Unilateral Striatal Dopamine Depletion Research Articles

Differential sensitivity of cranial and limb motor function to nigrostriatal dopamine depletion

The present study determined the differential effects of unilateral striatal dopamine depletion on cranial motor versus limb motor function. Forty male Long Evans rats were first trained on a comprehensive motor testing battery that dissociated cranial versus limb motor function and included: cylinder forepaw placement, single pellet reaching, vermicelli pasta handling; sunflower seed opening, pasta biting acoustics, and a licking task. Following baseline testing, animals were randomized to either a 6-hydroxydopamine (6-OHDA) (n=20) or control (n=20) group. Animals in the 6-OHDA group received unilateral intrastriatal 6-OHDA infusions to induce striatal dopamine depletion. Six-weeks following infusion, all animals were re-tested on the same battery of motor tests. Near infrared densitometry was performed on sections taken through the striatum that were immunohistochemically stained for tyrosine hydroxylase (TH). Animals in the 6-OHDA condition showed a mean reduction in TH staining of 88.27%. Although 6-OHDA animals were significantly impaired on all motor tasks, limb motor deficits were more severe than cranial motor impairments. Further, performance on limb motor tasks was correlated with degree of TH depletion while performance on cranial motor impairments showed no significant correlation. These results suggest that limb motor function may be more sensitive to striatal dopaminergic depletion than cranial motor function and is consistent with the clinical observation that therapies targeting the nigrostriatal dopaminergic system in Parkinson's disease are more effective for limb motor symptoms than cranial motor impairments.

Striatal Dopamine Depletion Induces Forelimb Motor Impairments and Disrupts Forelimb Movement Representations within the Motor Cortex

While limb motor deficits of Parkinson's disease are well characterized, the effects of striatal dopamine depletion on the motor cortex is poorly understood. We therefore aimed to 1) examine the effects of striatal dopamine depletion on forelimb function and cortical motor map topography and 2) explore potential relationships between forelimb function and cortical movement representations in an animal model of PD. Twenty-four male Long Evans rats were randomized to control or 6-hydroxydopamine (6-OHDA) groups. Animals in the 6-OHDA group underwent four unilateral 6-OHDA infusions into the striatum to induce striatal dopamine depletion. Four weeks later, animals were tested on a comprehensive battery of behavioral limb motor tasks followed by intracortical microstimulation to derive high-resolution topographic maps of forelimb movement representations. Standard tyrosine hydroxylase (TH) immunohistochemistry was performed and near infrared densitometry analysis utilized to assess TH depletion. Unilateral striatal dopamine depletion induced significant reductions in limb motor function that were reflected neurophysiologically as a reduction in cortical forelimb movement representations. Voluntary forelimb use, pasta handling, sunflower seed manipulation, and forelimb motor maps were all significantly impaired in 6-OHDA animals. A positive correlation was observed between forelimb function and motor map size, as well as two negative correlations between TH depletion with 1) motor map size and 2) forelimb function. The results clearly show how dysfunction within the basal ganglia thalamocortical loop resulting from nigrostriatal dopamine depletion disrupts corticospinal function.

The Vermicelli and Capellini Handling Tests: Simple quantitative measures of dexterous forepaw function in rats and mice

Previous characterizations of rodent eating behavior have revealed that they use coordinated forepaw movements to manipulate food pieces. We have extended upon this work to develop a simple quantitative measure of forepaw dexterity that is sensitive to lateralized impairments and age-dependent changes. Rodents learn skillful forepaw and digit movements to manage thin pasta pieces, which they eagerly consume. We have previously described methods for quantifying vermicelli handling in rats and showed that the measures are very sensitive to forelimb impairments resulting from unilateral ischemic lesions, middle cerebral artery occlusions and unilateral striatal dopamine depletion [Allred, R.P., Adkins, D.L., Woodlee, M.T., Husbands, L.C., Maldonado M.A., Kane, J.R., Schallert, T. & Jones, T.A. The Vermicelli Handling Test: a simple quantitative measure of dexterous forepaw function in rats. J. Neurosci. Methods 170, 229-244 (2008)]. Here we present a more detailed protocol for this test in rats and compare it with a newly developed version for mice, the Capellini Handling Test. Rats and mice are videotaped while handling short lengths of uncooked vermicelli or capellini pasta, respectively, with a camera positioned to optimize the view of paw movements. Slow motion video playback allows for the identification of forepaw adjustments, defined as any distinct removal and replacement of the paw, or of any number of digits, on the pasta piece after eating commences. Forepaw adjustments per piece are averaged over trials per each testing session. Repeated testing permits sensitive quantitative analysis of changes in forepaw dexterity over time. Protocols for pre-testing habituation and handling practice, as well as procedures for characterizing atypical handling patterns, are described. Because rats and mice perform the pasta handling tests slightly differently, species-specific differences in administration and scoring of these tests are highlighted. All animal use was in accordance with protocols approved by the University of Texas at Austin Animal Care and Use Committee.

