mature slower than neurons born in
early postnatal development [97], and this pattern continues throughout adult life: neurons
born in middle-aged mice (8–12 months) extend dendrites, and gain spines and functional
synaptic inputs at slower rates than neurons born in young adult mice [98]. Twelve-day-old
neurons also have larger dendritic trees in young adult rats than in middle to old-aged rats,
suggesting prolonged development with age [73]. Thus, while fewer neurons are added with
age, they retain distinct properties and may provide significant plasticity for longer portions of
the lifespan.

A second line of evidence comes from studies of experience-dependent modification of adult-

born neurons. Initial studies reported that spatial water maze training increases the dendritic
length and spine density of 1-week-old adult-born neurons in rats, but not putative older
neurons [99]. Subsequent work revealed that enhanced structural plasticity is also observed
in 2- and 4-month-old adult-born neurons, and that removal of these older cohorts of adult-
born cells impaired learning [100]. Our own unpublished work also reveals that, while 4-week-
old adult-born neurons in rats are structurally comparable to neurons born in infancy, growth
of spines and presynaptic terminals surpasses infant-born neurons if examined at later
intervals, when cells are 2–6 months old. Collectively, these data raise fundamental questions
about exactly how long new neurons retain enhanced plasticity and they suggest that
important functional roles of newborn neurons may persist much longer than is generally
appreciated.

Recalibration Based on the Speed of Neuronal Maturation

While the full timeframe of new neuron development is unknown, some cellular features are
clearly limited to defined windows of immaturity. Translating the developmental trajectory of

8 Trends in Neurosciences, Month Year, Vol. xx, No. yy

 TINS 1479 1–15

new neurons across species is therefore necessary to determine the timeframe of new neuron
functions in humans (Figure 1). This is difficult because there are few precise non-rodent
studies of DG neuron development. However, clues from longer-lived mammals suggest that
neuronal maturation is likely to be longer in humans than mice and rats. Naked mole rats,
which live up to 30 years, undergo extended development and retention of immature neural
features compared with mice [101,102]. Red foxes also have disproportionately high num-
bers of doublecortin-positive cells given their low rates of proliferation, suggesting prolonged
maturation and/or preservation of immature features as a compensatory source of plasticity
[103]. In mice and rats, doublecortin is primarily expressed for the first 2–3 weeks of neuronal
development [104] but in primates it is expressed for at least 6 months [62,91]. This is a 10
difference in duration, which also approximates the difference in lifespan between primates
and rodents. Applying this rule to the critical period for enhanced LTP (6 weeks [40]),
newborn DG neurons might be expected to have enhanced synaptic plasticity for over a year
in primates and even longer in humans. Similarly, if the enhanced capacity for morphological
plasticity, which lasts at least 4 months in rats [100], is scaled according to human lifespan
(30), DG neurons in humans would be expected to retain this heightened plasticity for at
least a decade.

The data suggest that even DG neurons born in childhood in humans could retain unique
functions in adolescence and adulthood. Indeed, other aspects of human neurodevelopment,
such as the pruning of prefrontal neurons, extend well into adulthood [105]. A similarly long
period of development may also apply to the human DG. Calbindin expression patterns, as a
crude measure of neuronal maturity, indicate that human DG neurons develop over the first
decade of life [106]. Neuroanatomical gradients of calbindin loss suggest that later-born
neurons in the adult human DG are more vulnerable to epilepsy-related damage [107]. Finer
aspects of maturation may occur over even longer intervals, as suggested by observations that
DG neuron dendrites do not reliably reach the hippocampal fissure in primates as they do in
rodents [108–110]. Quantitative support comes from reports that human DG neurons continue
to extend dendrites through old age [111,112]. In this context it is notable that Alzheimer’s
pathology can begin in the upstream entorhinal cortex long before old age [113]. Thus, the
prolonged ‘development’ of late-generated DG neurons could overlap with disorders that
emerge many years after they were born.

DG Neurogenesis and Ontogenetic Diversity

Neurodevelopmental studies often characterize the spatiotemporal patterns by which different
cell types are generated. For example, the excitatory neurons of the different layers of the
neocortex are comprised of distinct populations that are generated sequentially and in a
stereotyped fashion. Despite originating in the same germinal zone, neurons in the various
layers are functionally distinct in their physiology and circuit connectivity [114]. This persistent
form of cellular heterogeneity is distinct from the maturation-based heterogeneity described
above because differences do not disappear as cells age, but depend on when in the lifespan
the cell was born.

While appearing homogeneous upon superficial inspection, pyramidal neurons in the

hippocampus also display a surprising degree of variation that depends on neurodeve-
lopmental timing. In CA1, pyramidal neurons are arranged in layers that are generated at
different stages of development and have distinct morphology, connectivity, and behav-
ioral functions [115,116]. In CA3, a unique subset of highly-active pyramidal
neurons are generated in a brief, early window of prenatal development [117]. Develop-
mental timing also dictates intrahippocampal connectivity, where subcircuits of

Trends in Neurosciences, Month Year, Vol. xx, No. yy 9

 TINS 1479 1–15

preferentially-connected neurons are embedded in the trisynaptic pathway based on

neuronal birthdate [118].

Despite its protracted development, the role that ontogenetic timing plays in DG cellular
heterogeneity is surprisingly underexplored. In rodents and primates, DG neurons are added
along ventral to dorsal, suprapyramidal to infrapyramidal, and superficial to deep gradients
[119,120]. Patterns of activity-dependent gene expression [121], morphology [122], physiology
[123], and behavioral functions [124] vary across the same gradients, broadly linking cellular
properties to developmental birthdate.

More precise ontogenetic relationships are only beginning to be investigated. By tagging age-
defined cohorts of DG neurons, it was recently revealed that physiologically-distinct semilunar
granule cells [125] are born around embryonic day 14 in mice [126,127], and their dendritic
patterning is substantially different from neurons born just a few days later, on the day of birth
[127]. Early work demonstrated that superficially-located, presumably older, cells in rats have
more primary dendrites, greater total dendritic length, and broader dendritic arborization [122].
The ontogenetic basis of many of these morphological differences was recently confirmed
[127]. Given the important role of dendritic architecture in integrating/processing synaptic
inputs [128], this suggests that DG neurons are likely to perform distinct computational
functions based on their birthdate. Indeed, reconstruction of recorded DG neurons has
revealed that neurons with higher-order dendritic branching patterns are preferentially active
during spatial navigation [129].

The extent to which adult-born neurons are fundamentally different from other neurons, or
simply in a protracted stage of development, is unclear. Some observations suggest that
functional differences may extend into cellular maturity, arguing in favor of the former scenario.
For instance, 4-month-old adult-born neurons in rats show unique patterns of experience-
dependent zif268 expression relative to 4-month-old infant-born neurons [130]. Differences
may also extend to cells born at different times in adult life, as old neurons born in young adult
rats show greater zif268 expression than old neurons born in middle-aged rats [131]. Patterns
of neuronal persistence also suggest fundamental differences: adult-born neurons in rodents
survive indefinitely once they have reached 4 weeks of age [132,133] but some infant-born DG
neurons die off between 2 and 6 months of cell age [133,134]. Finally, some superficially-
located neurons, which are unlikely to substantially differ in age, are capable of synaptic LTP
whereas others exhibit none [37,40].

In summary, cell age cannot fully explain differences in cellular properties between DG
neurons. Instead, heterogeneous properties depend, at least in part, on when in the lifespan
a neuron was born. Future work can examine if neurodevelopmental timing can explain
other intriguing types of heterogeneity in the DG, such as neurons with twice the normal
spine density [108,109,135] and neurons with unusually long and plastic mossy fiber
extensions [136].

Recalibrating According to Ontogeny

How might the relative timing and order in which neurons are generated result in meaningful,
persistent functional differences between cells? One possibility is that protracted DG neuro-
genesis is needed to produce a continuous gradient of cell types. For instance, a continuum of
anatomical and physiological differences could facilitate the separation of cortical input pat-
terns, one of the hypothesized core functions of the DG in memory [137]. A similar argument
has been put forth based on patterns of gene expression across hippocampal neurons [138],

