Plasticity in the Adult Brain: From Genes to Neurotherapy

463 Pages·2002·71.89 MB·English

by  M.A. Hofman

G. De Wert, Institute of Bioethics, University of Maastricht, P.G. Box 616, 6200 MD
Maastricht, The Netherlands
F. De Winter, Netherlands Institute for Brain Research, Meibergdreef 33, 1105 AZ
Amsterdam, The Netherlands
J. De Wit, Netherlands Institute for Brain Research, Meibergdreef 33, 1105 AZ Amsterdam,
The Netherlands
M. Di Luca, Department of Pharmacological Sciences, University of Milan, Milan, Italy
M.C. Diamond, Department of Integrative Biology, University of California, Berkeley CA
94720-3 140, USA
E.J.G. Dubelaar, Netherlands Institute for Brain Research, Meibergdreef 33, 1105 AZ
Amsterdam, The Netherlands
A.J. Eisch, Department of Psychiatry, The University of Texas Southwestern Medical
Center, 5323 Harry Hines Boulevard, Dallas TX 75390-9070, USA
P.S. Eriksson, Department of Clinical Neuroscience, Sahlgrenska University Hospital,
Goteborg University, S-4 13 45 Goteborg, Sweden
P. Ernfors, Division of Molecular Neurobiology, Department of Medical Biochemistry and
Biophysics, Karolinska Institutet, S-171 77 Stockholm, Sweden
T.C. Foster, Department of Molecular and Biomedical Pharmacology, University of Ken-
tucky, College of Medicine, Lexington KY 40536, USA
L. Fusani, Max Planck Institue of Behavioural Physiology, 823 19 Seewiesen, Germany
M. Gahr, Institute of Neuroscience, Department of Developmental Neurobiology, Vrije
Universiteit, Amsterdam 108 1 HV Amsterdam, The Netherlands
F, Gardoni, Department of Pharmacological Sciences, University of Milan, Milan, Italy
W.H. Gispen, Department of Medical Pharmacology, Rudolf Magnus Institute of Neuro-
science, University Medical Centre Utrecht, Universiteitsweg 100, 3508 TC Utrecht,
The Netherlands
S.A. Goldman, Department of Neurology and Neuroscience, Cornell University Medical
Center, 1300 York Avenue Room E607, New York NY 10021, USA
J.A. Gorter, Swammerdam Institute for Life Sciences, University of Amsterdam, Kruislaan
320, 1098 SM Amsterdam, The Netherlands
W.T. Greenough, Beckman Institute, Neuroscience Program, Cell and Structural Biology,
University of Illinois at Urbana-Champaign, 405 N. Mathews, Urbana IL 6 1801, USA
A.W. Grossman, Beckman Institute, Neuroscience Program, University of Illinois at
Urbana-Champaign, 405 N. Mathews, Urbana IL 61801, USA
W. Hasenkamp, Departments of Pharmacology, Psychiatry and Behavioral Sciences, Yerkes
Regional Primate Research Center, Neuroscience Division, Emory University School of
Medicine, Atlanta GA 30329, USA
S.E. Hemby, Departments of Pharmacology, Psychiatry and Behavioral Sciences, Yerkes
Regional Primate Research Center, Neuroscience Division, Emory University School of
Medicine, Atlanta GA 30329, USA
J. Hjerling-Leffler, Division of Molecular Neurobiology, Department of Medical Biochem-
istry and Biophysics, Karolinska Institutet, S-171 77 Stockholm, Sweden
M.A. Hofman, Netherlands Institute for Brain Research, Meibergdreef 33, 1105 AZ
Amsterdam, The Netherlands
A.J.G.D. Holtmaat, Netherlands Institute for Brain Research, Meibergdreef 33, 1105 AZ
Amsterdam, The Netherlands
