Recalibrating the Relevance of Adult

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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

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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

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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.
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Trends in Neurosciences, Month Year, Vol. xx, No. yy 15
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 When the disease has existed for a certain time, sub-epithelial
hæmorrhages, ulcerations, vegetations and points of sclerosis may all
co-exist, a fact which shows that the disease does not develop all at
once, but that, on the contrary, every little lesion develops separately
and continuously. This fact also explains the length of time for which
blood may be passed, despite the presence of old or healed lesions.
Finally, in very old standing cases dating from several years back
(Moussu saw an animal aged twenty-eight years which had suffered
from this disease for more than twenty years, but in a very
intermittent fashion), it is not exceptional to find numerous
papilliform vegetations 1 or 2 inches in length, either with a fine
pedicle or largely sessile, invading one-half or two-thirds of the
internal surface of the bladder.
These vegetations sometimes, though rarely, invade the ureters.
When they occur towards the point where these conduits enter the
bladder, they obstruct the passage of urine, and lead to the
development of hydro-nephrosis or pyelo-nephritis.
Symptoms. The early symptoms often escape notice, because
general disturbance is rare. The first appreciable signs are cystitis
and frequent urination.
The urine passed is turbid, particularly towards the end of the act
of urination; then it is of a pink or red colour, and all intermediate
shades between a pale pink and a bright arterial red colour may be
observed.
The patients sometimes seem to pass unaltered blood in the urine,
but on microscopic examination this blood is found to be extremely
diluted. Provided the bladder is not gravely infected by the
(secondary) penetration of germs into its cavity the blood corpuscles
remain normal, or are scarcely changed. As soon as the bladder,
however, becomes secondarily infected an almost immediate change
takes place; the red blood corpuscles become crenated, broken up
and dissociated; the hæmoglobin is also partly dissolved and
modified, and at this stage the urine is red-brown or coffee-coloured,
according to the length of time it has been retained in the bladder.
In other cases, chiefly when hæmaturia has existed for some time,
the extravasated blood coagulates in the bladder, and the urine
passed contains filamentous clots the size of a man’s thumb, a
pigeon’s egg, or more. If the clots formed are too large to be passed,
which is often the case in the ox, they may obstruct the urethra,
causing retention of urine and all the accidents which accompany
this condition, even including rupture of the bladder. This, in the ox,
is a frequent termination. In the cow the dilatability and shortness of
the urethra render retention of urine much rarer. It is certainly
possible, however, and it is not exceptional, to find from 4 to 6 lbs. of
clotted matter in the distended bladder. All these conditions can be
detected by rectal exploration, and by attention to the symptoms of
obstruction of the urethra.
Whenever there is retention of clots dysuria is extremely marked
and, so to speak, permanent, the animals having continual tenesmus.
Hæmaturia observes a slow, progressive course, which, in time,
ends in death by exhaustion, though this is not invariably the case.
Hæmaturia is frequently intermittent, and, after having been very
marked for weeks or months, may suddenly or gradually cease, and
only reappear a long time afterwards. This fact is explained by a
study of the development of the lesions. When ulceration occurs the
sub-epithelial vessels of the mucous membrane, which have
contributed to the formation of the hæmorrhagic spot, are widely
open, and a capillary hæmorrhage results; but as soon as a small clot
