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The Journal of Neuroscience, March 1, 1998, 18(5):1806-1817
Intrastriatal Mesencephalic Grafts Affect Neuronal Activity in
Basal Ganglia Nuclei and Their Target Structures in a Rat Model of
Parkinson's Disease
Naoyuki
Nakao,
Mitsuhiro
Ogura,
Kunio
Nakai, and
Toru
Itakura
Department of Neurological Surgery, Wakayama Medical College,
7-27, Wakayama, Japan
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ABSTRACT |
Nigrostriatal dopamine (DA) lesions lead to changes of neuronal
activity in basal ganglia nuclei such as the globus pallidus (GP, the
rodent homolog of lateral globus pallidus), entopeduncular nucleus (EP,
the rodent homolog of medial globus pallidus), substantia nigra pars
reticulata (SNR), and subthalamic nucleus (STN). We investigated in
rats whether embryonic mesencephalic DA neurons grafted in the striatum
may affect the lesion-induced alterations of neuronal activity in these
structures. Regional neuronal activity was determined by use of
quantitative cytochrome oxidase histochemistry. It was also examined in
lesioned rats whether the grafts may regulate the expression of c-Fos
after systemic administration of apomorphine in the basal ganglia
nuclei as well as their target structures, including the ventromedial
thalamic nucleus (VM), superior colliculus (SC), and pedunculopontine
nucleus (PPN). Lesioned rats exhibited an increased activity of CO in
the GP, EP, SNR, and STN ipsilateral to the lesion. Intrastriatal
nigral grafts reversed the increases in the CO activity in the EP and
SNR, whereas the grafts failed to affect the enzyme activity in the GP
or STN. Apomorphine induced an increased expression of c-Fos in the GP,
STN, VM, SC, and PPN on the lesioned side. The enhanced expression of
this protein in all the structures except for the STN was attenuated by
nigral grafts. The present results indicate that intrastriatal DA
neuron grafts can normalize the lesion-induced changes of neuronal
activity in the output nuclei of the basal ganglia as well as their
target structures.
Key words:
neural transplantation; dopamine neurons; c-Fos; cytochrome oxidase; basal ganglia; Parkinson's disease
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INTRODUCTION |
Embryonic dopamine (DA) neurons
grafted into the previously DA-denervated striatum survive, reinnervate
the host striatum, and improve various behavioral abnormalities (for
review, see Björklund, 1992 ; Brundin et al., 1994). The
behavioral recovery could be attributed to the graft-mediated
restoration of the neurochemical and electrophysiological parameters in
the lesioned striatum. Thus, the grafts normalize the DA
denervation-induced hypersensitivity of D1 and/or D2 receptors (Freed
et al., 1983; Dawson et al., 1991; Gagnon et al., 1991; Rioux et al.,
1991; Blunt, 1992; Savasta et al., 1992) and the altered levels of
several neurotransmitters in the striatum (Sirinathsinghji and Dunnett,
1991; Centi et al., 1993). DA neuron grafts also reverse the
denervation-induced increase in the basal firing rate of striatal
neurons (Strömberg et al., 1985; Hudson et al., 1994).
The depletion of DA in the striatum can modify the function of striatal
projection neurons, which could in turn affect the activity of neurons
in several striatal targets. Previous experiments have used
quantitative 2-[14C]deoxyglucose autoradiography
to demonstrate changes in the rate of glucose metabolism in several
brain regions, including striatofugal systems in animals with lesions
of the nigrostriatal DA pathway (Kozlowski et al., 1980; Wooten and
Collins, 1981; Porrino et al., 1987; Schwartzman et al., 1988; Mitchell
et al., 1989; Palombo et al., 1990). Nigrostriatal lesions also modify
the rate and pattern of spontaneous firing rate in basal ganglia
nuclei, such as the globus pallidus (GP), the entopeduncular nucleus
(EP), the substantia nigra pars reticulata (SNR), and the subthalamic nucleus (STN) (Pan and Walters, 1988; Hollerman and Grace, 1992; Burbaud et al., 1995; Hassani et al., 1996). The functional changes in
these brain structures have been extensively discussed from the
viewpoint of mechanisms underlying motor abnormalities in Parkinson's
disease (Albin et al., 1989; DeLong, 1990). To date, few studies have
examined in any systematic way the issue of whether intrastriatal DA
neuron grafts may affect such trans-synaptic changes in animal models
of Parkinson's disease. Because clinical trials of human fetal tissue
transplantation in Parkinson's disease patients have revealed that
intrastriatal nigral grafts survive and to some extent ameliorate
parkinsonian symptoms such as bradykinesia and rigidity (Lindvall,
1994; Olanow et al., 1996), it is highly warranted to investigate
effects of intrastriatal DA neuron grafts on neuronal activity in basal
ganglia nuclei, particularly in the EP and SNR, both of which play an
important role in the regulation of motor functions as the output
station of the basal ganglia (Albin et al., 1989; DeLong, 1990).