The Vermicelli and Capellini Handling Tests: Simple quantitative measures of dexterous forepaw function in rats and mice

Previous characterizations of rodent eating behavior have revealed that they use coordinated forepaw movements to manipulate food pieces. We have extended upon this work to develop a simple quantitative measure of forepaw dexterity that is sensitive to lateralized impairments and age-dependent changes. Rodents learn skillful forepaw and digit movements to manage thin pasta pieces, which they eagerly consume. We have previously described methods for quantifying vermicelli handling in rats and showed that the measures are very sensitive to forelimb impairments resulting from unilateral ischemic lesions, middle cerebral artery occlusions and unilateral striatal dopamine depletion [Allred, R.P., Adkins, D.L., Woodlee, M.T., Husbands, L.C., Maldonado M.A., Kane, J.R., Schallert, T. & Jones, T.A. The Vermicelli Handling Test: a simple quantitative measure of dexterous forepaw function in rats. J. Neurosci. Methods 170, 229-244 (2008)]. Here we present a more detailed protocol for this test in rats and compare it with a newly developed version for mice, the Capellini Handling Test. Rats and mice are videotaped while handling short lengths of uncooked vermicelli or capellini pasta, respectively, with a camera positioned to optimize the view of paw movements. Slow motion video playback allows for the identification of forepaw adjustments, defined as any distinct removal and replacement of the paw, or of any number of digits, on the pasta piece after eating commences. Forepaw adjustments per piece are averaged over trials per each testing session. Repeated testing permits sensitive quantitative analysis of changes in forepaw dexterity over time. Protocols for pre-testing habituation and handling practice, as well as procedures for characterizing atypical handling patterns, are described. Because rats and mice perform the pasta handling tests slightly differently, species-specific differences in administration and scoring of these tests are highlighted. All animal use was in accordance with protocols approved by the University of Texas at Austin Animal Care and Use Committee.

Within-session analysis of amphetamine-elicited rotation behavior reveals differences between young adult and middle-aged F344/BN rats with partial unilateral striatal dopamine depletion

Preclinical modeling of Parkinson's disease using 6-hydroxydopamine (6-OHDA) has been valuable in developing and testing therapeutic strategies. Recent efforts have focused on modeling early stages of disease by infusing 6-OHDA into the striatum. The partial DA depletion that follows intrastriatal 6-OHDA is more variable than the near-complete depletion following medial forebrain bundle infusion, and behavioral screening assays are not as well characterized in the partial lesion model. We compared relationships between amphetamine-elicited rotation behavior and DA depletion following intrastriatal 6-OHDA (12.5 μg) in 6 month vs. 18 month F344/BN rats, at 2-weeks and 6-weeks post-lesion. We compared the total number of rotations with within-session (bin-by-bin) parameters of rotation behavior as indicators of DA depletion. Striatal DA depletion was greater in the young adult than in the middle-aged rats at 2 weeks but not at 6 weeks post-lesion. The total number of rotations for the whole session and striatal DA depletion did not differ between the two age groups. Regression analysis revealed a greater relationship between within-session parameters of rotation behavior and DA depletion in the middle-aged group than in the young adult group. These results have implications for estimating DA depletion in preclinical studies using rats of different ages.

Effects of development and dopamine depletion on striatal NMDA receptor-mediated calcium uptake

