The present chapter deals with technical issues and relevant questions regarding the quantification of whole-body involuntary movements (WBIM) such as Huntington’s disease (HD) chorea and levodopa-induced dyskinesia (LID) in Parkinson’s disease (PD). We also present results from an experiment where patients with HD chorea and age- and gender-matched control subjects had to perform a rapid alternating movement (RAM) task, which provides a measure of bradykinesia while WBIM was quantified. The RAM task was performed by subjects using their dominant and non-dominant hands independently (single-hand condition), in addition to both hands simultaneously (bimanual condition). Results showed that WBIM was higher in the HD group in all conditions, confirming the presence of chorea. A significant increase in the amplitude of chorea during RAM was also observed in the HD group in all conditions. In the control group, a significant increase in motor overflow during RAM was only observed in the bimanual condition. The range of pronation–supination cycles was systematically greater for the HD group than for control subjects in the single-hand and bimanual conditions. RAM velocity was greater in the HD group in the single-hand condition, but equal in the bimanual condition. Our results support the notion that bradykinesia is not a systematic feature of adult-onset HD. Using previous data obtained in PD patients having LID, we discuss the implications of the present findings for basal ganglia pathophysiology involved in the generation of WBIM.
Previous studies from our laboratory have demonstrated that application of SKF 89976A, a selective inhibitor of the GABA transporter GAT-1, reduces the activity of pallidal neurons in monkeys. However, the functional role of GAT-1 on GABAergic synaptic transmission in the globus pallidus (GP) is poorly understood. In the present study, we applied the whole-cell patch clamp recording technique to study the effects of blockade of GAT-1 on GABAA receptor-mediated inhibitory postsynaptic currents (IPSCs) recorded from rat GP slice preparations. Under maximal striatal stimulation (15–20 V) in parasagittal slices, SKF 89976A (10 μM) significantly prolonged the decay time, without significant effect on the amplitude, of IPSC. In contrast, SKF 89976A increased the amplitude, but did not prolong the decay time, of IPSCs under minimal striatal stimulation (2–5 V). We did not find any significant effect of SKF 89976A on IPSCs evoked locally from GP coronal slices. Furthermore, neither the amplitude nor the frequency of miniature IPSCs were changed following bath application of SKF 89976A. These results demonstrate that GABA reuptake through GAT-1 plays a major activity-dependent role in regulating GABAergic transmission at striatopallidal synapses in the GP.
Nitric oxide (NO) signalling plays an important role in the integration of information processed by the basal ganglia nuclei. Accordingly, considerable evidence has emerged indicating a role for NO in pathophysiological conditions such as Parkinson's disease (PD), schizophrenia and drug addiction. To further investigate the NO modulation of dopaminergic function in the basal ganglia circuitry, in this study we used in vivo electrophysiology and microdialysis in freely-moving rats. Pharmacological manipulation of the NO system did not cause any significant changes either in the basal firing rate and bursting activity of the dopamine (DA) neurons in the substantia nigra pars compacta (SNc) or in DA release in the striatum. In contrast, the disruption of endogenous NO tone was able to counteract the phasic dopaminergic activation induced by nicotine treatment in both experimental approaches. These results further support the possibility that nicotine acts via a NO mechanism and suggest a possible state-dependent facilitatory control of NO on the nigrostriatal DA pathway. Thus, NO selectively modulates the DA exocytosis associated with increased DA functiov n.
Nigrostriatal dopaminergic neurons are usually considered to interface the ventral limbic and dorsal sensorimotor striatum, since the shell of the nucleus accumbens (Acb shell) projects to the ventral tegmental area/substantia nigra pars compacta (VTA/SNC) complex. However, both the organization of Acb shell projections to the nigrostriatal neurons innervating the sensorimotor striatum and the synaptic influence exerted by the Acb shell on these neurons remain to be determined. These questions were addressed in the rat using neuroanatomical and electrophysiological approaches.Combined anterograde tracing from the Acb shell with retrograde tracing from the sensorimotor region of the dorsal striatum revealed that labeled fibers from the Acb shell overlap retrogradely labeled nigrostriatal neurons located in the medial SNC and the lateral VTA but avoid the nigrostriatal neurons located laterally. In addition, stimulation of the Acb-shell induced an inhibition of dopaminergic nigrostriatal neurons projecting to the sensorimotor striatal territory. In agreement with the anatomical observations, these responses were observed in nigrostriatal neurons located in the medial SNC and the lateral VTA but not in nigrostriatal neurons located laterally.These data further establish the existence of a functional link between the Acb shell and the sensorimotor striatum via dopaminergic nigrostriatal neurons. The present study also reveals that among the dopaminergic nigrostriatal neurons innervating the sensorimotor striatal territory, only the subpopulation located in the medial SNC and lateral VTA receives an inhibitory input from the Acb shell. This indicates a functional heterogeneity within the population of dopaminergic neurons innervating a given striatal territory.
