Impaired Performance in a Conditioned Reaction Time Task After Thermocoagulatory Lesions of the Fronto-parietal Cortex in Rats
Christelle Baunez, Pascal Salin, André Nieoullon and Marianne Amalric
The present study examined whether cortical damage in rats may disrupt the integrative processes and motor control involved in the performance of a reaction time (RT) task. To investigate the nature of the deficits in the conditioned task, rats were subjected, after learning, to a coagulation of pia brain surface of varying extent, including the frontal and parietal cortical areas. They were then tested daily for over one month. The behavioural task required the rats to hold a lever down during a variable and random delay and react quickly to the onset of a visual cue by releasing the lever within a RT limit for food reinforcement. Extensive bilateral cortical lesions had no effect on spontaneous motor activity, but severely impaired RT performance. Latencies to release the lever after the cue were dramatically increased during the first postoperative sessions and gradually returned to baseline levels within 3 weeks, whereas less dramatic but long-lasting increase in premature responding (anticipatory response before the visual cue) was observed throughout the testing sessions. More restricted lesions to the frontoparietal cortex produced a similar pattern of incorrect responding with a faster recovery of delayed responses and a strong deficit in premature responding. The major effects of lesions confined to the rostral pole of the frontal cortex were observed on premature responding, however. The present results demonstrate that the impairment in movement initiation is rapidly recovered within 2–3 weeks even after extensive thermocoagulatory lesions of the frontal and parietal areas. This recovery suggests the involvement of adaptive processes developing progressively and probably reflecting the remarkable synaptic plasticity of the extrapyramidal motor output. In contrast, the long-lasting increase in premature responding, supposed to reflect some attentional deficits, may produce anatomofunctional long-term disorganization of subcortical structures such as the basal ganglia. Interestingly enough, these results show that the rat neocortex supports functions very similar to those of primates and provide a good model for studying these higher functions in operant motor procedures that require prior associative learning and appropriate motor coordination.
capabilities to retrieve food pellets from narrow slots. Locomotor behaviour and postural mechanisms are also altered after sensorimotor cortex lesions (Maier, 1935; Gentile et al., 1978; Whishaw et al., 1981; Brailowsky et al., 1986; Goldstein and Davis, 1990). While there is an extensive literature on the role of rat cerebral cortex in the execution of these classical sensorimotor tests, only a few reports have used operant procedures to study the consequences of cortical lesions on more complex integrative processes such as attentional or learning functions (Oak ley and Russell, 1979; Bussey et al., 1996; Muir et al., 1996). The purpose of this study was thus to examine the effects of a bilateral cortical lesion on rats’ performance in an operantconditioned reaction time (RT) task. Rats were previously trained to release a lever after the presentation of a visual cue within a RT limit for food reinforcement. This task involved prior associative learning and attentional processes to estimate for the visual cue onset and appropriate sensorimotor coordination to react rapidly to the cue. Considering the lack of dramatic abnormality of spontaneous motricity after sensorimotor cortex lesion, it was therefore particularly relevant to determine the deficits produced by extensive frontoparietal cortical lesions on RT performance as an index of ‘voluntary’ movements. In addition, the specific cortical implication of frontal or parietal regions in the different aspects of the task performance was further adressed. In general, previous studies of cortical function in the rat have used aspirative lesions, usually unilateral, to investigate the nature of motor deficits. These methods produce acute major cortical damage which are less likely to reproduce cortical infarctions in humans following stroke. In the present study, rats were subjected to a superficial coagulation of pial vessels that produced ischaemic lesions of the frontoparietal cortex, which can be related to ischemia. This procedure results in a gradual loss of the cerebral cortex underlying the thermocoagulated area. The time course and