The present study was designed to explore whether intrastriatal
mesencephalic grafts may affect the nigrostriatal lesion-induced alterations of neuronal activity in several nuclei of the basal ganglia, including the GP, EP, SNR, and STN. To detect the alterations of neuronal activity, we determined the activity of cytochrome oxidase
(CO), which is an oxidative enzyme of the mitochondrial respiratory
chain and is enriched in the somatodendritic compartment (Kageyama et
al., 1982). Because a direct relationship has been demonstrated between
neuronal functional activity and oxidative energy metabolism
(Wong-Riley, 1989; Hevner et al., 1995; Vila et al., 1996a),
quantitative CO histochemistry is suitable for studying the effects of
intrastriatal nigral grafts on trans-synaptic changes of
neuronal activity in specific brain regions. We also monitored c-Fos
protein expression in the basal ganglia nuclei, including GP, EP, SNR,
and STN, and their target structures, such as ventromedial thalamic
nucleus (VM), superior colliculus (SC), and pedunculopontine nucleus
(PPN), in 6-hydroxydopamine (6-OHDA)-lesioned rats after systemic
apomorphine challenge, and we determined whether grafted DA neurons can
influence the level of the protein expression. Immunohistochemistry for
c-Fos has been used previously to label polysynaptically activated
neurons (Dragunow and Robertson, 1987; Sagar et al., 1988).
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MATERIALS AND METHODS |
Unilateral 6-hydroxydopamine lesions and
apomorphine-induced circling behavior. Male Sprague Dawley rats,
weighing 180-200 gm at the start of the experiment, were used. They
were maintained under a 12 hr dark/light cycle with free access to food
and water. All surgical procedures described below were performed under
sodium pentobarbital anesthesia (50 mg/kg). To make unilateral lesions of the ascending mesostriatal dopamine pathway, 6-OHDA (Sigma, St.
Louis, MO) (3 mg/ml in 0.2 mg/ml ascorbate/saline) was injected at two
sites: (1) 2 µl at 4.0 mm posterior to the bregma, 0.8 mm to the
right, and 8.0 mm below the dural surface with the tooth-bar set at 3.4 mm above the interaural line; and (2) 2.5 µl at 4.4 mm posterior to
the bregma, 1.2 mm to the right, and 8.0 mm below the dura with the
tooth-bar set at 2.3 mm below the interaural line. The rate of 6-OHDA
infusion was 1 µl/min, and the cannula was left in situ
for an additional 3 min.
Two weeks after the lesion surgery, the effect of the 6-OHDA lesion was
assessed by monitoring apomorphine (0.25 mg/kg, s.c.)-induced turning
behavior over a period of 60 min. The rats that exhibited a net
rotational asymmetry of at least five full turns per minute away from
the lesioned side were selected for a series of experiments described
below, because this degree of apomorphine-induced rotational asymmetry
corresponds to >90% depletion of striatal DA (Hefti et al., 1980). In
addition, the drug-induced rotational behavior was tested at 20 weeks
after grafting.
Preparation of graft tissue and transplantation surgery.
Cell suspension was prepared from ventral mesencephalic tissue obtained from rat embryos of Sprague Dawley strain (embryonic day 14; crown-rump length, 12-13 mm) as described previously (Nakao et al., 1994). The
viability of the cell suspension just before grafting was >95%, and
the cell concentration was 3.97 × 104/µl.
Two stereotaxic deposits, each of 2 µl cell suspension, were injected
into the lesioned striatum of recipient rats as described previously
(Nakao et al., 1994). As sham controls, the lateral ganglionic eminence
(LGE) tissues dissected from the same embryos as above were implanted
into the striatum in an identical manner. The cell concentration of
suspension of the dissociated LGE tissue was 5.31 × 104/µl.