Calcium (Ca(2+)) is the currency of N-methyl-D-aspartate (NMDA) receptor mediated signal transduction pathways involved in the modification of synaptic efficacy during regulation of excitatory inputs into the striatum. The aim of the present study was to investigate the effects of development and dopamine depletion on NMDA receptor function. NMDA receptors were stimulated by incubation of striatal sections (350 microm) in buffer containing NMDA (100 microm) for 2 min, the slices were washed and uptake of radioactively labelled calcium ((45)Ca(2+)) was measured. Dopamine depletion has been reported to result in alterations of glutamate receptor expression and upregulation of NMDA receptor activity. However, the results of the present study show that dopamine depletion does not alter NMDA-stimulated Ca(2+) uptake into rat striatal slices in vitro. Unilateral striatal dopamine depletion was achieved by infusion of 6-hydroxydopamine (6-OHDA, 13.5 microg/4.5 microl) into the medial forebrain bundle (MFB) of the left hemisphere of ten rats. NMDA-stimulated (45)Ca(2+) uptake into striata following dopamine depletion was not significantly different from NMDA-stimulated (45)Ca(2+) uptake into striata obtained from sham-operated rats. Other factors that induce changes in NMDA receptor function include development and aging. In young rats aged 7 weeks old (n = 7) and 16 weeks old (n = 6) a significant 2-3 fold decrease in striatal NMDA receptor function was observed with increasing age over the 9 week period of development. To our knowledge these are the first results to show developmental decreases of NMDA receptor function in the striatum of juvenile rats.

Unilateral striatal dopamine depletion: time-dependent effects on cortical function and behavioural correlates.

Previously, we showed that unilateral blockade of D1 dopamine receptors in the striatum inhibits immediate-early gene expression bilaterally throughout large parts of the cortex, including sensory-evoked expression in the barrel cortex. To further investigate this dopamine regulation of cortical function, we examined the effects of dopamine depletion on cortical gene regulation and behavioural correlates. Two days after unilateral infusion of 6-hydroxydopamine into the midbrain, rats displayed a (to some degree) bilateral reduction in cortical zif 268 expression that was more pronounced on the lesioned side. This decrease was found across motor, somatosensory, insular and piriform, but not cingulate, cortex, similar to the effects of blockade of striatal D1 receptors. Furthermore, whisker stimulation-evoked c-fos and zif 268 expression in the barrel cortex ipsilateral to the lesion was also attenuated by acute dopamine depletion. These cortical deficits were accompanied by a breakdown of spontaneous behaviours in an open-field test. In contrast, 21 days after dopamine depletion, both basal and sensory-evoked gene expression in the cortex were near-normal. This cortical recovery was paralleled by recovery in locomotion and in sensory-guided behaviour (scanning) related to the hemisphere contralateral to the lesion, but not in scanning by the dopamine-depleted hemisphere. Our results suggest that striatal dopamine exerts a widespread facilitatory influence on cortical function that is necessary, but not sufficient, for normal behaviour. Moreover, the mechanisms mediating this cortical facilitation appear to be subject to substantial neuroplasticity after dopamine perturbation.

Reaction time performance following unilateral striatal dopamine depletion and lesions of the subthalamic nucleus in the rat

The akinesia resulting from Parkinson's disease or striatal dopamine depletion in experimental animals can be ameliorated or reversed by inactivation of the subthalamic nucleus. This inactivation might be effective by restoring balance to the basal ganglia motor circuits. Alternatively, new movement-related deficits might be introduced which mask the original impairments (e.g. hyperkinesia might replace hypokinesia). In the present study, striatal dopamine depletion was effected unilaterally, in order to dissociate generalized effects, e. g. hyperkinesia, from response-specific initiation effects. Rats were trained in a lateralized visual reaction time task and then assigned to one of four groups: striatal dopamine depletion; cell body lesion of the subthalamic nucleus; combined striatal dopamine depletion and subthalamic nucleus lesion; or control. As expected, rats with striatal dopamine depletion exhibited slower reaction time and a bias to respond to the ipsilateral side. The subthalamic nucleus lesion resulted in no reaction time change (in particular, there was no evidence of faster reaction times), but there was an increase in anticipatory responding. The group with the combined striatal dopamine depletion and subthalamic nucleus lesion had no reaction time impairment. This group showed an increase in anticipatory errors and a contralateral response bias. These data demonstrate that lesions of the subthalamic nucleus do not merely cancel the akinesia which follows striatal dopamine depletion by the addition of a hyperkinetic impairment. Rather, there appears to be a change in the balance of the motor system.

Effects of unilateral striatal dopamine depletion on tongue force and rhythm during licking in rats.

To quantitatively assess the orolingual dysfunctions produced by unilateral striatal dopamine depletions, rats first received 6-hydroxydopamine injections into the nigrostriatal bundle and were then trained to lap water from a force-sensing disk in 2-min sessions. Compared with controls and rats with moderate (<75%) dopamine depletions, subjects with substantial (>75%) dopamine depletions showed decreases in number of licks, lick rhythm, and lick peak force. Rats with substantial lesions were also impaired in making initial, within-session adjustments in lick peak force but not in lick rhythm. The results confirm the presence of Parkinson-like deficits in tongue dynamics during consummatory licking behavior in rats. The methods used here should prove useful in providing quantitative measures of the efficacy of experimental therapies in this rodent model of Parkinson's disease.