long-term effects of the lesion were analysed by testing the subjects daily for 35 days beginning on the seventh postoperative day. One major consequence of cortical neurons degeneration is the loss of excitatory projections to subcortical structures. Previous studies using this procedure have shown at the cellular level that unilateral lesion of frontoparietal cortex by thermocoagulation in the rat produced long-term changes of neurotransmitter expression such as neuropeptide Y (Kerkerian et al., 1990), enkephalin, substance P and γ-aminobutyric acid (GABA) in striatal neurons and efferent structures (Salin and Chesselet, 1992, 1993). Recent work comparing the effects of cortical lesions induced by aspiration of the frontoparietal cortex or by thermocoagulation of the pial blood vessels on axonal and glial molecules associated with neuronal plasticity has shown both differences and similarities in the various markers in the striatum
Introduction Cortical involvement in motor processes has been extensively investigated for the last three decades in non-human primates and ‘lower’ mammals. Earlier studies reported that in ‘higher’ animals marked motor impairment was produced by frontal sensorimotor cortex ablation, whereas rather subtle effects were observed in the rat, which occupies a relatively low phylogenetic position. Further studies involving appropriately designed behavioural tasks suggested, however, that the role of the rat’s cerebral cortex in the execution of skilled forelimb movements may not differ greatly from that of primates. Deficits in the manipulative capacity in the forepaw contralateral to a unilateral motor cortical lesion were observed in rats trained to reach for and grasp food pellets (Peterson and Barnett, 1961) or to manipulate a force transducer (Price and Fowler, 1981). Castro (1972a) further demonstrated that rats bearing bilateral motor cortical lesions were impaired in their digital motor
Laboratoire de Neurobiologie Cellulaire et Fonctionnelle (associé à l’Université Aix-Marseille II), CNRS, 31 Ch. Joseph Aiguier, 13402 Marseille Cedex 20, France
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depending on the procedure by which the lesions are induced (Szele et al., 1995). Furthermore, substantial evidence has shown that suppression of cortical projections enhances striatal dopaminergic activity, and modulation of striatal dopamine activity has been previously found to modify RT performance (Amalric et al., 1995; Baunez et al., 1995). We have thus compared in the present study the changes in RT performance after cortical lesion to those produced by alteration of dopaminergic transmission at the striatal level.
Materials and Methods Subjects Experiments were conducted on male Wistar rats (Charles River, France), weighing 130–140 g at the beginning of the experiment, housed three per cage and maintained on a 12 h day/night cycle (07.00–19.00 h). They were deprived by restricting the food supply (standard laboratory chow) to 15–17 g/rat/day in order to keep their weight at 80% of the free-feeding weight of control rats for the total duration of the experiment. Water was provided ad libitum. At the end of the experiment the animals’ weight ranged from 365 to 420 g. All procedures were conducted in accordance with the requirements of the French ‘Ministère de l’agriculture et de la pêche’ Décret no. 87–848, October, 19, 1987. Apparatus The test apparatus consisted of four standard operant chambers (23 × 22 × 30 cm) (Campden Ltd, UK). Each chamber was supplied with a retractable lever requiring a force of 0.8 N to operate a switch, a stimulus light (2.8 W bulb) placed above the lever and a food pellet dispenser. The operant boxes were controlled and data collected online by a microcomputer and a laboratory interface (Paul Fray Inc., Cambridge, UK). Behavioural Paradigm The rats were first trained to hold down the lever and wait for a light-cue conditioning stimulus (CS) presented after randomly and equiprobable generated intervals (0.5, 0.75, 1.0 and 1.25 s). They then had to release the lever as fast as possible within a time period arbitrarily set at 500 ms by the experimenter. Each correct trial was rewarded by a 45 mg food pellet (Bioserv Inc. Frenchtown, NJ). During each daily session, the subjects were tested in 100 trials during 10–15 min depending on the subjects. The performance was measured as the number of correct (release of the lever within 500 ms after the CS) and incorrect responses (non-rewarded) per session. Incorrect responses could fall into two categories: anticipated responses (premature