forms in this position, or local capillary thrombosis occurs, the
hæmorrhage ceases, with the result that the hæmaturia disappears.
Unfortunately, however, the obliterating clots are not permanent,
any more than the local thrombosis—or, in the event of their proving
permanent, another small lesion develops at a different point, and
this lesion may at any time cause the reappearance of the hæmaturia;
the process goes on until the animal succumbs. Should the lesions
heal successively, spontaneous recovery may take place, but such
recovery is exceptional.
The animals may not appear to suffer from the passage of blood
for weeks or even months, but after a time they become less capable
of replacing the loss. They become anæmic, the number of corpuscles
falls from the normal figure of from six to seven millions of red
corpuscles per cubic millimètre to three millions, two millions, one
million, and even to five hundred or eight hundred thousand.
The richness in hæmoglobin simultaneously diminishes; wasting
progresses to the point of cachexia, and the appetite diminishes
while diarrhœa appears; swellings are noticeable about certain parts
of the body; and the animals, continuing to pass blood, die in a state
of absolute exhaustion, without apparent suffering.
This termination is the most common, unless slaughter is
determined on, and is very different from the premature end which
follows the formation of clots and obstruction of the urethra.
Externally the patients only show feebleness, pallor of the visible
mucous membranes, and difficulty in urination. The bunch of hair at
the lower commissure of the vulva is always soiled with blood-
stained urine or little clots.
Hæmaturia may cause death by exhaustion in from six weeks to
two months, but not infrequently it lasts for months or even years.
Diagnosis. The diagnosis presents no difficulty when the urine
can be examined; but in the periods of intermittence no opinion can
be advanced. These intermittences are so frequent that in parts of the
country ravaged by this disease it is a usual custom, when selling, to
grant or refuse guarantees for a longer or shorter term.
The condition can be distinguished from parasitic hæmoglobinuria
(piroplasmosis) or from Brou’s disease (a febrile disease of rapid
development) by simply examining the urine or blood.
Prognosis. The prognosis is extremely grave, for, up to the
present, no really efficacious treatment has been discovered, and
although some animals may live for years without their lives being in
any way endangered, this cannot possibly be foreseen, and there is
no economic advantage in keeping them.
Treatment. No curative treatment is known.
It is true that iron salts, tonics, Rabel’s liquid, decoctions of certain
plants, such as plantain, have been recommended, but apart from the
fact that they are of doubtful efficacy, they cannot be used over long
periods. All these preparations also tend to increase the coagulability
of the blood; but considering that the disease is beyond question of a
parasitic character, good results cannot always be expected of them.
Preventive treatment appears more hopeful, although even in this
connection, the best informed appear to have considerable doubts.
All those who have studied the question agree in recommending
drainage of the pasturages, and their improvement by the use of
various manures, particularly superphosphates and lime. These
improvements alter the character of the pasture, render the soil
healthier, and may perhaps prove sufficient to diminish or prevent
the local growth of the germs. Under such conditions, Boudeaud
declares that he has seen hæmaturia disappear from farms where it
had previously been in permanent possession. It has also been
recommended that the affected cattle should be sent elsewhere to
places where the disease does not exist, and experience shows that
spontaneous recovery is more frequent under such conditions.
It is probable that, during attacks of hæmaturia in a contaminated
country, successive parasitic infestations occur, which would explain
the persistence with which blood is passed, a symptom which does
not occur in a healthy country. This view, however, is still only an
hypothesis.
 CHAPTER III.
DISEASES OF THE KIDNEYS.