Effects of unilateral striatal dopamine depletion on tongue force and rhythm during licking in rats.

Effects of unilateral striatal dopamine depletion on tongue force and rhythm during licking in rats.

Excitotoxic lesions of the subthalamic nucleus ameliorate asymmetry induced by striatal dopamine depletion in the rat

We investigated the effect of unilateral dorsal striatal dopamine depletion (by intrastriatal infusion of 6-OHDA), ibotenic acid lesions of the subthalamic nucleus (STN) and combined dopamine depletion and STN lesions on sensorimotor asymmetry using a test of somatosensory asymmetry [T. Schallert et al., Pharmacol. Biochem. Behav. 16 (1982) 455–462]. The unilateral striatal dopamine depletion resulted in a somatosensory asymmetry. This asymmetry was ameliorated in the rats with combined dopamine depletion and STN lesion, indicating the potential beneficial nature of STN inactivation in rats with striatal dopamine depletion.

Behavioral asymmetries and recovery in rats with different degrees of unilateral striatal dopamine depletion

A detailed behavioral analysis during the first postoperative week was performed in rats which had sustained various degrees of unilateral neostriatal dopamine (DA) lesions by administration of the neurotoxin 6-hydroxydopamine into the substantia nigra. These animals were assigned to different groups according to their residual DA levels in the damaged neostriatum (as percentage of the intact side). On the first day after toxin injection into the substantia nigra, turning asymmetries (tight turns) toward the side of the lesion were observed in animals with a mean residual DA level of 32% or less. Out of these, the strongest asymmetries were observed in animals with a mean residual DA of 3%. After one week, the asymmetry in tight turns had totally recovered except in those groups with mean residual DA levels of 17% or less. Partial recovery was found in animals with mean residual DA of 9 and 17%, whereas no indication for recovery was found in animals with the most severe lesions (mean residual DA 3%). Measurement of thigmotactic scanning also revealed an asymmetry for the side of the lesion on the first post-operative day. This asymmetry was observed over a wider range of DA lesion than that observed in turning, namely up to a mean residual DA level of 78%. Furthermore, recovery to symmetry was observed in all lesion-groups except in those with more severe lesions (mean residual DA 17% or less). In contrast to turning, the strongest asymmetries were not displayed by the animals with the most severe lesions. Furthermore, locomotor activity was affected by the lesion, since on the first postoperative day locomotion was reduced in animals with mean residual DA of 39% or less. On day 7, this lesion-dependent deficit had recovered to control levels. Finally, the analysis of net turns allowed the prediction of lesion size in animals with residual DA levels of less than 15%. These results are discussed with respect to mechanisms of recovery, the role of lesion size, and the value of different behavioral measures to predict the degree of DAergic lesion.

Asymmetrical orientation to edges of an openfield: modulation by striatal dopamine and relationship to motor asymmetries in the rat

Rats with unilateral 6-hydroxydopamine (6-OHDA, 4 or 8 μg) or sham lesions of the substantia nigra were examined (undrugged) for asymmetrical orientation to edges of a large openfield. Lesioned rats preferentially aligned with the edge such that the intact striatum was contralateral to the edge. The magnitude of this asymmetry was greatest in rats lesioned with the highest dose of 6-OHDA. There was no population left/right hemispheric asymmetry in the extent to which unilateral striatal dopamine (DA) depletion produces this behavioral bias. In sham-lesioned rats, endogenous imbalances in striatal DA activity (DOPAC/DA) were related to the direction of edge orientation, such that the more active striatum tended to be contralateral to the edge. Also in shams, the direction of this orientational asymmetry was not significantly related to the direction of motor bias measured as amphetamine- and apomorphine-induced turning behavior in rotometers (having no edges). However, the magnitudes of sensorimotor (edge behavior) and motor (turning) asymmetries were negatively correlated. The results extend previous findings that asymmetrical edge behavior is a sensitive index of imbalances in striatal DA activity, not only in DA-depleted rats, but in intact rats as well. Furthermore, sensorimotor ana motor asymmetries, while both under DAergic influence, are largely independent processes.