Striatal dopamine (DA) neurotransmission plays a fundamental role in the reinforcing and ultimately addictive effects of nicotine. Both nicotine and endogenous acetylcholine (ACh) regulate striatal DA release via β2 subunit-containing (β2*) nicotinic acetylcholine receptors (nAChRs) on striatal axons. The subfamily of β2*-nAChRs responsible for these potent synaptic effects could offer a molecular target for therapeutic strategies in nicotine addiction. We explored the role of the α6β2*-nAChRs in the nucleus accumbens (NAc) and caudate-putamen (CPu) by observing action potential-dependent DA release from synapses in real time using fast-scan cyclic voltammetry at carbon-fibre microelectrodes in mouse striatal slices. We show that α6β2*-nAChRs dominate in the control of DA release by ACh and nicotine in NAc but have a more minor role in CPu alongside other β2*-nAChRs (e.g. α4*). These data offer new insights to suggest striatal α6*-nAChRs as a molecular target for a therapeutic strategy for nicotine addiction.
Associative learning requires the ability to learn the connections between events. Fundamental to the learning process is acquiring the expectation that certain events lead to certain outcomes. Indeed, studies have shown that when an expected outcome is changed, so does the subsequent behavior. It has also been demonstrated that basal ganglia neuronal activity is highly modulated by the expectation of future reward. However, the direct link between reward expectation, basal ganglia neuronal activity, and the final change in behavior is not clear. Electrical stimulation enables a direct manipulation of neuronal activity and has been shown to cause behavioral changes. From another perspective, high-frequency deep brain electrical stimulation (DBS) is used as treatment of advanced neurological disorders, yet the underlying mechanism is still a topic of debate. We investigated the effect of high-frequency stimulation of the external segment of the globus pallidus, the central nucleus of the basal ganglia networks, on monkey’s expectations of both reward and aversive events. We show that long-duration (30 min), high-frequency (130 Hz) stimulation changed the monkey’s behavior in a classical conditioning task, enhancing its expectation of reward. The effect we observed was gradual and persisted even after stimulation had ceased, implying a plastic change. The results support the notion of asymmetric coding of the positive vs. negative domains in the basal ganglia and may suggest the GPe as another possible target for DBS therapy of depression.
The notion of the pedunculopontine nucleus (PPN) is being updated in light of increasing evidence that identifies it as a key structure in the processing of exteroceptive information and its transmission to the forebrain, influencing the activity of PPN’s multiple targets (from basal ganglia to the cerebral cortex). Here we review the anatomical evidence supporting the existence of a local network that forms the basis for such processing functions and propose a more complex relationship with its efferent systems. We also identify some of the critical issues that remain to be answered in order to have a comprehensive understanding of the roles of the PPN. A better insight into this connectivity will also help to understand the contribution of the PPN to the diverse systems it influences.
The use of deep brain stimulation (DBS) to control severely disabling neurological and psychiatric conditions is an exciting and fast emerging area of neuroscience. Deep brain stimulation has generally the same clinical effects as a lesion with respect to the improvement of clinical disability, but has more advantages such as its adjustability and reversibility. To this day, fundamental knowledge regarding the application of electrical currents to deep brain structures is far from complete. Despite improving key symptoms in movement disorders, DBS can be associated with the occurrence of a variety of changes in cognitive and limbic functions both in humans and animals. Furthermore, in psychiatric disorders, DBS is primarily used to evoke cognitive and limbic changes to reduce the psychiatric disability. Preclinical DBS experiments have been carried out to investigate the mechanisms underlying the clinical effects of DBS for at least three (interrelated) reasons: to increase our scientific knowledge, to optimize/refine the technology, or to prevent/reduce side effects. In this review, we will discuss the behavioural effects of DBS in experimental neurological and psychiatric disorders.
We have analyzed whether the subcellular location of GABA-B receptors and the electrophysiologic effects of local administration of GABA-B receptor ligands in the external and internal segments of the globus pallidus (GPe and GPi, respectively) in monkeys change with the induction of parkinsonism. Rhesus monkeys were rendered parkinsonian by treatment with MPTP. Electron microscopy immunoperoxidase for GABA-B R1 was performed in GPe and GPi. Compared with normal monkeys, the overall density of GABA-B R1-immunoreactive dendrites remained the same, but the density of immunolabeled axons increased significantly in both pallidal segments of MPTP-treated monkeys. Single unit recordings in awake monkeys showed that blockade of GABA-B receptors did not consistently affect the activity of GPe or GPi. However, in all neurons tested, application of a GABA-B agonist inhibited the firing rate. These results suggest that dopamine depletion induces an increased presynaptic expression of GABA-B receptors in both pallidal segments, perhaps facilitating a more prominent role of GABA-B-mediated presynaptic regulation of neurotransmitter release in the pallidum.