AD. Huberman, Center for Neuroscience, University of California, Davis, 1544 Newton
Court, Davis CA 95616, USA
0. Isacson, Udall Parkinson’s Disease Research Center of Excellence, Neuroregeneration
Laboratories, McLean Hospital/Harvard Medical School, 115 Mill Street, Belmont MA
02478, USA
J.H. Kaas, Department of Psychology, Vanderbilt University, 301 David K. Wilson Hall,
111 21st Avenue South, Nashville TN 37203, USA
A. Kamal, Department of Medical Pharmacology, Rudolf Magnus Institute of Neuro-
science, University Medical Centre Utrecht, Universiteitsweg 100, 3508 TC Utrecht,
The Netherlands
J.A. Kleim, Canadian Centre for Behavioural Neuroscience, University of Lethbridge,
Lethbridge AB, Canada
J.H. Kordower, Department of Neurological Sciences and Research Center for Brain
Repair, Rush University, 2242 W. Harrison Street, Chicago IL 60612, USA
E.D. Laywell, Departments of Neuroscience and Neurosurgery, The M&right Brain
Institute, Shands Cancer Center and University of Florida, Program in Stem Cell
Biology, P.O. Box 100244, 100 S. Newell Drive, Gainesville FL 32610, USA
S. Leitner, Max-Planck Institute of Behavioural Physiology, 82319 Seewiesen, Germany
F.H. Lopes Da Silva, Swammerdam Institute for Life Sciences, University of Amsterdam,
Kruislaan 320, 1098 SM Amsterdam, The Netherlands
A.K. McAllister, Center for Neuroscience, University of California, Davis, 1544 Newton
Court, Davis CA 95616, USA
J.L. McBride, Department of Neurological Sciences and Research Center for Brain Repair,
Rush University, 2242 W. Harrison Street, Chicago IL 60612, USA
B.L. McNaughton, Arizona Research Laboratories, Department of Neural Systems, Mem-
ory and Aging, University of Arizona, Tucson AZ 85724, USA
D.A. Merrill, Department of Neurosciences - 0626, University of California, San Diego, La
Jolla CA 92093-0626, USA
A.H. Mohammed, Division of Geriatric Medicine, NEUROTEC, Karolinska Institutet,
S-141 86 Huddinge, Sweden
H. Neville, Psychology Department, 1227 University of Oregon, Eugene OR 97403-1227,
USA
C.M.A. Pennartz, Graduate School Neurosciences Amsterdam, Netherlands Institute for
Brain Research, Meibergdreef 33, 1105 AZ Amsterdam, The Netherlands
P. Rakic, Department of Neurobiology, Yale University School of Medicine, 333 Cedar
Street, New Haven CT 065 10, USA
G.M.J. Ramakers, Department of Medical Pharmacology, Rudolf Magnus Institute of
Neuroscience, University Medical Centre Utrecht, Universiteitsweg 100, 3508 TC
Utrecht, The Netherlands
J.P. Rauschecker, Department of Physiology and Biophysics, Georgetown Institute for Cog-
nitive and Computational Sciences, Georgetown University Medical Center, Washington
DC 20007, USA
R.F. Riemersma, Graduate School Neuroscience Amsterdam, Netherlands Institute for
Brain Research, Meibergdreef 33, 1105 AZ Amsterdam, The Netherlands
F. Rybak, Institute of Neuroscience, Department of Developmental Neurobiology, Vrije
Universiteit Amsterdam, 108 1 HV Amsterdam, The Netherlands
E.J.A. Scherder, Free University, Department of Clinical Psychology, Amsterdam, The
Netherlands
M. Segal, Department of Neurobiology, The Weizmann Institute, Rehovot 76100, Israel
. . .