Adrenal medulla grafts in the hemiparkinsonian rat: profile of behavioral recovery predicts restoration of the symmetry between the two striata in measures of pre- and postsynaptic dopamine function

Following unilateral striatal dopamine depletion, the hemiparkinsonian rat exhibits rotational behavior in response to amphetamine and apomorphine. The rotational behaviors induced by these drugs are thought to reflect an asymmetry in presynaptic striatal dopamine release and an asymmetry in postsynaptic striatal dopamine receptor function, respectively. Grafts of adrenal medulla cells in the lateral ventricle of hemiparkinsonian rats have been reported to reduce behavioral asymmetry. More than one profile of behavioral recovery, however, is observed. Some animals show a graft-induced decrease only in the response to apomorphine, but others show a decrease in the response to amphetamine, and still others show a decrease in the behavioral responses to amphetamine and apomorphine. In this report, amphetamine- and apomorphine-induced turning behaviors were determined in hemiparkinsonian rats prior to and following intraventricular grafts of adrenal medulla or control tissue. Both bilateral intrastriatal microdialysis in freely moving animals and quantitative dopamine receptor autoradiography procedures were conducted in each animal so as to determine the relations between pre- and postsynaptic dopaminergic measures as well as the association between these measures and the different profiles of behavioral recovery after adrenal medulla grafts. We report here that in animals with an adrenal medulla graft-induced decrease in the behavioral response to amphetamine, the balance between the two striata in extracellular striatal dopamine concentrations and D2 dopamine receptor binding was restored. Furthermore, enhanced extracellular striatal dopamine concentrations were highly correlated with the graft-induced symmetry in striatal D2 dopamine receptor binding. In contrast to animals with decreased amphetamine-induced turning, in animals with a graft-induced decrease exclusively in response to apomorphine, the presynaptic symmetry was not restored and there was a significantly smaller effect on D2 receptor binding. We conclude that those animals that show decreased amphetamine-induced turning after adrenal medulla grafts had the most effective grafts, and suggest that methods designed to optimize this behavioral profile are most likely to lead to enhanced clinical efficacy with this procedure.

SIMPLE AND CHOICE REACTION TIME PERFORMANCE FOLLOWING UNILATERAL STRIATAL DOPAMINE DEPLETION IN THE RAT

Rats were trained to perform a visual spatial discrimination, where stimulus luminance provided information regarding the required direction of response. The visual stimuli were presented either in advance of a temporally unpredictable auditory imperative stimulus (simple reaction time condition) or simultaneously with the imperative stimulus (choice reaction time condition). Following unilateral striatal dopamine depletion, produced by intracerebral infusion of 6-hydroxydopamine, there was not only a marked spatial response bias towards the side of the dopamine depletion but also an abolition of the delay-dependent speeding of reaction time that reflects motor readiness, on the side contralateral to the lesion. Nevertheless, the rats continued to show a benefit in performance of the simple reaction time condition compared with the choice reaction time condition, indicating that they were able to use advance information to select and prepare responses. The results are discussed in the context of differential deficits shown by patients with Parkinson's disease in simple versus choice reaction time performance, and of the functions of parallel corticostriatal loops subserving the normal control of action.

Deficits in response space following unilateral striatal dopamine depletion in the rat

Hungry rats were trained to report the occurrence and location of brief, unpredictable visual stimuli presented to the left of their heads in 1 of 2 response locations. After training, they received unilateral infusions of 6-hydroxydopamine, depleting dopamine throughout the head of the caudate putamen, either on the left or the right side, that is, either ipsilateral or contralateral to the side on which they were required to respond. Following an ipsilateral lesion there were no impairments in localization of the visual discriminanda and there was no lengthening of reaction time. The contralaterally lesioned rats, however, showed considerably lengthened reaction times to both stimuli and a profound bias to the nearer of the 2 response locations. Evidence from probe trials in which the visual stimuli were presented separately or simultaneously showed that the impairment was not due to a failure to localize the stimuli in contralateral space but, rather, resulted from a deficit in directing responses in contralateral space. It is suggested that this may be due to a distortion in the representation of response space.

