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The Journal of Neuroscience, April 1, 1998, 18(7):2697-2708
Dopamine Axon Varicosities in the Prelimbic Division of the Rat
Prefrontal Cortex Exhibit Sparse Immunoreactivity for the Dopamine
Transporter
Susan R.
Sesack1,
Valerie A.
Hawrylak1,
Claudia
Matus2,
Margaret A.
Guido1, and
Allan I.
Levey3
Departments of 1 Neuroscience and Psychiatry, and
2 Statistics, University of Pittsburgh, Pennsylvania 15260, and 3 Department of Neurology, Emory University, Atlanta,
Georgia 30322
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ABSTRACT |
The dopamine transporter (DAT) critically regulates the duration of
the cellular actions of dopamine and the extent to which dopamine
diffuses in the extracellular space. We sought to determine whether the
reportedly greater diffusion of dopamine in the rat prefrontal cortex
(PFC) as compared with the striatum is associated with a more
restricted axonal distribution of the cortical DAT protein. By light
microscopy, avidin-biotin-peroxidase immunostaining for DAT was
visualized in fibers that were densely distributed within the
dorsolateral striatum and the superficial layers of the dorsal anterior
cingulate cortex. In contrast, DAT-labeled axons were distributed only
sparsely to the deep layers of the prelimbic cortex. By electron
microscopy, DAT-immunoreactive profiles in the striatum and cingulate
cortex included both varicose and intervaricose segments of axons.
However, DAT-labeled processes in the prelimbic cortex were almost
exclusively intervaricose axon segments. Immunolabeling for tyrosine
hydroxylase in adjacent sections of the prelimbic cortex was localized
to both varicosities and intervaricose segments of axons. These
qualitative observations were supported by a quantitative assessment in
which the diameter of immunoreactive profiles was used as a relative
measure of whether varicose or intervaricose axon segments were
labeled. These results suggest that considerable extracellular
diffusion of dopamine in the prelimbic PFC may result, at least in
part, from a paucity of DAT content in mesocortical dopamine axons, as
well as a distribution of the DAT protein at a distance from synaptic
release sites. The results further suggest that different populations
of dopamine neurons selectively target the DAT to different subcellular
locations.
Key words:
Key words; cingulate cortex; dopamine; dopamine transporter; prefrontal cortex; prelimbic; striatum; tyrosine hydroxylase
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INTRODUCTION |
The dopamine transporter (DAT) is a
crucial protein in the regulation of dopamine transmission, serving to
remove dopamine from the extracellular space after its release. Studies
in animals lacking expression of the DAT gene (Giros et al., 1996 )
suggest that this protein is perhaps the single most important
determinant of the extraneuronal concentration and duration of
dopamine. The DAT is also a protein of considerable clinical
significance. For example, psychostimulant drugs of abuse block or
reverse the action of the DAT and increase dopamine levels in key
forebrain regions (Moghaddam and Bunney, 1989; Kuhar et al., 1991;
Giros et al., 1996). Furthermore, DAT content in the basal ganglia is
reduced significantly during the normal course of aging (Bannon et al., 1992) and in patients with Parkinson's disease (Niznik et al., 1991;
Harrington et al., 1996). The DAT also has been implicated as a
potential site for uptake of environmental neurotoxins that might cause
Parkinson's disease (Uhl, 1992), whereas low DAT levels may be
associated with resistance to such lesions (Cerruti et al., 1993;
Harrington et al., 1996).
Although the function of the DAT has been studied most extensively in
the basal ganglia, the cortex also receives a significant dopamine
innervation (Descarries et al., 1987; Berger et al., 1991) that is
important for cognitive functioning (Brozoski et al., 1979; Simon et
al., 1980). In the prelimbic division of the rat prefrontal cortex
(PFC) (Krettek and Price, 1977), dopamine appears to undergo less
regulation by DAT-mediated re-uptake when compared with the striatum,
as evidenced by a greater extracellular diffusion distance (Garris et
al., 1993; Garris and Wightman, 1994; Cass and Gerhardt, 1995). This
difference may result simply from the lower dopamine innervation
density in the mesocortical versus the nigrostriatal system. However,
an alternative interpretation is that dopamine axons and varicosities
in the prelimbic PFC have a lower content of DAT and, hence, a reduced
uptake capacity. A similar hypothesis has been suggested for the
ventral striatum, where there appear to be fewer dopamine uptake sites
as compared with the dorsal striatum, despite a comparable innervation
density (Marshall et al., 1990; Jones et al., 1996). Moreover, these
observations are consistent with the lower immunoreactivity and mRNA
signal for DAT in the ventral tegmental area (VTA) as compared with the substantia nigra (Shimada et al., 1992; Ciliax et al., 1995).
We sought to test the hypothesis that the neurochemical profile of
dopamine overflow and diffusion in the rat prelimbic PFC is associated
with a restricted distribution of the DAT protein within individual
dopamine axons. We used an electron microscopic immunocytochemical
approach to compare the distribution of DAT protein in the dorsolateral
striatum and the deep layers of the prelimbic PFC. The relative
specificity of the results obtained in the prelimbic cortex with DAT
was assessed by comparison with another PFC region, the anterior
cingulate cortex, the superficial layers of which are innervated by a
separate group of dopamine axons (Berger et al., 1991). Finally, as a
positive procedural control, the distribution of immunoreactivity for
DAT within the deep layers of the prelimbic PFC was compared in
adjacent sections to the localization of another marker for dopamine
axons, the catecholamine synthetic enzyme tyrosine hydroxylase
(TH).