Tissue processing. The animals were transcardially perfused
with physiological saline followed by 4% paraformaldehyde/0.1 M phosphate buffer, pH 7.4. After 6 hr of post-fixation in
the same fixative, the brains were immersed in 20% sucrose in 0.1 M phosphate buffer at 4°C until they sank. Sections were
cut at 30 µm in a cryostat, and the free-floating sections were
collected in 0.1 M PBS.
CO histochemistry was performed as described elsewhere (Wong-Riley,
1979), with minor modifications. Briefly, free-floating sections were
incubated for 4 hr at 37°C in 0.1 M PBS, pH 7.4, containing 1.7 mM 3,3'-diaminobenzidine (Sigma) and 8 µM cytochrome c (Sigma). After incubation, the
sections were thoroughly rinsed with 0.1 M PBS and mounted
on gelatin-coated slides. Specificity of CO reaction was confirmed by
the lack of staining on sections processed for histochemistry in the
presence of rotenone.
For immunohistochemistry, the brain sections were preincubated in 10%
blocking serum/0.2% Triton X-100/0.1 M PBS for 1 hr at
room temperature. The sections were incubated overnight at room
temperature with primary antibodies against tyrosine hydroxylase (TH)
(1:800; Chemicon, Temecula, CA) or c-Fos (1:1000; Cambridge Research
Biochemicals). Subsequently, the tissue was exposed to the following
biotinylated secondary antibodies for 1 hr at room temperature:
anti-mouse IgG (1:200; Vector Laboratories, Burlingame, CA) and
anti-rabbit IgG (1:200; Vector) for TH and c-Fos, respectively. The
bound antibodies were visualized using an avidin-biotin-peroxidase complex system (Vectastain ABC Elite Kit, Vector), with
3,3'-diaminobenzidine as chromogen.
Computer-assisted image analyses. Image analyses below were
made on blind-coded slides. Measurements of CO staining intensity were
made by densitometric analysis with a Macintosh-based computerized image processing system. Histological sections were digitized by use of
a high resolution CCD video camera (Victor, Tokyo) and analyzed using
Image software (IPLab Spectrum, Signal Analytics, Vienna). Anatomical
regions of interest were identified on brain sections according to the
rat brain atlas (Paxinos and Watson, 1982) and delineated on the basis
of their stained structures using a mouse-controlled cursor. The
optical density of the staining was measured in the delineated areas on
both lesioned and unlesioned sides and corrected by subtracting
background levels that were determined in regions outside the brain
sections on individual slides. Regions of interest were the GP (AP,
0.92 mm), EP (AP, 2.30 mm), SNR (AP, 5.30 mm), and STN (AP, 4.16 mm)
(Paxinos and Watson, 1982). For each region of interest, the
measurements of the optical density were made on two consecutive
sections from individual animals, and the obtained values were
averaged. The optical density on the lesioned side was expressed as a
percentage of that on the intact side when compared between groups.
The density of c-Fos-positive cell nuclei was quantified in several
brain regions using the same computerized image processing system as
described above. Brain sections that had been processed for c-Fos
immunohistochemistry were digitized. The digitized images were
converted to binary images by use of a threshold function to count the
number of cells with unequivocally positive staining. Cell counts were
made bilaterally in the GP, EP, SNR, STN, VM (AP, 2.56 mm), SC
(intermediate gray layer of the SC; AP, 6.04 mm), and PPN
(pedunculopontine tegmental nucleus; AP, 7.80 mm) (Fig.
1) (Paxinos and Watson, 1982). The
adjacent sections processed for CO histochemistry helped to identify
the anatomical areas of interest. For counting cells in the GP, EP,
SNR, STN, VM, and SC, a sampling grid of rectangular shape was placed
at the center of the anatomical regions on each side (Fig. 1). For
estimations of cell numbers in the PPN, the grid was positioned just
lateral to the decussation of the superior cerebellar peduncle (Fig.
1). The sizes of the sampling grid for the determination of
c-Fos-positive cell density were 0.27 mm2 for the
GP, EP, SNR, VM, and SC, and 0.02 mm2 for the STN.
Data obtained from two consecutive sections were averaged in individual
animals and expressed as the number of the immunopositive cells per
analyzed area for each structure.
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Figure 1.