lever release before the CS) and delayed responses (lever release after the 500 ms time restriction). In addition, the latency to release the lever (i.e. the RT, taken as the time elapsing from the CS onset to the lever release) was recorded at each trial. The animals were trained for ∼2 months in order to meet the criterion of 60–70% correct trials with RTs below 500 ms. Surgery The animals were deeply anaesthetized with a solution of xylazine (15 mg/kg)–ketamine (100 mg/kg) injected i.m. They were then secured in a Kopf stereotaxic instrument and were assigned to one of four treatment conditions. (i) Control group (n = 14): the animals received sham cortex lesions, which consisted of anaesthesia, deinsertion of the cranial muscles and wound suture. (ii) Extensive lesion group (n = 24): the skull overlying the frontal and parietal cortices was removed and the underlying cortical areas were destroyed bilaterally by superficial large thermocoagulation of the pia. The thermocoagulation was extensive, including the frontoparietal cortex and in some cases the rostral part of the occipital cortex. The wound was filled with sterile gelfoam and the scalp was closed with wound clips. (iii) Frontoparietal cortex group (n = 11): thermocoagulation was intended to remove the sensorimotor cortical area, as defined by the evoked contralateral forelimb movement induced by microstimulation of discrete cortical areas (further described and illustrated in Fig. 4). (iv) Frontal cortex group (n = 11): the thermocoagulation probe was applied to the dura in the most rostral regions of
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the frontal cortex where the microstimulation did not elicit any movement of the forelimb (see Fig. 5). The limits of the frontoparietal and frontal cortex lesions were defined in anaesthetized subjects in which two monopolar electrodes were applied to the dura after the skull overlying the frontal and parietal cortices had been removed (as previously described by Kerkerian and Nieoullon, 1988). Square pulses (train duration 100 ms; each shock, 0.5 ms; frequency 300 Hz) were applied at a frequency of 0.3 Hz for 30 s through a stimulus isolation unit (Grass). The stimulus intensity was set to the threshold for visible contralateral limb movements (50–100 µA). In the frontoparietal cortex group, the thermocoagulation was performed in the cortical areas in which the stimulation elicited evoked responses of the forelimb and more generally the anterior part of the body (i.e. neck muscles and vibrissae, see Fig. 4). The frontal cortex lesions were performed rostral to these areas where the stimulating electrodes did not elicited any visible response (Fig. 5). After surgery, all the animals received 2 ml of a glucose solution (5 %) i.p. before returning to their home cage, and liquid diet food was provided when necessary (to the animals unable to feed themselves on laboratory chow). After a postoperative recovery period of 7 days, the animals were then tested in the RT task daily for 35 days beginning on the seventh day. 0n postoperative days 16 and 26, rats’ locomotor activity was recorded for a 120 min period after completion of RT performance.
Locomotor Measures Locomotor activity was tested in a bank of 16-wire and Plexiglas photocell cages. The individual cages were 40 cm long, 25 cm deep and 23 cm high, with two parallel horizontal infrared beams 2.3 cm above the f loor, 12 cm from each end of the cage and perpendicular to the long axis of the cage. The beam breaks, registered over a 1 min period by a microcomputer (Tandon PCA 12SL), were summed accross 10 min time bins during the total duration of the locomotor test (120 min).
Histology At the end of behavioural testing (35 days post-surgery), animals were killed either by decapitation or perfusion with 10% formaldehyde solution under deep anaesthesia with choral hydrate (400 mg/kg i.p.). The brains were removed and examined individually to determine the apparent rostrocaudal extent of the lesion, which was plotted on standard diagrams of the cortex. The brains were then frozen to –80°C. Brains of representative subjects were sectioned into frontal 60 µm thick sections and stained with cresyl violet. In addition, animals that received thermocoagulatory lesions but were not tested on the behavioural task were killed 5 and 12 days after surgery and compared to the animals killed at 35 days to examine the dorsoventral extent of the lesion at different time points. Only rats showing homogenous bilateral extensive cortical lesions were included in the statistical analysis.