Some of these data have been reported in preliminary form (Sesack et
al., 1996).
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MATERIALS AND METHODS |
Immunocytochemistry. Eleven naive adult male Sprague
Dawley rats were anesthetized deeply and perfused transcardially with 10 ml of heparin saline (1000 U/ml), followed by fixative. For 10 rats,
the fixative consisted of 50 ml of 3.75% acrolein and 2%
paraformaldehyde in 0.1 M phosphate buffer, pH 7.4 (PB),
followed by 250 ml of 2% paraformaldehyde. To determine whether the
degree of DAT immunostaining was dependent on the fixative that was
used, we perfused the remaining animal with 500 ml of 4%
paraformaldehyde with 0.2% glutaraldehyde. The brains were removed,
post-fixed in the final fixative for 30 min, and sectioned at 50 µm
on a vibratome. To improve antigenicity and reduce nonspecific
immunolabeling, we subsequently treated the sections for 30 min with
1% sodium borohydride (Leranth and Pickel, 1989) and rinsed them in
PB. To reduce further the nonspecific labeling before incubation in primary antibody, we treated sections for 30 min in a blocking solution
consisting of 1% bovine serum albumin and 3% normal goat serum in 0.1 M Tris-buffered saline (TBS), pH 7.6. Sections for light
microscopy were exposed to 0.4% Triton X-100 to enhance antibody
penetration. Steps taken to enhance immunostaining for electron
microscopy included the use of rapid freeze-thaw or 0.04% Triton
X-100 and, in several experiments, two consecutive night incubations in
primary antibody.
The qualitative assessment of DAT immunoreactivity was based on two
different primary antibodies: rabbit polyclonal (1:100) and rat
monoclonal (1:1000). Both antibodies were directed against the N
terminus of the DAT protein (Ciliax et al., 1995; Hersch et al., 1997;
Miller et al., 1997) and produced comparable immunocytochemical staining. However, only the rat monoclonal antibody was used in quantitative studies. The specificity of both antibodies was
demonstrated by Western blot analysis against cloned transporter
expressed in mammalian cells and against the native transporter
expressed in brain. Interestingly, this analysis detected abundant DAT
protein in the striatum but produced no detectable signal in the
frontal cortex. This may have reflected the inclusion not only of the prelimbic and anterior cingulate cortices in the sample but of several
cortical divisions that receive only a minor dopamine input (Hersch et
al., 1997).
Additional tests for antibody specificity have included
immunoprecipitation of digitonin-solubilized striatal DAT binding sites
and loss of immunoreactivity in experimental animals after neurotoxic
lesion with 6-hydroxydopamine (6-OHDA) or in postmortem human brain as
a result of Parkinson's disease (Ciliax et al., 1995; Hersch et al.,
1997; Miller et al., 1997). In a further control experiment for the
present study the rat anti-DAT antibody was preadsorbed for 2 hr with
100 µg/ml of the fusion protein antigen and then tested for
immunocytochemical staining.
Because our pilot study found minimal immunoreactivity for DAT in the
deep layers of the rat prelimbic PFC (Sesack et al., 1996), it became
important to localize another marker for dopamine terminals in this
region as a positive control for our immunolabeling procedure. To this
end, adjacent sections through the prelimbic PFC of three animals were
incubated in rabbit anti-TH antiserum (1:1000), obtained commercially
from Eugene Tech (Ridgefield Park, NJ). The specificity of this
antibody has been established in previous studies (Joh et al., 1973),
and the relative selectivity of TH antisera for cortical dopamine
axons, as opposed to norepinephrine fibers, has been documented
extensively (Gaspar et al., 1989; Lewis and Sesack, 1997). We also have
compared TH and dopamine immunolabeling directly in the prelimbic PFC
of rats (Sesack et al., 1995), and our quantitative comparison revealed
no difference in the synaptic contacts of these terminals. Furthermore,
studies of dopamine  -hydroxylase or norepinephrine immunostaining in rat cortex report that few labeled varicosities form identifiable synapses (Descarries and Umbriaco, 1995; Branchereau et al., 1996), whereas the synaptic incidence for terminals immunolabeled for dopamine
or TH is much higher (Van Eden et al., 1987; Séguéla et
al., 1988; Descarries and Umbriaco, 1995; Sesack et al., 1995). Despite
this difference in synaptic incidence, the relative size of dopamine
versus norepinephrine varicosities is roughly equivalent (Descarries
and Umbriaco, 1995). Thus, the TH antibodies that we used appear to
label preferentially the dopamine terminals in the region that was
examined (i.e., deep layers of the prelimbic cortex) where the dopamine
innervation markedly exceeded that of norepinephrine (Berger et al.,
1976; Lindvall and Björklund, 1984). Nevertheless, we cannot
exclude the contribution of a few noradrenergic axons to the sample of
TH-immunoreactive profiles.