10 Trends in Neurosciences, Month Year, Vol. xx, No. yy

 TINS 1479 1–15

where graded differences in cell type may help tune neuronal receptive fields to the array of Outstanding Questions
incoming sensory signals. How many subpopulations of DG neu-
rons exist, and how can one define
them? In some instances, such as the
Another possibility is that there are more fundamental differences in DG cell types. For semilunar granule neuron, the birthdate,
example, differences in immediate-early gene expression and morphological plasticity are morphology, and physiology are
likely to impact memory storage [92,122,123,131], and differential susceptibility to cell death defined and distinct. In contrast, while
old adult-born neurons differ from
might underlie distinct roles in memory turnover [133,134]. It is unknown whether differential
infant-born neurons in immediate-early
connectivity with medial and lateral entorhinal cortex persists or disappears as new neurons gene expression and morphological
mature [139,140]. This question is significant because these subregions provide the hippo- plasticity, the corresponding physiolog-
campus with the contextual and content-related components of experience, respectively ical properties remain unknown. Given
that neurogenesis may also interact with
[141]. Unique connectivity will therefore dictate which aspects of sensory experience DG
other lifespan processes (e.g., hor-
neurons are responsive to. mones and environment) a fuller under-
standing requires a detailed
Finally, the vast majority of psychiatric and neurological disorders are associated with cell investigation of neurons born at different
stages of life.
type-specific vulnerability. For example, aging and Alzheimer’s disease are associated with
specific loss of layer 2 entorhinal cortex neurons [142,143]. Nigral dopaminergic neurons, and
Which properties of newborn neurons
other specific cell types, are highly vulnerable in Parkinson’s disease [144]. Cellular hetero- are due to their immature state and
geneity in the DG may therefore result in some populations being more vulnerable than others which are permanent features? Proper-
to various pathologies. Furthermore, impaired neurogenesis may be involved in the reduced ties related to cellular development can
be expected to disappear with time and
hippocampal volume that is observed in disorders such as depression [145], schizophrenia age, as neurogenesis declines. In con-
[146], mild cognitive impairment [147], and Alzheimer’s disease [148]. However, given the trast, permanent features would lead to
unique pattern of delayed death of earlier-born DG neurons in rats [133,134], it is also functions that persist throughout the life-
possible that earlier-born cells are more vulnerable to pathology. Indeed, in a mouse model of span. With this knowledge, one could
make better predictions about how neu-
Alzheimer’s disease, superficially-located, presumably earlier-born, neurons undergo greater rogenesis could be harnessed to
dendritic atrophy [149]. Finally, in the context of epilepsy, given the different electrophysio- improve health throughout life.
logical profiles and activity patterns that have been observed in DG neurons, it is also plausible
that subpopulations of neurons differentially contribute, or are vulnerable, to seizure-related How can we better model human DG
neurogenesis? Transgenic mouse
hippocampal damage [150].
models are invaluable for studying
age-defined cohorts of DG neurons
Concluding Remarks and Future Perspectives and addressing mechanistic ques-
Reports of limited neurogenesis in adult humans have been difficult to reconcile with animal tions, but their translational relevance
is limited, partly due to neurodevelop-
work demonstrating persistent neurogenesis throughout life, and with human studies arguing
mental differences. Conversely, pri-
for lifelong neurogenesis. Our review suggests that, once developmental timing is accounted mates present a closer model for
for, the human and animal literatures are generally consistent with one another: the human some aspects of human neurogenesis,
hippocampus develops largely prenatally, leaving less opportunity for postnatal neurogenesis. but are often costly and time-consum-
ing, and for certain applications can be
In contrast, the rodent DG forms postnatally and is typically studied in adolescence and young
ethically challenging. Shorter-lived ani-
adulthood, when neurogenesis rates remain high. Thus, some confusion has arisen as a result mals that are born with a relatively
of modeling adult humans with juvenile rodents. While it remains unresolved whether neuro- mature brain, or primate models such
genesis drops to zero in adult humans, our comparative analysis suggests that it falls to low as marmosets that are experimentally
more practical, may provide new
rates for much of adult life in all species. insights into the nature of human DG
neurogenesis.
What then is the relevance of adult neurogenesis for humans? Our review offers several
perspectives for interpreting the literature and guiding future research questions. First, low Can the age-related decline in neuro-
rates of neurogenesis in adulthood, over years and decades, may have substantial additive genesis be reversed or offset? This is
an ongoing pursuit, and the low neuro-
effects that promote long-term health. Second, higher rates in early life may play a significant genesis observed in aged rodents
role in childhood and adolescent brain function, when many mental health disorders originate. makes them a suitable model for this
Third, an ontogenetic perspective may help identify heterogeneous cell types in the DG, and problem.
how they differentially contribute to health and disease. Uncertainties about human–animal
Cell types are often defined by differ-
differences, and the extent to which cellular properties reflect maturational states versus
ences in gene expression. Do DG
persistent features, also highlight opportunities for future research (see Outstanding

