Brain Size and Limits to Adult Neurogenesis
Brain Size and Limits to Adult Neurogenesis
Mercedes F. Paredes,1‡ Shawn F. So
ells,2,3‡ Jose M. Garcia-Verdugo,4 and Arturo Alvarez-Buylla5*
1Department of Neurological Surgery, University of California, San Francisco, CA 94143, USA
2Department of Neurological Surgery, University of California, San Francisco, CA 94143, USA
3University of California, San Francisco, CA 94143, USA
4Laboratory of Comparative Neurobiology, Instituto Cavanilles, Universidad de Valencia, CIBERNED 46980 Valencia, Spain
5Department of Neurological Surgery and The Eli and Edythe Broad Center of Regeneration Medicine and Stem Cell Research, Uni-
versity of California, San Francisco, CA 94143, USA
ABSTRACT
The walls of the cere
al ventricles in the developing
em
yo ha
or the primary neural stem cells from which
most neurons and glia derive. In many verte
ates, neuro-
genesis continues postnatally and into adulthood in this
egion. Adult neurogenesis at the ventricle has been most
extensively studied in organisms with small
ains, such as
eptiles, birds, and rodents. In reptiles and birds, these pro-
genitor cells give rise to young neurons that migrate into
many regions of the fore
ain. Neurogenesis in adult
odents is also relatively widespread along the lateral ven-
tricles, but migration is largely restricted to the rostral
migratory stream into the olfactory bulb. Recent work indi-
cates that the wall of the lateral ventricle is highly regional-
ized, with progenitor cells giving rise to different types of
neurons depending on their location. In species with large
ains, young neurons born in these spatially specified
domains become dramatically separated from potential
final destinations. Here we hypothesize that the increase in
size and topographical complexity (e.g., intervening white
matter tracts) in larger
ains may severely limit the long-
term contribution of new neurons born close to, or in, the
ventricular wall. We compare the process of adult neuronal
irth, migration, and integration across species with differ-
ent
ain sizes, and discuss how early regional specification
of progenitor cells may interact with
ain size and affect
where and when new neurons are added. J. Comp. Neurol.
524:646–664, 2016.
VC 2015 The Authors The Journal of Comparative Neurology Published by
Wiley Periodicals, Inc.
INDEXING TERMS: neuronal replacement; regional specification;
ain evolution; comparative neuroanatomy;
plasticity
In his book Degeneration and Regeneration of the
Nervous System, Ram�on y Cajal XXXXXXXXXXwrote that: “In
adult centres the nerve paths are something fixed,
ended, immutable. Everything may die, nothing may be
egenerated.” Following Ram�on y Cajal’s identification
of nerve cells as independent units of
ain circuits, it
ecame deeply established in the neurosciences, as
well as by the general public, that no new neurons are
added to the
ain once fetal development is complete.
This dogma persisted for most of the 20th century until
[3H]thymidine became available for cellular birthdating.
The incorporation of [3H]thymidine into dividing cells
was used in conjunction with Nissl staining to identify
newly born cells with neuronal morphology. Work using
this approach suggested that new neurons are born in
multiple
ain regions in adulthood. The regions where
labeled cells were found included the cortex of the rat,
the granule cell layer of the hippocampal dentate
gyrus in the rat and the cat (Altman, 1963), and the
at olfactory bulb (OB) (Altman and Das, 1967; Baye
and Altman, XXXXXXXXXXSubsequent ultrastructural studies
This is an open access article under the terms of the Creative Commons
Attribution-NonCommercial-NoDerivs License, which permits use and dis-
tribution in any medium, provided the original work is properly cited, the
use is non-commercial and no modifications or adaptations are made.
Arturo Alvarez-Buylla is the Heather and Melanie Muss Endowed Chai
of Neurological Surgery at UCSF.
‡The first two authors contributed equally to this work.
Grant sponsor: U.S. National Institutes of Health; Grant numbers:
NS28478 and HD032116; Grant sponsor: California Regenerative Medi-
cine Clinical Fellowship (to M.P.); Grant sponsor: National Research
Service Award, National Institutes of Health Fellowship; Grant number:
F32MH XXXXXXXXXXto S.S.).
*CORRESPONDENCE TO: Arturo Ivarez-Buylla, University of California,
San Francisco, Department of Neurological Surgery, 35 Medical Cente
Way RMB-1038, Box 0525, San Francisco, CA XXXXXXXXXXE-mail:
XXXXXXXXXX
Received Fe
uary 27, 2015; Revised August 28, 2015;
Accepted September 8, 2015.
DOI XXXXXXXXXX/cne.23896
Published online September 28, 2015 in Wiley Online Li
ary
(wileyonlineli
ary.com)
VC 2015 The Authors The Journal of Comparative Neurology Published by
Wiley Periodicals, Inc.
646 The Journal of Comparative Neurology |Research in Systems Neuroscience 524:646– XXXXXXXXXX)
REVIEW
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supported the idea that the adult rat dentate gyrus and
OB contain young neurons (Kaplan and Hinds, 1977).
The interpretation of these results was questioned fo
several reasons: 1) the possibility that [3H]thymidine
labeling was not in new neurons but in closely adjoining
proliferative glial cells; 2) the radioactive labeling (rela-
tively few grains per cell) might have been insufficient
to reflect true cell division; and 3) the putative labeled
cells could have incorporated [3H]thymidine due to DNA
epair (Rakic, 1985, 2002a). Although controversial, this
initial work was the first evidence of adult incorporation
of new neurons in the subgranular zone (SGZ) of the
dentate gyrus (DG) of the hippocampus and the OB,
sites that have been confirmed in subsequent studies
(reviewed in Fuentealba et al., 2012; Yu et al., 2014).