Sections were incubated in primary antibody for 15 hr at room
temperature or for 40 hr at 4°C. The secondary antibodies used were
biotinylated goat anti-rabbit IgG (1:400) or donkey anti-rat IgG
(1:100). Avidin-biotin-peroxidase complex (Vectastain Elite, Vector
Laboratories, Burlingame, CA) was applied at 1:200 (Hsu et al., 1981).
The avidin-biotin-peroxidase immunostaining procedure was chosen
because of its sensitivity for low-abundance antigens despite its
relatively indiscrete subcellular localization (Hsu et al., 1981; Chan
et al., 1990; Nirenberg et al., 1996). All incubations and rinses were
performed in TBS with constant agitation. Bound peroxidase was
visualized by the addition of 0.022% 3,3'-diaminobenzidine and 0.003%
H2O2 for 5 min.
Sections for light microscopy were slide-mounted, dehydrated, and
coverslipped. Sections for electron microscopy were post-fixed in 2%
osmium tetroxide in PB, dehydrated via increasing strengths of ethanol
and propylene oxide, and plastic-embedded with Epon-812 (Electron
Microscopy Sciences, Fort Washington, PA). Small regions within the
cortex and striatum were cut from these thick sections and glued onto
blocks of embedding plastic. The regions of interest were trimmed
further (Fig. 1) and then sectioned at
60-70 nm on an ultramicrotome. The ultrathin sections were collected
on copper mesh grids and stained with uranyl acetate and lead citrate
before being viewed in a Zeiss 902 transmission electron microscope
(Oberkochen, Germany).
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Figure 1.
Schematic drawings illustrating the regions
sampled in coronal sections of rat forebrain. Shading
indicates the approximate density of the dopamine innervation to the
prelimbic division of the PFC (PL), which is heaviest in
layers V-VI, the rostral anterior cingulate cortex
(CING), which is most dense in layers I-III, and the
corpus striatum (STR), which receives a dense dopamine input throughout its dorsoventral extent. The black
trapezoids indicate the regions sampled by electron microscopy.
These regions also are illustrated by light microscopy in Figure 3.
ac, Anterior commissure; cc, corpus
callosum.
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Quantitative image analysis. The approximate density and
morphological features of fibers immunoreactive for the DAT were assessed qualitatively, and a quantitative approach was used to further
estimate the relative distribution of DAT protein to varicose or
intervaricose segments of axons. The quantitative assessment was based
on the measurement of profile diameter, keeping in mind that, although
diameter is not an index of morphology, small profiles have a greater
probability of being axons, whereas large profiles have a greater
probability of being varicosities.
The electron microscopic results from six rats with the best morphology
and most robust staining with the rat anti-DAT antibody were quantified
in three regions (Fig. 1): dorsolateral striatum, layers I-III of the
rostral, dorsal anterior cingulate cortex, and layers V-VI of the
prelimbic cortex (Krettek and Price, 1977). The cortical layers that
were examined were chosen on the basis of the known distribution of
dopamine fibers in the rat supragenual and pregenual mesocortical
projections, respectively (Berger et al., 1991). For three of the six
rats, adjacent thick sections through the prelimbic PFC were stained
with rabbit anti-TH antibody and examined both qualitatively and
quantitatively. The cingulate cortex was not included in this analysis
of TH immunolabeling.
One to two thick tissue sections per region per animal were examined,
and the surface of the tissue where antibody penetration was maximal
was sampled at random. The specific immunoperoxidase reaction product
for DAT was identified as an electron-dense flocculent precipitate that
accumulated within the cytoplasm, along the inner plasmalemmal surface,
and along the outer membranes of organelles, including synaptic
vesicles. Such flocculent precipitate can be distinguished from other
electron dense structures in the tissue, even when it is present at low
levels (Sesack et al., 1994; Delle Donne et al., 1996, 1997).
Furthermore, this flocculent product was not observed in presumed
unlabeled structures in the immediately adjacent neuropil or in any
structures viewed at greater depths from the surface.
At least 40 profiles immunoreactive for DAT (all regions) or TH
(prelimbic cortex) were photographed at 13,000× and printed at 2.5×
enlargement. Immunolabeled profiles were identified as varicose or
intervaricose portions of axons (Peters et al., 1991) on the basis of
their small size, location in fields of small unmyelinated axons,
presence of synaptic vesicles, and/or occasional formation of synapses
on spines or dendrites. Compared with intervaricose axon segments,
varicosities were typically larger, contained more vesicles, and were
more likely to form synapses. A few profiles contained small patches of
weak immunoreaction product that were considered to be nonspecific.
These profiles were excluded from analysis, as were densely
immunolabeled profiles that did not have well delineated boundaries.
The remaining profiles were numbered sequentially on the micrographs
from upper left to lower right, and a random number generator was used
to select 30 profiles per region per animal. This number of profiles
was determined from a pilot study to be the minimum sample size per
animal needed to detect a 30% difference among means between regions
or markers with 80% power, using a Student's t test. In
total, 180 immunoreactive profiles per region for DAT and 90 profiles
for TH in the prelimbic PFC were selected.
