Neurogenesis

8
NEUROGENESIS IN ADULT BRAIN
FRED H. GAGE
AND HENRIETTE VAN PRAAG

HISTORIC PERSPECTIVE
The idea that the adult brain retains the capacity to generate
new neurons has been proposed several times over the last
40 years, and in each case both conceptual and technical
constraints have led to resistance. Joseph Altman first reported that some dividing cells in the adult brain survived
anddifferentiated into cells with morphology similar to
neurons using tritiated thymidine autoradiography (1).
Over the subsequent years he and his colleagues confirmed
these initial observations and focused on the few areas where
neurogenesis was apparent in the adult, at the light microscopic level, while systematically documenting the birth
dates of neurons throughout the brain duringdevelopment
(2). When contrasting adult neurogenesis with the extensive
neurogenesis in development, adult neurogenesis seemed
almost like an epiphenomenon. The continued skepticism
surrounding adult neurogenesis and the absence of definitive phenotypic markers limited the development of the
field. In the mid-1970s and early 1980s Michael Kaplan
reexamined the initial observations using theelectron microscope and added substantial confidence that not only
could neurogenesis occur in the adult brain, but also that
the cells appear ultrastructurally, similar to sister cells in the
dentate gyrus of the hippocampus, one of the structures
shown to be neurogenic (3). In the mid-1980s, Fernando
Nottebohm and his student Steve Goldman further stimulated this fledgling field by showing thatsongbirds experience a seasonal cell death and neurogenesis in a region of
the brain important for song production (4). They have
continued to reveal more about the environment and molecular regulators of this process in the adult avian brain (5).
Despite these observations of neurogenesis in the adult
brain, confusion over the mechanism origin of cell genesis
in the adult brain persisted. Inthe early 1990s a series of
papers in the adult mouse and rat revealed that cells with
stem cell properties could be isolated and expanded in cul-

Fred H. Gage and Henriette van Praag: The Laboratory of Genetics,
The Salk Institute for Biological Studies, La Jolla, California.

ture. Under a variety of culture conditions with different
factors, these isolated cells can be induced todifferentiate
into glia and neurons (6–9). This later observation provided
a mechanism for the neurogenesis in the adult. Mature committed neurons were not dividing, but rather a population
of immature stem-like cells exists in the brain and it is likely
that it is the proliferation and differentiation of this population that is resulting in neurogenesis. With this conceptual
framework the originalstatement by Cajal that, ‘‘Once development was ended, the fonts of growth and regeneration
of the axons and dendrites dried up irrevocably. In adult
center, the nerve paths are something fixed and immutable:
everything may die, nothing may be regenerated,’’ still holds
true for most areas of the adult brain. The new lesson that
we have learned is that development never ended in some
areasof the brain.
CHARACTERIZATION OF CELL GENESIS
IN VIVO
Areas of Neurogenesis
Neurogenesis is a process that includes cell division, migration, and differentiation. There appear, at present, to be
only two areas of the brain where stems cells initially reside
and proliferate prior to migration and differentiation. Those
areas are the lateral subventricular and subgranular zones of
thedentate gyrus. The exact cell that corresponds to the
initiating stem cell in the lateral ventricle is a point of contention. One view is that this cell is the ependymal cell
facing the ventricle (10), whereas an alternative view is that
a glial population one cell layer in from the ependyma are
the stem cells (11). In any case, after cell division one of
the stem cells begins to differentiate...