Basal Ganglia Information PDF

Chapter 17 Modulation of Movement by the Basal Ganglia Overview As described in the preceding chapter, motor regions of the cortex and brainstem contain upper motor neurons that initiate movement by controlling the activity of local circuit and lower motor neurons in the brainstem and spinal cord. T...

Chapter 17 Modulation of Movement by the Basal Ganglia Overview As described in the preceding chapter, motor regions of the cortex and brainstem contain upper motor neurons that initiate movement by controlling the activity of local circuit and lower motor neurons in the brainstem and spinal cord. This chapter and the next discuss two additional regions of the brain that are important in motor control: the basal ganglia and the cerebellum. In contrast to the components of the motor system that harbor upper motor neurons, the basal ganglia and cerebellum do not project directly to either the local circuit or lower motor neurons; instead, they influence movement by regulating the activity of upper motor neurons. The term basal ganglia refers to a large and functionally diverse set of nuclei that lie deep within the cerebral hemispheres. The subset of these nuclei relevant to this account of motor function includes the caudate, putamen, and the globus pallidus. Two additional structures, the substantia nigra in the base of the midbrain and the subthalamic nucleus in the ventral thalamus, are closely associated with the motor functions of these basal ganglia nuclei and are included in the discussion. The motor components of the basal ganglia, together with the substantia nigra and the subthalamic nucleus, effectively make a subcortical loop that links most areas of the cortex with upper motor neurons in the primary motor and premotor cortex and in the brainstem. The neurons in this loop respond in anticipation of and during movements, and their effects on upper motor neurons are required for the normal course of voluntary movements. When one of these components of the basal ganglia or associated structures is compromised, the patient cannot switch smoothly between commands that initiate a movement and those that terminate the movement. The disordered movements that result can be understood as a consequence of abnormal upper motor neuron activity in the absence of the supervisory control normally provided by the basal ganglia. Projections to the Basal Ganglia The motor nuclei of the basal ganglia are divided into several functionally distinct groups (Figure 17.1). The first and larger of these groups is called the corpus striatum, which includes the caudate and putamen. These two subdivisions of the corpus striatum comprise the input zone of the basal ganglia, their neurons being the destinations of most of the pathways that reach this complex from other parts of the brain (Figure 17.2). The name corpus striatum, which means “striped body,” reflects the fact that the axon fascicles that pass through the caudate and putamen result in a striped appearance when cut in cross section. The destinations of the incoming axons from the a7 418 Chapter Seventeen 2 (B) (a) = Figure 17.1 VA/VL complex of thalamus Cerebrum (+] Frontal cortex © Motor components of the human basal ganglia. (A) Basic circuits of the basal ganglia pathway: (+) and (-) denote excitory and inhibitory connections. (B) Idealized coronal section S;‘l’,?d"sus \ ) \_~ Subthalamic external and internal segments Midbrain Substantia nigra pars compacta Substantia nigra pars reticulata through the brain showing anatomical cortex are the dendrites of a class of cells called medium spiny neurons in locations of structures involved in the the corpus striatum (Figure 17.3). The large dendritic trees of these neurons allow them to integrate inputs from a variety of cortical, thalamic, and brain- basal ganglia pathway. Most of these structures are in the telencephalon, although the substantia nigra is in the midbrain and the thalamic and subthal- amic nuclei are in the diencephalon. The ventral anterior and ventral lateral thal- amic nuclei (VA/VL complex) are the targets of the basal ganglia, relaying the modulatory effects of the basal ganglia to upper motor neurons in the cortex. stem structures. The axons arising from the medium spiny neurons converge on neurons in the globus pallidus and the substantia nigra pars reticulata. The globus pallidus and substantia nigra pars reticulata are the main sources of output from the basal ganglia complex. Nearly all regions of the neocortex project directly to the corpus striatum, making the cerebral cortex the source of the largest input to the basal ganglia by far. Indeed, the only cortical areas that do not project to the corpus striatum are the primary visual and primary auditory cortices (Figure 17.4). Of those cortical areas that do innervate the striatum, the heaviest projections are from association areas in the frontal and parietal lobes, but substantial contributions also arise from the temporal, insular, and cingulate cortices. All sylvius of these projections, referred to collectively as the corticostriatal pathway, travel through the internal capsule to reach the caudate and putamen directly (see Figure 17.2). The cortical inputs to the caudate and putamen are not equivalent, however, and the differences in input reflect functional differences between these two nuclei. The caudate nucleus receives cortical projections primarily from multimodal association cortices, and from motor areas in the frontal lobe that control eye movements. As the name implies, the association cortices do not process any one type of sensory information; rather, they receive inputs from a number of primary and secondary sensory cortices and associated Modulation of Movement by the Basal Ganglia Cerebrum Figure 17.2 419 Anatomical organization of the inputs to the