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The Journal of Neuroscience, November 15, 1998, 18(22):9539-9546
Relationships between the Prefrontal Cortex and the Basal Ganglia
in the Rat: Physiology of the Corticosubthalamic Circuits
Nicolas
Maurice1,
Jean-Michel
Deniau2,
Jacques
Glowinski1, and
Anne-Marie
Thierry1
1 Chaire de Neuropharmacologie, Institut National de la
Santé et de la Recherche Médicale U 114, Collège de
France, 75231 Paris Cedex 05, France, and
2 Université Pierre et Marie Curie, Département
de Neurochimie-Neuroanatomie, Institut des Neurosciences, Unité
de Recherche Associée 1488, 75230 Paris Cedex 05, France
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ABSTRACT |
The prelimbic-medial orbital areas (PL/MO) of the
prefrontal cortex are connected to the medial part of the subthalamic
nucleus (STN) through a direct projection and an indirect circuit that involves the core of the nucleus accumbens (NAcc) and the ventral pallidum (VP). In the present study, the influence of the PL/MO on the
discharge of STN cells has been characterized. The major pattern of the
responses observed after stimulation of PL/MO consisted of two
excitatory peaks often separated by a brief inhibitory period. The
early excitation was most likely to be caused by the activation of
direct cortical inputs because its latency matches the conduction time
of the prefrontal STN projections. The late excitation resulted from
the activation of the indirect PL/MO-STN pathway that operates through
a disinhibitory process. Indeed, the late excitation was no longer
observed after acute blockade of the glutamatergic corticostriatal
transmission by CNQX application into the NAcc. A similar effect was
obtained after the blockade of the GABAergic striatopallidal
transmission by bicuculline application into the VP. Finally, the brief
inhibition that followed the early excitation was likely to result from
the activation of a feedback inhibitory loop through VP because this
inhibition was no longer observed after the blockade of STN inputs by
CNQX application into the VP. This study further indicates the
implication of STN in prefrontal basal ganglia circuits and underlines
that in addition to a direct excitatory input, medial STN receives an
indirect excitatory influence from PL/MO through an NAcc-VP-STN
disinhibitory circuit.
Key words:
basal ganglia circuits; prefrontal cortex; subthalamic
nucleus; ventral striatum; nucleus accumbens; ventral pallidum; in
vivo single unit recordings; rat
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INTRODUCTION |
The subthalamic nucleus (STN) is a
major component of the basal ganglia, and its critical role in the
control of movement is well established. Pathological damage to the STN
in humans or STN lesions in monkeys induce hemiballism (Whittier, 1947 ; Carpenter et al., 1950; Crossman, 1987). In
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated monkeys, an animal
model of Parkinson's disease, abnormal activity of STN neurons has
been observed, and lesions or high-frequency stimulation of the STN
ameliorates akinesia and rigidity (Bergman et al., 1990; Benazzouz et
al., 1993). High-frequency stimulation of the STN is now successfully
applied to improve akinesia and rigidity in Parkinsonian patients
(Limousin et al., 1995).
In current models of the basal ganglia circuitry, the striatum and the
STN are the two major structures through which cortical signals are
transmitted to the output structures of the basal ganglia, i.e., the
substantia nigra pars reticulata (SNR) and the internal segment of the
globus pallidus (GPi) (Alexander and Crutcher, 1990; Parent and
Hazrati, 1995a,b). Indeed, both the striatum and the STN receive direct
excitatory cortical inputs and send projections to the SNR and the GPi.
Because the projection neurons of the striatum are GABAergic, whereas
those of the STN are glutamatergic, these two structures exert opposing
effects (inhibitory vs excitatory) on basal ganglia output neurons. In addition to the direct cortico-STN pathway, the cerebral cortex is
connected to the STN through a multisynaptic circuit involving the
striatum and the external segment of the globus pallidus (GPe). It has
been proposed that through this indirect circuit the cerebral cortex
activates STN via a disinhibitory process because the striatopallidal and the pallidosubthalamic pathways are GABAergic. However, the occurrence of such a disinhibitory process and the functional role of
this indirect circuit is still debated and remains to be clarified.