Trends in Neurosciences, Month Year, Vol. xx, No. yy 11

 TINS 1479 1–15
Questions). In summary, consideration of the broader neurodevelopmental context will help us
take advantage of the benefits that neurogenesis may offer for human mental health.
Acknowledgments
Work in the Snyder Laboratory is supported by the Canadian Institutes of Health Research, the Natural Sciences and
Engineering Research Council of Canada and the Michael Smith Foundation for Health Research.
Supplemental Information
Supplemental information associated with this article can be found online at https://doi.org/10.1016/j.tins.2018.12.001.
References
1. Altman, J. and Das, G.D. (1965) Autoradiographic and histolog-
ical evidence of postnatal hippocampal neurogenesis in rats. J.
Comp. Neurol. 124, 319–335
2. Altman, J. (2011) The discovery of adult mammalian neuro-
genesis. In Neurogenesis in the Adult Brain I, pp. 3–46, Springer
3. Gross, C.G. (2000) Neurogenesis in the adult brain: death of a
dogma. Nat. Rev. Neurosci. 1, 67–73
4. Rakic, P. (1985) Limits of neurogenesis in primates. Science
227, 1054–1056
5. Gould, E. et al. (1998) Proliferation of granule cell precursors in
the dentate gyrus of adult monkeys is diminished by stress.
Proc. Natl. Acad. Sci. U. S. A. 95, 3168–3171
6. Kornack, D.R. and Rakic, P. (1999) Continuation of neurogen-
esis in the hippocampus of the adult macaque monkey. Proc.
Natl. Acad. Sci. U. S. A. 96, 5768–5773
7. Rakic, P. (2002) Neurogenesis in adult primate neocortex: an
evaluation of the evidence. Nat. Rev. Neurosci. 3, 65–71
8. Gould, E. (2007) How widespread is adult neurogenesis in
mammals? Nat. Rev. Neurosci. 8, 481–488
9. Knoth, R. et al. (2010) Murine features of neurogenesis in the
human hippocampus across the lifespan from 0 to 100 years.
PLoS One 5, e8809
10. Spalding, K.L. et al. (2013) Dynamics of hippocampal neuro-
genesis in adult humans. Cell 153, 1219–1227
11. Eriksson, P.S. et al. (1998) Neurogenesis in the adult human
hippocampus. Nat. Med. 4, 1313–1317
12. Boldrini, M. et al. (2018) Human hippocampal neurogenesis
persists throughout aging. Stem Cell 22, 589–599.e5
13. Sorrells, S.F. et al. (2018) Human hippocampal neurogenesis
drops sharply in children to undetectable levels in adults. Nature
555, 377–381
14. Tartt, A.N. et al. (2018) Considerations for assessing the extent
of hippocampal neurogenesis in the adult and aging human
brain. Stem Cell 23, 782–783
15. Kempermann, G. et al. (2018) Human adult neurogenesis: evi-
dence and remaining questions. Cell Stem Cell 23, 25–30
16. Kuhn, H.G. et al. (2018) Adult hippocampal neurogenesis: a
coming-of-age story. J. Neurosci. 38, 10401–10410
17. Arellano, J.I. et al. (2018) Adult human hippocampus: no new
neurons in sight. Cereb. Cortex 28, 2479–2481
18. Lee, H. and Thuret, S. (2018) Adult human hippocampal neu-
rogenesis: controversy and evidence. Trends Mol. Med. 24,
521–522
19. Charvet, C.J. and Finlay, B.L. (2018) Comparing adult hippo-
campal neurogenesis across species: translating time to predict
the tempo in humans. Front. Neurosci. 12, 706
20. Paredes, M.F. et al. (2018) Does adult neurogenesis persist in
the human hippocampus? Stem Cell 23, 780–781
21. Del Bigio, M.R. (1999) Proliferative status of cells in adult human
dentate gyrus. Microsc. Res. Tech. 45, 353–358
22. Blümcke, I. et al. (2001) Increase of nestin-immunoreactive
neural precursor cells in the dentate gyrus of pediatric
patients with early-onset temporal lobe epilepsy. Hippocampus
11, 311–321
12 Trends in Neurosciences, Month Year, Vol. xx, No. yy
neurons of different ages, and ones
born at different stages of the lifespan,
have unique genetic signatures? If so,
this could lend support to the ontoge-
netic diversity model, and facilitate
strategies for targeting neuronal pop-
ulations in animal models and possibly
for treatment of human disorders.
23. Seress, L. et al. (2001) Cell formation in the human hippocampal
formation from mid-gestation to the late postnatal period. Neu-
roscience 105, 831–843
24. Dennis, C.V. et al. (2016) Human adult neurogenesis across the
ages: an immunohistochemical study. Neuropathol. Appl. Neu-
robiol. 42, 621–638
25. Cipriani, S. et al. (2018) Hippocampal radial glial subtypes and
their neurogenic potential in human fetuses and healthy and
Alzheimer’s disease adults. Cereb. Cortex 27, 16
26. Lipp, H.-P. and Bonfanti, L. (2016) Adult neurogenesis in mam-
mals: variations and confusions. Brain Behav. Evol. 87, 205–221
27. Lledo, P.-M. and Valley, M. (2016) Adult olfactory bulb neuro-
genesis. Cold Spring Harb. Perspect. Biol. 8, a018945
28. Cameron, H.A. and Dayer, A.G. (2008) New interneurons in the
adult neocortex: small, sparse, but significant? Biol. Psychiatry
63, 650–655
29. Inta, D. et al. (2015) New neurons in the adult striatum: from
rodents to humans. Trends Neurosci. 38, 517–523
30. Anacker, C. and Hen, R. (2017) Adult hippocampal neurogen-
esis and cognitive flexibility – linking memory and mood. Nat.
Rev. Neurosci. 18, 335–346
31. Cameron, H.A. and Glover, L.R. (2015) Adult neurogenesis:
beyond learning and memory. Annu. Rev. Psychol. 66, 53–81
32. Opendak, M. and Gould, E. (2015) Adult neurogenesis: a sub-
strate for experience-dependent change. Trends Cogn. Sci. 19,
151–161
33. Toda, T. et al. (2018) The role of adult hippocampal neuro-
genesis in brain health and disease. Mol. Psychiatry 145, 1
34. Yun, S. et al. (2016) Re-evaluating the link between neuropsy-
chiatric disorders and dysregulated adult neurogenesis. Nat.
Med. 22, 1239–1247
35. Zhao, C. et al. (2006) Distinct morphological stages of dentate
granule neuron maturation in the adult mouse hippocampus. J.
Neurosci. 26, 3–11
36. Espósito, M.S. et al. (2005) Neuronal differentiation in the adult
hippocampus recapitulates embryonic development. J. Neuro-
sci. 25, 10074–10086
37. Wang, S. et al. (2000) Heterogenous properties of dentate
granule neurons in the adult rat. J. Neurobiol. 42, 248–257
38. Snyder, J.S. et al. (2001) Effects of adult neurogenesis on
synaptic plasticity in the rat dentate gyrus. J. Neurophysiol.
85, 2423–2431
39. Schmidt-Hieber, C. et al. (2004) Enhanced synaptic plasticity in
newly generated granule cells of the adult hippocampus. Nature
429, 184–187
40. Ge, S. et al. (2007) A critical period for enhanced synaptic
plasticity in newly generated neurons of the adult brain. Neuron
54, 559–566
41. Gu, Y. et al. (2012) Optical controlling reveals time-dependent
roles for adult-born dentate granule cells. Nat. Neurosci. 15,
1700–1706
42. Marín-Burgin, A. and Schinder, A.F. (2012) Requirement of
adult-born neurons for hippocampus-dependent learning.
Behav. Brain Res. 227, 391–399
 TINS 1479 1–15
43. Temprana, S.G. et al. (2015) Delayed coupling to feedback
inhibition during a critical period for the integration of adult-born
granule cells. Neuron 85, 116–130
44. Chancey, J.H. et al. (2013) GABA depolarization is required for
experience-dependent synapse unsilencing in adult-born neu-
rons. J. Neurosci. 33, 6614–6622
45. Pardi, M.B. et al. (2015) Differential inhibition onto developing
and mature granule cells generates high-frequency filters with
variable gain. eLife 4, e08764
46. Gould, E. et al. (1999) Learning enhances adult neurogenesis in
the hippocampal formation. Nat. Neurosci. 2, 260–265
47. Epp, J.R. et al. (2007) Hippocampus-dependent learning pro-
motes survival of new neurons in the dentate gyrus at a specific
time during cell maturation. Neuroscience 149, 273–285
48. Dupret, D. et al. (2007) Spatial learning depends on both the
addition and removal of new hippocampal neurons. PLoS Biol.
5, e214
49. Bergami, M. et al. (2015) A critical period for experience-depen-
dent remodeling of adult-born neuron connectivity. Neuron 85,
710–717
50. Alvarez, D.D. et al. (2016) A disynaptic feedback network acti-
vated by experience promotes the integration of new granule
cells. Science 354, 459–465
51. Becker, S. (2017) Neurogenesis and pattern separation: time for
a divorce. WIREs Cogn. Sci. 8, e1427
52. Aimone, J.B. et al. (2009) Computational influence of adult
neurogenesis on memory encoding. Neuron 61, 187–202
53. Danielson, N.B. et al. (2016) Distinct contribution of adult-born
hippocampal granule cells to context encoding. Neuron 90,
101–112
54. Snyder, J.S. et al. (2005) A role for adult neurogenesis in spatial
long-term memory. Neuroscience 130, 843–852
55. Shors, T.J. et al. (2001) Neurogenesis in the adult is involved in
the formation of trace memories. Nature 410, 372–376
56. Denny, C.A. et al. (2012) 4- to 6-week-old adult-born hippo-
campal neurons influence novelty-evoked exploration and con-
textual fear conditioning. Hippocampus 22, 1188–1201
57. Laplagne, D.A. et al. (2006) Functional convergence of neurons
generated in the developing and adult hippocampus. PLoS Biol.
4, e409
58. Stone, S.S.D. et al. (2011) Functional convergence of develop-
mentally and adult-generated granule cells in dentate gyrus
circuits supporting hippocampus-dependent memory. Hippo-
campus 21, 1348–1362
59. Lisman, J. (2011) Formation of the non-functional and functional
pools of granule cells in the dentate gyrus: role of neurogenesis,
LTP and LTD. J. Physiol. (Lond.) 589, 1905–1909
60. Alme, C.B. et al. (2010) Hippocampal granule cells opt for early
retirement. Hippocampus 20, 1109–1123
61. Arnold, S.E. and Trojanowski, J.Q. (1996) Human fetal hippo-
campal development: I. Cytoarchitecture, myeloarchitecture,
and neuronal morphologic features. J. Comp. Neurol. 367,
274–292
62. Jabès, A. et al. (2010) Quantitative analysis of postnatal neuro-
genesis and neuron number in the macaque monkey dentate
gyrus. Eur. J. Neurosci. 31, 273–285
63. Amrein, I. et al. (2015) Septo-temporal distribution and lineage
progression of hippocampal neurogenesis in a primate (Callithrix
jacchus) in comparison to mice. Front. Neuroanat. 9, 85
64. Bayer, S.A. et al. (1993) Timetables of neurogenesis in the
human brain based on experimentally determined patterns in
the rat. Neurotoxicology 14, 83–144
65. Workman, A.D. et al. (2013) Modeling transformations of neuro-
developmental sequences across mammalian species. J. Neu-
rosci. 33, 7368–7383
66. Amrein, I. et al. (2011) Comparing adult hippocampal neuro-
genesis in mammalian species and orders: influence of chro-
nological age and life history stage. Eur. J. Neurosci. 34,
978–987
67. Abrous, D.N. and Wojtowicz, J.M. (2015) Interaction between
neurogenesis and hippocampal memory system: new vistas.
Cold Spring Harb. Perspect. Biol. 7, a018952
68. Encinas, J.M. et al. (2011) Division-coupled astrocytic differen-
tiation and age-related depletion of neural stem cells in the adult
hippocampus. Cell Stem Cell 8, 566–579