vu1
D. Smith, Department of Neurosciences - 0626, University of California, San Diego, La
Jolla CA 92093-0626, USA
D.A. Steindler, Departments of Neuroscience and Neurosurgery, The McKnight Brain
Institute, Shands Cancer Center and University of Florida, Program in Stem Cell
Biology, P.O. Box 100244, 100 S. Newell Drive, Gainesville FL 32610, USA
J. Stewart, Center for Studies in Behavioral Neurobiology, Department of Psychology,
Concordia University, 1455 de Maisonneuve Boulevard, West, Montreal QC H3G lM8,
Canada
D.F. Swaab, Netherlands Institute for Brain Research, Meibergdreef 33, 1105 AZ Amster-
dam, The Netherlands
M.H. Tuszynski, Department of Neurosciences - 0626, University of California, San Diego,
La Jolla CA 92093-0626, USA
H.B.M. Uylings, Graduate School Neurosciences Amsterdam, Netherlands Institute for
Brain Research, Meibergdreef 33, 1105 AZ Amsterdam, The Netherlands
H.L. Vahlsing, Department of Neurosciences - 0626, University of California, San Diego,
La Jolla CA 92093-0626, USA
E.J.W. Van Someren, Netherlands Institute for Brain Research, Meibergdreef 33, 1105 AZ
Amsterdam, The Netherlands
J. Verhaagen, Netherlands Institute for Brain Research, Meibergdreef 33, 1105 AZ Amster-
dam, The Netherlands
R.W.H. Verwer, Netherlands Institute for Brain Research, Meibergdreef 33, 1105 AZ
Amsterdam, The Netherlands
B. Winblad, Division of Geriatric Medicine, NEURCYTEC, Karolinska Institutet, S-141 86
Huddinge, Sweden
S.W. Zhu, Division of Geriatric Medicine, NEUROTEC, Karolinska Institutet, S-141 86
Huddinge, Sweden
ix
Preface
The 22nd International Summer School of Brain Research was held in Amsterdam from
20-24 August, 2001 at the Auditorium of the University of Amsterdam. The Summer
School was organized by the Netherlands Institute for Brain Research (NIBR), one of
the institutes of the Royal Netherlands Academy of Arts and Sciences, according to a
long-standing biennial tradition. The history of the NIBR dates back to the beginning of
the last century. At the meeting of the International Association of Academies held in
Paris in 1901, the anatomist Wilhelm His proposed that research on the nervous system
should be placed on an international footing. In 1904 this resulted in the formation of the
International Academic Committee for Brain Research, which set itself the task of “. . .
organizing a network of institutions throughout the civilized world, dedicated to the study
of the structure and functions of the central organ . . . “. Several governments responded
to this ambition by founding brain research institutes, among which was the Netherlands
(Central) Institute for Brain Research, which opened its doors on 8 June 1909. Professor
C.U. Ariens Kappers (1877-1946) became the first director of the institute, a position he
held until his death. In honor of its first director the institute decided to create the C.U.
AriCns Kappers Award, which during this Summer School was presented to Dr. Mark H.
Tuszynski (La Jolla, USA) for his pioneering work on transplantation and gene therapy
strategies in brain repair.
Already in those early years, the idea that the structure of the central nervous system
of humans and other mammals remains fixed soon after birth was universally held by the
main figures of the time, including Wilhelm His and Santiago Ramdn y Cajal. Because
the elaborate architecture of the brain remained relatively stable in appearance, the idea
of postnatal neurogenesis in mammals was, understandably, inconceivable. Recent findings
challenge this central dogma of neuroscience and show that new neurons are continually
added to the brain throughout life. The acceptance of adult neurogenesis is part of a more
general paradigm shift in our view of the plasticity and stability of the adult brain. Indeed,
recent findings clearly indicate that the central nervous system is not a fixed, static system,
but is far more flexible and capable of changing and adapting in form and function than we
have thought for more than a century.