Behavioural Measures and Statistical Analysis On representative sessions (on preoperative day 4 and postoperative days 8 and 21) a specific representation of the general RT distribution was performed in each subject by summing up the number of trials with RT at every interval chosen (i.e. 50 ms). Values of RTs exceeding 800 ms (less than 10% of the trials) were considered not to be linked to the stimulus onset and were discarded from the analysis. Furthermore, the effects of the various cortical lesions on RT performance were evaluated on each motor parameters (i.e. number of correct, premature, delayed responses and RTs) averaged by session. Means were obtained on each pre- and post-lesion session and subjected to a three-factor ANOVA. The different subgroups (sham/extensive/frontoparietal/frontal cortex lesion) were the independent factor, performance pre- and post-surgery by block of six sessions the first dependent factor (the first block corresponding to the six preoperative sessions and the following four blocks corresponding respectively to postoperative days 7–12, 13–18, 19–25 and 26–35) and performance within one block of six consecutive sessions the second dependent factor. If the overall ANOVA was found to be significant, subsequent two-factor ANOVA were performed within the same group followed by paired t-test comparison of pre- and post-lesion performance
and between the various subgroups followed by the Newman–Keuls a posteriori test. Measures of locomotor activity were analysed using two-factor ANOVA with groups as independent factor and repeated measures on time (10 min bins). A significant interaction in the ANOVAs was followed by post-hoc comparisons using the Newman–Keuls test.
Results Histology Thermocoagulation of pia overlying the frontoparietal cortex produced a progressive destruction of the cortical layers. The time course observation of the lesion showed that 5 days after surgery the cortical tissue was still oedematous, then a progressive atrophy of the cortex was observed from day 12 and was maximal at 35 day to reach the corpus callosum (Fig. 1). The rostrocaudal extent of the cortical lesion was examined on fresh tissue and is illustrated in Figure 2A on a schematic diagram of a rat brain belonging to the extensive lesion group. The cortical lesion included the whole frontal and parietal cortical areas and in some instances could encroach upon the rostral part of the occipital cortex. Four animals presenting either a unilateral or a small, incomplete lesion were discarded from the behavioural analysis. Examination of coronal Nissl-stained sections demonstrated the complete destruction of all cortical layers at 35 days (hatched area in Fig. 2B) without impinging on the corpus callosum and subcortical structures. The median cortex including the anterior cingulate and infralimbic cortices was spared by the thermocoagulatory lesion (Fig. 2B). The microscopic general appearance of the striatal cells was not altered after cortical lesions. Frontoparietal lesions were centred primarily on the medial precentral area of the frontal cortex according to the nomenclature of Krettek and Price (1977). The lesion extended in many instances rostrally on the frontal lobe but was generally restricted caudally to the most anterior regions of the parietal cortex (Fig. 4). In contrast, frontal lesions were discrete and confined to the very rostral aspects of the frontal cortex, sparing the parietal cortex as shown in Figure 5. Three subjects of the frontal group with unilateral lesion were discarded from the behavioural analysis. General Observations For 1–2 days after cortical ablation, the animals showed a slight reduction in spontaneous motricity, but this was quick ly attenuated. The most striking impairment was observed when the animals attempted to grasp the laboratory chow given ad libitum in their home cages. They were thus injected i.p. with a glucose solution daily for the first 2–3 days and liquid diet food was provided to every animal so that they recovered their preoperative weight within the 2 weeks post-surgery. After a few days animals showed no overt abnormalities in routine activities such as grooming, ambulation and feeding in their home cages and the first test session in the operant cages was performed 7 days post-lesion. Performance in the RT Task As illustrated in Figures 3–5, during the last six sessions preceding surgery, all the animals reached a preoperative level of 60–65% correct responses. The duration of a 100 trial session lasted 10–15 min depending on subjects. Incorrect responses were distributed between premature and delayed responses, averaging ∼25–30% and ∼10% respectively. No significant difference between groups was revealed by statistical analysis
Figure 1. Photomicrographs of brain sections from rats 5 (A), 12 (B) and 35 days (C) after thermocoagulatory lesions of the frontoparietal cortex. Thermocoagulation resulted in a progressive loss of neurons. Cortical tissue was oedematous 5 days after surgery, after which progressive atrophy of the cortex occurred, reaching the level of the corpus callosum (cc) 35 days after surgery when the lesion extended to all frontoparietal cortical layers.
performed on the number of correct and incorrect responses before surgery.