69. Zhou, Y. et al. (2018) Autocrine Mfge8 signaling prevents devel-
opmental exhaustion of the adult neural stem cell pool. Stem Cell
23, 1–14
70. Pilz, G.-A. et al. (2018) Live imaging of neurogenesis in the adult
mouse hippocampus. Science 359, 658–662
71. Kronenberg, G. et al. (2003) Subpopulations of proliferating cells
of the adult hippocampus respond differently to physiologic
neurogenic stimuli. J. Comp. Neurol. 467, 455–463
72. Heine, V.M. et al. (2004) Prominent decline of newborn cell
proliferation, differentiation, and apoptosis in the aging dentate
gyrus, in absence of an age-related hypothalamus-pituitary-
adrenal axis activation. Neurobiol. Aging 25, 361–375
73. Rao, M.S. et al. (2006) The window and mechanisms of major
age-related decline in the production of new neurons within the
dentate gyrus of the hippocampus. Aging Cell 5, 545–558
74. Gould, E. et al. (1999) Hippocampal neurogenesis in adult Old
World primates. Proc. Natl. Acad. Sci. U. S. A. 96, 5263–5267
75. Ngwenya, L.B. et al. (2015) Age-related changes in dentate gyrus
cell numbers, neurogenesis, and associations with cognitive
impairments in the rhesus monkey. Front. Syst. Neurosci. 9, 1–16
76. Kempermann, G. et al. (1997) More hippocampal neurons in
adult mice living in an enriched environment. Nature 386, 493–
495
77. West, M.J. et al. (1991) Unbiased stereological estimation of the
total number of neurons in the subdivisions of the rat hippocam-
pus using the optical fractionator. Anat. Rec. 231, 482–497
78. Jabès, A. et al. (2011) Postnatal development of the hippocam-
pal formation: a stereological study in macaque monkeys. J.
Comp. Neurol. 519, 1051–1070
79. Monje, M.L. et al. (2007) Impaired human hippocampal neuro-
genesis after treatment for central nervous system malignan-
cies. Ann. Neurol. 62, 515–520
80. Lazic, S.E. (2012) Modeling hippocampal neurogenesis across
the lifespan in seven species. Neurobiol. Aging 33, 1664–1671
81. McCutcheon, J.E. and Marinelli, M. (2009) Age matters. Eur. J.
Neurosci. 29, 997–1014
82. Snyder, J.S. and Cameron, H.A. (2012) Could adult hippocam-
pal neurogenesis be relevant for human behavior? Behav. Brain
Res. 227, 384–390
83. DeCarolis, N.A. et al. (2013) In vivo contribution of nestin- and
GLAST-lineage cells to adult hippocampal neurogenesis. Hip-
pocampus 23, 708–719
84. Akers, K.G. et al. (2014) Hippocampal neurogenesis regulates
forgetting during adulthood and infancy. Science 344, 598–602
85. Wei, L. et al. (2011) Affiliative behavior requires juvenile, but not
adult neurogenesis. J. Neurosci. 31, 14335–14345
86. Lee, F.S. et al. (2014) Mental health. Adolescent mental health –
opportunity and obligation. Science 346, 547–549
87. Lupien, S.J. et al. (2009) Effects of stress throughout the lifespan
on the brain, behaviour and cognition. Nat. Rev. Neurosci. 10,
434–445
88. Kessler, R.C. et al. (2005) Lifetime prevalence and age-of-onset
distributions of DSM-IV disorders in the National Comorbidity
Survey Replication. Arch. Gen. Psychiatry 62, 593–602
89. Kim-Cohen, J. et al. (2003) Prior juvenile diagnoses in adults with
mental disorder: developmental follow-back of a prospective-
longitudinal cohort. Arch. Gen. Psychiatry 60, 709–717
90. Miller, B.R. and Hen, R. (2015) The current state of the neuro-
genic theory of depression and anxiety. Curr. Opin. Neurobiol.
30, 51–58
91. Heim, C. et al. (2008) The link between childhood trauma and
depression: insights from HPA axis studies in humans. Psycho-
neuroendocrinology 33, 693–710
Trends in Neurosciences, Month Year, Vol. xx, No. yy 13
 TINS 1479 1–15
92. Halligan, S.L. et al. (2007) Disturbances in morning cortisol
secretion in association with maternal postnatal depression
predict subsequent depressive symptomatology in adolescents.
Biol. Psychiatry 62, 40–46
93. Mandyam, C.D. and Koob, G.F. (2012) The addicted brain
craves new neurons: putative role for adult-born progenitors
in promoting recovery. Trends Neurosci. 35, 250–260
94. Lewis, D.A. and Levitt, P. (2002) Schizophrenia as a disorder of
neurodevelopment. Annu. Rev. Neurosci. 25, 409–432
95. Breslau, N. et al. (1999) Previous exposure to trauma and PTSD
effects of subsequent trauma: results from the Detroit Area
Survey of Trauma. Am. J. Psychiatry 156, 902–907
96. Paus, T. et al. (2008) Why do many psychiatric disorders emerge
during adolescence? Nat. Rev. Neurosci. 9, 947–957
97. Overstreet-Wadiche, L.S. et al. (2006) Delayed development of
adult-generated granule cells in dentate gyrus. J. Neurosci. 26,
2326–2334
98. Trinchero, M.F. et al. (2017) High plasticity of new granule cells in
the aging hippocampus. Cell Rep. 21, 1129–1139
99. Tronel, S. et al. (2010) Spatial learning sculpts the dendritic arbor
of adult-born hippocampal neurons. Proc. Natl. Acad. Sci. U. S.
A. 107, 7963–7968
100. Lemaire, V. et al. (2012) Long-lasting plasticity of hippocampal
adult-born neurons. J. Neurosci. 32, 3101–3108
101. Orr, M.E. et al. (2016) Extended postnatal brain development in
the longest-lived rodent: prolonged maintenance of neotenous
traits in the naked mole-rat brain. Front. Neurosci. 10, 473–17
102. Penz, O.K. et al. (2015) Protracted brain development in a
rodent model of extreme longevity. Sci. Rep. 5, 11592
103. Amrein, I. and Slomianka, L. (2010) A morphologically distinct
granule cell type in the dentate gyrus of the red fox correlates
with adult hippocampal neurogenesis. Brain Res. 1328, 12–24
104. Brown, J.P. et al. (2003) Transient expression of doublecortin
during adult neurogenesis. J. Comp. Neurol. 467, 1–10
105. Petanjek, Z. et al. (2011) Extraordinary neoteny of synaptic
spines in the human prefrontal cortex. Proc. Natl. Acad. Sci.
U. S. A. 108, 13281–13286
106. Abrahám, H. et al. (2009) Ontogeny of calbindin immunoreac-
tivity in the human hippocampal formation with a special empha-
sis on granule cells of the dentate gyrus. Int. J. Dev. Neurosci.
27, 115–127
107. Abrahám, H. et al. (2011) Degree and pattern of calbindin
immunoreactivity in granule cells of the dentate gyrus differ in
mesial temporal sclerosis, cortical malformation- and tumor-
related epilepsies. Brain Res. 1399, 66–78
108. Seress, L. and Frotscher, M. (1990) Morphological variability is a
characteristic feature of granule cells in the primate fascia den-
tata: a combined Golgi/electron microscope study. J. Comp.
Neurol. 293, 253–267
109. Seress, L. (1992) Morphological variability and developmental
aspects of monkey and human granule cells: differences between
therodent and primate dentate gyrus. Epilepsy Res. Suppl. 7, 3–28
110. Claiborne, B.J. et al. (1986) A light and electron microscopic
analysis of the mossy fibers of the rat dentate gyrus. J. Comp.
Neurol. 246, 435–458
111. Flood, D.G. et al. (1985) Age-related dendritic growth in dentate
gyrus of human brain is followed by regression in the ‘oldest old’.
Brain Res. 345, 366–368
112. Flood, D.G. et al. (1987) Dendritic extent in human dentate gyrus
granule cells in normal aging and senile dementia. Brain Res.
402, 205–216
113. Braak, H. et al. (2011) Stages of the pathologic process in
Alzheimer disease: age categories from 1 to 100 years. J.
Neuropathol. Exp. Neurol. 70, 960–969
114. Molyneaux, B.J. et al. (2007) Neuronal subtype specification in
the cerebral cortex. Nat. Rev. Neurosci. 8, 427–437
115. Slomianka, L. et al. (2011) Hippocampal pyramidal cells: the
reemergence of cortical lamination. Brain Struct. Funct. 216,
301–317
14 Trends in Neurosciences, Month Year, Vol. xx, No. yy
116. Li, Y. et al. (2017) A distinct entorhinal cortex to hippocampal
CA1 direct circuit for olfactory associative learning. Nat. Neuro-
sci. 20, 559–570
117. Marissal, T. et al. (2012) Pioneer glutamatergic cells develop into
a morpho-functionally distinct population in the juvenile CA3
hippocampus. Nat. Commun. 3, 1316
118. Deguchi, Y. et al. (2011) Temporally matched subpopulations of
selectively interconnected principal neurons in the hippocam-
pus. Nat. Neurosci. 14, 495–504
119. Schlessinger, A.R. et al. (1975) An autoradiographic study of the
time of origin and the pattern of granule cell migration in the
dentate gyrus of the rat. J. Comp. Neurol. 159, 149–175
120. Rakic, P. and Nowakowski, R.S. (1981) The time of origin of
neurons in the hippocampal region of the rhesus monkey. J.
Comp. Neurol. 196, 99–128
121. Snyder, J.S. et al. (2009) Anatomical gradients of adult neuro-
genesis and activity: young neurons in the ventral dentate gyrus
are activated by water maze training. Hippocampus 19, 360–
370
122. Claiborne, B.J. et al. (1990) Quantitative, three-dimensional
analysis of granule cell dendrites in the rat dentate gyrus. J.
Comp. Neurol. 302, 206–219
123. Scharfman, H.E. et al. (2002) Structural and functional asym-
metry in the normal and epileptic rat dentate gyrus. J. Comp.
Neurol. 454, 424–439
124. Kheirbek, M.A. et al. (2013) Differential control of learning and
anxiety along the dorsoventral axis of the dentate gyrus. Neuron
77, 955–968
125. Larimer, P. and Strowbridge, B.W. (2010) Representing infor-
mation in cell assemblies: persistent activity mediated by semi-
lunar granule cells. Nat. Neurosci. 13, 213–222
126. Save, L. et al. (2018) Temporal embryonic origin critically deter-
mines cellular physiology in the dentate gyrus. Cereb. Cortex 32,
6688
127. Kerloch, T. et al. (2018) Dentate granule neurons generated
during perinatal life display distinct morphological features com-
pared with later-born neurons in the mouse hippocampus.
Cereb. Cortex 301, 365
128. Lefebvre, J.L. et al. (2015) Development of dendritic form and
function. Annu. Rev. Cell Dev. Biol. 31, 741–777
129. Diamantaki, M. et al. (2016) Sparse activity of identified dentate
granule cells during spatial exploration. eLife 5, e20252
130. Tronel, S. et al. (2015) Influence of ontogenetic age on the role of
dentate granule neurons. Brain Struct. Funct. 220, 645–661
131. Ohline, S.M. et al. (2018) Adult-born dentate granule cell excit-
ability depends on the interaction of neuron age, ontogenetic
age and experience. Brain Struct. Funct. 383, 335
132. Kempermann, G. et al. (2003) Early determination and long-term
persistence of adult-generated new neurons in the hippocam-
pus of mice. Development 130, 391–399
133. Dayer, A.G. et al. (2003) Short-term and long-term survival of
new neurons in the rat dentate gyrus. J. Comp. Neurol. 460,
563–572
134. Cahill, S.P. et al. (2017) Early survival and delayed death of
developmentally-born dentate gyrus neurons. Hippocampus
49, 553
135. Williams, R.S. and Matthysse, S. (1983) Morphometric analysis
of granule cell dendrites in the mouse dentate gyrus. J. Comp.
Neurol. 215, 154–164
136. Galimberti, I. et al. (2010) EphA4 signaling in juveniles estab-