Dopamine acts through the D1-like (D1, D5) and D2-like (D2, D3, D4) receptor families. Various studies have shown a preponderance of presynaptic dopamine D1 receptors on axons and terminals in the internal globus pallidus (GPi) and substantia nigra reticulata (SNr), but little is known about D5 receptors distribution in these brain regions. In order to further characterize the potential targets whereby dopamine could mediate its effects in basal ganglia output nuclei, we undertook a comparative electron microscopic analysis of D1 and D5 receptors immunoreactivity in the GPi and SNr of rhesus monkeys. At the light microscopic level, D1 receptor labeling was confined to small punctate elements, while D5 receptor immunoreactivity was predominantly expressed in cellular and dendritic processes throughout the SNr and GPi. At the electron microscopic level, 90% of D1 receptor labeling was found in unmyelinated axons or putative GABAergic terminals in both basal ganglia output nuclei. In contrast, D5 receptor labeling showed a different pattern of distribution. Although the majority (65–75%) of D5 receptor immunoreactivity was also found in unmyelinated axons and terminals in GPi and SNr, significant D5 receptor immunolabeling was also located in dendritic and glial processes. Immunogold studies showed that about 50% of D1 receptor immunoreactivity in axons was bound to the plasma membrane providing functional sites for D1 receptor-mediated effects on transmitter release in GPi and SNr. These findings provide evidence for the existence of extrastriatal pre- and postsynaptic targets through which dopamine and drugs acting at D1-like receptors may regulate the basal ganglia outflow and possibly exert some of their anti-parkinsonian effects.
Involuntary movements are of numerous types. It is difficult to treat involuntary movements by medication, and the mechanisms underlying involuntary movements are unclear. Stereotactic surgery has been effective for the treatment of involuntary movements. Outcomes of surgical treatments are excellent indicators for understanding the clinical differentiation or pathophysiological mechanism of involuntary movements. The clinical observations of involuntary movements following stereotactic surgery are described in this chapter.
The subthalamic region (ST) embraces the subthalamic nucleus (STN), zona incerta (ZI), Forel’s fields (H, H1 and H2), and their nucleus (FF). JB Luys of Paris first described STN in human brain atlases, in 1865 as drawings and in 1873 in photographs of brain slices. He completely ignored ZI and Forel’s fields. As an industrious neurologist and neuropathologist, he treated many mental patients by hypnosis. In his later public demonstrations, he neglected proper scientific controls, and was duped by collusive patients to believe in bizarre sensory properties and symptom transfer. In 1877 Forel produced the first adequate description of ST, in serial sections. He later specialised in neurology and psychiatry, directing the Zurich mental asylum. In combatting alcoholism as a cause of insanity he adopted the strategy of total abstinence. He was renowned also for his scientific work on ants. Dejerine and his wife Augusta Klumpke were an outstanding neurological team in Paris. In their great two-volume work on the anatomy of nervous centres, they established the detailed structure of ST, still largely accepted. Their devoted neurological work with the war wounded soldiers led to the exhausted Dejerine’s death in 1917. His widow continued the work until her death in 1927.
Deep brain stimulation (DBS) has been playing an increasing role in the treatment of various movement disorders with the most common being Parkinson’s disease (PD). Currently, the preferred target for treating PD motor symptoms is the subthalamic nucleus (STN). Microelectrode recordings are frequently used to aid in the determination of the optimal target for implanting the DBS electrode. Changes in cellular activity are typically used to detect the borders of the STN during microelectrode recordings. Although the dorsal border of the STN is usually clear, its ventral border with the substantia nigra pars reticulata (SNr) is sometimes more difficult to identify. Our previous studies of the effects of microstimulation in the internal globus pallidus (GPi), which is functionally similar to SNr, and STN revealed that firing in GPi but not STN neurons is readily inhibited by low current stimulation through an adjacent microelectrode. The aim of the current study was to examine and compare the aftereffects of local high-frequency microstimulation through the recording electrode on the firing of STN and SNr neurons to determine whether this might be a useful technique for differentiating STN from SNr. Neurons in the SNr and STN were identified as well isolated high-amplitude spikes and were stimulated extracellulary through the recording microelectrode with 0.5-s trains of high-frequency (200 Hz) and low current (<5 μA). In the majority (89%) of SNr neurons, this type of stimulation led to a period of inhibition lasting several hundreds of milliseconds following the end of the train. A much smaller proportion of STN neurons (9%) was similarly affected by this type of stimulation. These findings indicate that almost all SNr neurons but few STN neurons display prolonged inhibition following very low current microstimulation through the recording electrode. This characteristic provides a useful additional finding that can be used to identify the border between STN and SNr.