CONGESTION OF THE KIDNEYS.

Congestion of the kidneys is not a morbid condition in the strict

sense of the term, for it is merely the forerunner of nephritis caused
by infectious diseases or intoxications (primary active congestions)
or the final consequence of other diseases, such as diseases of the
heart or liver, mechanical compression of the vena cava or renal
veins (secondary passive congestion, cardiac kidney).
Nevertheless, under certain circumstances the development of
nephritis may be arrested at the primary congestive stage, and it is
only then that an opportunity occurs of studying it as a definite
complaint.
Causation. All infections accompanied by lesions of the kidneys,
and these are numerous (gangrenous coryza, anthrax, parasitic
hæmoglobinuria), produce congestion of the kidneys.
Cold also acts directly under certain conditions, as do large doses
of diuretics, irritant foods the principles of which are eliminated
through the urine (fermenting or putrid sugar-pulp, for example),
and foods rich in resins, essential oils, various glucosides, tannin, etc.
(young shoots of trees during the spring-time).
Symptoms. The symptoms are difficult to define accurately, and
the diagnosis can only be arrived at with the aid of the history.
Renal congestion produces pain, indicated by dull colic and
repeated and ineffectual attempts to urinate, suggesting acute
cystitis. The patients lose appetite, and present all the general
symptoms of marked visceral inflammation, viz., fever, acceleration
of breathing, somewhat tumultuous action of the heart, etc.
External or internal examination of the kidneys reveals abnormal
sensitiveness. The urine is of a dark or bright-red tint, owing to the
presence of red blood corpuscles. These blood corpuscles are
precipitated on placing the fluid in a tall glass, and can be detected,
together with renal epithelium, by microscopic examination.
 The diagnosis is somewhat difficult, and it requires very careful
attention to distinguish between congestion of the kidney and true
nephritis.
The prognosis should always be reserved until it is certain that
acute nephritis will not ultimately develop.
The treatment consists in removing the cause of the congestion;
rich foods, or foods containing irritant principles, should, therefore,
be avoided, as also the administration of diuretics, etc.
Otherwise, the treatment is similar to that employed in all visceral
inflammations: bleeding to the extent of two to four quarts,
according to the size of the animals, warm poultices to the loins and
flanks, dry friction, mucilaginous drinks and emollient decoctions of
barley or pellitory. The animals should be kept in a warm place.
In cases of passive and secondary congestion, treatment must be
directed towards improving the condition of the organ primarily
affected, whether it be the heart, liver, or lymphatic glands.

ACUTE NEPHRITIS.

The term nephritis applies to inflammation of the renal tissues.

Clinically, two forms only can be distinguished, the acute and the
chronic.
As regards its pathological anatomy, the inflammation may
principally affect either the interstitial tissue or the epithelial
parenchyma, a fact which has suggested the division of the condition
into epithelial nephritis, interstitial nephritis, and mixed nephritis.
Clinically, such distinctions are impossible; and in reality all forms of
nephritis are to a varying degree mixed, the lesions predominating in
one or other of the constituent tissues. These lesions depend on the
extent, intensity, and duration of the inflammatory attack, whatever
the primary causes. All the constituent tissues of the kidney may be
affected, simultaneously or individually: the Malpighian corpuscles,
the convoluted tubules, the collecting tubules, or the interstitial
connective tissue.
Causation. Cold seems to be an important factor. All acute or
chronic intoxications in which the toxic principles are eliminated by
the kidneys, such as poisoning by cantharides, fermented beet pulp,
young shoots of trees or toxic plants, may cause acute nephritis.
Infectious diseases, such as gangrenous coryza, hæmoglobinuria,
tuberculosis and post-partum infections, also play an important part,
whether the nephritis be direct, that is to say, the result of the
infecting agent itself, or indirect, i.e., produced by toxins generated
in the body. In female animals gestation is an often unsuspected
cause. Moussu believes that albuminuria is frequent during
gestation, and although in most cases it is only of moderate degree,
he thinks it is often associated with subacute nephritis, which might
be aggravated by an accidental cause.
Many forms of nephritis are overlooked in consequence of their
slight character.
Symptoms. The early symptoms are similar to those of
congestion of the kidney, viz., dull colic, excessive sensitiveness over
the region of the loins, passage of pink urine, loss of appetite, and
fever. At a later stage, in cases of acute nephritis due to cold, the
animal stands with the limbs close together and remains stationary,
arching the loins and back, which are held stiffly. The animal
obstinately refuses to move in consequence of the pain produced by
so doing.
The general condition becomes grave, respiration is rapid, the
pulse frequent, the artery tense, the muzzle dry, the accessible
mucous membranes are injected, and appetite is almost entirely lost.
Urine is frequently passed, but the act causes pain, and the
quantity is small. Absolute anuria is rare, and does not last long.
The urine is generally sanguinolent, at least at first, but to a very
varying extent. It is always albuminous, the quantity of albumen
varying enormously, and on microscopic examination, is usually
found to contain red and white blood corpuscles, epithelium from
the kidney hyaline or epithelial cylinders, and, towards the end, pus
corpuscles.
Œdema or anasarca, though common in mankind, does not occur
in a very marked form, except in intense acute nephritis. Epistaxis is
also rare.
Diagnosis. The diagnosis requires some care, because unless the
urine be examined the symptoms might lead to error. Nevertheless,
it is always possible to distinguish between this condition and
hæmaturia or accidental renal hæmorrhage.
Prognosis. The prognosis is grave, because absolute recovery is
rare, and because the condition is very apt to become chronic.
The degree of anuria and the respiratory difficulty are of great
service in confirming the prognosis. As soon as urine is freely passed
the prognosis becomes more favourable.
Treatment. Among the most effective methods of treatment must
be included bleeding, which always produces some improvement.
Dry friction over the kidneys and flanks, hot moist applications, and
the application of a sheep-skin to the loins are also of service.
Internally, mucilaginous drinks, diuretic decoctions and milk give
the best results. The proportion of albumen rapidly diminishes,
dysuria becomes less marked, urine is passed in greater quantities,
and in from eight to ten days all the alarming symptoms disappear.
Bicarbonate of soda may then be given for a fortnight.
In very grave cases camphor, bromide of camphor, injections of
camphorated oil (1 to 2½ drachms internally, or 1 to 1¼ drachms in
subcutaneous injections) give excellent results in modifying the pain
and moderating the inflammation.
From ½ to 1 drachm of digitalis in powder, or better still an
injection of from 5 milligrammes to 1 centigramme of digitalin may
also be given when dyspnœa is very great and is accompanied by
anasarca. Medicines such as oil of turpentine and considerable doses
of nitrate of potash, however, are contra-indicated.