In rat, the major cortical afferents to the STN originate from the
motor and premotor areas (Afsharpour, 1985; Canteras et al., 1990). As
shown more recently, the STN also receives projections from the
prefrontal cortex, suggesting that it participates not only in
sensorimotor but also in prefrontal circuits of the basal ganglia
(Berendse and Groenewegen, 1991). In addition, we have recently shown
that PL/MO areas of the prefrontal cortex may also influence the
activity of STN cells through an indirect disinhibitory circuit
that involves a restricted region of the ventral striatum, the core of
nucleus accumbens (NAcc), and the ventral pallidum (VP) (Montaron
et al., 1996; Maurice et al., 1997, 1998).
The present study was undertaken to determine the respective influence
of the direct and indirect prefrontal cortex-subthalamic circuits on
the discharge of STN neurons. The responses evoked by PL/MO stimulation
on STN neurons were characterized, and the contribution of the direct
cortico-STN and the indirect NAcc-VP-STN pathways on these
responses was determined. For this purpose, we have reversibly blocked
the synaptic transmission in the NAcc or in the VP and analyzed the
responses of STN cells to PL/MO stimulation.
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MATERIALS AND METHODS |
Experiments were performed on 30 adult male Sprague Dawley rats
(weight 275-300 gm; Charles River, St Aubin les Elbeuf, France). For
all experimental procedures, rats were anesthetized with ketamine (100 mg/kg, i.p., supplemented by 50 mg/kg, i.m.; Imalgène 500, Rhône-Mérieux, France) and fixed in a conventional
stereotaxic apparatus (Horsley Clarke Apparatus; Unimécanique,
Epinay-sur-Seine, France). Body temperature was monitored and
maintained at 37°C with an homeothermic warming blanket (Harvard
Apparatus, Kent, UK).
Electrophysiological analysis. Single-unit activity
was recorded extracellularly using glass micropipettes (6-10 M )
filled with a 0.6 M sodium chloride solution containing 4%
Pontamine sky blue. Action potentials of single neurons were amplified
with a World Precision Instruments DAM-5A differential preamplifier and
displayed on a Tektronix memory oscilloscope. Spikes were separated
from noise using a window discriminator and sampled on-line by a
computer connected to a CED 1401 (Cambridge Electronic Design Ltd.,
Cambridge, UK) interface. Peristimulus time histograms were
generated from 50-100 stimulation trials using 1 msec bins and plotted
on a Hewlett Packard plotter. The criterion used to establish the
existence of an excitatory response was an increase >50% in the
number of spikes as compared with the prestimulus frequency for at
least three consecutive bins. Medial prefrontal neurons were identified
by antidromic activation after stimulation of the ipsilateral medial
STN. In some experiments, STN neurons were identified by antidromic
activation after stimulation of the ipsilateral medial SNR or the
ipsilateral dorsal VP. Antidromic spikes were characterized by their
fixed latency at threshold, their collision with spontaneous discharges
within an appropriate time interval, and their ability to follow
high-frequency stimulation.
Electrical stimulation of the PL/MO areas of prefrontal cortex,
ipsilateral to the recording STN site, was performed through a co-axial
stainless steel electrode (diameter, 400 µm; tip-barrel distance, 300 µm) positioned stereotaxically [anterior (A), 12.7; lateral (L),
0.6; height (H), 5.5 mm from the interaural line] according to the
atlas of Paxinos and Watson (1986). Electrical stimuli consisted of
monopolar pulses of 0.6 msec width and 200-600 µA intensity at a
frequency of 1.4 Hz. In some experiments, STN neurons were identified
by their antidromic activation from the VP (A, 8.7; L, 2.5; H, 2.4) or
from the SNR (A, 3.7; L, 1.8; H, 1.6).