lishes topographic specificity of structural plasticity in the hip-
pocampus. Neuron 65, 627–642
137. Yassa, M.A. and Stark, C.E.L. (2011) Pattern separation in the
hippocampus. Trends Neurosci. 34, 515–525
138. Cembrowski, M.S. and Menon, V. (2018) Continuous variation
within cell types of the nervous system. Trends Neurosci. 41,
337–348
139. Vivar, C. et al. (2012) Monosynaptic inputs to new neurons in the
dentate gyrus. Nat. Commun. 3, 1107
 TINS 1479 1–15
140. Woods, N.I. et al. (2018) Preferential targeting of lateral entorhi-
nal inputs onto newly integrated granule cells. J. Neurosci. 38,
5843–5853
141. Knierim, J.J. et al. (2014) Functional correlates of the lateral and
medial entorhinal cortex: objects, path integration and local-
global reference frames. Philos. Trans. R. Soc. B Biol. Sci.
369, 20130369
142. Kordower, J.H. et al. (2001) Loss and atrophy of layer II ento-
rhinal cortex neurons in elderly people with mild cognitive
impairment. Ann. Neurol. 49, 202–213
143. Gómez-Isla, T. et al. (1996) Profound loss of layer II entorhinal
cortex neurons occurs in very mild Alzheimer’s disease. J.
Neurosci. 16, 4491–4500
144. Giguère, N. et al. (2018) On cell loss and selective vulnerability of
neuronal populations in Parkinson’s disease. Front. Neurol. 9,
455
145. McKinnon, M.C. et al. (2009) A meta-analysis examining clinical
predictors of hippocampal volume in patients with major depres-
sive disorder. J. Psychiatry Neurosci. 34, 41–54
146. Harrison, P.J. (2004) The hippocampus in schizophrenia: a
review of the neuropathological evidence and its pathophysi-
ological implications. Psychopharmacology (Berl) 174, 151–
162
147. Yassa, M.A. et al. (2010) High-resolution structural and func-
tional MRI of hippocampal CA3 and dentate gyrus in patients
with amnestic mild cognitive impairment. Neuroimage 51,
1242–1252
148. Jack, C.R. et al. (2000) Rates of hippocampal atrophy correlate
with change in clinical status in aging and AD. Neurology 55,
484–489
149. Wu, C.-C. et al. (2004) Selective vulnerability of dentate granule
cells prior to amyloid deposition in PDAPP mice: digital morpho-
metric analyses. Proc. Natl. Acad. Sci. U. S. A. 101, 7141–7146
150. Scharfman, H.E. and Myers, C.E. (2016) Corruption of the
dentate gyrus by “dominant” granule cells: implications for den-
tate gyrus function in health and disease. Neurobiol. Learn.
Mem. 129, 69–82
151. Ge, S. et al. (2006) GABA regulates synaptic integration of newly
generated neurons in the adult brain. Nature 439, 589–593
152. Snyder, J.S. et al. (2009) Adult-born hippocampal neurons are
more numerous, faster maturing, and more involved in behavior
in rats than in mice. J. Neurosci. 29, 14484–14495
153. Tashiro, A. et al. (2007) Experience-specific functional modifica-
tion of the dentate gyrus through adult neurogenesis: a critical
period during an immature stage. J. Neurosci. 27, 3252–3259
154. Gonçalves, J.T. et al. (2016) In vivo imaging of dendritic pruning
in dentate granule cells. Nat. Neurosci. 19, 788–791
155. Marín-Burgin, A. et al. (2012) Unique processing during a period
of high excitation/inhibition balance in adult-born neurons. Sci-
ence 335, 1238–1242
156. Restivo, L. et al. (2015) Development of adult-generated cell
connectivity with excitatory and inhibitory cell populations in the
hippocampus. J. Neurosci. 35, 10600–10612
157. Drew, L.J. et al. (2016) Activation of local inhibitory circuits in the
dentate gyrus by adult-born neurons. Hippocampus 26, 763–
778
158. Nakashiba, T. et al. (2012) Young dentate granule cells mediate
pattern separation, whereas old granule cells facilitate pattern
completion. Cell 149, 188–201
159. Rao, M.S. et al. (2005) Newly born cells in the ageing dentate
gyrus display normal migration, survival and neuronal fate choice
but endure retarded early maturation. Eur. J. Neurosci. 21, 464–
476
160. Kohler, S.J. et al. (2011) Maturation time of new granule cells in
the dentate gyrus of adult macaque monkeys exceeds six
months. Proc. Natl. Acad. Sci. U. S. A. 108, 10326–10331
161. Coleman, P.D. and Flood, D.G. (1987) Neuron numbers and
dendritic extent in normal aging and Alzheimer’s disease. Neu-
robiol. Aging 8, 521–545
162. Angevine, J.B., Jr (1965) Time of neuron origin in the hippo-
campal region. An autoradiographic study in the mouse. Exp.
Neurol. Suppl. (Suppl 2), 1–70
163. Ben Abdallah, N.M.-B. et al. (2010) Early age-related changes in
adult hippocampal neurogenesis in C57 mice. Neurobiol. Aging
31, 151–161
164. Mathews, E.A. et al. (2010) A distinctive layering pattern of
mouse dentate granule cells is generated by developmental
and adult neurogenesis. J. Comp. Neurol. 518, 4479–4490
165. Kronenberg, G. et al. (2006) Physical exercise prevents age-
related decline in precursor cell activity in the mouse dentate
gyrus. Neurobiol. Aging 27, 1505–1513
166. Altman, J. and Das, G.D. (1966) Autoradiographic and histolog-
ical studies of postnatal neurogenesis. I. A longitudinal investi-
gation of the kinetics, migration and transformation of cells
incorporating tritiated thymidine in neonate rats, with special
reference to postnatal neurogenesis in some brain regions. J.
Comp. Neurol. 126, 337–389
167. Kuhn, H.G. et al. (1996) Neurogenesis in the dentate gyrus of the
adult rat: age-related decrease of neuronal progenitor prolifera-
tion. J. Neurosci. 16, 2027–2033
168. Yang, P. et al. (2014) International Journal of Developmental
Neuroscience. Int. J. Dev. Neurosci. 38, 1–9
169. Imura, T. et al. (2018) Differential expression of a stress-regu-
lated gene Nr4a2 characterizes early- and late-born hippocam-
pal granule cells. Hippocampus Published online October 26,
2018. http://dx.doi.org/10.1002/hipo.23045
170. Berg, D.A. et al. (2018) Radial glial cells in the adult dentate
gyrus: what are they and where do they come from?
F1000Research 7, 277
171. Hochgerner, H. et al. (2018) Conserved properties of dentate
gyrus neurogenesis across postnatal development revealed by
single-cell RNA sequencing. Nat. Neurosci. 21, 1–15
172. Lugert, S. et al. (2010) Quiescent and active hippocampal neural
stem cells with distinct morphologies respond selectively to
physiological and pathological stimuli and aging. Cell Stem Cell
6, 445–456
Trends in Neurosciences, Month Year, Vol. xx, No. yy 15
Another random document with
no related content on Scribd:
shaken by chance into the same box, yet scarcely are we therein settled
when we begin putting forth feelers of sympathy and recognition. There
was one young man who seemed to me a master in the art of making
desirable acquaintances for the trip. He entered upon his work ere the
Golden Gate had sunk below the horizon. He had a friendly word for all.
His approach and address were prepossessing. He spoke to me kindly. I was
miserable and flung myself upon him for sympathy. The wretch was merely
testing me as a compagnon de voyage. He found me unsuitable. He flung
me from him with easy but cold politeness, and consorted with an
“educated German gentleman.” I revenged myself by playing the same
tactics on a sea-and love-sick German carriage-maker. “An eye for an eye, a
tooth for a tooth,” you know.
We touched at Magdalena Bay and Punta Arenas. We expected to stay at
Punta Arenas twelve hours to discharge a quantity of flour. Four times
twelve hours we remained there. Everybody became very tired of Costa
Rica. The Costa Rican is not hurried in his movements. He took his own
time in sending the necessary lighters for that flour. A boat load went off
once in four hours. The Costa Ricans came on board, men and women,
great and small, inspected the Sacramento, enjoyed themselves, went on
shore again, lay down in the shade of their cocoanut palms, smoked their
cigarettes and slept soundly, while the restless, uneasy load of humanity on
the American steamer fretted, fumed, perspired, scolded at Costa Rican
laziness and ridiculed the Costa Rican government, which revolutionizes
once in six months, changes its flag once a year, taxes all improvements,
and acts up to the principle that government was made for the benefit of
those who govern. Many of the passengers went on shore. Some came back
laden with tropical flowers, others full of brandy. The blossoms filled the
vessel the whole night with perfume, while the brandy produced noise and
badly-sung popular melodies.
The Grinder went on shore with the rest. On returning he expressed
disgust at the Costa Ricans. He thought that “nothing could ever be made of
them.” He had no desire that the United States should ever assimilate with
any portion of the Torrid Zone. He predicted that such a fusion would prove
destructive to American energy and intelligence. We had enough southern
territory and torpor already. The man has no appreciation of the indolence
and repose of the tropics. He knows not that the most delicious of
enjoyments is the waking dream under the feathery palm, care and
restlessness flung aside, while the soul through the eye loses itself in the
blue depths above. He would doom us to an eternal rack of civilization and
Progress-work—grind, jerk, hurry, twist and strain, until our nerves, by
exhaustion unstrung and shattered, allow no repose of mind or body; and
even when we die our bones are so infected by restlessness and
goaheaditiveness that they rattle uneasily in our coffins.
Panama sums up thus: An ancient, walled, red-tiled city, full of convents
and churches; the ramparts half ruined; weeds springing atop the steeples
and belfries; a fleet of small boats in front of the city; Progress a little on
one side in the guise of the Isthmus Railroad depot, cars, engines, ferry-
boat, and red, iron lighters; a straggling guard of parti-colored, tawdry and
most slovenly-uniformed soldiers, with French muskets and sabre bayonets,
drawn up at the landing, commanded by an officer smartly dressed in blue,
gold, kepi, brass buttons and stripes, with a villainous squint eye, smoking a
cigar. About the car windows a chattering crowd of blacks, half blacks,
quarter blacks, coffee, molasses, brown, nankeen and straw colored natives,
thrusting skinny arms in at the windows, and at the end of those arms
parrots, large and small, in cages and out, monkeys, shells, oranges,
bananas, carved work, and pearls in various kinds of gold setting; all of
which were sorely tempting to some of the ladies, but ere many bargains
were concluded the train clattered off, and we were crossing the continent.
The Isthmus is a panorama of tropical jungle; it seems an excess, a
dissipation of vegetation. It is a place favorable also for the study of
external black anatomy. The natives kept undressing more and more as we