CHRONIC NEPHRITIS

True chronic nephritis, i.e., a condition strictly limited to the renal

tissue, and unaccompanied by pyelitis, is still little known among our
domestic animals. The symptoms characterising it have not always
been carefully noted, and the diagnosis is very often uncertain.
Nevertheless, one of the most common forms has been carefully
studied by Seuffert, viz., chronic hypertrophic nephritis.
Causation. Chronic nephritis is the common sequel to the acute
forms, whatever their origin, but it may also occur primarily from
repeated chills produced by such conditions as exposure to heavy
continued rain when at grass, chills contracted during cold nights
and the great variations in temperature in spring and autumn. The
conditions, however, thus produced are rather of the nature of
subacute nephritis than of chronic nephritis, properly so called.
These forms of chronic nephritis may also occur primarily in
consequence of chronic hepatic lesions with pressure on the
posterior vena cava, producing blood stasis in the kidneys. Finally,
they may represent the delayed effects of slight lesions which have
escaped notice and have developed during grave diseases or as a
consequence of repeated gestation.
From the anatomico-pathological standpoint, the only conditions
hitherto recognised are the chronic hypertrophic forms of nephritis
(large, white sclerotic kidney with lardaceous degeneration and
sometimes marbling). This is probably because the animals are
slaughtered as soon as they suffer in condition, but if they were kept
long enough they would undoubtedly suffer also from the atrophic
chronic forms of nephritis found in man and in the dog. In the case
of man observation has shown that these two forms only represent
different stages in the development of one disease, the large,
hypertrophied kidney of the early stages afterwards undergoing
marked progressive atrophy.
The symptoms are at first so vague that diagnosis would be
impossible on a single examination. Seuffert states that the condition
develops as follows:—
The first sign, loss of appetite, is soon followed by constipation and
dull colic, due to congestion of the kidney; the pain is often so great
as to cause intermittent groaning.
The urine passed is always turbid, and sometimes blood-stained,
but this staining rarely lasts longer than a week. The urine then
gradually resumes its normal appearance, is passed in small
quantities, and contains more or less albumen. The yield of milk
markedly and progressively diminishes.
If treatment is resorted to at this stage laxatives and diuretics
appear to effect a real improvement. Unfortunately, however, the
apparent improvement is but temporary; the kidneys become
hypertrophied, and the right soon occupies the whole of the
sublumbar space, its margin extending as far as the extremity of the
transverse processes near the anterior angle of the hollow of the
flank.
This hypertrophy and the extreme sensitiveness can be detected by
external palpation. Internal examination confirms the facts so
observed as regards both the kidneys.
The patients eat little and become thin, whatever treatment be
adopted. They progressively waste, and die after some months in a
state of marasmus, exhausted and intoxicated.
It is very probable that the digestive disturbances are complicated
by respiratory and cardiac trouble, as in man and the dog; but
neither cardiac nor uræmic disease of the kidney has been recorded.
Diagnosis. When the urine is analysed the diagnosis becomes
comparatively easy. Persistent albuminuria and hypertrophy of the
kidneys during the early stages are significant indications. There can
be little hesitation except in so far as pyelo-nephritis and hydro-
nephrosis are concerned, but the conditions are distinguished by the
character of the urine in the two latter cases, together with the
condition of the pelvis of the kidney, and of the ureters.
Prognosis. The prognosis is grave, and Seuffert believes that
recovery never occurs. This is also true, generally speaking, as
regards all forms of chronic nephritis.
Treatment. As the disease must be regarded as incurable there is
really no justification for treatment. Nevertheless, if for special
reasons the owner wishes to keep the animals for a certain time, as in
the case of a cow near its time of calving, recourse may be had to the
internal treatment suggested in acute nephritis, viz., mucilaginous
drinks, diuretic infusions, milk, bicarbonate of soda, stimulating
applications to the loins, etc.