basal ganglia. An idealized coronal section through the human brain, showing the projections from the cere- bral cortex and the substantia nigra pars comparta to the caudate and putamen. Substantia nigra pars compacta thalamic nuclei (see Chapter 25). The putamen, on the other hand, receives input from the primary and secondary somatic sensory cortices in the parietal lobe, the secondary (extrastriate) visual cortices in the occipital and temporal lobes, the premotor and motor cortices in the frontal lobe, and the auditory association areas in the temporal lobe. The fact that different cortical areas project to different regions of the striatum implies that the corticostriatal pathway consists of multiple parallel pathways serving different functions. This interpretation is supported by the observation that the segregation is maintained in the structures that receive projections from the striatum, and in the pathways that project from the basal ganglia to other brain regions. There are other indications that the corpus striatum is functionally subdivided according to its inputs. For example, visual and somatic sensory cortical projections are topographically mapped within different regions of the putamen. Moreover, the cortical areas that are functionally interconnected at the level of the cortex give rise to projections that overlap extensively in the striatum. Anatomical studies by Ann Graybiel and her colleagues at the Massachusetts Institute of Technology have shown that regions of different cortical areas concerned with the hand (see Chapter 8) converge in specific rostrocaudal bands within the striatum; conversely, regions in the same corti- 420 Chapter Seventeen (A) neuron Dopaminergic neuron | Local” circuit neuron Medium spiny neuron Cortical pyramidal neurons Globus pallidus or Substantia nigra pars reticulata neuron Medium spiny’ neuron External Putamen Internal Globus pallidus Figure 17.3 Neurons and circuits of the basal ganglia. (A) Medium spiny neurons in the caudate and putamen. (B) Diagram showing convergent inputs onto a medium spiny neuron from corti- cal neurons, dopaminergic cells of the substantia nigra, and local circuit neurons. The primary output of the medium spiny cells s to the globus pallidus and to the substantia nigra pars reticulata. Substantia nigra pars reticulata cal areas concerned with the leg converge in other striatal bands. These rostrocaudal bands therefore appear to be functional units concerned with the movement of particular body parts. Another study by the same group showed that the more extensively cortical areas are interconnected by corticocortical pathways, the greater the overlap in their projections to the striatum. A further indication of functional subdivision within the striatum is the spatial distribution of different types of medium spiny neurons. Although medium spiny neurons are distributed throughout the striatum, they occur in clusters of cells called “patches” or “striosomes,” in a surrounding “matrix” of neurochemically distinct cells. Whereas the distinction between the patches and matrix was originally based only on differences in the types of neuropeptides contained by the medium spiny cells in the two regions, the cell types are now known to differ as well in the sources of their inputs from the cortex and in the destinations of their projections to other parts of the basal ganglia. For example, even though most cortical areas project to medium spiny neurons in both these compartments, limbic areas of the cortex (such as the cingulate gyrus; see Chapter 28) project more heavily to the patches, whereas motor and somatic sensory areas project preferentially to the neurons in the matrix. These differences in the connectivity of medium spiny neurons in the patches and matrix further support the conclusion that functionally distinct pathways project in parallel from the cortex to the striatum. Modulation (A) Lateral view of Movement by the Basal Ganglia (B) Medial view Primary visual cortex Figure 17.4 Primary visual cortex 421 Regions of the cerebral cortex (shown in purple) that project to the caudate, putamen, and ventral stria- tum (see Box C) in both lateral (A) and medial (B) views. The caudate, putamen, and ventral striatum receive cortical projections primarily from the association areas of the frontal, parietal, and temporal lobes. auditory cortex The nature of the signals transmitted to the caudate and putamen from the cortex is not understood. It is known, however, that collateral axons of corticocortical, corticothalamic, and corticospinal pathways all form excitatory glutamatergic synapses on the dendritic spines of medium spiny neurons (see Figure 17.3B). The arrangement of these cortical synapses is such that the number of contacts established between an individual cortical axon and a single medium spiny cell is very small, whereas the number of spiny neurons contacted by a single axon is extremely large. This divergence of axon terminals allows a single medium spiny neuron to integrate the influences of thousands of cortical cells. The medium spiny cells also receive noncortical inputs from interneurons, from the midline and intralaminar nuclei of the thalamus, and from brainstem aminergic nuclei. In contrast to the cortical inputs to the dendritic spines, the local circuit neuron and thalamic synapses are made on the dendritic shafts and close to the cell soma, where they can modulate the effectiveness of corti- cal synaptic activation arriving from the more distal dendrites. The aminergic inputs are dopaminergic and they originate in a subdivision of the substantia nigra called pars compacta because of its densely packed cells. The dopaminergic synapses are located on the base of the spine, in close proximity to the cortical synapses, where they more directly modulate cortical input (see Figure 