Turning behavior after unilateral lesion of the subthalamic nucleus in the rat

Unilateral stereotaxic lesions of the subthalamic nucleus of rats with kainic acid induced a transient spontaneous ipsiversive turning which was present for several days, and which could be blocked by i.p. administration of haloperidol. After the 20th postoperative day, when no spontaneous turning activity was present, i.p. administration of apomorphine or amphetamine in the kainic acid lesioned rats induced ipsiversive turning, while i.p. haloperidol in the same rats induced contraversive turning. These findings suggest that the subthalamic nucleus is involved in the dopaminergic mechanisms mediating turning behavior of rats.     

Turning behavior in rats with unilateral lesion of the subthalamic nucleus: synergism between D1 and D2 receptors

Summary Rats with unilateral kainic acid lesion of the subthalamic nucleus showed a dose dependent rotational response to the lesioned side (ipsilateral) after systemic administration of the non-selective dopaminergic agonist apomorphine. Both D2 and D1 selective antagonists ((–)sulpiride and SCH23390) inhibited the response to apomorphine in these rats. Selective D2 and D1 agonists (quinpirole and SKF38393) were unable to induce turning behavior. However, an ipsilateral circling response was obtained after the simultaneous application of both agonists. The interaction mechanism between dopaminergic receptor subtypes seems to be similar to that of other normosensitive models of turning previously studied (Barone et al, 1986; Robertson and Robertson, 1986; Arnt and Perregard, 1987; Asim et al., 1990; Pazo et al., 1993). It is proposed that the ipsilateral turning response to dopaminergic agonists in rats with subthalamic nucleus lesion results from an impaired behavioral expression of the action of dopaminergic agonists on one side, leading the rats to turn away from the intact hemisphere.     

Evolution of changes in neuronal activity in the subthalamic nucleus of rats with unilateral lesion of the substantia nigra assessed by metabolic and electrophysiological measurements

Cellular expression of cytochrome oxidase subunit I (COI) mRNA has recently been used as a metabolic marker for neuronal activity to study the functional changes in the subthalamic nucleus (STN) in parkinsonism. The previous experimental studies have been performed when the pathological state was stabilized at a maximal level. In order to determine the evolution of changes in neuronal activity in the STN after nigrostriatal denervation, we analysed by in situ hybridization the cellular expression of COI mRNA in the subthalamic neurons at different times, from 6 h to 14 days, after unilateral intranigral microinjection of 6-hydroxydopamine (6-OHDA) in rats. In parallel, the time-dependent changes of the unit neuronal activity of subthalamic neurons have been recorded. Levels of COI mRNA increased by 41% in subthalamic neurons from 24 h after 6-OHDA intoxication, to 14 days (+26%). Similarly, electrical activity started to increase slightly 24 h after lesion (+20%) and remained significantly higher at 14 days after the lesion (+189%). Changes in neuronal mean discharge rate were associated with changes in the pattern of spiking activity, from a regular firing pattern to an irregular one with a high bursting activity. These results show that: (i) the hyperactivity of the STN represents a very early phenomenon in the physiopathology of parkinsonian syndromes; and (ii) that changes in COI mRNA expression slightly precede changes in electrical neuronal activity.     

Bilateral subthalamic nucleus lesion reverses L-dopa-induced motor fluctuations and facilitates dyskinetic movements in hemiparkinsonian rats

Glutamatergic overactivity might be involved in L-dopa-induced motor complications since glutamate antagonists reverse and prevent L-dopa-induced shortening in motor response duration in 6-hydroxydopamine-lesioned (6-OHDA) rats and improve L-dopa-induced dyskinesias in parkinsonian monkeys and in patients with Parkinson's disease (PD). An increase in the subthalamic nucleus (STN) glutamatergic activity is believed to contribute to the pathophysiology of PD. However, the role of STN activity in L-dopa-induced motor complications is not so clear. In this study, the effect of STN lesions on L-dopa-induced motor response complications was investigated in rats with a nigrostriatal pathway lesion induced by 6-OHDA. Animals were injected with 6-OHDA in the medial forebrain bundle and treated with L-dopa or saline for 22 days. On day 16, animals were randomly distributed in groups that underwent surgery in the STN ipsilateral or contralateral to 6-OHDA lesion, or bilateral. Rotational behavior was measured on days 1, 15, and 22. Attenuation of STN activity by contralateral and bilateral, but not ipsilateral, STN lesion reversed the shortening in motor response duration induced by L-dopa. L-dopa administration, but not saline, induced prominent dyskinesias in 6-OHDA-lesioned rats with additional bilateral STN lesions. The results indicate that bilateral lesions of STN potentiate the duration of L-dopa-induced motor response and facilitate chronic L-dopa-induced abnormal involuntary movements in 6-OHDA-lesioned rats. The characteristics of the abnormal involuntary movements observed in these animals are similar to L-dopa-induced dyskinesias in parkinsonian patients and might be useful as an experimental model for the study of L-dopa-induced dyskinesia.     