Effects of unilateral dorsal and ventral striatal dopamine depletion on visual neglect in the rat: A neural and behavioural analysis

Rats were trained in a specially designed apparatus to detect brief, unpredictable visual stimuli presented to either side of the head. In one condition, rats reported the detection of the visual stimulus by removing their heads from a central location and responding in one of two adjacent side-holes where the visual stimulus had occurred. In the other condition, rats were trained to respond in the hole on the opposite side to where the visual stimulus had occurred. Following training all rats received striatal infusions of 6-hydroxydopamine leading to profound striatal dopamine depletion. One group received unilateral intra-nucleus accumbens 6-hydroxydopamine infusions. Two groups received 6-hydroxydopamine unilaterally into the caudate nucleus. Two other groups received two infusions of 6-hydroxydopamine, intra-accumbens and intra-caudate, on either the same side or on opposite sides. The results showed that all groups, except that receiving only intra-accumbens 6-hydroxydopamine, exhibited a significant bias in responding towards the side of the lesion which correlated with dopamine depletion in the head of the caudate nucleus, regardless of the type of discrimination or pre-operative strategy. These biased groups were also slower to initiate, but not to complete, contralateral responses. Detailed analysis of the behavioural evidence suggested that unilateral striatal dopamine depletion does not produce sensory loss or sensory inattention but rather an output type neglect, perhaps related to hemiakinesia or “intentional neglect”. The bias recovered to preoperative levels by 7 weeks after surgery, but could be reinstated by pretreatment with alpha-methyl- para-tyrosine, thus suggesting the involvement of presynaptic mechanisms in recovery. Although unilateral dopamine depletion from the nucleus accumbens alone had no effects on visual neglect, it produced a lateralized bias in premature responding away from the side of the lesion, contrasting with the bias towards the side of the lesion seen in all of the other groups. These effects appeared to summate in this and in another condition in which a more eccentric response was required for stimulus detection, to suggest an interaction in function between the dorsal and ventral striatum.

6-Hydroxydopamine-induced turning behaviour in the rat: The significance of acetylcholinesterase in cerebrospinal fluid

In the substantia nigra, acetylcholinesterase may have a novel function related not to cholinergic transmission, but to the homeostasis of dopaminergic nigrostriatal neurones. The initial aim of this study was thus to see whether, in the rat, release of the enzyme into cerebrospinal fluid would reflect turning behaviour following unilateral 6-hydroxydopamine lesions of varying severity. It was found that acetylcholinesterase levels, lower than those in the cerebrospinal fluid of control rats, were accompanied by marginal circling behaviour and a small loss of striatal dopamine: on the other hand, elevated acetyl-cholinesterase activity was observed in the cerebrospinal fluid of rats displaying vigorous turning behaviour and with large depletion of striatal dopamine. It has already been demonstrated that exogenous acetylcholinesterase, applied locally to nigral neurones, has both electrophysiological and behavioural effects reminiscent of dopamine agonists. Hence it is possible that exogenous acetylcholinesterase could modify turning behaviour resulting from unilateral striatal dopamine depletion. Purified acetylcholinesterase, administered by cisternal puncture, attenuated circling behaviour for up to 7 days. The possible mechanisms are discussed by which endogenous acetylcholinesterase in cerebrospinal fluid could serve as an index of dopamine depletion in the nigrostriatal pathway and how exogenous enzymes might alleviate the accompanying motor dysfunction.

Differential time-course of reaction time recovery depending on variations in the amplitude of a goal-directed movement after nigrostriatal lesion in monkeys

Unilateral striatal dopamine depletion induced by 6-hydroxydopamine injections into the substantia nigra of behaving monkeys was found to increase the latency of a visually guided pointing movement performed by the contralateral forelimb. The time-course of recovery of the movement latency was faster in small displacements of the limb than in movements with larger amplitudes. The efficiency of putative compensatory mechanisms that may develop progressively in response to the striatal dopamine deficit depends on the amplitude of the movement to be initiated.

Complementary effects of unilateral striatal dopamine depletion and amphetamine infusions on a lateralized visual reaction time task in rats

When rats trained to forage in one environment are exposed to a second, highly similar environment, their hippocampal place code exhibits a partial remapping in the new environment that becomes more complete with repeated exposures (Shapiro, Tanila, Eichenbaum, Hippocampus 7 (6) (1997) 624–642, Bostock, Muller, Kubie, Hippocampus 1 (2) (1991) 193–206). If the perforant path projection to CA3 functions as a pattern completion mechanism, and the DG projection via the mossy fibers performs pattern separation (O'Reilly, McClelland, Hippocampal conjunctive encoding, storage, and recall: avoiding a trade-off, Hippocampus 4 (6) (1994) 661–682), then partial remapping can be understood as the combined effect of these two projections. We investigated learning rules that could be responsible for the gradual separation of two maps, and found that, while simple Hebbian learning and Hebbian covariance learning would not produce the separation effect, BCM learning was one rule that would.