The electron micrographic negatives were scanned by a digital camera
into an image analysis system (Advanced Imaging Concepts, Princeton,
NJ). The immunoreactive processes were traced by a single investigator,
and a set of rules was established to minimize variability in the
tracing. For example, (1) when profiles were labeled heterogeneously,
only the portions that contained immunoreaction product were traced;
(2) when the plasma membrane was clearly visible, tracing was done
directly along the membrane; (3) when the plasma membrane was obscured
slightly by immunoreaction product or plane of section, tracing was
done along the outer edge of the immunoreactivity; (4) when
immunolabeled profiles were apposed to each other (primarily in the
striatum), tracing was done along the inner edge of each apposed
membrane so that the traced profiles did not merge.
An unbiased, computerized algorithm was used to determine the maximum
diameter of each traced profile along its short axis by counting in one
pixel layer at a time from the perimeter and forming a "topographic
map" of the profile (Fig. 2). For
immunoreactive profiles with eccentric shape, such as longitudinal
sections through both varicose and intervaricose portions of an axon
(e.g., Fig. 2C), this diameter measurement represented the
most varicose portion of the profile. The data were analyzed
statistically by a two-way ANOVA, with the main effects being either
region and animal for DAT or marker and animal for DAT versus TH. The
interactions between main effects were determined also, and post
hoc analyses were performed with Tukey's studentized range
test.
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Figure 2.
Schematic drawing illustrating the measurement of
diameter after the perimeter of immunolabeled profiles has been traced. The representative profiles include (a) a
varicosity cut in cross section, (b) a
longitudinally sectioned axon, and (c) an
eccentrically shaped profile representing both varicose and
intervaricose segments of an axon. In each case the number of pixel
layers from the perimeter is counted until each counted pixel is
bounded by other counted pixels. This represents the pixel radius,
which is doubled to obtain the pixel diameter (arrows)
and then converted to micrometers with a calibration. This dimension
represents the maximal diameter through the short axis of each
profile.
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RESULTS |
Light microscopy
Light microscopic examination of the dorsolateral striatum
revealed immunoreactivity for DAT that was localized densely and diffusely to the neuropil surrounding unlabeled perikarya and bundles
of myelinated axons (Fig. 3A).
The density of the peroxidase reaction product precluded the
visualization of individual fibers. Examination of the same striatal
region in sections incubated in antibody preadsorbed with the DAT
antigen revealed no detectable immunoreactivity (Fig.
3B).
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Figure 3.
Light micrographs illustrating peroxidase
immunoreactivity for DAT in the rat forebrain. A, In the
dorsolateral striatum, dense peroxidase product for DAT is localized to
the neuropil immediately beneath the corpus callosum
(cc). Perikarya (asterisks) and bundles
of myelinated axons (m) are unlabeled.
B, No DAT immunoreactivity is detected in the same
striatal region of sections incubated in primary antibody preadsorbed
with the DAT antigen. C, In the rostral portion of the
anterior cingulate cortex, a dense cluster of DAT-immunoreactive fibers
is visualized in layer III. These presumed axons exhibit the branching
(small arrows) and beading (large arrows)
that are characteristic of terminal fibers. D, In layer
VI of the prelimbic cortex from the same section as that shown in
C, sparse fibers immunoreactive for DAT are observed. Although some are beaded or branched, others appear to be fibers of
passage (open arrows) exiting the white matter. In
A-D, up is dorsal and
left is medial. Scale bar, 150 µm.
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In the rostral portion of the anterior cingulate cortex,
DAT-immunoreactive fibers were localized diffusely throughout layers I-III and often were clustered densely within layer III (Fig. 3C). DAT-immunoreactive axons in these clusters exhibited
evidence of both branching and varicose beading. In the adjacent
prelimbic division of the PFC, DAT-immunoreactive fibers were markedly
sparse within the deep layers V-VI, even when the tissue was viewed
with differential interference contrast (DIC) optics (Fig.
3D). A few of the DAT-immunoreactive axons were beaded or
branched, whereas the remainder appeared to be fibers en
passant. This weak immunolabeling in the prelimbic PFC was
observed despite the use of two night incubations in primary antibody
that contained a high concentration of detergent to enhance
penetration. Furthermore, this low level of DAT immunoreactivity also
was observed in the more ventral infralimbic division of the PFC,
although this region was not explored further during this
investigation.
Electron microscopy
By electron microscopic examination of the dorsolateral striatum,
dense peroxidase immunoreactivity for the DAT was expressed abundantly
in axon varicosities and preterminal axons (Fig.
4A) that exhibited
features characteristic of dopamine fibers: lack of myelination, small
size, content of mostly clear synaptic vesicles, and occasional
formation in single sections of punctate symmetric synapses on spines
or distal dendrites (Pickel et al., 1981; Bouyer et al., 1984; Freund
et al., 1984; Descarries et al., 1996). In the superficial layers of
the anterior cingulate cortex, similar immunoreactive profiles were
observed. However, small-diameter vesicle-containing processes that
probably represented intervaricose axon segments appeared qualitatively
to contain a lower density of DAT immunoreactivity (Fig.