At the end of each recording session, the tips of the stimulating
electrodes were marked by an electrical deposit of iron (15 µA
anodal, 20 sec) and observed on histological sections after a
ferriferrocyanide reaction. The tip of the recording electrode was
marked by iontophoretic ejection of Pontamine sky blue (8 µA
cathodal, 20 min), which allowed the determination of the position of
the recording cells. Brains were removed and fixed in a 10% formalin
solution, and the positions of electrodes were microscopically identified on serial frozen sections (100 µm) stained with safranin.
Drug applications. Pharmacological blockade of the
glutamatergic transmission in the NAcc and the VP or of the GABAergic
transmission in the VP was performed by local application of CNQX and
bicuculline, respectively. CNQX (500 µM; Research
Biochemicals, Natick, MA) and bicuculline (500 µM; Sigma,
St Louis, MO) were applied through a microdialysis probe (CMA 102;
Microdialysis AB, Stockholm, Sweden; exposed length, 2 mm). The
microdialysis probes were positioned stereotaxically into the NAcc (A,
10.7; L, 1.7; H, 2.1) or the VP (A, 8.7; L, 2.5; H, 1.4) according to
the atlas of Paxinos and Watson (1986). At the beginning of each
experiment, the probe was perfused with a Ringer's phosphate solution
(in mM; NaCl, 120; KCl, 4.8; CaCl2, 1.2;
MgCl2, 1.2; and
NaH2PO4, 15.6) at a flow rate of 2 µl/min. When an STN cell responding to PL/MO stimulation was
recorded, a peristimulus time histogram (60 stimuli) corresponding to
the control situation was generated. The microdialysis pump was then
permuted from the Ringer's solution to the antagonist solution. The
activity of the cell was continuously recorded and, each fifth minute,
its response to PL/MO stimulation was monitored and a peristimulus time
histogram generated. The receptor antagonists were considered to have
an effect when the responses evoked by PL/MO stimulation increased or
decreased by at least 50%. The drug was then washed out by perfusion
with the Ringer's phosphate solution, and the same cell was recorded
until the recovery of the control response. In cases in which more than
one cell was tested in the same animal, drug perfusions were separated
by at least 2 hr after the recovery of the control response in the
preceding cell.
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RESULTS |
Identification of medial prefrontal cortex neurons projecting to
the subthalamic nucleus
The neurons of the medial prefrontal cortex projecting to the STN
were electrophysiologically identified using the antidromic activation
method in three rats. Stimulation of the medial STN evoked an
antidromic spike in 63 (21.1%) of the 299 neurons recorded in the
prefrontal cortex. The mean latency of the antidromic spikes was
4.5 ± 0.2 msec (range, 2.0-9.0 msec). As shown in Figure
1, the antidromically driven cells were
mainly located within the layer V of the dorsal anterior cingulate and
the prelimbic and the medial and ventral orbital areas of the
prefrontal cortex.
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Figure 1.
Localization of the cells in the prefrontal cortex
antidromically driven by medial STN stimulation. A,
Identification of the antidromic response elicited by STN stimulation
in a prefrontal cortical cell. From top to
bottom, Fixed latency (3.4 msec), collision with
spontaneous spikes, recovery of the antidromic response for a greater
time interval between the spontaneous spikes and the stimulation, and
ability to follow high-frequency stimulation (250 Hz).
B, Localization of the antidromically driven cells in
two frontal sections. Each dot represents a cell
antidromically driven from the STN. Numbers indicate the
distance in millimeters from the interaural line. ACd,
Anterior cingulate area dorsal; MO/VO,
medial orbital and ventral orbital areas; PL, prelimbic
area; PrCm, medial precentral area.