Early twentieth century theories of telencephalic evolution maintained that the parts of the telencephalon appeared in serial order in vertebrate phylogeny – the globus pallidus in fish, the striatum in amphibians, and the cerebral cortex in reptiles. The notion of serial appearance of the parts of the basal ganglia is reflected in the frequent use of the terms paleostriatum and neostriatum as synonyms for globus pallidus and caudate–putamen, respectively. Moreover, in older theories of basal ganglia evolution, the cerebral cortex was thought to supplant the basal ganglia in motor control in the mammalian lineage, resulting in the replacement of a supposed reptilian stereotyped motor repertoire with the adaptable mammalian motor capacity. Modern evidence, in fact, shows that both striatum and pallidum have been the basal ganglia constituents since the earliest jawed fish. Moreover, the striatal part of the basal ganglia appears to have been organized into separate direct and indirect striatal output pathways by this time as well. Modern findings also show that during most of its evolutionary history (i.e., prior to mammals), the basal ganglia mediated its role in motor control via output pathways to motor layers of the midbrain roof, via midbrain targets of the striatum such as the substantia nigra pars reticulata. Output pathways to the pallium emerged in the amniote lineage, but remained of lesser significance in living members of the sauropsid lineage (birds and reptiles) than the circuitry to the tectum. With the appearance of neocortex in mammals, however, basal ganglia outputs to motor cortex via thalamus became of greater significance, especially in primates, in which a parallel expansion of cerebral cortex and basal ganglia occurred.
Parkinson’s disease (PD) is characterized by the loss of dopaminergic neurons located in the substantia nigra (SN). Data from our group and others indicate that metals, oxidative stress, and bioavailable reductants provide a possible mechanism for the neurodegeneration observed in PD. 6-Hydroxydopamine (6-OHDA) injection into the nigra of mice resulted in quantified loss of dopaminergic neurons. Oral administration of the metal–protein binding compound clioquinol (CQ) commencing on the day of lesion led to a significant reduction in lesion size. This finding elaborates upon our previous study that long-term pre-treatment with CQ reduced the susceptibility of SN neurons to another neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrapyridine (MPTP) (Kaur et al. 2003), suggesting metals as a common pathway for propagation of these lesions. Human neuroblastoma M17 cells were susceptible to metal, 6-OHDA and dopamine-induced cell death that was partially recoverable by co-incubation with CQ or catalase. These results support the concept that CQ or a similar moderate-affinity transition metal ligand could modulate neuronal oxidative stress and therefore may be a novel class of drug that may be useful for the treatment of PD.
The basal ganglia contribute to a variety of forms of learning. The first goal of this chapter is to review the different tasks (instrumental conditioning, visual discrimination, arbitrary visuomotor learning, rule learning, categorization, and decision making) that have been used to study basal-ganglia-dependent learning in rodents, monkeys, and humans. These tasks have several features in common: in each, the subject is first presented with a stimulus within a behavioral context, is then required to respond with an appropriate behavior, and finally receives a reward or positive feedback for correct behavior. The second goal of this chapter is to examine how these different features (stimulus, response, and reward) involve the independent corticostriatal loops that connect the basal ganglia with cerebral cortex. The visual corticostriatal loop is involved in aspects of visual stimulus processing; the motor corticostriatal loop is involved in response selection; and the executive and motivation corticostriatal loops are involved in processing feedback and reward. The chapter concludes with a discussion of how the corticostriatal loops interact during learning.
Neurons of the neostriatum are organized in anatomically and chemically distinct patch and matrix compartments. Dopaminergic neurons of the substantia nigra and ventral tegmental area provide early input to the embryonic neostriatum and may play an important role in neostriatal morphogenesis. Our group and others have demonstrated early loss of dopaminergic neurons in the Pitx3-deficient aphakia mouse, associated with a >90% reduction in neostriatal dopamine levels and a hypokinetic movement disorder. Here, we show scant or absent dopaminergic fibers in the adult aphakia dorsolateral and medial neostriatum, altering the chemical anatomy of mu-opioid receptor stained patches. Furthermore, neostriatal neuron numbers are comparable in aphakia and wild-type animals, but the volume of the aphakia neostriatum and its neurons is significantly reduced. We propose that early nigrostriatal dopaminergic loss in aphakia mice results in loss of trophic support to the developing neostriatum.