In the past decade neuronal plasticity has become a major theme of modem neurobiol-
ogy, from cellular and molecular mechanisms of synapse formation in worms and insects to
behavioural recovery from strokes in elderly humans. For this reason the focus of interest
in the present volume of Progress in Bruin Research is on the topic of neuroplasticity in
mature organisms, including humans. Contributions range from neurogenesis and synaptic
plasticity in the adult primate brain, to neural mechanisms of learning and memory, and
the influence of environmental factors and aging on the functional potential of the central
nervous system. Moreover, several contributions focus on recent developments in neural
regeneration and brain repair, providing challenging evidence that the use of stem cell neu-
rotberapy may be beneficial to humans suffering from various neurological and psychiatric
diseases. This volume intends to integrate new information on the cellular and molecular
X
mechanisms of neuroplasticity and to highlight the most challenging future questions in
this exciting and topical area of neuroscience.
The enthusiasm with which a great number of scientists have agreed to come to
Amsterdam and to contribute to this volume is very gratifying. We would like to
acknowledge the generosity of both the Royal Netherlands Academy of Arts and Sciences
and the Graduate School Neurosciences Amsterdam, under whose joint auspices the
Summer School was being held, as well as many other generous financial supporters.
Finally, we would like to express our special gratitude to Tini Eikelboom, Bar-t Fisser, Olga
Path, Henk Stoffels, Wilma Top and Wilma Verweij for their invaluable organizational and
editorial assistance.
Michel A. Hofman
Gerard J. Boer
Anthony J.G.D. Holtmaat
Eus J.W. van Someren
Joost Verhaagen
Dick F. Swaab
Editors
xi
Acknowledgements
The 22nd International Summer School of Brain Research was organized by:
The Netherlands Institute for Brain Research
under the auspices of
The Royal Netherlands Academy of Arts and Sciences
and
The Graduate School Neurosciences Amsterdam
Financial support was further obtained from:
Company of Biologists Ltd.
GlaxoSmithKline
Merck Sharp and Dohme
Netherlands Society for the Advancement of Natural Sciences, Medicine and Surgery
Noldus Information Technology B.V.
Sanofi-Syntbelabo
Society of Experimental and Clinical Neurosciences (EKN)
Solvay Pharmaceuticals
Van den Houten Foundation
World Precision Instruments Germany
M.A. Hofman,G.J.Boer,A.J.G.D.Holtmaat,E.J.W.VanSomeren, J.VerhaagenandD.F.Swaab(Eds.)
Pmgress in Brain Research, Vol. 138
0 2002 Elsevier Science B.V. All rights reserved
CHAPTER 1
Neurogenesis in adult primates
Pasko Rakic *
Department of Neurobiology, Yale University School of Medicine, 333 Cedar Street, New Haven, CT 06.510, USA
Introduction our present understanding of neuronal production in
the mammalian brain in general. In terms of adult
Among the many forms of neuronal plasticity that neurogenesis, the unambiguous evidence in adult ro-
were the subject of discussion at the International dents has been established for the interneurons of
Summer School of Brain Research, one was the the olfactory bulb and dentate gyrus (e.g. Luskin,
regulation of the addition and/or renewal of neu- 1993; Lois and Alvarez-Buylla, 1994; Kempermann
rons in the mammalian brain during adulthood. A et al., 1997). Since a considerable difference in the
phenomenon of continuous neurogenesis and natu- magnitude of neurogenesis exists among vertebrates
ral turnover of neurons has been well established in and even within the same (rodent) species depending
the adult central nervous system of many vertebrate on genetic background (Kempermann et al., 1997),
classes, including fish, amphibians, reptiles and birds it is reasonable to ask what is the situation in larger,
(e.g. Kirsche, 1957; Jacobson, 1970; Meyer, 1978; more slowly developing mammals, such as primates.