Schematic representation of
anatomical regions in which c-Fos-positive cell numbers were evaluated
(drawn on atlas of Paxinos and Watson, 1982). Closed
boxes represent the regions at which a sampling grid for the
determination of c-Fos-positive cell density was placed.
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Statistical analyses. All data were expressed as the
mean ± SEM. Multiple comparisons were made using one-way ANOVA
with post hoc Scheffé's test. Paired two-tailed
Student's t test was used to compare values on the two
sides of the brain. A probability value of <0.05 was considered
significant.
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RESULTS |
Cytochrome oxidase activity in basal ganglia after nigrostriatal
dopamine lesion
We first determined the temporal pattern of changes of the CO
activity in basal ganglia, including the GP, EP, SNR, and STN, at 2 (n = 4), 4 (n = 4), 6 (n = 4), or 8 weeks (n = 4) after
nigrostriatal DA lesions. In normal rats (n = 4), there
was no difference in measured values representing optical density of CO
staining between the lesioned and intact sides in all the structures
examined. At 2 weeks after the lesion, a tendency toward increased
optical density was noted in the STN on the lesioned side. The increase reached a statistically significant level at 4 weeks after the lesion.
The optical densities ipsilateral to the lesion in the GP, EP, and SNR
were increased from 4 to 6 weeks after 6-OHDA lesions and were
significantly higher than those on the intact side at 8 weeks after
lesioning. Compared with unlesioned normal animals, the lesioned rats
exhibited increased CO activity ipsilateral to the lesion by ~30% in
the GP (p < 0.01), 20% in the EP
(p < 0.001), 25% in the SNR
(p < 0.001), and 35% in the STN
(p < 0.001) at 8 weeks after the lesion.
Apomorphine-induced circling behavior
Because all the nuclei of the basal ganglia examined showed
significant increases in the CO staining intensity at 8 weeks after
nigrostriatal DA depletion, we chose to implant embryonic mesencephalic
tissue in recipient animals ("nigral graft group") (n = 9) at this time point after the lesion. In
addition, as sham controls, the LGE tissues were grafted in four
lesioned rats ("LGE graft group"). Seven animals with similar
conditions of 6-OHDA lesioning served as controls ("control lesion
group"). Before transplantation, there was no difference in
rotational asymmetry among animals in the control lesion (7.3 ± 1.1 turns/min), the LGE graft (7.1 ± 1.2 turns/min), and the
nigral graft (7.5 ± 1.3 turns/min) groups. At 20 weeks after
grafting, the nigral graft group exhibited lower net asymmetry values
than the control lesion group (p < 0.0001)
(Fig. 2). There was no significant
difference in rotational scores between the control lesion and the LGE
graft groups (Fig. 2). Thus, rats receiving intrastriatal DA neuron grafts displayed rotational asymmetry of 2.1 ± 1.3 turns/min away from the lesion side, whereas animals in the control lesion and the LGE
graft groups exhibited robust contralateral turning (8.7 ± 1.2 turns/min for the control lesion group and 8.2 ± 1.4 turns/min for the LGE graft group).
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Figure 2.
Net contralateral apomorphine-induced rotation
asymmetry (full turns per minute) over the 60 min test session. Data
represent the mean ± SEM. *p < 0.0001;
significant difference from controls (one-way ANOVA with post
hoc Scheffé's test).
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Graft survival
The 6-OHDA lesions of the mesostriatal bundle produced a virtually
complete loss of TH-positive DA neurons in the substantia nigra. In all
the rats receiving nigral tissue, two grafts with many TH-positive
cells in their periphery were seen in the rostral part of the host
striatum and were found to extend numerous TH-positive fibers into the
DA-depleted striatum. Cell counts on every third section with a
correction according to the formula of Abercrombie (1946) revealed that
each rat with two graft deposits had a mean number of 2276 TH-positive
neurons.
Effects of intrastriatal mesencephalic grafts on cytochrome oxidase
activity in basal ganglia
In the control lesion group compared with the age-matched normal
animals (n = 4), significant increases in the CO
activity were noted in the GP, EP, SNR, and STN ipsilateral to the
lesion (p < 0.0001) (Figs.