Effect of microiontophoretic application of dopamine on subthalamic nucleus neuronal activity in normal rats and in rats with unilateral lesion of the nigrostriatal pathway

The subthalamic nucleus (STN) receives dopamine inputs from the substantia nigra but their implication in the pathophysiology of parkinsonism is still debated. Extracellular microrecordings were used to study the effect of microiontophoretic injection of dopamine and the D1 receptor agonist SKF 38393 on the activity of STN neurons in normal and 6-hydroxydopamine-lesioned rats under urethane anaesthesia. Dopamine and SKF induced an increase in the firing rate of the majority of STN neurons in both normal and 6-OHDA rats. In rats with 6-OHDA lesions, the percentage of firing rate increase did not differ from that of controls. When GABA, glutamate and dopamine were all applied to the same individual STN neurons, GABA induced an inhibitory effect and glutamate and dopamine caused an excitatory effect in both groups. This excitatory response was suppressed by the application of GABA. Systemic administration of apomorphine provoked a decrease in the firing rate of STN neurons in rats with 6-OHDA lesions. These results show that dopamine exerts an excitatory influence on STN neurons, suggesting that the inhibitory effect induced by the systemic injection of apomorphine is due to the GABAergic inputs from the globus pallidus as predicted by the current model of basal ganglia organization. In addition, we show that dopamine, GABA and glutamate can act on the same STN neuron and that GABA can reverse the excitatory effect of dopamine and glutamate, suggesting the predominant influence of GABAergic inputs to the subthalamic nucleus.     

Effects of MK-801 upon local cerebral glucose utilisation in conscious rats following unilateral lesion of caudal entorhinal cortex

Local cerebral glucose utilisation was examined in 62 discrete regions of conscious rats following unilateral ibotenic acid lesion of the caudal entorhinal cortex, and subsequent pharmacological challenge with (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801), a non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist. Fourteen days after unilateral lesion of the entorhinal cortex, there were no significant alterations in local cerebral glucose use except within the lesioned entorhinal cortex (reduced by 31% compared to sham-operated control animals). In sham-operated animals, systemic administration of MK-801 (0.5 mg/kg, i.v.) induced anatomically organised alterations in glucose use with increases in olfactory areas, subicular complex and some limbic areas (posterior cingulate cortex, mammillary body and anteroventral thalamic nucleus), and decreases in the inferior colliculus and neocortex (auditory, sensory-motor, somatosensory and frontal cortices). In animals with unilateral entorhinal cortex lesions, the metabolic response to MK-801 differed significantly from the response to the drug in sham-lesioned animals in a number of regions, viz. hippocampus, molecular layer (ipsilateral to lesion), entorhinal cortex (ipsilateral), dentate gyrus (ipsilateral), presubiculum (bilateral), parasubiculum (bilateral) and nucleus accumbens (bilateral). The ability of MK-801 to reduce glucose use in the neocortex was not altered by entorhinal cortex lesion. These data suggest that the functional consequences of non-competitive NMDA receptor blockade are dependent in some areas upon the integrity of the perforant pathway from the entorhinal cortex to the hippocampus.     

Improvements in motor behavioral tests during deep brain stimulation of the subthalamic nucleus in rats with different degrees of unilateral parkinsonism

Deep brain stimulation (DBS) improves motor performance in Parkinson's disease (PD) patients. To evaluate the effects of subthalamic nucleus (STN)-DBS on impaired motor behavior, we studied improvements in motor performance after delivery of unilateral stimulation to the STN in rats with mild and severe lesions of the nigrostriatal dopamine system caused by injecting 6-hydroxydopamine into the striatum. The rats were trained and performed motor behavioral tests including rotational behavior test, stepping test, and rotarod test before and after receiving DBS. We demonstrated that stimulation at a current strength of 200 microA, which stopped most of the D-amphetamine-induced rotational behaviors in these two groups, improved movement impairments in both the mild and severe groups and that the improvements in the mild group were significantly better than those in the severe group. More experimental and clinical studies are needed to evaluate the efficiency of STN-DBS for different stages of PD.     