Extensive Cortical Lesions A lthough the animals did not show gross sensorimotor disabilities when placed in the operant cages, the extensive cortical lesion profoundly affected the rats’ ability to release the lever after a cue-light, as indicated in Figure 3. The number of
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Figure 2. Schematic representation of the extent of bilateral cortical lesions induced by thermocoagulation of pial blood vessels. (A) Light and dark hatched areas on standard diagrams of rat brain indicate respectively the maximal and minimal rostrocaudal extent of the lesion. The largest cortical lesions extended on the surface of the brain from the rostral frontal cortex to the rostral pole of the occipital cortex including the whole parietal cortex. The smallest lesions (represented on one side only) were reduced in the lateral to medial aspects. (B) Representation onto standard frontal sections from the atlas of Pellegrino et al. (1979) of the dorsoventral extent of the lesion (hatched shading). The values give the distance in mm from the bregma according to the atlas of Pellegrino et al. (1979).
correct trials was significantly decreased as compared with preoperative scores [ANOVA F(4,76) = 41.74, P < 0.01; paired t-test] and with performance of sham-operated animals for the total duration of the test [i.e. in the four blocks of six sessions; ANOVA F(1,32) = 85.48, 21.25, 11.07 and 10.14 respectively, followed by Newman–Keuls test P < 0.01]. A fter an initial dramatic drop in correct performance, rats showed a tendency to improve their score without returning to baseline levels within 35 days after surgery, however. Decrease in correct performance after cortical lesion was highly dependent on variations of lever releases after the RT limit (i.e. delayed responses). The strong increase in delayed responses obser ved in the first postoperative sessions (days 7–10) gradually declined over time with a return to control values within 18 days, as shown by a significant ANOVA performed on the two first blocks of six sessions [F(1,32) = 26.74 and 9.85 respectively, followed by Newman–Keuls test]. Incorrect responses made prior to the onset of the visual cue (premature responses) were not similarly affected. Preoperatively, lesioned rats averaged 28 premature responses in each test session. Seven days after surgery, the number of premature responses averaged 44 per session and decreased to an average of 33 per session 15 days later. In contrast to the delayed responses, this deficit was sustained throughout the testing sessions and was significantly higher than preoperative levels [ANOVA F(4,76) = 6.23, P < 0.01 paired t-test]. In comparison to sham-operated animals, which showed a trend towards improvement of performance expressed by a postoperative decrease in premature responding, the increase in premature responses was maintained in the lesion group for the entire duration of the test up to 35 days after surgery [ANOVA F(1,32) = 26.15, 18.92, 9.39 and 10.2 respectively, P < 0.01 followed by Newman–Keuls test].
304 Frontal or Parietal Cortical Lesion and RT Performance in Rats • Baunez et al.
Figure 3. Top: schematic representation of the maximal extent of bilateral cortical lesions induced by thermocoagulation of pial blood vessels. Bottom: pre- and post-lesion performance of sham-operated (open square; n = 14) and lesion rats (solid circle; n = 20) in the RT task. The animals were tested daily 5 days a week in 100 trial sessions. Results are illustrated for the six preoperative and 24 postoperative sessions (corresponding to days 7–35 post-lesion). Each circle shows the mean number (±SEM) of correct, premature (lever release before the visual cue) and delayed responses (lever release after the 500 ms RT restriction) per session. ¥¥ Significantly different from sham-operated animals, P < 0.01, Newman–Keuls test.
Frontoparietal Cortex Lesions Six days after bilateral lesion of the frontoparietal cortex, the number of correct responses was dramatically reduced, reaching a mean of 25 responses/session (Fig. 4). This reduction was observed from 7 to 35 days following the lesion, although the animals showed a tendency to improve their performance over the daily sessions. One-way ANOVA revealed that lesions of the frontoparietal cortex significantly reduced correct performance when compared with preoperative sessions [F(4,40) = 17.37, P < 0.01, paired t-test]. In addition, Newman–Keuls post-hoc
Figure 4. Top: delimitation of the bilateral thermocoagulation of pial vessels overlying the frontoparietal cortex after microstimulation. Thermocoagulation (hatched area) was performed on the surface of the frontoparietal cortex where the microstimulation of the dura evoked responses of the forelimb and more generally the anterior part of the body [including neck muscles and vibrissae (vib.) as described in Materials and Methods]. Lesions of the frontoparietal cortex group extended from the caudal pole of the frontal area to the rostral region of the parietal cortex. Bottom: effects of bilateral cortical lesions restricted to the frontoparietal cortical territories on RT performance. Results are illustrated for the six preoperative and 24 postoperative sessions (corresponding to days 7–35 post-lesion) on the mean number (±SEM) of correct, premature and delayed responses per session in sham-operated (open circle, n = 14) and lesioned (solid circle, n = 11) animals. ¥,¥¥ Significantly different from sham-operated animals, P < 0.05 and P < 0.01 Newman–Keuls test.
