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neurons are generated after birth in rodents. They next
extended the labeling period to the second and third
postnatal weeks and found that in one particular
region, the olfactory bulb, thymidine-labeled cells
were still found up to four weeks postnatally. These
cells were generated in the subventricular zone in the
forebrain and then migrated to the olfactory bulb
(Figure 3.31). In recent years, it has been recognized
that this neurogenesis also occurs in the adult hip-
pocampus, and several studies have now shown that
these cells are multipotent, like progenitor cells in
the embryonic brain (Lois and Alvarez-Buylla, 1993;
Luskin, 1993; Reynolds and Weiss, 1992).
In the last few years, Fred Gage and his colleagues
have shown that the new neurons generated in the hip-
pocampus are functionally integrated into the circuitry
(Van Praag et al., 2002). To assay the function of the
newly generated neurons, they used retroviral labeling
in adult rats, similar to that which was described in the
beginning of the chapter for labeling progenitors in the
developing brain. Since a retrovirus will only infect and
integrate into mitotically active cells, they were able to
label the mitotically active hippocampal precursors
with a retrovirus expressing the green fluorescent
protein. When the authors examined the GFP-labeled
cells after only 48 hours, the cells had a very immature
morphology and resembled progenitors, like those
found in the developing brain. However, when the
animals were allowed to survive for four weeks, many
of the GFP-labeled cells now expressed markers of dif-
ferentiated neurons. Over the next three months these
neurons continue to mature. To what extent are the new
GFP cells functionally integrated into the hippocampal
circuitry? The hippocampus can be sliced into thin
sections while still functionally active, and the
electrophysiological activity of the neurons monitored
with microelectrodes (Figure 3.32). The newly gener-
ated granule cells had electrophysiological properties
similar to those found in mature granule neurons, and
they receive inputs from the major afferent pathway.
Thus, newly generated neurons in the adult hippocam-
pus integrate into the existing circuitry and function
like those neurons generated during embryogenesis.
Why do mammals generate new neurons in these
regions? Frogs and fish have eyes that grow, birds learn
a new song. What is the advantage to the mammal?
Although there are no studies of a change in the
animal's abilities that correlate with this cellular addi-
tion in mammals, several possibilities may be enter-
tained. Since both the olfactory and the hippocampus
are involved in the formation of olfactory memories,
the neuronal turnover in these regions could be impor-
tant in a seasonal change in nests or mates. Altman
observed that the neurogenesis of the brain proceeds
in two basic phases. The large projection neurons
(or macroneurons) are generated early in embryonic
granule cell
Newly generated
granule cell
50 m m
Inject GFP
Hippocampal slice
FIGURE 3.32 Adult-generated hippocampal neurons are functionally integrated with preexisting
neurons. Van Praag et al. labeled proliferating cells in the hippocampus with a GFP-expressing retrovirus let
the animals run on wheels to increase their production of new neurons, and then recorded from the GFP-
labeled cells in hippocampal slices. The adult-generated neurons integrated into the hippocampal circuit and
showed electrophysiological responses similar to their mature granule cell neighbors. (Modified from Reh,
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