HYDRO-NEPHROSIS.

Hydro-nephrosis, i.e., retention of urine in the pelvis of the kidney

and in the collecting and secreting tubules, is a somewhat common
malady of the bovine species. It is usually confined to one kidney.
 Causation.
Anything which
obstructs the
discharge of
urine through
the ureters may
cause hydro-
nephrosis.
Thus, vesical
tumours
pressing on the
orifices of the
ureters, calculi
which have
become fixed in
them, torsion or
“kinking” of the
ureters, may
bring about
hydro-
nephrosis. The
urine secreted
Fig. 228.—Hydro-nephrosis of the kidney. by the kidney
being unable to
escape,
accumulates in the pelvis of the kidney, in the ureter, and uriniferous
tubules, producing dull colic, which escapes observation, or the exact
cause of which is not discovered, because the second kidney
vicariously acts for the one affected, and urination continues
regularly. Secretion continuing in spite of the obstruction, that
portion of the ureter above the obstructed point, together with the
pelvis and the uriniferous tubules, gradually becomes dilated, until
the whole mass of the kidney is hypertrophied.
The ureter sometimes becomes enlarged to the size of a man’s arm,
the kidney double, treble, or quadruple its normal side: the
interlobular divisions are lost, and each circumscribed lobule soon
forms a cystic cavity varying in size. The pressure due to the
accumulated urine causes the renal tissue, first the medullary
substance and afterwards the peripheral zone, to undergo atrophy.
 The kidney is represented by a vast cystic cavity, and the lobules by
culs-de-sac; the cortical layer may become atrophied to such a degree
as to form merely a fibrous sheath, the primary constituent elements
of which are difficult to discover. From 20 to 40 pints of liquid may
sometimes be found in the cystic kidney.
Diagnosis. The condition is rarely diagnosed, because, as one of
the kidneys continues to act, no acute disturbance follows. Only in
cases where the cystic kidney projects into the flank are suspicions
aroused. Examination per rectum will then permit of the diagnosis
being made.
Prognosis. Hydro-nephrosis being, as a rule, unilateral, the
prognosis is not very grave as regards immediate danger. As the
condition is hopeless, however, the lesions being irreparable, the
animal should be prepared for slaughter.
Treatment. Practically there is no treatment. Puncture of the
cystic cavity or even the removal of the hydro-nephrotic kidney
certainly suggests itself, but, as such operations are usually opposed
to the interests of the owner, they are rarely or never practised.