Goldman and Nottebohm, 1983; Perez-Canellas and
Garcia-Verdugo, 1996). However, adult neurogen- Studies in primates
esis in mammals has received renewed attention
only after the introduction of the bromodeoxyuri- All mammals share most of the basic principles of
dine (BrdU) labeling as a readily accessible method brain development. Therefore, for numerous biologi-
for detection of neuronal production (Nowakowski cal and practical reasons, the mouse (Mus musculus)
et al., 1989). Most of what we know in mammals is considered a preferred experimental model of hu-
about the time of neuron origin, often referred to man neurological disorders (Rakic, 2000). However,
as ‘neuronal birthday’, has been learned from the there are also some notable species-specific peculiar-
autoradiographic studies done in mice and rats us- ities and differences in developmental sequences and
ing radioactive thymidine (3H-dT) (e.g. Angevine, programs that have to be taken into account, particu-
1965; Sidman, 1970; Bayer and Altman, 1995). Al- larly when considering the capacity for regeneration
though there are some species-specific differences and restoration of brain function (e.g. Steward et al.,
in the timing and sequences of neurogenesis, stud- 1999). Thus, it is essential to examine the neuroge-
ies in rodents have provided a basic background for netic periods in an animal that is in size, duration of
development and neural organization more similar to
human. For this reason we have initiated a longitu-
dinal study designed to systematically examine the
* Correspondence to: F! Rakic, Department of Nenrobio-
logy, Yale University School of Medicine, 333 Cedar time of neuronal origin in an Old World non-human
Street, New Haven, CT 06510, USA. Tel.: [phone]- primate (Macaca mulatta) that is phylogenetically
4330; Fax: fl-203-785-5263; close to human. Pregnancy in this species lasts 165
E-mail: [email protected] days and the time of conception can be accurately
4
placed at the middle of the 28-day menstrual cycle. 1974, 1976, 1977, 1982, 1985a,b; Lenn et al., 1978;
This project, which started in the early 1970s at Har- Brand and Rakic, 1979, 1980; Schmechel and Ra-
vard Medical School, continued in the 1980s at Yale kit, 1979a,b; Kostovic and Rakic, 1980; Cooper and
University School of Medicine and has over time, in- Rakic, 1981; Gould and Rakic, 1981; Ogren and Ra-
volved 30 researchers from eight different countries kit, 1981; Rakic and Nowakowski, 1981; Levitt and
who have analyzed the extensive material prepared Rakic, 1982; Eckenhoff and Rakic, 1988; Kordower
from a series of macaque monkeys exposed to 3H-dT and Rakic, 1990; LaVail et al., 1991; Schwartz et al.,
and more recently BrdU at various pre- and postnatal 1991; Kordower et al., 1992; Rapaport et al., 1992,
ages (see Acknowledgements). 1995; Van Eerdenburg and Rakic, 1994; Granger et
Since 3H-dT is incorporated into nuclear DNA dur- al., 1995; Knyhar-Csillik et al., 1999; Zecevic and
ing the S phase of the cell cycle and the amount of in- Rakic, 2001). Only a brief review of the major find-
corporation in a given cell is directly proportional to ings relevant to the theme of this Summer School is
the number of silver grains overlaying it, a high level provided below.