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Effects of medial prefrontal cortex stimulation on the activity of
subthalamic cells
Electrical stimulation of the PL/MO areas evoked excitatory
responses in 92 of the 141 STN cells recorded in 12 rats. As shown in
Figure 2 and Table
1, different patterns of responses were observed. The major type of response (47 of the 92 responding cells)
induced by PL/MO stimulation consisted in two excitatory peaks with
short-latency (7.6 ± 0.2 msec) and long-latency (21.4 ± 0.5 msec) onsets. In most cases, the duration of the late excitatory response was longer than the duration of the early excitatory peak. In
16 of these 47 cells, the two excitatory responses were separated by a
short-duration inhibition [duration (D) = 6.7 ± 0.4 msec].
In another population of cells (20 of the 92 responding cells), PL/MO
stimulation induced a prolonged excitatory response with a
short-latency (8.2 ± 0.5 msec) onset. Finally, a late (21.2 ± 0.6 msec) excitatory response was observed after PL/MO stimulation in the 25 remaining responding cells. In most cases (69 of the 92 responding cells), excitatory responses were followed by a long-lasting
inhibition (D = 155.2 ± 10.9 msec; range, 50-300 msec). As
shown in Figure 3, the neurons that
presented excitatory responses to PL/MO stimulation were located in the
medial part of the STN, whereas the cells that did not respond were
located more laterally. In the medial STN, the cells that presented
distinct patterns of excitatory responses were observed in each animal and showed no obvious topographical distribution.
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Figure 2.
Patterns of responses evoked by PL/MO stimulation
within STN cells. A, C, Two excitatory
peaks with short- and long-latency onsets that are interrupted or
uninterrupted by a brief inhibitory period; B, prolonged
excitatory response with a short-latency onset; D, late
excitatory response.
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Figure 3.
Localization of STN cells that presented
excitatory responses to PL/MO stimulation. Note that responding cells
are located in the medial part of the STN, whereas more laterally
located cells do not respond to PL/MO stimulation (Not
responding cells). Each dot represents a tested
cell. Numbers indicate the distance in millimeters from
the interaural line.
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In some of these experiments (8 of the 12 rats) STN cells were
identified by antidromic activation as projecting to either the medial
SNR (four rats) or the VP (four rats). PL/MO stimulation induced
excitatory responses in 25 of the 31 cells identified as projecting to
the SNR (Fig. 4) and in all of the 13 cells identified as projecting to the VP. The different types of
excitatory responses described above were observed in both the cells
projecting to the SNR or the VP.
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Figure 4.
Excitatory responses evoked by PL area stimulation
in an STN cell antidromically identified as projecting to the medial
SNR. Left, Identification of the antidromic response.
From top to bottom, Fixed latency (3.3 msec), collision with spontaneous spikes, recovery of the antidromic
response for a greater time interval between the spontaneous spike and
the stimulation, and ability to follow high-frequency stimulation (200 Hz). Right, Top, Excitatory response
evoked by PL stimulation in the same STN cell (poststimulus time
histogram, 50 superimposed sweeps); bottom, interspike
interval histogram (500 intervals) illustrating the spontaneous
activity of the cell (left) and the experimental design
(right). PL, Prelimbic area;
SNR, substantia nigra pars reticulata;
STN, subthalamic nucleus.
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Effect of CNQX application into the NAcc on subthalamic excitatory
responses evoked by PL/MO stimulation
The effect of a blockade of the glutamatergic corticostriatal
transmission by application of CNQX into the NAcc was examined in 10 STN cells that exhibited two excitatory peaks in response to PL/MO
stimulation. CNQX application markedly decreased the late excitatory
response in all the cells tested without significantly modifying the
early excitatory response (Fig. 5). The
maximal effect (52-96% decrease) was observed 10-30 min after the
beginning of CNQX application. In six of the cells held long
enough, the recovery of the late excitatory response occurred 20-65
min after the cessation of CNQX application. Interestingly, although
the two excitatory peaks were not separated by an inhibition in control conditions (9 of the 10 cells tested), under CNQX a short-duration inhibition [latency (L) = 17.8 ± 1.2 msec; D = 7.1 ± 1.0 msec] appeared in seven cells (Fig. 5). Finally, in
one cell in which the two excitatory peaks were separated by a
short-lasting inhibition of 6 msec in control conditions, this duration
of the inhibition was increased to 16 msec under CNQX.