INFECTIOUS PYELO-NEPHRITIS.
 Fig. 229.—Section of a kidney affected with hydro-nephrosis. The gland
substance is almost entirely atrophied, and each lobule shows marked
dilatation.

The term “infectious pyelo-nephritis” describes an inflammation

which may involve any portion of the mucous membrane of the
urinary tract, and which is produced by a special bacillus. As a rule,
this inflammation commences in the mucous membrane of the
calices and pelvis (pyelitis). It afterwards extends into the depths of
the uriniferous canaliculi (nephritis), but in grave and old-standing
cases the mucous membrane of the ureters and the bladder may also
be affected. The disease had long been known in France (Rossignol,
1848). It was afterwards described in Germany (Siedamgrotsky,
1875; Pflug, 1876), in Switzerland (Hess, 1888), and also in France
(Lucet, 1892; Masselin and Porcher, 1895).
Causation. Female animals are more frequently affected than
males, because the lesions are produced by an ascending infection,
originating very frequently in genital infection after delivery.
Nevertheless, calculus formation is also an important factor in
producing the disease.
Many different agents are capable of producing pyelo-nephritis.
Hofflich in 1891 described a bacillus about 2 to 8 micromillimètres in
length, which stained readily with aniline colours and with Gram
solution. Lucet in 1892 found a short bacillus which did not stain
with Gram, and later another thin bacillus which did. Kitt has
described cocci, but no other organisms. Masselin and Porcher
discovered a cocco-bacillus which stained with Gram and reproduced
the disease in an animal lent by Moussu, after a single intra-vesical
injection of the culture. Cadéac has met with staphylococci, and
Moussu has discovered various bacilli, some resembling the colon
bacillus, and pyogenic streptococci.
There is no doubt that many different organisms may produce
pyelo-nephritis by ascending infection. The most common seem to
be forms of paracoli, such as the Bacillus ureæ. Moussu nevertheless
believes that Hofflich’s bacillus, which was rediscovered by Porcher,
is that which produces typical pyelo-nephritis. It grows in the
bladder without producing cystitis, and is succeeded by an ascending
infection of the ureters without causing primary ureteritis, the local
inflammation occurring chiefly, it would seem, in the pelvis and the
kidney. All the other organisms which Moussu has tested have
caused lesions of cystitis and of ureteritis, together with those of
pyelo-nephritis.
In these latter cases the pyelo-nephritis assumes the acute form,
and is accompanied not infrequently by cellulitis and abscess
formation in the tissue around the kidney.
Symptoms. Pyelo-nephritis develops in one of two principal
forms, the slow chronic form, which is the most frequent, or an acute
or subacute form, much more rapid in its development.
The chronic form for a time escapes notice. There is no doubt that
at first some general disturbance occurs, such as diminution of
appetite, disturbed nutrition, unhealthy general appearance, staring
of the coat, tightness of the hide, wasting, etc., but such symptoms
are in no wise characteristic, being found in all grave diseases.
 The signs only become really significant from the clinical
standpoint when the urine appears modified in character, and such
modification does not occur until the pelvis of the kidney and the
kidneys themselves are already gravely diseased.
The urine is then turbid, of a brownish colour, and charged with
sediment, filaments of mucin, pus corpuscles, and earthy
phosphates. On analysis it is found to contain more or less albumen.
At a late stage it may even become glairy, blood-stained, or of the
colour of blood, and when the pelvis or the calices of the kidney are
ulcerated may, on standing, deposit considerable quantities of red
blood corpuscles.