of silver grains over the cell nucleus in autoradio- The time and sequence of neurogenesis in the
grams, observed following a single i.v. injection can major CNS structures of the macaque monkey is
be used as a sign of a neuron’s ‘birthday’ (Angevine, graphically represented in Fig. 1. The series of over
1965). Although, the total duration of the cell cycle 100 animals were exposed to 3H-dT starting from
is 3-4 times longer in primates than in rodents, the 25 embryonic (E) days delivered at term (165th
S phase of DNA synthesis is very similar in both postconceptual day) and sacrificed postnatally. Even
orders (Kornack and Rakic, 1998). In the macaque a cursory examination of Fig. 1 shows that, with the
monkey following i.v. injection, 3H-dT is present in exception of the granule cells of the olfactory bulb,
the bloodstream for less than 10 min and thus pro- cerebellum and hippocampus, which continue their
vides a highly precise tool for dating the time of last genesis after birth, all other classes of neurons were
cell division in this species (Nowakowski and Rakic, generated during a specific and highly restricted
1974). To be able to obtain precise and unambigu- gestational period. Another aspect that has emerged
ous data it was essential to give a single injection of from the data presented in Table 1 is that the duration
3H-dT to each animal. We have also adopted the cri- of the neurogenetic period is quite variable, and
terion that neurons can be considered new only if the does not depend on the final number of neurons
number of overlaying silver grains is at least 50% of encountered in a given structure. For example, 1.2
that recorded in maximally labeled nuclei in the same million retinal ganglion cells are generated during
specimen (Rakic, 1973,1977). Such a stringent crite- 40 days (E30-E70, LaVail et al., 1991), whereas 1.5
rion is needed to avoid misinterpreting light labeling million neurons in their synaptic targets, the lateral
due to background or other biological and technical geniculate nucleus, are produced in a five times
artifacts as a sign of cell division (Nowakowski and shorter period (E36-E43, Rakic, 1977). Even taking
Hayes, 2000; Rakic, 1985c, 2002a,b). into account that these two visual system structures
At the beginning of the project it was expected display a somewhat different rate of apoptosis (Rakic
that because of the prolonged brain maturation in pri- and Riley, 1983; Williams and Rakic, 1988), the
mates, neurogenesis likely continues long after birth. duration of the neurogenetic period is significantly
However, surprisingly, our analysis indicated that different for neuronal populations of a similar size.
the analogous classes of neurons in the monkey are The final number of neurons in a given structure
generated at comparatively earlier embryonic stages depends on the initial size of the founder cell pool in
than in rodents. This became evident when the tim- the proliferative zones that becomes exhausted at a
ing of neurogenetic periods of the major structures of specific time (Rakic, 1977, 1985b).
the monkey brain are compared to the time of birth
(Fig. 1). Details of studies of the time of neuron or& Postdevelopmental neurogenesis
gin in various brain structures of the macaque mon-
key were published separately, and those interested It is important to distinguish between the postnatal,
are referred to the original source (e.g. Rakic, 1973, postdevelopmental and adult periods. Since the time
5
I
P20 P40 P60 Pea P 0
Inf. olive -
E sup. olive
a” Ponitin gray
08 Tmp.body -
L. coerul. -
4 Rephe caud.
$ coch.fus.
E - Oct.
- gran -
Purkinje
5 Gdg II
= lntemeumns
4 Granule c.
2 Dentate
Inerpo.
3 Fastigeal
W
Pulvinar
3 VA&VL -
3 Med. dors. -
g cent. med. -
I Subthal. I -
IHypothal 1
IGanglion 1
1 Rods I
Neostriatum
! Accum. septi
5
G. pall. (mj
S$ G. pall. (I)
j’”
Septal araa
? Amygdala
N. bazalis
Enotorhinal
Subiculum
St. pyram. . . ..*.*.**..........
Dent. gyr.
Molar A4
Som. A3
i! Visual A17
8 Visual Al8
Audit. A41
&
Pariet. A7
Z Front. All
Front. A48
Cina. A21
Fig. 1. Time of neuron origin of the major classes of neurons in the macaque central nervous system. The age of animals in post-
conceptual (E = embryonic) days is represented on the horizontal line, ending at term (El65 = birth) and thereafter in postnatal (P)
days. The horizontal lines corresponding to each neuronal class indicate the animal’s age when an injection of 3H-thymidine results in
heavily labeled neuronal nuclei when the monkeys are sacrificed postnatally. The dotted line corresponding to the dentate gyms indicates
continued neurogenesis based on the data obtained by BrdU/NeuN double labeling in adult monkeys. See the text for further explanation.