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Figure 5.
Effect of CNQX application into the NAcc on the
response evoked by PL/MO stimulation in an STN cell. From
top to bottom, The response exhibited two
excitatory peaks in control conditions, CNQX application into the NAcc
did not significantly modify the early peak but markedly decreased the
late excitatory response, the maximal effect was observed 15 min after
the beginning of CNQX application, and the recovery of the late
excitatory response occurred 25 min after the cessation of CNQX
application. Note that although the two excitatory peaks were not
separated by an inhibition in control conditions
(Control, Recovery), during CNQX
application a short inhibitory period was observed. Each poststimulus
time histogram represents 60 superimposed sweeps. Arrow
indicates the stimulation artifact.
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Effect of bicuculline application into the ventral
pallidum on subthalamic excitatory responses evoked by PL/MO
stimulation
Bicuculline was applied into the VP to block the GABAergic
transmission of the NAcc-VP pathway. The effect of bicuculline application on the excitatory responses evoked in STN by PL/MO stimulation was examined in eight cells. In five cells that exhibited two excitatory peaks in control conditions, bicuculline decreased the
late excitatory response but not the early excitatory peak (Fig.
6). The maximal effect (50-98%
decrease) was observed 10-25 min after the beginning of bicuculline
application, and recovery of the response occurred 30-80 min after the
cessation of bicuculline application. While in control conditions, the
two excitatory peaks were not interrupted by an inhibition, a short
inhibitory period (D = 8.7 ± 1.1 msec) appeared during
bicuculline application in three of these five cells (Fig. 6). In two
cells that presented a prolonged excitatory response to PL/MO
stimulation under control conditions, bicuculline induced decreased (77 and 84%) excitatory responses 15 min after the beginning of
bicuculline application, and the response recovery was observed 60 min
after the cessation of bicuculline infusion. Finally, in one cell that
presented a late excitatory response to PL/MO stimulation under control
conditions, this excitation was decreased by 59% 8 min after the
beginning of bicuculline application and recovered 25 min after the
cessation of bicuculline application.
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Figure 6.
Effect of bicuculline application into the VP on
the response evoked by PL/MO stimulation in an STN cell. From
top to bottom, The response exhibited two
excitatory peaks in control conditions, bicuculline application into
the VP decreased the late excitatory response without modifying the
early excitatory peak, the maximal effect was observed 20 min after the
beginning of bicuculline application, and the recovery of the late
excitatory response occurred 35 min after the cessation of bicuculline
application. Note that, although the two excitatory peaks were not
separated by an inhibitory period in the control conditions
(control, recovery), during the infusion
of bicuculline a short-duration inhibition appeared. Each poststimulus
time histogram represents 60 superimposed sweeps. Arrow
indicates the artifact of stimulation.
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Effect of CNQX application into the ventral pallidum on subthalamic
excitatory responses evoked by PL/MO stimulation
Because the STN and the VP are reciprocally connected, CNQX was
applied into the VP to block the glutamatergic input from the STN and
to investigate the possible influence of this circuit on the
PL/MO-evoked responses. The effect of CNQX application into the VP on
the excitatory responses evoked by PL/MO stimulation was examined in
nine STN cells. In eight cells that produced two excitatory peaks in
control conditions, the application of CNQX induced an increase of the
late excitatory response, a maximal effect (66-250%) occurring 20-30
min after the beginning of CNQX infusion (Fig.