Altered local cerebral glucose utilization by unilateral frontal cortical ablations in rats

Alterations in local cerebral glucose utilization (LCGU) following ablations of the unilateral frontal cortex in rats were studied to elucidate the effect of the lesion on the functional activity in the related cerebral structures. Frontal cortical ablations (areas 2, 4, 6 and 10) were made by aspiration on the left side, and LCGU was evaluated at 7 days after the operation, using the [14C]deoxyglucose method. Significant decreases in LCGU in rats with unilateral frontal cortical ablations, were observed in the ipsilateral thalamic nuclei (ventroanterior-ventrolateral (VAL), ventrobasal (VB), reticular), red nucleus and pontine nucleus. The ipsilateral globus pallidus showed a significant LCGU increase. The contralateral cerebellar cortex showed a tendency toward a decrease in LCGU. The striatum, which receives direct projections from the frontal cortex, showed no LCGU change. These results indicated that ablations of unilateral frontal cortex in rats produced LCGU changes in the cerebral structures which have direct or indirect neuronal connections with the ablated area. These LCGU changes were, for the most part, brought about by alteration in the neuronal activity. Particularly, the LCGU increase in the globus pallidus which receives transsynaptic neuronal input from the frontal cortex, without changes in the striatum, which receives direct projection, was attributed to the functional alteration of the globus pallidus produced by the cortical ablation. Destructive lesion of a cerebral structure, therefore, does not necessarily cause functional depressions in the pertinent structures, but it may enhance the function of some structures, depending on the functional characteristics of each neuronal connection and functional organization of those structures.     

The role of the subthalamic nucleus in 'compulsive' behavior in rats

Different lines of evidence point to dysfunction of basal ganglia-thalamocortical circuits in obsessive-compulsive disorder (OCD). It has been hypothesized that the circuits' dysfunction in OCD may be characterized by a relative under-activity of the indirect compared with the direct pathway within these circuits. The present study tested whether lesions of the subthalamic nucleus (STN), a major node of the indirect pathway, would affect compulsive behavior, using the signal attenuation rat model of OCD. In this model, compulsive lever-pressing is induced by the attenuation of an external signal of reward delivery; an attenuation that is hypothesized to simulate the deficient response feedback suggested to underlie obsessions and compulsions in patients with OCD. Rats sustaining lesions to the STN showed a selective increase in compulsive lever-pressing compared with sham-operated rats. A post mortem biochemical analysis revealed a decrease in serotonin content in the prelimbic and infralimbic cortices, caudate-putamen (but not nucleus accumbens), globus pallidus and substantia nigra-ventral tegmental area, as well as a decrease in dopamine content in the caudate-putamen in STN-lesioned compared with sham rats. A comparison to recent findings that lesions to the orbitofrontal cortex, which also result in a selective increase in compulsive lever-pressing, lead to a decrease in serotonin and dopamine content in the caudate-putamen suggests that there may be a final common pathway by which different brain pathologies may lead to a pro-compulsive state.     

Local cerebral glucose metabolic rates in obsessive-compulsive disorder. Patients treated with clomipramine

In a recent study, we reported abnormal local cerebral glucose metabolic rates in the orbital frontal cortex of patients with obsessive-compulsive disorder. Eight patients with obsessive-compulsive disorder scanned previously were scanned again during treatment with the tricyclic antidepressant clomipramine hydrochloride. Comparisons of local cerebral glucose metabolic rates for both groups showed a relative decrease in regions of the orbital frontal cortex and the left caudate, and an increase in other areas of the basal ganglia, including the right anterior putamen. When comparing patients who responded well to clomipramine with those who were either poor or partial responders, we found significant decreases only in the left caudate of patients who responded well to the drug. The present study suggests that clomipramine-induced improvement in obsessive-compulsive symptoms is associated with a return of regional brain metabolism to a more normal level in regions of the orbital frontal cortex and the caudate nucleus.     