4B).
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Figure 4.
Electron micrographs illustrating peroxidase
immunoreactivity for DAT in the rat forebrain. A, In the
dorsolateral striatum, immunoreactivity for DAT is localized to axon
varicosities (DAT-v) that contain numerous synaptic
vesicles surrounded by dense peroxidase product. One immunoreactive
varicosity appears to form a small symmetric synapse on a dendritic
process (thick arrow). B, In the
cingulate cortex, DAT immunoreactivity is observed both in a varicose
structure and in small axon-like profiles (DAT-a, thin arrows), some of which contain synaptic vesicles.
C, In the prelimbic cortex, immunoreactivity for DAT is
seen almost exclusively in small axon-like profiles (thin
arrows). Immunonegative structures that exhibit similar size
and morphology are indicated at the open arrows.
D, DAT immunolabeling in the prelimbic cortex is visualized clearly in an axon cut longitudinally (thin
arrow), whereas the contiguous varicosity forms a synapse on a
dendritic spine (thick arrow) but otherwise is unlabeled
for DAT. Scale bar, 0.5 µm.
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In the deep layers of the prelimbic PFC, peroxidase immunolabeling for
the DAT was localized almost exclusively to the intervaricose segments
of axons (Fig. 4C,D) and was qualitatively less dense than
that observed in the dorsolateral striatum. Occasionally, immunoreactive axons were sectioned longitudinally, and it was possible
to visualize the varicosities to which they gave rise. In such
instances, the varicose portions of the axons invariably were devoid of
DAT immunoreactivity, whereas the intervaricose regions contained a
moderate density of peroxidase product (Fig. 4D).
Consistent findings were obtained regardless of the fixative used, the
primary antibody used (rat monoclonal, Fig. 4C or rabbit polyclonal, Fig. 4D), the use of one or two night
incubations in antibody, or the use of Triton X-100 detergent versus
freeze-thaw to enhance antibody penetration. Peroxidase labeling in
striatal and cortical sections virtually was eliminated by
preadsorption of the primary antibody with the DAT antigen.
In adjacent sections of the prelimbic PFC, immunoreactivity for TH was
detected in numerous axons and varicosities in the deep layers, some of
which formed synapses on spines and small dendrites (Fig.
5).
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Figure 5.
Electron micrographs illustrating peroxidase
immunoreactivity for TH in the rat prelimbic PFC. In the deep layers of
the prelimbic cortex, peroxidase immunoreactivity for TH was localized
in axon varicosities (TH-v) as well as in intervaricose
axon segments (TH-a, thin arrow). The
varicosities sometimes formed synapses on small dendrites (thick
arrows). Scale bar, 0.5 µm.
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Quantitative analysis
By quantitative analysis over all of the animals, the mean
diameter (± SD) of DAT-immunoreactive profiles was smaller in the prelimbic cortex (0.137 ± 0.049) than in the anterior cingulate cortex (0.180 ± 0.074) or the dorsolateral striatum (0.218 ± 0.084). Furthermore, this same pattern of mean diameter being
smallest in the prelimbic cortex, larger in the cingulate cortex, and
largest in the striatum was observed for each of the six animals. By
two-way ANOVA, there was a significant overall effect of region
(p < 0.0001) and no effect of animal. However,
a significant interaction between region and animal
(p < 0.012) suggested that some of the regional effect might be explained by animal differences. Because the region effects were similar for all animals, pairwise comparisons of main
effects for regions were conducted with Tukey's studentized range
test, with a simultaneous significance of p < 0.05. All three regions were found to be significantly different from each other.
To explore further the nature of the interaction between region and
animal, we did post hoc analyses with Tukey's procedure (again, with simultaneous significance of p < 0.05) on
all 18 animal-region comparisons. These comparisons revealed that a
significant difference in diameter between the prelimbic cortex and the
striatum occurred in all six animals. For the anterior cingulate
cortex, significant differences with the prelimbic cortex were detected in three of the six animals and with the striatum in two of the six
animals. However, it must be reemphasized that the same pattern of
regional variation in mean diameter occurred for each animal, regardless of whether these differences reached statistical
significance with the sample size chosen for this analysis.
Within the deep layers of the prelimbic PFC, DAT-immunoreactive
profiles were smaller in mean diameter than those labeled in adjacent
sections for TH (0.215 ± 0.088). By two-way ANOVA there was an
overall significant effect of marker (p < 0.0001), with no effect of animal and no interaction effect.
In addition to the statistical analysis of means, it was considered
useful to provide a full description of the data by using a frequency
histogram of all 180 observations per region for DAT and all 90 observations for TH in the prelimbic PFC (Fig.
6). From this perspective a majority of
DAT-immunoreactive profiles in the prelimbic cortex were of small
diameter, whereas a greater proportion of DAT-immunoreactive profiles
in the cingulate cortex and striatum was of larger diameter. The latter
was also true for TH-immunolabeled profiles in the prelimbic
cortex.
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Figure 6.