rolled on. For a mile or two after leaving Panama they did affect the shirt.
Beyond this, that garment seemed to have become unfashionable, and they
stood at their open doors with the same unclothed dignity that characterized
Adam in the Garden of Eden before his matrimonial troubles commenced.
Several young ladies in our care first looked up, then down, then across,
then sideways: then they looked very grave, and finally all looked at each
other and unanimously tittered.
Aspinwall! The cars stop; a black-and-tan battalion charge among us,
offering to carry baggage. They pursue us to the gate of the P. M. S. S.
depot; there they stop; we pass through one more cluster of orange, banana,
and cigar selling women; we push and jam into the depot, show our tickets,
and are on board the Ocean Queen. We are on the Atlantic side! It comes
over us half in awe, half in wonder, that this boat will, if she do not reach
the bottom first, carry us straight to a dock in New York. The anticipation of
years is developing into tangibility.
We cross the Caribbean. It is a stormy sea. Our second day thereon was
one of general nausea and depression. You have perhaps heard the air,
“Sister, what are the wild waves saying?” On that black Friday many of our
passengers seemed to be earnestly saying something over the Ocean
Queen’s side to the “wild, wild waves.” The Grinder went down with the
rest. I gazed triumphantly over his prostrate form laid out at full length on a
cabin settee. Seward, Bancroft, politics, metaphysics, poetry, and
philosophy were hushed at last. Both enthusiasm and patriotism find an
uneasy perch on a nauseated stomach.
But steam has not robbed navigation of all its romance. We find some
poetry in smoke, smoke stacks, pipes, funnels, and paddles, as well as in the
“bellying sails” and the “white-winged messengers of commerce.” I have a
sort of worship for our ponderous walking-beam, which swings its many
tons of iron upon its axis as lightly as a lady’s parasol held ’twixt thumb and
finger. It is an embodiment of strength, grace, and faithfulness. Night and
day, mid rain and sunshine, be the sea smooth or tempestuous, still that
giant arm is at its work, not swerving the fractional part of an inch from its
appointed sphere of revolution. It is no dead metallic thing: it is a
something rejoicing in power and use. It crunches the ocean ’neath its
wheels with that pride and pleasure of power which a strong man feels
when he fights his way through some ignoble crowd. The milder powers of
upper air more feebly impel yon ship; in our hold are the powers of earth,
the gnomes and goblins, the subjects of Pluto and Vulcan, begrimed with
soot and sweat, and the elements for millions and millions of years
imprisoned in the coal are being steadily set free. Every shovelful generates
a monster born of flame. As he flies sighing and groaning through the wide-
mouthed smokestack into the upper air, he gives our hull a parting shove
forward.
A death in the steerage—a passenger taken on board sick at Aspinwall.
All day long an inanimate shape wrapped in the American flag lies near the
gangway. At four P.M. an assemblage from cabin and steerage gather with
uncovered heads. The surgeon reads the service for the dead; a plank is
lifted up; with a last shrill whirl that which was once a man is shot into the
blue waters; in an instant it is out of sight and far behind, and we retire to
our state-rooms, thinking and solemnly wondering about that body sinking,
sinking, sinking in the depths of the Caribbean; of the sea monsters that
curiously approach and examine it; of the gradual decay of the corpse’s
canvas envelope; and far into the night, as the Ocean Queen shoots ahead,
our thoughts wander back in the blackness to the buried yet unburied dead.
The Torrid Zone is no more. This morning a blast from the north sweeps
down upon us. Cold, brassy clouds are in the sky; the ocean’s blue has
turned to a dark, angry brown, flecked with white caps and swept by blasts
fresh from the home of the northern floe and iceberg. The majority of the
passengers gather about the cabin-registers, like the house-flies benumbed
by the first cold snap of autumn in our northern kitchens. Light coats,
pumps and other summer apparel have given way to heavy boots, over-
coats, fur caps and pea-jackets. A home look settles on the faces of the
North Americans. They snuff their native atmosphere: they feel its bracing
influence. But the tawny-skinned Central Americans who have gradually
accumulated on board from the Pacific ports and Aspinwall, settle
inactively into corners or remain ensconced in their berths. The air which
kindles our energies wilts theirs. The hurricane-deck is shorn of its awnings.
Only a few old “shell-back” passengers maintain their place upon it, and yet
five days ago we sat there in midsummer moonlit evenings.
We are now about one hundred miles from Cape Hatteras. Old Mr.
Poddle and his wife are travelling for pleasure. Came to California by rail,
concluded to return by the Isthmus. Ever since we started Cape Hatteras has
loomed up fearfully in their imaginations. Old Mr. Poddle looks knowingly
at passing vessels through his field-glass, but doesn’t know a fore-and-aft
schooner from a man-of-war. Mrs. Poddle once a day inquires if there’s any
danger. Mr. Poddle does not talk so much, but evidently in private meditates
largely on hurricanes, gales, cyclones, sinking and burning vessels. Last
night we came in the neighborhood of the Gulf Stream. There were flashes
of lightning, “mare’s tails” in the sky, a freshening breeze and an increasing
sea. About eleven old Mr. Poddle came on deck. Mrs. Poddle, haunted by
Hatteras, had sent him out to see if “there was any danger;” for it is evident
that Mrs. Poddle is dictatress of the domestic empire. Mr. Poddle ascended
to the hurricane-deck, looked nervously to leeward, and just then an old
passenger salt standing by, who had during the entire passage
comprehended and enjoyed the Poddletonian dreads, remarked, “This is
nothing to what we shall have by morning.” This shot sent Poddle below.
This morning at breakfast the pair looked harassed and fatigued.
 The great question now agitating the mind of this floating community is,
“Shall we reach the New York pier at the foot of Canal street by Saturday
noon?” If we do, there is for us all long life, prosperity and happiness: if we
do not, it is desolation and misery. For Monday is New Year’s Day. On
Sunday we may not be able to leave the city: to be forced to stay in New
York over Sunday is a dreadful thought for solitary contemplation. We
study and turn it over in our minds for hours as we pace the deck. We live
over and over again the land-journey to our hearthstones at Boston,
Syracuse, and Cincinnati. We meet in thought our long-expectant relatives,
so that at last our air-castles become stale and monotonous, and we fear that
the reality may be robbed of half its anticipated pleasure from being so
often lived over in imagination.
Nine o’clock, Friday evening. The excitement increases. Barnegat Light
is in sight. Half the cabin passengers are up all night, indulging in
unprofitable talk and weariness, merely because we are so near home. Four
o’clock, and the faithful engine stops, the cable rattles overboard, and
everything is still. We are at anchor off Staten Island. By the first laggard
streak of winter’s dawn I am on the hurricane-deck. I am curious to see my
native North. It comes by degrees out of the cold blue fog on either side of
the bay. Miles of houses, spotted with patches of bushy-looking woodland
—bushy in appearance to a Californian, whose oaks grow large and widely
apart from each other, as in an English park. There comes a shrieking and
groaning and bellowing of steam-whistles from the monster city nine miles
away. Soon we weigh anchor and move up toward it. Tugs dart fiercely
about, or laboriously puff with heavilyladen vessels in tow. Stately ocean
steamers surge past, outward bound. We become a mere fragment of the
mass of floating life. We near the foot of Canal street. There is a great deal
of shouting and bawling and counter-shouting and counter-bawling, with
expectant faces on the wharf, and recognitions from shore to steamer and
from steamer to shore. The young woman who flirted so ardently with the
young Californian turns out to be married, and that business-looking,
middle-aged man on the pier is her husband. Well, I never! Why, you are
slow, my friend, says inward reflection. You are not versed in the customs
of the East. At last the gangway plank is flung out. We walk on shore. It is
now eighteen years since that little floating world society cemented by a
month’s association scattered forever from each other’s sight at the Canal
street pier.
THE WHITE CROSS LIBRARY
Is a MONTHLY system of publication, showing how results may be
obtained in all business and art, through the force of thought and silent
power of mind.
SUBSCRIPTION RATES: $1.50 PER YEAR; SINGLE COPIES, 15
CENTS.
VOLUME I.
No. 1—You travel when you sleep.
“ 2—Where you travel when you sleep.
“ 3—The process of re-embodiment.
“ 4—Re-embodiment universal in nature.
“ 5—The art of forgetting.
“ 6—How thoughts are born.
“ 7—The law of success.
“ 8—How to keep your strength.
“ 9—Consider the lilies.
“ 10—Art of study.
“ 11—Profit and loss in associates.
“ 12—The slavery of fear.
“ 13—What are spiritual gifts.
VOLUME II.
No. 14—Some laws of health and beauty.
“ 15—Mental intemperance.
“ 16—Law of marriage.
“ 17—The God in yourself.
“ 18—Force, and how to get it.
“ 19—The doctor within.
“ 20—Co-operation of thought.
“ 21—The religion of dress.
 “ 22—The necessity of riches.
“ 23—Use your riches.
“ 24—The healing and renewing force of spring.
“ 25—Positive and negative thought.
VOLUME III.
No. 26.—The practical use of reverie.
“ 27.—Your two memories.
“ 28.—Self teaching; or, the art of learning how to learn.
“ 29.—How to push your business.
“ 30.—The religion of the drama.
“ 31.—The uses of sickness.
“ 32.—Who are our relations?
“ 33.—The use of a room.
“ 34.—Man and wife.
“ 35.—Cure for alcoholic intemperance.
“ 36.—The church of silent demand.
“ 37.—The mystery of sleep, or our double existence.
“Your Forces and How to Use Them,” FIRST, SECOND AND THIRD
VOLUMES.
Each Volume containing one year’s issue of the White Cross Library. Price,
$2.00 each.
THE “SWAMP ANGEL” (by Prentice Mulford,) 1.25.
Prentice Mulford’s Story, (36 Chapters—300 pages,) 1.50.
This list embraces all numbers issued to May, 1889.
Copies of all Numbers issued can be obtained.
Address, F. J. NEEDHAM,
Publisher White Cross Library,
52 WEST 14th STREET, NEW YORK CITY, U. S. A.