7). The duration of this late excitation
(D = 14.5 ± 1.1 msec, control conditions) was significantly
increased (D = 26.6 ± 2.0 msec; p < 0.001)
under CNQX application without a significant change of the latency
(control, L = 23.1 ± 1.0 msec; CNQX, L = 21.4 ± 1.2 msec). In three cells, a slight (45%) increase in the early
excitatory peak was also observed. In two cells, in which the early and
late excitatory responses were separated by an inhibition in control
conditions, this inhibition disappeared under CNQX (Fig. 7). In five
cells that were held long enough, the recovery of responses was
observed 45-75 min after the cessation of CNQX perfusion. Finally, in
one cell responding to PL/MO stimulation by a late excitatory response
(L = 22 msec; D = 11 msec) under control conditions, the
response was increased by 220% (L = 18 msec; D = 35 msec) 20 min after the beginning of CNQX application.
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Figure 7.
Effect of CNQX application into the VP on the
response evoked by PL/MO stimulation in an STN cell. From
top to bottom, The response exhibited two
excitatory peaks separated by a brief inhibitory period in the control
conditions, CNQX application into the VP induced an enhancement of the
late excitatory response and a disappearance of the inhibitory period,
the maximal effect was observed 20 min after the beginning of CNQX
application, and the recovery of the responses occurred 50 min after
the cessation of CNQX application. Each poststimulus time histogram
represents 60 superimposed sweeps. Arrow indicates the
artifact of stimulation.
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DISCUSSION |
The present study was undertaken to determine the functional
characteristics of the PL/MO-STN circuits in the rat. The data show
that PL/MO stimulation induced excitatory responses in the medial part
of the STN, which mainly consisted of two excitatory peaks separated in
some cases by a brief inhibitory period. The early response is likely
caused by the activation of the direct prefrontal cortex-STN
projection, whereas the late response involves the indirect
cortico-NAcc-VP-STN pathway. Indeed, application of CNQX into the
NAcc or bicuculline into the VP blocked the late but not the early
excitatory peak. In addition, the present data indicate that the VP is
also involved in an inhibitory feedback control of the STN through the
reciprocal circuit.
Origin of the early excitatory response
Converging evidence indicates that cortico-STN projections use
glutamate as neurotransmitter. Cortical terminals are enriched in
glutamate and form asymmetrical synaptic contacts with the dendrites of
subthalamic neurons (Bevan et al., 1995). The synaptic effects of the
cortico-STN pathway are well established for STN inputs from the
sensorimotor cortex. Stimulation of the sensorimotor cortex in the rat
evokes short-latency monosynaptic excitatory responses in STN cells
that are blocked by local application of glutamatergic antagonists
(Kitai and Deniau, 1981; Rouzaire-Dubois and Scarnati, 1987; Ryan and
Clark, 1991; Fujimoto and Kita, 1993). Early excitatory responses
evoked by PL/MO stimulation in the STN are also likely to be
monosynaptic. Indeed, the latency of such early responses was found to
be in the range of the conduction time of prefrontal-STN pathway
determined by antidromic activation. Moreover, in agreement with the
topographical organization of prefrontal-STN projections cells that
responded to PL/MO stimulation were located in the medial STN (Berendse
and Groenewegen, 1991). It has been previously reported that
stimulation of the prelimbic cortex evoked a late, but not an early
excitation of STN cells (Ryan and Clark, 1991). This could be explained
by the localization of the recording sites because, in our study, cells
that responded to PL/MO stimulation were found in the medial STN and
not more laterally.
Origin of the late excitatory response
Previous findings have indicated that electrical stimulation of
the sensorimotor cortex evokes two excitatory peaks within STN neurons,
often interrupted by a brief inhibition (Ryan and Clark, 1991; Fujimoto
and Kita, 1993). However, the origin of the second excitatory peak
remained unclear. The involvement of the indirect striato-pallido-STN
circuit has been questioned from data obtained in lesioned rats.