Histogram illustrating the frequency of diameters
measured for profiles immunoreactive for DAT or TH in the rat
forebrain. Each bar represents the total number
(frequency) of profiles having a particular diameter that were
immunoreactive for DAT in the prelimbic cortex (PL,
black), anterior cingulate cortex (CING, hatched), or dorsolateral striatum (STR,
gray) or for tyrosine hydroxylase in the prelimbic
cortex (TH, white). For each region 30 profiles for each of six animals are represented in the case of DAT and
for each of three animals in the case of TH. The histogram includes all
of the raw data from which means and SD were calculated; see Results
for the statistical analysis.
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In previous studies of dopamine axons in forebrain regions, profiles
smaller than 0.2 µm typically have been considered preterminal axons
and often have been excluded from analysis of varicosities (Bouyer et
al., 1984; Freund et al., 1984; Séguéla et al., 1988; Smiley and Goldman-Rakic, 1993; Descarries et al., 1996). Although we
applied no such exclusion criterion to our analysis, it was of interest
to determine the proportion of DAT-immunoreactive profiles in the
present study that had a diameter  0.2 µm. Across all of the
animals, only 12% (range per animal, 3-20%) of DAT-immunoreactive profiles in the prelimbic cortex met this criterion, whereas 35% (range, 17-53%) of those in the cingulate cortex and 56% (range, 50-67%) of those in the striatum were of this diameter or larger. Similarly, in the prelimbic cortex, 51% (range, 50-53%) of profiles immunoreactive for TH were 0.2 µm in diameter. These differences across regions and within the prelimbic PFC for the two markers were
significantly different (p < 0.0001) by
Fisher's exact test (Matthews and Farewell, 1996). Similar regional
and marker differences were obtained when the criterion was set at 0.23 or 0.29 µm. In the latter case, only a single DAT-immunoreactive
profile in the prelimbic PFC had a diameter that exceeded 0.29 µm.
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DISCUSSION |
The combined light and electron microscopic results suggest that
dopamine axon varicosities in the rat prelimbic PFC express relatively
low levels of DAT protein and a localization of DAT that is distant
from synaptic release sites. These findings are consistent with
observations of low DAT protein and mRNA in some VTA dopamine neurons
and suggest that individual dopamine cells are capable of selectively
targeting this important protein to different locations within the
axon. Furthermore, the results agree with neurochemical studies
reporting greater extracellular diffusion of dopamine in the prelimbic
PFC as compared with the dorsal striatum. Although the data appear to
support a greater paracrine role for cortical dopamine, the actual
sphere of influence of dopamine in the PFC may be limited by the low
density of its receptors. These observations and hypotheses are
depicted schematically in Figure 7.
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Figure 7.
Schematic diagrams illustrating the putative
distribution of DAT proteins in the dorsolateral striatum and prelimbic
cortex. In the striatum, dopamine released at synaptic sites is subject to extensive re-uptake by DAT localized to the plasma membrane adjacent
to the presynaptic zone and along preterminal portions of these axons.
In the prelimbic PFC, evidence for perisynaptic DAT is lacking,
although a low density of DAT protein is observed along preterminal
portions of presumed dopamine axons. Thus, synaptically released
dopamine is subject to less extensive uptake and greater extracellular
diffusion. The functional impact of this extracellular dopamine may be
limited by the low density of receptors for dopamine, which are
substantially less abundant in the cortex than in the striatum.
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Methodology and comparison to published findings
Light microscopy
The present light microscopic distribution of DAT compares well
with previous immunocytochemical studies showing a dense localization to the striatum and weaker labeling of cortex (Ciliax et al., 1995;
Freed et al., 1995; Nirenberg et al., 1996). However, the cortical
pattern of DAT labeling does not match previous accounts of dopamine
axons that used other markers (Descarries et al., 1987; Van Eden et
al., 1987; Séguéla et al., 1988; Berger et al., 1991).
Although the distribution of DAT in the superficial layers of the
anterior cingulate cortex matches the innervation by dopamine axons,
the DAT fiber density in the deep layers of the prelimbic and
infralimbic cortices underestimates the known distribution of dopamine
axons in these areas. These observations are supported by biochemical
reports of low DAT protein levels in the medial PFC (Vaughan et al.,
1996) and by autoradiographic studies describing fewer DAT sites in the
deep layers of the prelimbic cortex versus the cingulate cortex or
subcortical sites [Scatton et al. (1985); Coulter et al. (1995); but
see Descarries et al. (1987)]. These findings suggest that the density
of DAT in terminal regions reflects differences in the dopamine cells
of origin, because the superficial layers are innervated by the
substantia nigra whereas the deep layer input derives from the VTA
(Berger et al., 1991).
The potential contribution of technical factors to the sparsity of DAT
in the prelimbic PFC seems unlikely, because the antibody incubation
conditions produced robust labeling of the striatum and adjacent
cingulate cortex in the same animals. It is possible that the dopamine
neurons projecting to the prelimbic PFC express a different transporter
gene product. However, a second DAT gene has not yet been identified
(Uhl, 1992; Lorang et al., 1994; Bannon et al., 1995). Moreover, recent
biochemical evidence suggests that the DAT protein in the striatum,
accumbens, PFC, and midbrain is the product of a single gene (Vaughan
et al., 1996). Alternatively, the DAT in mesoprefrontal dopamine
neurons may be modified biochemically after translation in a manner
that prevents antibody recognition. For example, differences in
phosphorylation or glycosylation of the DAT (Lew et al., 1992; Vaughan
et al., 1996; Huff et al., 1997) might alter both function and antibody
binding. However, to date, neither phosphorylation nor glycosylation
has been shown to alter recognition by DAT antibodies directed against
four different epitopes (Patel et al., 1994; Vaughan et al., 1996; Huff
et al., 1997).