Fig. 230.—Pyelo-nephritis with

hæmorrhagic pyo-nephrosis of one
side. One ureter is dilated and
blocked with a blood clot.
 Exposed to the air, the urine rapidly assumes a brown tint and
smells strongly of ammonia.
Percussion of the loins in the region of the kidneys causes pain, as
does external palpation by the flank. On rectal examination at this
period the ureters are found to be distended and hard, and they give
the impression of rigid or bosselated fibrous cords, sometimes as
large as a child’s arm. The corresponding kidney, often both kidneys,
are enlarged, sometimes to double or treble their normal volume,
and are painful on pressure and fluctuating, at least in the region of
the pelvis. On vaginal examination the meatus urinarius is usually
found to be inflamed, rough and turgid.
In this condition the animals rapidly lose flesh, the appetite
becomes irregular, the general condition gradually gets worse, and
they die as a result of continued uro-septic fever or uræmic troubles.
The acute form takes a much more rapid course, with fever, more
marked general disturbance, acceleration of pulse and breathing, the
passage of turbid and sometimes purulent urine with a strong
ammoniacal smell. Pyo-nephrosis is the most frequent and
characteristic end. Ordinary chronic pyelo-nephritis may also occur
in these cases, and the acute course may be determined simply by
accidental ascending infections.
Diagnosis. During the early stages diagnosis is extremely
difficult, unless a careful examination of the urine be made.
Afterwards it becomes easy, the appearance of the urine and the
indications furnished by rectal exploration being perfectly
characteristic. In very exceptional cases there may be some doubt, as
where the urine remains normal, in spite of hydro-nephrosis, or
where there is old-standing hæmaturia or renal tuberculosis. In
simple hæmaturia the lesions are confined to the bladder and
ureters, the kidneys not being affected, and in renal tuberculosis the
diagnosis can always be confirmed by the use of tuberculin.
Prognosis. The prognosis is extremely grave, for the lesions
produced are irreparable, and, moreover, local intervention is
impossible.
Treatment. There is no curative treatment. All that is possible is
palliative treatment with the object of facilitating the function of the
kidney and of disinfecting the urinary passages by administering
antiseptic substances which are excreted by the kidney. It is not
possible, however, to administer active drugs of this kind (e.g.,
combinations of carbolic acid). As the kidney acts badly it soon
ceases to eliminate such substances, and the condition would not be
improved, but aggravated.
Benzoate of soda in doses of 2 to 2½ drachms per day dissolved in
diuretic liquids is the most useful drug, and sometimes holds the
disease in check for a sufficient time to allow of the animals being
fattened.
Treatment also comprises certain prophylactic precautions. As the
infection which produces pyelo-nephritis originates in the genital
tract, it is desirable to protect all animals in a receptive condition
(those about to calve or having recently calved) from infection;
hence, when the disease is detected in a cow-shed, the patients
should be isolated, and the shed thoroughly disinfected.

SUPPURATIVE NEPHRITIS AND PERINEPHRITIS.