Typographical errors corrected by the etext transcriber:

so may ghastly heaps=> so many ghastly heaps {pg 46}
 Is is ornamented=> It is ornamented {pg 117}
Theyr’e no use in bizness=> They’re no use in bizness {pg 151}
envied of many=> envy of many {pg 182}
many another county=> many another counties {pg 188}
as general propector=> as general prospector {pg 200}
succedeed in getting=> succeeded in getting {pg 200}
their first instalment=> their first installment {pg 200}
an aceptance of=> an acceptance of {pg 272}
well have endeavroed=> well have endeavored {pg 289}
came on broad=> came on board {pg 290}
fleecked with white caps=> flecked with white caps {pg 296}
 *** END OF THE PROJECT GUTENBERG EBOOK PRENTICE
MULFORD'S STORY: LIFE BY LAND AND SEA ***

Updated editions will replace the previous one—the old editions will
be renamed.

Creating the works from print editions not protected by U.S.

copyright law means that no one owns a United States copyright in
these works, so the Foundation (and you!) can copy and distribute it
in the United States without permission and without paying copyright
royalties. Special rules, set forth in the General Terms of Use part of
this license, apply to copying and distributing Project Gutenberg™
electronic works to protect the PROJECT GUTENBERG™ concept
and trademark. Project Gutenberg is a registered trademark, and
may not be used if you charge for an eBook, except by following the
terms of the trademark license, including paying royalties for use of
the Project Gutenberg trademark. If you do not charge anything for
copies of this eBook, complying with the trademark license is very
easy. You may use this eBook for nearly any purpose such as
creation of derivative works, reports, performances and research.
Project Gutenberg eBooks may be modified and printed and given
away—you may do practically ANYTHING in the United States with
eBooks not protected by U.S. copyright law. Redistribution is subject
to the trademark license, especially commercial redistribution.

START: FULL LICENSE

THE FULL PROJECT GUTENBERG LICENSE
 PLEASE READ THIS BEFORE YOU DISTRIBUTE OR USE THIS WORK

To protect the Project Gutenberg™ mission of promoting the free

distribution of electronic works, by using or distributing this work (or
any other work associated in any way with the phrase “Project
Gutenberg”), you agree to comply with all the terms of the Full
Project Gutenberg™ License available with this file or online at
www.gutenberg.org/license.

Section 1. General Terms of Use and

Redistributing Project Gutenberg™
electronic works
1.A. By reading or using any part of this Project Gutenberg™
electronic work, you indicate that you have read, understand, agree
to and accept all the terms of this license and intellectual property
(trademark/copyright) agreement. If you do not agree to abide by all
the terms of this agreement, you must cease using and return or
destroy all copies of Project Gutenberg™ electronic works in your
possession. If you paid a fee for obtaining a copy of or access to a
Project Gutenberg™ electronic work and you do not agree to be
bound by the terms of this agreement, you may obtain a refund from
the person or entity to whom you paid the fee as set forth in
paragraph 1.E.8.

1.B. “Project Gutenberg” is a registered trademark. It may only be

used on or associated in any way with an electronic work by people
who agree to be bound by the terms of this agreement. There are a
few things that you can do with most Project Gutenberg™ electronic
works even without complying with the full terms of this agreement.
See paragraph 1.C below. There are a lot of things you can do with
Project Gutenberg™ electronic works if you follow the terms of this
agreement and help preserve free future access to Project
Gutenberg™ electronic works. See paragraph 1.E below.
1.C. The Project Gutenberg Literary Archive Foundation (“the
Foundation” or PGLAF), owns a compilation copyright in the
collection of Project Gutenberg™ electronic works. Nearly all the
individual works in the collection are in the public domain in the
United States. If an individual work is unprotected by copyright law in
the United States and you are located in the United States, we do
not claim a right to prevent you from copying, distributing,
performing, displaying or creating derivative works based on the
work as long as all references to Project Gutenberg are removed. Of
course, we hope that you will support the Project Gutenberg™
mission of promoting free access to electronic works by freely
sharing Project Gutenberg™ works in compliance with the terms of
this agreement for keeping the Project Gutenberg™ name
associated with the work. You can easily comply with the terms of
this agreement by keeping this work in the same format with its
attached full Project Gutenberg™ License when you share it without
charge with others.

1.D. The copyright laws of the place where you are located also
govern what you can do with this work. Copyright laws in most
countries are in a constant state of change. If you are outside the
United States, check the laws of your country in addition to the terms
of this agreement before downloading, copying, displaying,
performing, distributing or creating derivative works based on this
work or any other Project Gutenberg™ work. The Foundation makes
no representations concerning the copyright status of any work in
any country other than the United States.

1.E. Unless you have removed all references to Project Gutenberg:

1.E.1. The following sentence, with active links to, or other

immediate access to, the full Project Gutenberg™ License must
appear prominently whenever any copy of a Project Gutenberg™
work (any work on which the phrase “Project Gutenberg” appears, or
with which the phrase “Project Gutenberg” is associated) is
accessed, displayed, performed, viewed, copied or distributed:
 This eBook is for the use of anyone anywhere in the United
States and most other parts of the world at no cost and with
almost no restrictions whatsoever. You may copy it, give it away
or re-use it under the terms of the Project Gutenberg License
included with this eBook or online at www.gutenberg.org. If you
are not located in the United States, you will have to check the
laws of the country where you are located before using this
eBook.

1.E.2. If an individual Project Gutenberg™ electronic work is derived

from texts not protected by U.S. copyright law (does not contain a
notice indicating that it is posted with permission of the copyright
holder), the work can be copied and distributed to anyone in the
United States without paying any fees or charges. If you are
redistributing or providing access to a work with the phrase “Project
Gutenberg” associated with or appearing on the work, you must
comply either with the requirements of paragraphs 1.E.1 through
1.E.7 or obtain permission for the use of the work and the Project
Gutenberg™ trademark as set forth in paragraphs 1.E.8 or 1.E.9.

1.E.3. If an individual Project Gutenberg™ electronic work is posted

with the permission of the copyright holder, your use and distribution
must comply with both paragraphs 1.E.1 through 1.E.7 and any
additional terms imposed by the copyright holder. Additional terms
will be linked to the Project Gutenberg™ License for all works posted
with the permission of the copyright holder found at the beginning of
this work.

1.E.4. Do not unlink or detach or remove the full Project

Gutenberg™ License terms from this work, or any files containing a
part of this work or any other work associated with Project
Gutenberg™.

1.E.5. Do not copy, display, perform, distribute or redistribute this

electronic work, or any part of this electronic work, without
prominently displaying the sentence set forth in paragraph 1.E.1 with
active links or immediate access to the full terms of the Project
Gutenberg™ License.
1.E.6. You may convert to and distribute this work in any binary,
compressed, marked up, nonproprietary or proprietary form,
including any word processing or hypertext form. However, if you
provide access to or distribute copies of a Project Gutenberg™ work
in a format other than “Plain Vanilla ASCII” or other format used in
the official version posted on the official Project Gutenberg™ website
(www.gutenberg.org), you must, at no additional cost, fee or expense
to the user, provide a copy, a means of exporting a copy, or a means
of obtaining a copy upon request, of the work in its original “Plain
Vanilla ASCII” or other form. Any alternate format must include the
full Project Gutenberg™ License as specified in paragraph 1.E.1.