Perhaps the most parsimonious explanation for the sparse distribution
of DAT immunoreactivity in the prelimbic PFC is the presence of
dopamine axons, for which the content of DAT protein is below
detectable levels. This suggestion is consistent with reports of
neurons that express mRNA for TH, but not DAT (Augood et al., 1993;
Lorang et al., 1994), in the medial VTA regions that project to the
prelimbic PFC (Swanson, 1982; Berger et al., 1991). A similar
observation also has been made in the primate VTA (Haber et al., 1995).
Immunoreactivity for the DAT is also weak in the medial VTA (Ciliax et
al., 1995), suggesting that reduced somatodendritic localization of DAT
protein accompanies sparse levels of DAT in axons. Low levels of DAT
also have been reported in the dopamine neurons of the hypothalamus,
retina, and olfactory bulb (Shimada et al., 1992; Cerruti et al., 1993; Lorang et al., 1994; Ciliax et al., 1995). Moreover, our results are
consistent with a preliminary report that some cortical serotonin axons
lack immunoreactivity for the serotonin transporter (Axt et al.,
1995).
Electron microscopy
In the present study the ultrastructural features of varicosities
labeled for DAT in the striatum and cingulate cortex match those
previously described with uptake of radiolabeled transmitter (Descarries et al., 1987) or antibodies against DAT (Nirenberg et al.,
1996; Hersch et al., 1997), dopamine (Descarries et al., 1996), or TH
(Pickel et al., 1981; Bouyer et al., 1984; Freund et al., 1984).
However, in the prelimbic PFC the almost exclusive distribution of DAT
to small-diameter intervaricose axon segments is discrepant with other
markers of dopamine fibers (listed above), which frequently label
varicosities as well as the intervaricose portions of axons (Descarries
et al., 1987; Van Eden et al., 1987; Séguéla et al., 1988;
Sesack et al., 1995).
Although the use of heavy metal counterstaining may have prevented the
detection of low levels of immunoperoxidase product for DAT in the
prelimbic PFC, the observation in longitudinal sections that the
varicose portions of otherwise immunoreactive axons contained no
detectable DAT labeling argues that technical factors did not
contribute significantly to the ultrastructural findings. It also
should be noted that the failure to localize DAT to varicosities within
the prelimbic PFC occurred despite the use of the sensitive
avidin-biotin immunoperoxidase method (Hsu et al., 1981) and the
ability of peroxidase product to diffuse short distances within labeled
structures (Courtoy et al., 1983). Although immunogold methods provide
better subcellular localization and have been used to demonstrate a
perisynaptic localization of DAT in the striatum (Nirenberg et al.,
1996; Hersch et al., 1997), these approaches were not chosen for the
present study because of their low sensitivity (Chan et al., 1990).
The distribution of DAT to intervaricose axon segments in the prelimbic
PFC suggests that this protein is localized primarily at a distance
from varicose sites of release. However, dopamine axons in the striatum
sometimes exhibit synapses along intervaricose regions (Freund et al.,
1984; Groves et al., 1994). Although we have not observed such
occurrences in our cortical studies and none has been reported to date
in the rodent or primate PFC (Séguéla et al., 1988; Smiley
and Goldman-Rakic, 1993), a complete serial reconstruction of dopamine
axons is required to address this issue fully. Furthermore, the widely
held view that transmitter release occurs via vesicle exocytosis at
active zones has not been proven conclusively in the CNS (Smith and
Augustine, 1988). Thus, the exact spatial relationship between sites of
dopamine release and re-uptake in individual cortical axons remains to
be determined.
Functional implications
Several neurochemical observations are consistent with the
observed paucity of DAT in the rat prelimbic PFC. For example, both
endogenously released (Garris et al., 1993; Garris and Wightman, 1994)
and exogenously applied (Cass and Gerhardt, 1995; Lee et al., 1996)
dopamine exhibit greater extracellular diffusion and slower clearance
in the PFC as compared with other forebrain areas. Although a direct
comparison between the prelimbic and anterior cingulate cortices has
not been made, Garris and colleagues (1993) did show that electrical
stimulation evoked a voltammetric signal for dopamine only in the
ventral, and not the dorsal, region of the anteromedial cortex.
Investigators also have noted that the ratio of dopamine in dialysate
to whole tissue levels is considerably higher in the PFC than in the
striatum or nucleus accumbens, suggesting that the cortex expresses a
proportionally greater amount of extracellular dopamine relative to
intraneuronal stores (Sharp et al., 1986; Maisonneuve et al., 1990;
Garris et al., 1993).