3, 4). In
the EP and the SNR of rats receiving nigral grafts, the optical density
of CO staining on the lesioned side was significantly decreased
compared with control lesioned animals (p < 0.0001) (Figs. 3, 4). No significant difference in the CO activity in
these structures was detected between the rats with nigral grafts and
the normal animals. The increased CO activity in the GP and the STN was
not affected by grafting nigral tissue. Implantation of LGE tissue
failed to affect the lesion-induced increase in the CO activity of any
structures examined. In all the groups, there were no side-to-side
differences in the optical density of CO staining in target structures
of the basal ganglia, including the VM, PPN, and SC (data not
shown).
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Figure 3.
Cytochrome oxidase (CO) activity ipsilateral to
nigrostriatal lesion in basal ganglia nuclei. CO activity on the
lesioned side is expressed as a percentage of that on the intact side. Data are the mean ± SEM. *p < 0.0001;
significant difference from normal animals (one-way ANOVA with
post hoc Scheffé's test). #p < 0.0001; significant difference from controls (one-way ANOVA with
post hoc Scheffé's test).
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Figure 4.
Digitized images of cytochrome oxidase (CO)
activity in basal ganglia nuclei. In rats with unilateral nigrostriatal
lesions, increased optical densities are noted in the GP
(A), EP (B), SNR (C), and STN (D)
ipsilateral to the lesion. In the lesioned animals with nigral grafts,
the increases in CO activity are attenuated in the EP
(E) and SNR
(F).
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Effects of intrastriatal mesencephalic grafts on
apomorphine-induced c-Fos activation in basal ganglia and their target
structures
Animals in all the groups were killed 1 hr after the completion of
the rotational asymmetry test, i.e., 2 hr after intraperitoneal injections of apomorphine. The age-matched normal animals
(n = 4) were also given an identical treatment with
apomorphine. In normal rats, there was a negligible number of
c-Fos-positive cell nuclei in the striatum on both sides after
apomorphine. By contrast, in both the control lesion and the LGE graft
groups a robust expression of c-Fos was noted in the DA-denervated
striatum, whereas there were very few nuclei stained for c-Fos in the
intact striatum. Intrastriatal grafts of DA neurons remarkably
attenuated the apomorphine-induced activation of c-Fos in the
denervated striatum. Because the present study was focused on the
neuronal activity in striatal projection areas as well as in targets of
the basal ganglia, precise evaluations of c-Fos expression in the
striatum were not made.
Apomorphine induced little or no expression of c-Fos protein in the
basal ganglia nuclei and their target structures on both sides in
normal animals. In the control lesion group, although there was little
expression of c-Fos on the intact side after apomorphine challenge, the
drug led to a marked increase in c-Fos-positive cell numbers in the GP,
STN, VM, SC, and PPN but not in the EP or SNR on the lesioned side
(Fig. 5). In the GP, STN, VM,
intermediate gray layer of the SC, and PPN, c-Fos-positive cell nuclei
were found to be homogeneously distributed within these anatomical regions of interest. Comparisons between the sides revealed a significant increase in the number of c-Fos-positive cell nuclei in the
GP, STN, VM, SC, and PPN on the lesioned side (p < 0.0001) (Figs. 6,
7). Intrastriatal nigral grafts
significantly attenuated the apomorphine-induced enhancement of c-Fos
expression in the GP, VM, SC, and PPN ipsilateral to the lesion
(p < 0.0001) (Figs. 6, 7). The c-Fos activation
in the STN was not affected by the nigral grafts. In the nigral graft
group, the numbers of c-Fos-positive cells in the VM, SC, and PPN on
the lesioned side still differed from those on the unlesioned side and
did not reach normal levels. The LGE grafts failed to affect the
apomorphine-induced c-Fos activation in the GP, STN, VM, SC, and PPN.
The number of c-Fos-positive cells on the unlesioned side in each
region examined did not differ between the groups.
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Figure 5.
Apomorphine-induced c-Fos activation in basal
ganglia nuclei and their target structures. Values are the mean ± SEM of numbers of c-Fos-immunopositive cells per analyzed area.
*p < 0.0001; significant difference from the
intact side (paired two-tailed Student's t test).
#p < 0.0001; significant difference from controls (one-way ANOVA with post hoc Scheffé's
test).
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Figure 6.