Indeed, after excitotoxic lesions of the striatum or the GPe, the
pattern of excitatory responses to cortical stimulation was almost the
same as in intact rats, and an enhancement of the late excitatory
component has also been reported (Ryan and Clark, 1992; Fujimoto and
Kita, 1993). Therefore, the second excitatory peak has been considered
as the late component of a single broad excitatory response interrupted
by a brief inhibition (Fujimoto and Kita, 1993). Several explanations
for the prolonged excitations have been proposed: activation of NMDA
receptors, amplification of small excitatory synaptic inputs by the
electrical membrane characteristics of STN cells, and the spread of
excitations within the STN through local axon collaterals (for review,
see Kita, 1994).
In contrast to the lesion experiments, the present study shows that the
late excitatory response induced by PL/MO stimulation in the STN was
markedly reduced after acute blockade of the corticostriatal neurotransmission by local application of CNQX into the NAcc. A similar
effect was observed after blockade of the striatopallidal neurotransmission by local application of bicuculline into the VP. In
both cases, the duration of the application of receptor antagonists
required to obtain a maximal effect showed some variability. This might
be related to the diffusion time necessary for the antagonist to block
the synaptic transmission in the whole NAcc or VP territory involved in
the PL/MO-STN circuit. Interestingly, the early excitatory peak was
not affected by local applications of CNQX or bicuculline. Thus, it can
be concluded that the early and late excitatory responses that are
evoked in STN cells by PL/MO stimulation result from the activation of
two distinct pathways, the direct cortico-STN pathway and the indirect
striato-pallido-subthalamic circuit, respectively. The apparent
discrepancy between the data reported after excitotoxic lesions and the
present study using acute blockade of the synaptic transmission may be
caused by a subsequent reorganization of synaptic inputs to STN cells
and/or modification of their excitability after lesions.
Altogether, the present data and those of our previous studies (Maurice
et al., 1997, 1998) indicate that late excitatory responses involving
the indirect cortico-striato-pallido-subthalamic circuit result from a
disinhibitory process. Indeed, stimulation of PL/MO areas induces an
activation of NAcc core neurons that send an inhibitory input on the
VP-STN cells. In addition, VP stimulation elicits an inhibition of STN
cells located in the medial part of this nucleus. Thus, phasic
activation of the striatopallidal pathway leads to an inhibition of the
tonically active inhibitory pallidosubthalamic neurons, resulting in a
disinhibition of STN. Also in favor of a disinhibitory process, the
latency of the late excitatory responses is compatible with the
conduction time of neurons within the indirect
cortico-striato-pallido-subthalamic circuit (Montaron et al., 1996;
Maurice et al., 1997). The efficacy of this disinhibitory
process could partly be caused by the high input resistance and the
resting membrane potential of the STN cells, which is close to the
threshold for a spike (Nakanishi et al., 1987).
Origin of the short-duration inhibitory response
STN and pallidum are two tightly interconnected structures (Kita
et al., 1983; Robledo and Féger, 1990; Kita and Kitai, 1991; Ryan
and Clark, 1992; Shink et al., 1996; Maurice et al., 1997, 1998). A
topographical organization of their reciprocal connections has been
described: GPe and VP receive inputs from different parts of the STN
and project back to the STN region from which they receive inputs
(Groenewegen and Berendse, 1990; Joel and Weiner, 1997).
Because the STN projections to the pallidum are excitatory, it has been
proposed that the activation of the STN cells projecting to pallidum by
the direct cortical inputs leads to an activation of the GABAergic
pallidosubthalamic neurons that result in a feedback inhibition of the
STN (Ryan and Clark, 1991; Fujimoto and Kita, 1993). Accordingly, the
present data indicate that the brief inhibitory period that follows the
early excitatory peak induced by PL/MO stimulation in STN cells is
likely to be caused by the activation of a feedback inhibitory circuit
through VP. Indeed, PL/MO stimulation induced early excitatory
responses in the STN cells identified as projecting to the VP. In
addition, the brief inhibitory period that follows the early excitatory
peak was no longer observed after blockade of the glutamatergic STN-VP
transmission by CNQX application into VP.