comparisons revealed that correct performance in these animals was significantly different from sham controls except in the last postoperative six session block [ANOVA F(1,23) = 50.22, 20.1 and 12.91, respectively, P < 0.01]. As previously obser ved after extensive cortical lesion, the number of delayed responses was markedly increased in the first
Figure 5. Top: delimitation of the bilateral thermocoagulation of pial vessels overlying the rostral pole of the frontal cortex after microstimulation. Thermocoagulation (hatched area) of the frontal cortex was performed on the most rostral part of the brain where the stimulating electrodes did not elicit any visible response. Bottom: effects of bilateral cortical lesions restricted to the frontal territory on RT performance. Results are illustrated for the six preoperative and 24 postoperative sessions (corresponding to days 7–35 post-lesion) on the mean number (±SEM) of correct, premature and delayed responses per session in sham-operated (open circle, n = 14) and lesioned (black cross, n = 8) animals. ¥,¥¥Significantly different from sham-operated animals, P < 0.05 and P < 0.01 Newman–Keuls test.
postoperative sessions. This deficit, however, was transient, as shown by a significant difference with sham control performance during the first block of postoperative sessions only (day 7–12) [F(1,23) = 21.89, P < 0.01, followed by post-hoc Newman-Keuls comparisons]. In contrast, a dramatic increase in premature responses was sustained for the entire postoperative period. This effect reached a level which was significantly higher than that of preoperative responses [F(4,40) = 9.59, P
0.05 NS). Twenty-six days after the lesion, both sham and lesion groups showed an overall increase of locomotor activity for the first 30 min, returning to baseline activity level after 40 min (Fig. 7B). No significant difference was observed between the two groups, however. The locomotor response of the two other lesion groups was not different from that of control animals when measured 16 days after the lesion (data not shown).
Discussion The present results indicate that bilateral thermocoagulation of the pia brain surface, including the frontal, parietal and rostral aspect of the occipital cortex, produces major deficits in RT performance as shown by an increase in the number of premature lever releases and delayed responses. The intensity and duration of these two types of incorrect responses were found to differ considerably, however. While the deficit expressed by a delay in responding to the cue-light was maximal in the first postoperative sessions (7 days post-lesion) and gradually returned to control level within 18 days, the increase in premature responding was less pronounced and sustained for the total duration of testing (over one month). Lesions restricted to the frontoparietal cortex produced a similar pattern of responding, although a more rapid recovery was observed on the delayed responses. Major deficits produced by discrete lesions of the rostral pole of the frontal cortex were manifest through premature responding, probably ref lecting perturbation of the cognitive processes determining the response set (stimulus–response association), with a milder and transient increase in delayed responses. The implication of the cerebral cortex in the control of skilled forelimb movements is well established in primates but poorly characterized in rodent studies. This is in part due to the fact that extensive cortical destruction in rats does not produce gross sensorimotor dysfunction, leading to the concept that motor impairment from cortical ablation only occurs in ‘higher’ species (see Kolb, 1984, for review). Disruption in discrete digit and forelimb movements after ablation of the motor cortex in rodents has been assessed, however, using classical sensorimotor tests, such as running on an elevated beam (Goldstein and Davis, 1990), reaching for or grasping small food pellets (Castro, 1972a,b), manipulatory behaviour in a latch-opening task (Gentile et al., 1978) or in a force task (Price and Fowler, 1981; Castro-Alamancos and Borrell, 1993a,b). After bilateral ablation of the forelimb primar y motor cortex, rats showed a great impairment in their capacity to perform rapid responses when required to press a lever with a force of 10 g but had no problems pressing the lever (Castro-Alamancos and Borrell, 1995). The present results further support the hypothesis that the frontal and parietal cortices of rats may also control the execution of skilled forelimb movements in operant procedure (Muir et al., 1996), establishing to some extent across-species generality of the earlier results on motor function in primates. In the present experiment, the most prominent deficit observed in animals with large bilateral lesions of the cortex and with lesions restricted to the frontoparietal areas was a major increase in delayed responses which gradually recovered over time and totally disappeared within 3 weeks. That this deficit ref lects an impairment of the initiation of movement is further demonstrated by a clear shift of the distribution of RTs to the right towards longer values on postoperative day 8, when the effect of the lesion was maximal. These results are in agreement with studies on primates where damage to the primary motor cortex is normally associated with a chronic loss of speed and force in both hand and limb movements (Kuypers, 1981), and in humans with hemiplegia and hemiparesis following cerebral infarction (Crisostomo et al., 1988), emphasizing the remarkable unity in motor cortical functions across mammalian phylogeny. The impairment of movement initiation and probably execution is not surprising since the destruction of the sensorimotor cortical areas presumably induces a loss of corticospinal projections onto interneurons modifying motoneuronal activity.