Photomicrographs demonstrating
c-Fos-immunopositive cells in the GP (A, B), EP
(C), SNR (D), and STN
(E) ipsilateral to nigrostriatal lesions after
systemic injections of apomorphine. In animals with unilateral
nigrostriatal lesions, the numbers of c-Fos-positive cells are
increased in the GP (A) and STN
(E) ipsilateral to the lesion after systemic
apomorphine. No differences in the c-Fos cell numbers between the
lesioned and intact sides are seen in the EP (C)
or SNR (D). The apomorphine-induced enhancement
of c-Fos expression in the GP (B) is attenuated
in the lesioned rats with nigral grafts. Scale bar, 100 µm.
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Figure 7.
Photomicrographs showing c-Fos-immunopositive
cells in the VM (A, B), SC (C, D), and
PPN (E, F) on the lesioned side after systemic
administrations of apomorphine. In the lesioned animals, the numbers of
c-Fos-positive cells are increased in the VM (A), SC (C), and PPN
(E) on the lesioned side after systemic
apomorphine challenge. The apomorphine-induced enhancement of c-Fos
expression in these structures is attenuated in the lesioned rats with
nigral grafts (B, D, F). Scale bar, 100 µm.
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DISCUSSION |
Cytochrome oxidase activity in basal ganglia nuclei
We found increased activity of CO in the GP, EP, SNR, and STN
ipsilateral to nigrostriatal lesions. These findings, except for the
increased activity in the GP, are consistent with a model of basal
ganglia organization that has been proposed to explain the
pathophysiology of clinical symptoms in Parkinson's disease (Albin et
al., 1989; DeLong, 1990). Thus, nigrostriatal DA denervation results in
increased activity in the EP and SNR by two independent mechanisms: the
suppression of direct inhibitory inputs from the striatum (direct
pathway) and the overactivity of excitatory afferents from the
STN, probably caused by the release of the tonic inhibitory effect
exerted by the GP (indirect pathway). According to this model, the GP is postulated to become hypoactive after DA denervation of the striatum. Nonetheless, a recent study by Porter et al. (1994) as
well as the present experiments, using histochemistry of mitochondrial
enzymes, indicate increased neuronal activity in the GP. The effect of
nigrostriatal lesions on the neuronal activity in the GP remains
controversial (for review, see Chesselet and Delfs, 1996; Levy et al.,
1997). In rats and monkeys with nigrostriatal DA denervation, levels of
glutamate decarboxylase, which can reflect the activity of GABAergic
neurons, have been shown to be increased or to remain unchanged in the
GP (the rodent homolog of lateral globus pallidus) (Segovia et al.,
1987; Kincaid et al., 1992; Soghomonian et al., 1992; 1994).
Electrophysiological studies have demonstrated that the GP exhibits an
increase in burst firing activity after nigrostriatal DA depletion (Pan
and Walters, 1988; Hassini et al., 1996). Because the GP receives glutamatergic excitatory afferents from the STN as well as GABAergic inhibitory inputs from the striatum (Kitai and Kita, 1987; Robledo and
Féger, 1990), the GP activity depends on the net outcome of these
reciprocal innervations. Thus, the currently observed increase in the
GP activity suggests that the excitatory effect of the
subthalamopallidal projection may surpass the inhibitory effect of the
striatopallidal projection in 6-OHDA-lesioned rats (Fig.
8). This hypothesis also raises the
possibility that the lesion-induced hyperactivity of the STN may be
mediated by mechanisms involving neural circuits other than the
striatopallido-subthalamic pathway. Experimental evidence has
indicated that the substantia nigra pars compacta sends DA efferents to
the STN to affect directly neuronal activity of this nucleus (Brown et
al., 1979; Meibach et al., 1979; Campbell, 1985). The activity of STN
neurons has also been shown to be regulated by direct glutamatergic
inputs from the neocortex, which receives nigral DA projection fibers (Berger et al., 1976; Afsharpour, 1985; Canteras et al., 1988). The
present lesion of the nigrostriatal bundle can deprive DA innervation
of the STN and the neocortex, which could in turn affect the neuronal
activity in the STN by direct and indirect mechanisms, respectively
(Fig. 8). In this context, homotopic (the substantia nigra), but not
ectopic (the striatum), placement of nigral grafts would be required to
affect the long-term changes of the GP and STN neuronal activity after
nigrostriatal lesions.
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Figure 8.
