Brain Development: Normal Processes and the Effects of Alcohol ...

continues throughout lif e (se e Hippocampal Forma -
tion, below).
In th e rat , afte r productio n of the pallia i preplate
cortical neuronogenesis begins on gestational day (G)
11 and ends on G21 (Bruckner et al, 1976; Lund and
Mustari, 1977 ; Miller , 1985 , 1988 ; Al-Ghou l an d
Miller, 1989) . Thi s proces s i s orderly and follow s a
well-defined inside-ou t sequence . Accordingly , th e
first neurons generate d becom e laye r Vi a neurons ;
later generations of neurons ar e destined for progressively
more superficial laminae.
Ethanol exposur e alter s th e numbe r an d se -
quence o f neuronogenesi s (Miller , 1986 , 1988) ,
delaying and extending the period of neuronal generation
b y 1 day each (Fig . 11-1) . O n eac h day , the
number of neurons with a particular time of origin is
reduced. The exceptio n to this pattern is the substantial
increas e in neurona l generatio n a s cortical neu -
ronogenesis i s winding down (after G19) . The earl y
depression i n neurona l generatio n i s followed by a
late surg e i n term s o f as neuronal density ; on G2 0
and succeedin g days, neuronal generation is signifi -
cantly greate r i n th e cortice s o f ethanol-treated rat s
than i n controls. Interpretation of these data leads to
four conclusions.
The first is that the delaye d onset of cortical neuronal
generation suggests an ethanol-related retarding
effect o n the acquisitio n of critical numbers of proliferating
cells required to initiate neuronal generation.
That is, the population of proliferating neural precursors
has to reach a threshold size before neuronal precursors
begin to pass through their final cell divisio n
and th e youn g neurons begi n to leav e the prolifera -
tive population . Thi s patter n i s consisten t wit h th e
concept of founder cells (see Chapter 2).
The secon d conclusio n i s that ethano l ha s com -
plex effects o n cell proliferation. Initially, the prolifer -
ation of neuronal precursor s is depressed an d late r it
is promoted. This conclusion is supported by various
studies discusse d belo w (se e Site s o f Proliferation,
below).
The thir d observation , fro m th e comple x time -
dependent effect s o f ethanol o n th e numbe r o f neurons
being generated, i s that the lat e surge may be an
effort o f the proliferative population to compensate for
the earl y depression . Indeed, th e densit y of neurons
generated ove r the entir e period of neuronogenesis is
unaffected b y ethanol exposure. This is an interestin g
finding in that the total number of cortical neurons, at
ETHANOL AND PROLIFERATION OF NEURONAL PRECURSORS 18 3
FIGURE 11- 1 Neurona l generatio n i n moto r cortex .
These dark-fiel d micrograph s sho w tha t i n contro l
rats, neurons generated on gestational day (G) 1 6 and
on G20 are distributed in deep and superficial cortex,
respectively. In ethanol-treated rats, neurons born on
G16 ar e als o distribute d i n dee p cortex , althoug h
their number s are fewe r an d the y ten d t o b e mor e
deeply disposed. Neurons generated o n G20 that are
properly distribute d i n superficia l cortex ar e als o of
fewer number . Man y late-generate d neurons , how -
ever, ar e ectopicall y distribute d i n dee p cortex .
(Source: Image s taken, with permission, from Mille r
(1986), Science 233:1308-1311.)
least in somatosensory cortex, is significantly lower in
ethanol-treated rats (Miller and Potempa, 1990) . The
implication i s that ethanol doe s not affec t th e num -
ber o f neuron s produce d fro m a n ontogeneti c col -
umn; rather, it reduces the numbe r of columns. An