6
of birth, time of sexual maturity, tempo of aging and proliferation of cells in the subgranular zone of the
duration of the life span vary greatly among mam- dentate gyms tapers off during the juvenile period
malian species, among different strains of animals and adolescence, it continues at a low rate even af-
as well as between genders, it seems imperative to ter sexual maturity, which is in this primate species
have a consensus of what is an adult organism (Ra- attained by the 3rd year of life. The technology avail-
kit, 1972). For example, in all mammalian species able in the 1980s did not allow conclusive distinction
examined, most granule cells of the cerebellum and between granule cells and astrocytes, which have
hippocampus are generated postnatally, but only in cytoplasm and a nucleus of the same size and tinc-
the dentate gyms does neurogenesis continue after torial properties in autoradiograms counter-stained
sexual maturity. However, a sexually mature ani- with classical histological methods. In the 1980s we
mal is not necessarily an adult. For example, in the acknowledged the difficulties in identifying the na-
rat, neurogenesis in the dentate gyrus decreases sig- ture of small 3H-dT labeled cells in the dentate gyms
nificantly with age, and by 21 months (about the of the adult monkey by concluding that “if neuroge-
midpoint in rat’s life span) it is an order of magni- nesis has been missed as a result of methodological
tude less than at the 6th month (Kuhn et al., 1996). limitations, the number of newly generated neurons
In macaque monkey, the level of brain maturation must be very small and thus hardly comparable to
in infants and juveniles is different from that after massive levels of neurogenesis reported in birds and
puberty, which in this primate occurs in the 3rd rodents” (Eckenhoff and Rakic, 1988). The more
year of life (Napier and Napier, 1967). Therefore, recent study, using immunohistochemistry for BrdU
the results obtained on 6-week-old rats or less than and the neuronal marker, NeuN, we confirmed per-
3-year-old monkeys should not be generalized to the sistent genesis of granule cells in both the dentate
adult brain. Likewise, neither sexual maturity nor the gyms and even followed the developmental history
body weight should be considered as reliable criteria of the cells from their last division and migration,
of brain maturation. The time of the initial mortality to their differentiation into granule cells in the den-
rate (IMR) or the time required for mortality to dou- tate gyms, (Komack and Rakic, 1999). We have also
ble (MRD) are suggested as criteria in the studies of examined, in the same set of animals, a possible
aging (Finch et al., 1990). The midpoint of the av- existence of neurogenesis in the primate olfactory
erage life span, which is approximately 1.5 years of bulb, that was not sampled in the original 3H-dT
age in mice, 10 years in macaque and about 30 years series. The use of BrdU and several cell type-specific
in human (Finch, 1990) may also serve as a rough markers revealed a chain of migrating neurons from
estimate of the tempo of aging among mammalian the SEZ via the rostra1 migratory stream to the olfac-
species. Thus, we have injected an additional series tory bulb where they differentiate into granule cells
of monkeys with 3H-dT that are older than 3 years (Komack and Rakic, 2001a).
(Rakic, 1985b). Our more recent BrdU immunohis- We estimated that in the dentate gyms of the adult
tochemical studies on adult neurogenesis have been monkey (5.5-16.5 years of age) one new granule cell
conduced on 5-17-year-old macaque monkeys (Kor- is generated each day per 24,000 existing cells, or
nack and Rakic, 1999,2001a,b). 0.004% of the granule cell population (Komack and
For the purpose of the present article it was Rakic, 1999). In contrast, in mice, each day about
noteworthy that among over 125 classes of neurons one new granule cell is generated per 2000 granule
examined, only the rod photoreceptors in the retina cells (Kempermann et al., 1997). This would indicate
and the small intemeurons (granule cells) in the ol- about one order of magnitude smaller rate of genesis
factory bulb, dentate gyrus and cerebellum continued in the primate. However, the longevity of the new
neurogenesis after birth in the macaque monkey (e.g. cells and the change in rate of neurogenesis over the
Fig. 1). While production of the rods stops a few life span of the primate is unknown.
days after birth (LaVail et al., 1991), the production We also found that the subependymal zone (SEZ)
of the cerebellar granule cells continues during in- in the adult monkey telencephalon, in addition to
fancy and juvenile period but was not observed after glial cells, also produces Tujl positive cells. These
the 3rd month (Rakic, 1985a). However, although cells migrate tangentially to the olfactory nerve via