Schematic representation of a hypothetical model
of the functional organization of the basal ganglia based on the
results of cytochrome oxidase histochemistry (modified from Albin et
al., 1989). Lesions of the nigrostriatal bundle can deprive DA
innervation of not only the striatum (STR) but also the
the subthalamic nucleus (STN) and cortex
(Cx). The hyperactivity of the entopeduncular nucleus
(EP) and substantia nigra pars reticulata
(SNR) is attributable to the lesion-induced suppression
of direct inhibitory inputs from the striatum (direct
pathway). In this model, the striatopallido-subthalamic pathway (indirect pathway) does not play a major role in
the increased activity of the STN. The DA denervation of the STN and
cortex could contribute to the overactivity of the STN through direct and indirect mechanisms, respectively. The hyperactivity of the STN may
result in the increased activity of the globus pallidus (GP). The graft-derived restoration of DA levels in the
striatum can attenuate the increased activity of the EP and SNR by a
trans-synaptic mechanism. On the other hand, the intrastriatal grafts
fail to affect the increased activity in the GP or STN.
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In the present study, the lesion-induced increase in the CO activity in
the EP and SNR is reversed by the grafts. It has been shown that an
increase in GABAergic activity in the internal segment of the GP (the
EP in rodents) and the SNR in nonhuman primates with nigrostriatal
lesions is reversed by chronic treatment with L-DOPA
(Herrero et al., 1996; Vila et al., 1996b). Vila et al. (1996a, 1997)
have also reported that chronic L-DOPA treatment normalizes
increased levels of CO in these nuclei in parkinsonian monkeys. A
recent study reported that intrastriatal DA neuron grafts reverse the
lesion-induced changes of mRNA levels for glutamate decarboxylase and
preprosomatostatin in the EP (Rajakumar et al., 1997). These findings
as well as the present ones indicate that restoration of DA levels in
the denervated striatum can lead to normalization of the altered
activity of the EP and SNR by a trans-synaptic mechanism (Fig. 8).
Apomorphine-induced c-Fos activation in basal ganglia nuclei and
their target structures
We found that intrastriatal DA neuron grafts suppress
apomorphine-induced c-Fos activation in the GP ipsilateral to the
lesion. Centi et al. (1992) also showed that nigral grafts normalized the apomorphine-induced increase in the c-Fos expression in the GP of
6-OHDA lesioned rats (Centi et al., 1992). The c-Fos activation may be
induced by disinhibition of pallidal neurons receiving afferents from
striatal GABAergic neurons with hypersensitive D2 receptors (Fig.
9). The normalization of the pallidal
c-Fos expression may therefore be a consequence of the graft-mediated attenuation of the supersensitivity of D2 receptors in the lesioned striatum (Freed et al., 1983; Dawson et al., 1991; Gagnon et al., 1991;
Rioux et al., 1991; Blunt, 1992; Savasta et al., 1992). On the other
hand, the grafts failed to affect the c-Fos activation in the STN. The
mechanism for the apomorphine-induced c-Fos activation in the STN
remains to be explained. As discussed earlier, the STN is regulated by
a direct projection of nigral DA neurons (Brown et al., 1979; Meibach
et al., 1979; Campbell, 1985) and both D1 and D2 receptors exist in
this nucleus (Savasta et al., 1986; Bouthenet et al., 1987; Fremeau et
al., 1991). The 6-OHDA lesions can lead to depletion of DA in the STN,
which may induce supersensitivity of D1 receptors in this nucleus. It
therefore is conceivable that apomorphine could directly cause c-Fos
activation by stimulating supersensitive D1 receptors (Robertson et
al., 1989) present in the STN. Indeed, a recent study indicated that
systemic injections of apomorphine increase the firing rate of STN
neurons through D1 receptors located in this structure (Kreiss et al.,
1996). Furthermore, neocortical glutamatergic neurons express D1 and D2
receptors (Gaspar et al., 1995), and the activation of these receptors
modulates the glutamatergic transmission (Law-Tho et al., 1994). The
lesion-induced DA denervation of the neocortex may therefore affect the
excitability of the STN and may account for the c-Fos expression in the
STN after injections of apomorphine (Fig. 9). These putative
mechanisms, which are not directly related to the striatum, could
explain the reason for the failure of intrastriatal DA neuron grafts to
exert significant effects on apomorphine-induced Fos activation in the
STN.
View larger version (17K):
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|
Figure 9.