There are several potential explanations for these findings. Compared
with other forebrain dopamine systems, mesocortical dopamine neurons
may have a greater capacity for release (Sharp et al., 1986; Hoffman et
al., 1988; Garris et al., 1993), consistent with their higher firing
rates, more efficient depolarization-release coupling, and absence of
autoreceptor inhibition of synthesis (Chiodo et al., 1984; White and
Wang, 1984; Wolf et al., 1986; Hoffman et al., 1988). Other
contributing factors could include variations in the levels of
metabolic enzymes or extracellular tortuosity factors that affect
diffusion (Nicholson, 1995). However, studies in mice lacking DAT gene
expression (Giros et al., 1996) suggest that dopamine synthesis,
autoreceptor density, and other factors have less impact on
extracellular dopamine than has the DAT protein itself. Thus, the
sparsity of DAT in the PFC might contribute to higher extracellular
levels, as compared with the striatum, if each cortical dopamine axon
contains proportionally less DAT protein and/or if the DAT is localized
further from the release sites.
Other findings that support this view include the reportedly reduced
efficacy of selective dopamine uptake blockers in the PFC as compared
with subcortical regions (Carboni et al., 1990; Cenci et al., 1992;
Pozzi et al., 1994). Cocaine is also less potent at blocking dopamine
uptake into synaptosomes or tissue slices from the PFC than those from
the striatum (Hadfield and Nugent, 1983; Izenwasser et al., 1990;
Elsworth et al., 1993). Furthermore, at all systemic doses, cocaine
produces a less profound increase in extracellular dopamine
in the PFC than in the striatum (Moghaddam and Bunney, 1989).
Despite the paucity of DAT in the prelimbic PFC, additional mechanisms
do exist to terminate the actions of dopamine, including diffusion,
extraneuronal metabolism (Sharp et al., 1986; Maisonneuve et al., 1990;
Karoum et al., 1994), and uptake by proteins other than the DAT. Of
particular note, dopamine is the preferred substrate for the
norepinephrine transporter (NET) (Bannon et al., 1995), and dopamine is
known to be taken up into norepinephrine axons in the PFC (Carboni et
al., 1990; Izenwasser et al., 1990; Elsworth et al., 1993; Pozzi et
al., 1994; Tanda et al., 1994; Gresch et al., 1995; Lee et al., 1996).
On the basis of these observations it has been suggested that the
clinical actions of antidepressant drugs that block the NET may include
an increase in dopamine levels in the PFC (Carboni et al., 1990; Pozzi
et al., 1994; Tanda et al., 1994). However, despite the availability of
this mechanism, the PFC still exhibits a reduced capacity for dopamine
clearance (Garris et al., 1993; Garris and Wightman, 1994; Cass and
Gerhardt, 1995), perhaps because of the sparsity of norepinephrine
terminals in the deep layers of the prelimbic PFC (Berger et al., 1976; Lindvall and Björklund, 1984). In support of this suggestion, the
NET appears to play a greater role in clearing exogenously applied
dopamine in the dorsal (i.e., cingulate) than in the ventral (i.e.,
prelimbic) PFC (Cass and Gerhardt, 1995).
Conclusions
It has been argued that dopamine primarily serves a paracrine role
in the PFC (Garris and Wightman, 1994), although other observations
argue against this hypothesis. First, as discussed above, there are
multiple mechanisms for dopamine clearance in the cortex, including the
sparse DAT protein that is present. Second, a significant number of
dopamine varicosities form conventional synapses in both the rat
(Séguéla et al., 1988) and monkey (Smiley and
Goldman-Rakic, 1993; Sesack et al., 1995) PFC and exhibit specificity
in their synaptic targets (Lewis et al., 1996). Finally, overall
dopamine receptor expression is substantially lower in the cortex, as
compared with the striatum, and many dopamine receptor subtypes exhibit
specificity in their neuronal distribution (Levey et al., 1993; Bergson
et al., 1995; Gaspar et al., 1995; Mrzljak et al., 1996). Such a
profile would not be predicted for a transmitter with widely
distributed actions on multiple cell types.
An alternative hypothesis is that synaptically released dopamine
produces the greatest functional impact, with additional extrasynaptic
actions occurring only over short distances. Establishing the validity
of this hypothesis will require exact knowledge about the concentration
gradients of extracellular dopamine and the location and affinity of
receptors relative to release sites. However, if this speculation has
credence, it suggests that mesoprefrontal dopamine neurons may express
little DAT protein because it is not critical for terminating the
actions of dopamine and because it is economical to avoid the
energy-requiring process of re-uptake.
| |
FOOTNOTES |
Received Aug. 15, 1997; revised Jan. 9, 1998; accepted Jan. 14, 1998.
We gratefully acknowledge the assistance of Drs. Allan Sampson and
Satish Iyengar in statistical analysis and Drs. Deborah King and Holly
Moore for editorial contributions. This work was supported by United
States Public Health Service Grants MH50314, MH45156 (S.R.S.), and
NS31937 (A.I.L.).
Correspondence should be addressed to Dr. Susan R. Sesack, Department
of Neuroscience, 446 Crawford Hall, University of Pittsburgh, Pittsburgh, PA 15260.
| |
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Top
Abstract
Introduction