1.E.7. Do not charge a fee for access to, viewing, displaying,

performing, copying or distributing any Project Gutenberg™ works
unless you comply with paragraph 1.E.8 or 1.E.9.

1.E.8. You may charge a reasonable fee for copies of or providing

access to or distributing Project Gutenberg™ electronic works
provided that:

• You pay a royalty fee of 20% of the gross profits you derive from
the use of Project Gutenberg™ works calculated using the
method you already use to calculate your applicable taxes. The
fee is owed to the owner of the Project Gutenberg™ trademark,
but he has agreed to donate royalties under this paragraph to
the Project Gutenberg Literary Archive Foundation. Royalty
payments must be paid within 60 days following each date on
which you prepare (or are legally required to prepare) your
periodic tax returns. Royalty payments should be clearly marked
as such and sent to the Project Gutenberg Literary Archive
Foundation at the address specified in Section 4, “Information
about donations to the Project Gutenberg Literary Archive
Foundation.”

• You provide a full refund of any money paid by a user who

notifies you in writing (or by e-mail) within 30 days of receipt that
s/he does not agree to the terms of the full Project Gutenberg™
License. You must require such a user to return or destroy all
 copies of the works possessed in a physical medium and
discontinue all use of and all access to other copies of Project
Gutenberg™ works.

• You provide, in accordance with paragraph 1.F.3, a full refund of

any money paid for a work or a replacement copy, if a defect in
the electronic work is discovered and reported to you within 90
days of receipt of the work.

• You comply with all other terms of this agreement for free
distribution of Project Gutenberg™ works.

1.E.9. If you wish to charge a fee or distribute a Project Gutenberg™

electronic work or group of works on different terms than are set
forth in this agreement, you must obtain permission in writing from
the Project Gutenberg Literary Archive Foundation, the manager of
the Project Gutenberg™ trademark. Contact the Foundation as set
forth in Section 3 below.

1.F.

1.F.1. Project Gutenberg volunteers and employees expend

considerable effort to identify, do copyright research on, transcribe
and proofread works not protected by U.S. copyright law in creating
the Project Gutenberg™ collection. Despite these efforts, Project
Gutenberg™ electronic works, and the medium on which they may
be stored, may contain “Defects,” such as, but not limited to,
incomplete, inaccurate or corrupt data, transcription errors, a
copyright or other intellectual property infringement, a defective or
damaged disk or other medium, a computer virus, or computer
codes that damage or cannot be read by your equipment.

1.F.2. LIMITED WARRANTY, DISCLAIMER OF DAMAGES - Except

for the “Right of Replacement or Refund” described in paragraph
1.F.3, the Project Gutenberg Literary Archive Foundation, the owner
of the Project Gutenberg™ trademark, and any other party
distributing a Project Gutenberg™ electronic work under this
agreement, disclaim all liability to you for damages, costs and
expenses, including legal fees. YOU AGREE THAT YOU HAVE NO
REMEDIES FOR NEGLIGENCE, STRICT LIABILITY, BREACH OF
WARRANTY OR BREACH OF CONTRACT EXCEPT THOSE
PROVIDED IN PARAGRAPH 1.F.3. YOU AGREE THAT THE
FOUNDATION, THE TRADEMARK OWNER, AND ANY
DISTRIBUTOR UNDER THIS AGREEMENT WILL NOT BE LIABLE
TO YOU FOR ACTUAL, DIRECT, INDIRECT, CONSEQUENTIAL,
PUNITIVE OR INCIDENTAL DAMAGES EVEN IF YOU GIVE
NOTICE OF THE POSSIBILITY OF SUCH DAMAGE.

1.F.3. LIMITED RIGHT OF REPLACEMENT OR REFUND - If you

discover a defect in this electronic work within 90 days of receiving it,
you can receive a refund of the money (if any) you paid for it by
sending a written explanation to the person you received the work
from. If you received the work on a physical medium, you must
return the medium with your written explanation. The person or entity
that provided you with the defective work may elect to provide a
replacement copy in lieu of a refund. If you received the work
electronically, the person or entity providing it to you may choose to
give you a second opportunity to receive the work electronically in
lieu of a refund. If the second copy is also defective, you may
demand a refund in writing without further opportunities to fix the
problem.

1.F.4. Except for the limited right of replacement or refund set forth in
paragraph 1.F.3, this work is provided to you ‘AS-IS’, WITH NO
OTHER WARRANTIES OF ANY KIND, EXPRESS OR IMPLIED,
INCLUDING BUT NOT LIMITED TO WARRANTIES OF
MERCHANTABILITY OR FITNESS FOR ANY PURPOSE.

1.F.5. Some states do not allow disclaimers of certain implied

warranties or the exclusion or limitation of certain types of damages.
If any disclaimer or limitation set forth in this agreement violates the
law of the state applicable to this agreement, the agreement shall be
interpreted to make the maximum disclaimer or limitation permitted
by the applicable state law. The invalidity or unenforceability of any
provision of this agreement shall not void the remaining provisions.
1.F.6. INDEMNITY - You agree to indemnify and hold the
Foundation, the trademark owner, any agent or employee of the
Foundation, anyone providing copies of Project Gutenberg™
electronic works in accordance with this agreement, and any
volunteers associated with the production, promotion and distribution
of Project Gutenberg™ electronic works, harmless from all liability,
costs and expenses, including legal fees, that arise directly or
indirectly from any of the following which you do or cause to occur:
(a) distribution of this or any Project Gutenberg™ work, (b)
alteration, modification, or additions or deletions to any Project
Gutenberg™ work, and (c) any Defect you cause.

Section 2. Information about the Mission of

Project Gutenberg™
Project Gutenberg™ is synonymous with the free distribution of
electronic works in formats readable by the widest variety of
computers including obsolete, old, middle-aged and new computers.
It exists because of the efforts of hundreds of volunteers and
donations from people in all walks of life.

Volunteers and financial support to provide volunteers with the

assistance they need are critical to reaching Project Gutenberg™’s
goals and ensuring that the Project Gutenberg™ collection will
remain freely available for generations to come. In 2001, the Project
Gutenberg Literary Archive Foundation was created to provide a
secure and permanent future for Project Gutenberg™ and future
generations. To learn more about the Project Gutenberg Literary
Archive Foundation and how your efforts and donations can help,
see Sections 3 and 4 and the Foundation information page at
www.gutenberg.org.

Section 3. Information about the Project

Gutenberg Literary Archive Foundation
The Project Gutenberg Literary Archive Foundation is a non-profit
501(c)(3) educational corporation organized under the laws of the
state of Mississippi and granted tax exempt status by the Internal
Revenue Service. The Foundation’s EIN or federal tax identification
number is 64-6221541. Contributions to the Project Gutenberg
Literary Archive Foundation are tax deductible to the full extent
permitted by U.S. federal laws and your state’s laws.

The Foundation’s business office is located at 809 North 1500 West,

Salt Lake City, UT 84116, (801) 596-1887. Email contact links and up
to date contact information can be found at the Foundation’s website
and official page at www.gutenberg.org/contact

Section 4. Information about Donations to

the Project Gutenberg Literary Archive
Foundation
Project Gutenberg™ depends upon and cannot survive without
widespread public support and donations to carry out its mission of
increasing the number of public domain and licensed works that can
be freely distributed in machine-readable form accessible by the
widest array of equipment including outdated equipment. Many small
donations ($1 to $5,000) are particularly important to maintaining tax
exempt status with the IRS.

The Foundation is committed to complying with the laws regulating

charities and charitable donations in all 50 states of the United
States. Compliance requirements are not uniform and it takes a
considerable effort, much paperwork and many fees to meet and
keep up with these requirements. We do not solicit donations in
locations where we have not received written confirmation of
compliance. To SEND DONATIONS or determine the status of
compliance for any particular state visit www.gutenberg.org/donate.

While we cannot and do not solicit contributions from states where

we have not met the solicitation requirements, we know of no
prohibition against accepting unsolicited donations from donors in
such states who approach us with offers to donate.

International donations are gratefully accepted, but we cannot make

any statements concerning tax treatment of donations received from
outside the United States. U.S. laws alone swamp our small staff.

Please check the Project Gutenberg web pages for current donation
methods and addresses. Donations are accepted in a number of
other ways including checks, online payments and credit card
donations. To donate, please visit: www.gutenberg.org/donate.

Section 5. General Information About Project

Gutenberg™ electronic works
Professor Michael S. Hart was the originator of the Project
Gutenberg™ concept of a library of electronic works that could be
freely shared with anyone. For forty years, he produced and
distributed Project Gutenberg™ eBooks with only a loose network of
volunteer support.

Project Gutenberg™ eBooks are often created from several printed

editions, all of which are confirmed as not protected by copyright in
the U.S. unless a copyright notice is included. Thus, we do not
necessarily keep eBooks in compliance with any particular paper
edition.

Most people start at our website which has the main PG search
facility: www.gutenberg.org.

This website includes information about Project Gutenberg™,

including how to make donations to the Project Gutenberg Literary
Archive Foundation, how to help produce our new eBooks, and how
to subscribe to our email newsletter to hear about new eBooks.