High-frequency stimulation of the subthalamic nucleus reverses limb-use asymmetry in rats with unilateral 6-hydroxydopamine lesions

Deep brain stimulation (DBS) is a widely used clinical treatment for Parkinson's disease (PD). A rodent model of DBS is a necessary tool for understanding the neural mechanisms of this method. Our previous study showed that high-frequency stimulation (HFS) of the subthalamic nucleus (STN) improved treadmill locomotion in rats with unilateral 6-hydroxydopamine (6-OHDA)-induced lesions of nigrostriatal dopamine (DA) neurons. The present study tested DBS effects on limb-use asymmetry (LUA) during vertical/lateral exploration in a cylindrical chamber in rats with similar unilateral nigrostriatal DA lesions. Limb-use asymmetry assessment has been used to detect functional capacity over a wide range of dopamine depletion. Before lesioning, rats exhibited regular rearing activity and used both forelimbs equally often to support weight during exploration of the walls of the cylinder. After unilateral nigrostriatal DA lesioning, rats displayed reduced rearing activity and predominant use of the ipsilateral (good) forelimb to touch the wall. HFS of the STN, but not of other nearby regions surrounding the STN, in the lesioned rats restored normal rearing activity and reversed the limb-use asymmetry caused by the unilateral DA depletion. This study is consistent with the possibility that there can be beneficial effects of STN-DBS on behavioral impairments in unilateral DA-depleted rats and may suggest an appropriate rodent model for DBS study.     

The nucleus locus coeruleus modulates local cerebral glucose utilization during noise stress in rats

Local cerebral glucose utilization (LCGU), estimated by the quantitative autoradiographic 2-deoxyglucose technique, was studied in rats with bilateral 6-hydroxydopamine lesions of the locus coeruleus (LC) and in vehicle-injected controls. Unanesthetized animals were studied during exposure to stressful levels of white noise (95 dB) or in relative silence (50 dB). Results indicated that noise caused greater and more widespread increases in LCGU in animals with LC lesions than in vehicle-injected controls. Lesions alone had little or no effect in animals not subjected to noise. Analyses of variance revealed significant treatment interaction effects (intact/lesion x silence/noise) for 37 of 109 regions measured. The pattern of results suggests that the LC acts during stress to limit unnecessary cerebral activity that might interfere with efficient sensory processing and/or the organization of appropriate behavioral responses. In this respect LC function may be similar to those actions of the peripheral sympathetic nervous system that suppress vegetative functions during stress to allow for the performance of coping responses.     

L-DOPA-induced dyskinesia in adult rats with a unilateral 6-OHDA lesion of dopamine neurons is paralleled by increased c-fos gene expression in the subthalamic nucleus

Levodopa (L-DOPA), the metabolic precursor of dopamine, is widely used as a pharmacological agent for the symptomatic treatment of Parkinson's disease. However, long-term L-DOPA use results in abnormal involuntary movements such as dyskinesias. There is evidence that abnormal cell signaling in the basal ganglia is involved in L-DOPA-induced dyskinesia. The subthalamic nucleus (STN) plays a key role in the circuitry of the basal ganglia and in the pathophysiology of Parkinson's disease. However, the contribution of the STN to L-DOPA-induced dyskinesias remains unclear. The objective of this work was to study the effects of acute or chronic systemic administration of L-DOPA to adult rats with a unilateral 6-hydroxydopamine (6-OHDA) lesion of dopamine neurons on c-fos expression in the STN and test the hypothesis that these effects correlate with L-DOPA-induced dyskinesias. c-fos mRNA expression was measured in the STN by in situ hybridization histochemistry at the single cell level. Our results confirm earlier evidence that the chronic administration of L-DOPA to rats with a unilateral 6-OHDA lesion increases c-fos expression in the STN. We also report that c-fos expression can be increased following an acute injection of L-DOPA to 6-OHDA-lesioned rats but not following a chronic injection of L-DOPA to sham-operated, unlesioned rats. Finally, we provide evidence that the occurrence and severity of dyskinesia is correlated with c-fos mRNA levels in the ipsilateral STN. These results suggest that altered cell signaling in the STN is involved in some of the behavioral effects induced by systemic L-DOPA administration.     

Age differences in intercorrelations between regional cerebral metabolic rates for glucose

Patterns of cerebral metabolic intercorrelations were compared in the resting state in 15 healthy young men (ages 20 to 32 years) and 15 healthy elderly men (ages 64 to 83 years). Controlling for whole-brain glucose metabolism, partial correlation coefficients were determined between pairs of regional cerebral metabolic rates for glucose determined by positron emission tomography using [18F]fluorodeoxyglucose and obtained in 59 brain regions. Compared with the young men, the elderly men had fewer statistically significant correlations, with the most notable reductions observed between the parietal lobe regions, and between the parietal and frontal lobe regions. These results suggest that cerebral functional interactions are reduced in healthy elderly men.     