A puzzling result was that a similar deficit, albeit milder, on delayed responses was observed in rats bearing cortical lesions restricted to the rostral pole of the frontal cortex. Although epidural microstimulation of the frontal cortex did not produce any forelimb movement in the present study, confirming previous investigations (Hall and Lindholm, 1974; Wise and Donoghue, 1986), it might be possible that direct intracortical stimulation of this rostral area elicits movements. In agreement with this idea, a rostral forelimb area related to the distal musculature controlling the digits has been described in the frontal pole (Neafsey and Sievert, 1982; Neafsey et al., 1986; Rouiller et al., 1993). Whether this rostral forelimb area is part of the primary or the supplementary motor area is still unresolved; however, thermocoagulatory lesions of this specific area may have produced the mild motor deficits observed in the RT task. In contrast to the transient effects on movement initiation, the deficits expressed by an increase in premature responding remained significant throughout the observation period (>35 days) and were similar in rats bearing the largest lesion and those with a lesion restricted either to the frontoparietal or the frontal cortex. This deficit might be attributed to a disruption of attentional processes controlling the response output or of time estimation of the various periods preceding the stimulus onset. Dysfunction of the frontal cortex in human, non-human primates and lesion of the medial prefrontal cortex in rats is known to produce a variety of deficits in the temporal organization of behaviour (Fuster, 1993), attentional processes (Muir et al., 1996), spatial orientation (Mishkin, 1964; Goldman and Rosvold, 1970; Granon and Poucet, 1995), social or affective behaviour (Kolb, 1984; Kolb and Taylor, 1981) and working memory (Goldman-Rakic, 1990, 1994). In the present conditioned task, correct performance requires appropriate selection, ordering and sequencing of behavioural and cognitive processes that could easily be disturbed after cortical lesion and expressed by inappropriate responses on the lever with no relation to the light-stimulus onset (i.e. premature responding). The corticofugal projections to subcortical structures, in particular the major connection towards the striatum (caudate– putamen complex), that is the input structure of the basal ganglia (Wise and Donoghue, 1986; McGeorge and Faull, 1989; Veening et al., 1980), may play a significant role in the mediation of these cognitive processes. A variety of behavioural situations mediated by the basal ganglia has been modified by damage to the frontal cortex, suggesting that it may have a modulatory inf luence on these structures (Pycock et al., 1980; Scatton et al., 1982; Warenycia et al., 1984; Itoh et al., 1985; Worms et al., 1985; Knable and Weinberger, 1997). Furthermore, the bilateral ablation of the frontoparietal cortex in rats was found to produce a marked potentiation of D-amphetamine-induced motor hyperactivity (Desole et al., 1992). The frontoparietal cortex is thus regarded as exerting an inhibitory inf luence on the subcortical DA mesostriatal and mesolimbic systems. In agreement with these findings, the behavioural deficit expressed by an increase in premature responding after cortical thermocoagulation was also obser ved in rats trained in the same RT task after DA activation following D-amphetamine injection or DA infusion in the striatum (Baunez et al., 1995). The finding that extensive frontoparietal cortical lesions produce a strong deficit on this parameter is puzzling and suggests other possible mechanisms. Alternatively, lever releases at a high rate unrelated to the stimulus onset could be an index of a more global behavioural activation. Importantly though, enhancement of basal locomotor activity following cortical