Renewed interest in adult neurogenesis came from
independent studies in songbirds, a model organism to
study vocal learning (Thorpe, 1954; Nottebohm, 2004).
Seasonal changes in the size of a key region of the song
control pathway, the high vocal center (HVC), were
found to co
elate with changing levels of testosterone
(Nottebohm, XXXXXXXXXXShort survivals after [3H]thymidine
exposure revealed the presence of dividing cells within
the ventricular zone (VZ) on the walls of the lateral ven-
tricles (Fig. 1). With longer [3H]thymidine postlabeling
intervals, labeled neurons were found in the HVC
(Goldman and Nottebohm, XXXXXXXXXXFurther work using
electrophysiology confirmed the neuronal identity of the
labeled cells (Paton and Nottebohm, XXXXXXXXXXNew neu-
ons were found to synaptically integrate within the HVC
(Paton and Nottebohm, 1984; Burd and Nottebohm,
1985) and send projections to the distant nucleus robus-
tus archistriatalis (RA) (Alvarez-Buylla and Kirn, 1997).
The amount of adult neurogenesis in birds co
elates
with seasonal and hormonal patterns, and with complex
experiences, suggesting a possible functional role in
plasticity and/or learning (Barnea and Nottebohm, 1994;
Nottebohm et al., 1994; Alvarez-Buylla and Kirn, 1997;
Nottebohm, XXXXXXXXXXThis work clearly demonstrated that
the newly added neurons can become part of functional
circuits in the adult
ain, and are involved in an ongoing
process of neuronal replacement (Nottebohm, 2004).
Early investigators assumed that the progenitor cells fo
adult neurogenesis would be simple and undifferentiated,
possibly cells retained from fetal development (Altman,
1969), but work in songbirds demonstrated that this is
not the case. Radial glia (RG) cells in the adult songbird
VZ (Fig. 2) were found to incorporate [3H]thymidine, and
their division co
elated with the production of young neu-
ons, providing the first evidence that these cells are the
adult neural stem cells (NSCs) (Alvarez-Buylla et al.,
1990a). These and other studies using birds provided sev-
eral levels of evidence for adult neurogenesis including
the identification of proliferating neuronal progenitors,
electrophysiological and ultrastructural identification of
the new neurons, and a possible functional importance fo
their integration into established adult circuits.
THE CHALLENGE OF ADDING NEW
NEURONS
The addition of new neurons into an adult network
equires the coordination of cell division, migration,
maturation, and integration into existing circuits. To
egin, progenitor cells must be maintained for extended
periods of time past em
yogenesis into adulthood to
generate new neurons. This continued proliferation in
the adult
ain must be regulated, as the presence of
dividing NSCs into adulthood has been proposed as a
possible source for
ain tumors (Jacques et al., 2010;
Alcantara Llaguno et al., 2011; Cuddapah et al., 2014).
Next, young neuroblasts need to migrate varying distan-
ces based on their birthplace using cues to guide them
to their final destination (Rousselot et al., 1995; Lim
et al., 1997; Wu et al., 1999; Hack et al., 2002; Bolteus
and Bordey, XXXXXXXXXXThe distances that separate sites of
origin from destinations in the juvenile and adult
ain
esult in migratory routes that 1) are orders of magnitude
longer than in the em
yo, when the
ain is relatively
small, (Figs. 3 and 4) contain more complexities, such as
extensive vascularization, increasing regions of white
matter, and a very dense network of mature dendrites,
axons, and synapses. Once the young neurons complete
this journey, they must begin the process of integration
into fully functional networks, without deleterious effects
on the working of these circuits (Nottebohm, 2004; Song
et al., 2005; Lazarini and Lledo, XXXXXXXXXXWe suggest that
amidst these challenges, one of the most important
estrictions to widespread adult neurogenesis is
ain
size. Given the early regional specification of NSCs in
development, the increased migration requirements on
young neurons and the changes in the architecture of
neurogenic zones in a larger
ain may impose strict limi-
tations for the delivery of neurons to many
ain regions.
These structural constraints may also lead to variability in
adult neurogenesis between species.
ADULT NEUROGENESIS IN SPECIES WITH
DIFFERENT BRAIN SIZES
Adult neurogenesis in the ventricular subventricula
zone (V-SVZ) has been described in greatest detail in
species with small
ains like rodents, birds, and rep-
tiles, making it difficult to evaluate the influence of
ain size on this process. Species with larger
ains
(especially humans) are more technically challenging to
study, which greatly limits our ability to accurately
Brain Size and Limits to Adult Neurogenesis
The Journal of Comparative Neurology |Research in Systems Neuroscience 647
Figure 1. Neurogenic zones and migration destinations across several species and their relationship to
ain size. Left column: Dorsal
view of the
ains of several species all scaled according to the 1-cm scale bar at the bottom left. Middle column: Sagittal view of each
ain at the parasagittal plane of the RMS and olfactory bulb in each species. Green regions indicate germinal zones. Red dots indicate
destinations of the migratory young neurons. Bottom row is scaled according to the lower left 1-cm scale bar; other sections are not to
scale. Right column: Coronal view of each
ain. (Reptile): The lizard P. hispanica is shown as an example of adult neurogenesis in the
eptile. (Bird): The canary is shown, highlighting the extensive ventricular germinal zone and regions that continue to receive adult born
neurons. (Rodent): The adult mouse has a pronounced rostral migratory stream from the ventricles as well as abundant hippocampal neu-
ogenesis. (Monkey): The macaque is one of the original non-human primates in which adult neurogenesis was studied. Progenitor cells
are abundant along the SVZ, cells proliferate and migrate along the RMS to the OB,