Ipsilateral turning behavior induced by unilateral microinjections of a cannabinoid into the rat subthalamic nucleus

The subthalamic nucleus contains cannabinoid receptors and cannabinoid receptor mRNA. However, the role of cannabinoid receptors in this nucleus has not been examined. In order to investigate the functional role of cannabinoid receptors in the rat subthalamic nucleus, turning activity was observed following unilateral microinjection of the synthetic cannabinoid CP 55,940. CP 55,940 (10 μg) induced ipsilateral turning. This effect was blocked by coadministration of the cannabinoid receptor antagonist SR141716A (5 μg). These results suggest that cannabinoid receptors in the subthalamic nucleus mediate an inhibition of motor activity.     

Intercorrelations of regional cerebral glucose metabolic rates in Alzheimer''s disease

Patterns of cerebral metabolic correlations were compared between 21 Alzheimer's disease patients and 21 healthy age-matched controls in the resting state. Cerebral metabolic rates for glucose were determined by positron emission tomography using [18F]2-fluoro-2-deoxy-D-glucose. Partial correlation coefficients, controlling for whole brain glucose metabolism, were evaluated between pairs of regional glucose metabolic rates in 59 brain regions. Reliable correlation coefficients were obtained with the 'jackknife' and 'bootstrap' statistical procedures. Compared with healthy controls, the Alzheimer patients had significantly fewer reliable partial correlation coefficients between frontal and parietal lobe regions, and more reliable correlations between the cerebellum and temporal lobe. The number of reliable correlations between many bilaterally symmetric brain regions was reduced in the Alzheimer patients, as compared with controls. These results suggest that in the early stages of Alzheimer's disease there is a breakdown of the organized functional activity between the two cerebral hemispheres, and between parietal and frontal lobe structures.     

伏隔核毁损对MAP模型大鼠行为及脑内DA受体的影响

目的 探讨立体定向伏隔核毁损对甲基苯丙胺（MAP）模型大鼠行为学及不同脑区多巴胺D2受体表达的影响。方法 将80只SD大鼠随机分为对照组、模型组、假手术组和手术组，每组各20只。经腹腔注射MAP制备精神分裂症模型，采用立体定向一直流电毁损伏隔核，观察大鼠刻板行为变化；并采用原位杂交法观察额叶、颞叶、边缘区及脑干部位的D2受体表达。结果 与对照组比较，模型组及假手术组大鼠刻板行为评分及各个脑区D2受体表达均显著性增加；与模型组及假手术组比较，手术组大鼠刻板行为评分及各脑区DA受体阳性细胞数目均显著性减少。结论 伏隔核毁损可能通过抑制MAP诱发的脑内D2表达亢进而改变其行为学异常。     

Dual effects of intermittent or continuous L-DOPA administration on gene expression in the globus pallidus and subthalamic nucleus of adult rats with a unilateral 6-OHDA lesion

Intermittent oral doses of levodopa (L-DOPA) are routinely used to treat Parkinson's disease, but with prolonged use can result in adverse motor complications, such as dyskinesia. Continuous administration of L-DOPA achieves therapeutic efficacy without producing this effect, yet the molecular mechanisms are unclear. This study examined, by in situ hybridization histochemistry, the effects of continuous or intermittent L-DOPA administration on gene expression in the globus pallidus and subthalamic nucleus of adult rats with a unilateral 6-hydroxydopamine (6-OHDA) lesion of the nigrostriatal pathway. Results were compared to 6-OHDA-treated rats receiving vehicle. Our results provide original evidence that continuous L-DOPA normalizes the 6-OHDA-lesion-induced increase in mRNA levels encoding for the 67 kDa isoform of glutamate decarboxylase in neurons of the globus pallidus and cytochrome oxidase subunit I mRNA levels in the subthalamic nucleus. The extent of normalization did not differ between the continuous and intermittent groups. In addition, intermittent L-DOPA induced an increase in the mRNA levels encoding for the 65 kDa isoform of glutamate decarboxylase in globus pallidus neurons ipsilateral to the lesion and a bilateral increase in c-fos mRNA expression in the subthalamic nucleus. These results suggest that continuous L-DOPA tends to normalize the 6-OHDA-lesion-induced alterations in cell signaling in the pallido-subthalamic loop. On the other hand, we propose that chronic intermittent L-DOPA exerts a dual effect by normalizing cell signaling in a subpopulation of neurons in the globus pallidus and subthalamic nucleus while inducing abnormal signaling in another subpopulation.