Functional considerations
In current working models of the basal ganglia (Alexander and
Crutcher, 1990; Parent and Hazrati, 1995b; Joel and Weiner, 1997), STN
is mainly viewed as a relay nucleus of the trans-striatal indirect
pathway and is also considered as an input structure because of its
direct cortical afferents. The STN, the only glutamatergic structure
within the basal ganglia, provides a major excitatory drive on output
structures that counteracts the inhibitory influence exerted by the
direct GABAergic striatopallidal and striatonigral pathways. It has
been assumed that a functional imbalance between the direct striatal
projections and the trans-STN circuits underlies the dyskinesias
observed in parkinsonism, chorea, and ballism (Albin et al., 1989;
Wichmann and DeLong, 1996; Obeso et al., 1997).
Our investigation on the functional relationships between the
prefrontal cortex and the STN indicates that the cortical excitatory influence on STN cells involves not only the direct cortico-STN pathway
but also the indirect cortico-striato-pallido-subthalamic circuit that
operates through a disinhibitory process (Fig.
8). Although these two pathways can
converge on the same STN cells, they might subserve different
functions. Indeed, they have different conduction times and mainly
originate from distinct cortical layers (layer V in the case of the
direct pathway and superficial layers in the case of the indirect
transstriatal circuit), suggesting that they are activated under
different conditions (Montaron et al., 1996; present study). Finally,
the present data indicate that, by its direct excitatory input on
STN-VP projecting neurons, the prefrontal cortex can activate a
feedback inhibitory loop and subsequently exert an inhibitory control
on the STN (Fig. 8). Thus, the VP participates in two intrinsic basal
ganglia circuits that exert opposite influences on the discharge of STN
cells. It might, therefore, be important to account for this dual and opposing role of the pallidum (VP and GPe) in the pathophysiological models of the basal ganglia.
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Figure 8.
Schematic representation of the pathways involved
in the STN responses to prefrontal cortical stimulation.
Broken and solid lines represent
glutamatergic and GABAergic pathways, respectively.
Bottom, Example of a complex response evoked in an STN
cell by prefrontal cortex stimulation. The early excitatory peak is
likely to be caused by the activation of a direct cortico-STN
projection. The brief inhibition that follows the early excitatory peak
results from the activation of a feedback inhibitory circuit through
the VP. The late excitatory response involves an indirect
cortico-NAcc-VP-STN pathway that operates via a disinhibitory
process. NAcc, Nucleus accumbens; PFC,
prefrontal cortex; STN, subthalamic nucleus;
VP, ventral pallidum.
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|
In conclusion, the STN, which is primarily implicated in the control of
motor functions, also participates in the limbic and cognitive
functions of basal ganglia as suggested in recent behavioral studies
(Baunez et al., 1995). In agreement with the concept of a parallel
architecture of the corticobasal ganglia circuits, information arising
from prefrontal and sensorimotor cortical areas are segregated within
the STN. It remains to determine the specific role of the medial STN in
the control of limbic and cognitive functions of the prefrontal cortex.
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FOOTNOTES |
Received May 29, 1998; revised Aug. 26, 1998; accepted Aug. 31, 1998.
This work was supported by Institut National de la Santé et de la
Recherche Médicale. Nicolas Maurice is recipient of a fellowship
from the Ministère de l'Enseignement Supérieur et de la Recherche.
We thank M. Saffroy and A. M. Godeheu for histological assistance
and L. Darracq for his advice in the microdialysis technique.
Correspondence should be addressed to Dr. Anne-Marie Thierry, Chaire de
Neuropharmacologie, Institut National de la Santé et de la
Recherche Médicale U 114, Collège de France, 11 place Marcelin Berthelot, 75231 Paris Cedex 05, France.
| |
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Top
Abstract
Introduction