Suppuration of the kidney may occur under two conditions. In the

majority of cases such suppuration occurs as a complication of pyelo-
nephritis; less frequently it is the consequence of infection from
within or infection of adjacent parts, leading to the formation of an
abscess.
When it results from an ascending infection the kidney becomes
swollen, congested and inflamed, and soon displays localised minute
hæmorrhages. Pus then forms within the calices, in the large straight
tubes, and diffuse suppuration invades all the uriniferous tubules.
The enlarged kidney is yellowish, firm under the knife, and when
sections are compressed pus exudes from the openings of the tubular
canaliculi.
When suppurative nephritis has resulted from accidental infection
of internal origin, an abscess is found to have produced more or less
extensive atrophy of a portion of the kidney while not affecting the
rest of the organ.
It is only in those favourable cases where the renal abscess opens
into the pelvis that suppuration may invade the whole of the kidney,
producing diffuse suppurative nephritis by secondary infection of the
uriniferous tubules. Such complications are rare. Usually the abscess
empties through the pelvis, and recovery may occur.
More frequently suppurative pyelo-nephritis develops, together
with ureteritis, cystitis, dilatation of the ureters, dilatation of the
pelvis of the kidney, and dilatation of the collecting tubules of the
pyramids, the final stage resembling the lesions of pyo-nephrosis.
Perinephritis and perinephritic cellulitis, i.e., inflammation with or
without abscess formation in the connective tissue and adipose layer
surrounding the kidney, always occur in cases of suppurative
nephritis or pyelo-nephritis. Such inflammations may also, in
exceptional cases, follow direct mechanical injury, but they almost
invariably represent complications, the organisms infecting the
kidney passing through the tissues and the layer of fibrous tissue, or
extending by the lymphatic paths, finally attaining the fatty tissue
surrounding the kidney and there undergoing multiplication. The
fatty tissue is infiltrated with reddish serosity, is inflamed, and may
become the seat of large abscesses communicating with or separate
from the abscesses of the kidney itself.
Symptoms. Suppurative nephritis is characterised by fever, loss
of appetite, arrest of rumination, and frequent attempts to urinate.
These attempts are painful, are accompanied by groaning, and end in
the passage of an insignificant quantity of blood-stained and
purulent urine.
Palpation, more especially palpation of the right flank, percussion
over the region of the loins, and examination of the kidneys through
the rectum are painful. Wasting is rapid.
If the suppurative nephritis develops rapidly, and particularly if it
be accompanied by perinephritis, the patients refuse to rise and
appear to be suffering from paraplegia, although not really so, both
sensation and motor power persisting in a greater or less degree.
Probably the condition is accompanied by reflex pain and irritation
of the nerve trunks of the lumbo-pubic plexus.
On the other hand, when suppurative nephritis tends to develop
slowly and assume a chronic form, lesions of pyo-nephrosis
gradually develop, and are identical in appearance with those of
hydro-nephrosis, except that the ureters, the pelvis and the
dilatations corresponding to the lobules, are filled with pus.
Fig. 231.—Leaf lard around kidney of pig.

Diagnosis. The diagnosis is not very difficult. The urinary trouble

and the composition of the urine itself always arouse suspicion. The
diagnosis is confirmed by careful and methodical examination per
rectum; the inflammation of the fatty tissue surrounding the kidney
can usually be detected.
Prognosis. The prognosis is extremely grave, and almost always
fatal, particularly in cases of diffuse nephritis.
Treatment. No curative treatment can be absolutely relied on.
Treatment, if attempted, is limited to the methods suggested for
pyelo-nephritis. Mucilaginous, emollient, and diuretic drinks, and
daily doses of 2 to 3 drachms of benzoate of soda given in the
drinking water, cause some improvement.
Stimulation of the region of the loins also undoubtedly has a
favourable effect, and should always be practised, particularly where
perinephritis is developing. It may check the course of the disease
and prevent the formation of abscesses. On slaughtering animals
suffering as above described the layer of tissue surrounding the
kidney is found to be lardaceous and fibro-fatty.
Any treatment through the bladder is contra-indicated, for even
the passage of a catheter may cause severe injury of the urethra or
the vesical mucous membrane and produce a fatal aggravation.
If these conditions are diagnosed early, while the function of the
kidney is more or less preserved, and if the animal is still in good
condition, it should be slaughtered.

THE KIDNEY WORM (SCLEROSTOMA

PINGUICOLA) OF SWINE.[7]

7. From Report of the U.S.A. Bureau of Animal Industry,

1899, p. 612. (Louise Taylor.)
In the United States of America a worm is
frequently found in the fat surrounding the kidneys
of pigs, and is supposed by farmers to be the cause of
paralysis of the hind limbs.
This so-called kidney worm of hogs (Sclerostoma
pinguicola) should not be confounded with the
kidney worm (Dioctophyme viscerale) of dogs and
man. Both of these parasites belong to the same
zoological family (Strongylidæ), but to different
subfamilies and genera. The kidney worm of dogs
grows to a length of 1 to 3 feet. The kidney worm of
hogs is much smaller, attaining at most something
less than 2 inches in length.
Fig. 232.—
Sclerostoma
pinguicola.
External view
of female. a,
Male, natural
size; b,
female,
natural size;
c, mouth; d,
buccal cavity;
e,
œsophagus;
f, intestine; g,
anus; h,
genital
opening; i,