Diagrammatic representation of a hypothetical
model of a cascade of changes of neuronal activity in the basal ganglia
after systemic injections of apomorphine (modified from Albin et al., 1989). After apomorphine (APO) challenge, the activity
of striatopallidal GABAergic neurons with hypersensitive D2 receptors
is suppressed, with consequent disinhibition of the globus pallidus
(GP). Apomorphine could directly induce c-Fos activation
in the DA-denervated subthalamic nucleus (STN).
The lesion-induced DA denervation of the neocortex (Cx)
could also affect the excitability of the STN to cause the c-Fos
activation in the STN after injections of apomorphine. Stimulation of
striatal D2 receptors with supersensitive state may suppress the
activity of the entopeduncular nucleus (EP) and
substantia nigra pars reticulata (SNR) through an
inhibition of the activity of glutamatergic STN neurons
(indirect pathway). The suppression of the activity of
the EP and SNR can lead to disinhibition of the activity in their
target structures, such as the ventromedial thalamic nucleus
(VM), superior colliculus (SC),
and pedunculopontine nucleus (PPN). Stimulation
of striatal D1 receptors, which directly suppresses the neuronal
activity in the EP and SNR (direct pathway), also leads
to bursting activity in the VM, SC, and PPN by a disinhibitory mechanism. The graft-mediated reversal of the increased levels of
striatal D1 and D2 receptors can partly reverse the altered activity of
basal ganglia circuitry to attenuate the apomorphine-induced bursting
activity of the GP as well as the basal ganglia target structures.
|
|
Stimulation of striatal D1 or D2 receptors by apomorphine provides
inhibitory effects on the neuronal activity in the EP and SNR through a
direct or indirect pathway, respectively (Albin et al., 1989; DeLong, 1990) (Fig. 9). The resultant suppression of the
activity in these nuclei can lead to disinhibition of the target
structures of the basal ganglia, such as VM, SC, and PPN (Fig. 9). This
was evidenced by the present c-Fos immunohistochemistry showing a
robust expression of c-Fos in these structures after apomorphine
challenge. These findings are consistent with the notion that c-Fos
immunohistochemistry can be a sensitive marker to detect
polysynaptically activated neurons (Dragunow and Robertson, 1987; Sagar
et al., 1988). The increased expression of c-Fos in the target
structures of the basal ganglia was significantly attenuated in rats
receiving intrastriatal mesencephalic grafts. This can be explained by
the graft-induced normalization of D1 and D2 receptor hypersensitivity
in the lesioned striatum (Dawson et al., 1991; Gagnon et al., 1991;
Rioux et al., 1991; Blunt, 1992; Savasta et al., 1992; Freed et al.,
1983). Thus, the reversal of the receptor hypersensitivity can
normalize the functional state of basal ganglia circuitry, which in
turn attenuates the disinhibition of the VM, SC, and PPN (Fig. 9). In
this hypothetical model, neuronal activities of the STN, EP, and SNR
are predicted to be increased after injections of apomorphine in rats
with nigral grafts compared with those in rats with the lesion alone.
Nonetheless, the nigral grafts induced no significant differences in
the number of c-Fos-positive neurons in these nuclei. There may be a
threshold for induction of c-Fos, under which there is little
relationship between levels of this protein expression and neuronal
activity.
Conclusions
Because the output nuclei of the basal ganglia as well as their
target structures play pivotal roles in motor functions, our results
provide experimental evidence for the alleviation of motor abnormalities in clinical trials of nigral tissue transplantation in
patients with Parkinson's disease (for review, see Lindvall, 1994;
Olanow et al., 1996). The absence of the effects of intrastriatal nigral grafts on the lesion-induced changes of the CO activity of the
GP and the STN suggests that DA depletion of the striatum may not play
a primary role in the long-term changes of neuronal activity of these
nuclei after nigrostriatal DA depletion. In experimental parkinsonian
models, therefore, homotopic placement of nigral grafts with extensive
reconstruction of the damaged neural circuit would be required to
achieve more complete restoration of neural activity of the brain
structures that are involved in the regulation of motor functions.
| |
FOOTNOTES |
Received Oct. 2, 1997; revised Dec. 1, 1997; accepted Dec. 9, 1997.
This study was supported in part by a grant-in-aid for scientific
research from the Ministry of Education, Japan.
Correspondence should be addressed to Dr. Naoyuki Nakao, Department of
Neurological Surgery, Wakayama Medical College, 7-27, Wakayama 640, Japan.
| |
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Abstract
Introduction