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ablation did not reach a significant level in rats tested in the photocell cages 16 days after thermocoagulation of the frontoparietal cortex during the light phase of their cycle. Whether this effect could be enhanced during the active phase of their cycle (dark phase) remains to be investigated. However, it is still possible that this mild locomotor hyperactivity was sufficiently disruptive to prevent the animals from holding down the lever long enough until the onset of the light stimulus. Taken together, these results are in line with previous studies showing that damage to the cortex in both rats and monkeys was found to increase motor activity, an effect which could be related to a ‘disinhibition’ of subcortical structures such as the basal ganglia (Scatton et al., 1982; Worms et al., 1985; Castro-Alamancos and Borrell, 1993b). Ablation of the restricted frontoparietal area could therefore preferentially disrupt the corticostriatal output pathways inducing major changes in the extrapyramidal pathway. Consistent with this, similar thermocoagulation of the frontoparietal cortex has been found to produce long-term changes in gene expression in the striatum and its efferent structures (Salin and Chesselet, 1992, 1993). Unilateral cortical lesions including the whole frontoparietal areas result in increased expression of mRNAs encoding enkephalin and substance P, two neuropeptides present in distinct striatal efferent neuronal populations, thus possibly contributing to the pattern of behavioural deficits seen after cortical lesion. Another important issue is the remarkable degree of functional recover y in the animals bearing cortical thermocoagulatory lesions. The deficits expressed by an increase in delayed responses are rapidly recovered within 2–3 weeks depending on the extension of the lesion, even after an almost complete removal of the cortex. In contrast, following aspirative lesion, disruption in digit and forelimb movements and postural ref lexes in the rat is still observed 6 months after surgery (Kolb and Whishaw, 1989). These discrepancies may come from the different procedure used to induce cortical degeneration. It has recently been shown that the cortical lesions induced either by aspiration or thermocoagulation of pial blood vessels differentially affect the expression of axonal and glial responses that may result in different levels of neuronal plasticity (Szele et al., 1995). For example, a prolonged decrease of the axonal marker GA P-43 in the dener vated striatum is obser ved after aspiration lesions, in contrast to the absence of significant changes after thermocoagulatory lesions (Szele et al., 1995). Whereas lesions by aspiration acutely remove cortical tissue and destroy both neuronal cell bodies and their axons in the cortex, thermocoagulatory lesions produce a progressive loss of cortical neurons that is not complete until 5–7 days after surger y. Differences in the synaptic plasticity produced by both types of lesion may thus account for the distinct timing in functional recovery. In conclusion, lesions of the cerebral cortex following ischaemia induced by thermocoagulation of pial blood vessels induce profound deficits in operant responding in a RT task without affecting basal locomotor activity. Different aspects of the deficits expressed by impairment in movement initiation and attentional dysfunction induced by cortical lesion could not be differentiated by restricted lesions to the frontal or the sensorimotor frontoparietal areas, suggesting that a global reactivity of subcortical structures such as the basal ganglia could also contribute to the deficits observed. The progressive effect and rapid functional recovery induced by thermocoagulatory lesion of the cortex may lead to therapeutic strategies to promote recovery from brain injury in pathological
308 Frontal or Parietal Cortical Lesion and RT Performance in Rats • Baunez et al.
situations associated with cortical lesions, such as cerebral palsy, stroke or ischaemia.
Notes The authors are grateful to D. Terramorsi for excellent care of the animals. This work was supported by grant from DRET (convention no. 9434124004707501). C.B. was supported by a fellowship from the Ministère de la Recherche et de l’Enseignement Supérieur. Address correspondence to M. Amalric, Laboratoire de Neurobiologie Cellulaire et Fonctionnelle, CNRS, 31 chemin J. Aiguier, 13402 Marseille Cedex 20, France. Email:
[email protected].
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