17.3B). As a result, inputs from both the cortex and the substantia nigra pars compacta are relatively far from the initial segment of the medium spiny neuron axon, where the nerve impulse is generated. Accordingly, the medium spiny neurons must simultaneously receive many excitatory inputs from cortical and nigral neurons to become active. As a result the medium spiny neu- rons are usually silent. When the medium spiny neurons do become active, their firing is associated with the occurrence of a movement. Extracellular recordings show that these neurons typically increase their rate of discharge just before an impending movement. Neurons in the putamen tend to discharge in anticipation of body movements, whereas caudate neurons fire prior to eye movements. These anticipatory discharges are evidently part of a movement selection process; in fact, they can precede the initiation of movement by as much as several seconds. Similar recordings have also shown that the discharges of some striatal neurons vary according to the location in space of the target of amovement, rather than with the starting position of the limb relative to the target. Thus, the activity of these cells may encode the decision to move toward the target, rather than simply the direction and amplitude of the actual movement necessary to reach the target. 422 Chapter Seventeen Projections from the Basal Ganglia to Other Brain Regions The medium spiny neurons of the caudate and putamen give rise to inhibitory GABAergic projections that terminate in another pair of nuclei in the basal ganglia complex: the internal division of the globus pallidus and a specific region of the substantia nigra called pars reticulata (because, unlike the pars compacta, axons passing through give it a netlike appearance). These nuclei are in turn the major sources of the output from the basal ganglia (Figure 17.5). The globus pallidus and substantia nigra pars reticulata have similar output functions. In fact, developmental studies show that pars reticulata is actually part of the globus pallidus, although the two eventually become separated by fibers of the internal capsule. The striatal projections to these two nuclei resemble the corticostriatal pathways in that they terminate in rostrocaudal bands, the locations of which vary with the locations of their sources in the striatum. A striking feature of the projections from the medium spiny neurons to the globus pallidus and substantia nigra is the degree of their convergence onto pallidal and reticulata cells. In humans, for example, the corpus striatum contains approximately 100 million neurons, about 75% of which are (A) © -] VA/VL thalamic nuclear complex ) Figure 17.5 Functional organization of the outputs from the basal ganglia. (A) Putamen I V- Diagram of the targets of the basal gan- glia, including the intermediate relay nuclei (the globus pallidus, internal and external segments, and the subthalamic nucleus), the superior colliculus, the thalamus, and the cerebral cortex. (B) ’ Superior colliculus external segment Globus pallidus, internal segment An idealized coronal section through the human brain, showing the structures and pathways diagrammed in (A). Subthalamic nucleus Substantia nigra pars reticulata Modulation of Movement by the Basal Ganglia medium spiny neurons. In contrast, the main destination of their axons , the globus pallidus, comprises only about 700,000 cells. Thus, on average, more than 100 medium spiny neurons innervate each pallidal cell. The efferent neurons of the internal globus pallidus and substantia nigra pars reticulata together give rise to the major pathways that link the basal ganglia with upper motor neurons located in the cortex and in the brainstem (see Figure 17.5). The pathway to the cortex arises primarily in the internal globus pallidus and reaches the motor cortex after a relay in the ventral anterior and ventral lateral nuclei of the dorsal thalamus. These thalamic nuclei project directly to motor areas of the cortex, thus completing a vast loop that originates in multiple cortical areas and terminates (after relays in the basal ganglia and thalamus) back in the motor areas of the frontal lobe. In contrast, the axons from substantia nigra pars reticulata synapse on upper motor neurons in the superior colliculus that command eye movements, without an intervening relay in the thalamus (see Figure 16.2 and Chapter 19). This difference between the globus pallidus and substantia nigra pars reticulata is not absolute, however, since many reticulata axons also project to the thalamus where they contact relay neurons that project to the frontal eye fields of the premotor cortex (see Chapter 19). Because the efferent cells of both the globus pallidus and substantia nigra pars reticulata are GABAergic, the main output of the basal ganglia is inhibitory. In contrast to the quiescent medium spiny neurons, the neurons in both these output zones have high levels of spontaneous activity that tend to prevent unwanted movements by tonically inhibiting cells in the superior colliculus and thalamus. Since the medium spiny neurons of the striatum also are GABAergic and inhibitory, the net effect of the excitatory inputs that reach the striatum from the cortex is to inhibit the tonically active inhibitory cells of the globus pallidus and substantia nigra pars reticulata (Figure 17.6). Thus, in the absence of body movements, the globus pallidus neurons, for example, provide tonic inhibition to the relay cells in the ventral lateral and anterior nuclei of the thalamus. When the pallidal cells are inhibited by activity of the medium spiny neurons, the thalamic neurons are disinhibited and can relay signals from other sources to the upper motor neurons in the cortex. This disinhibition is what normally allows the upper motor neurons to send commands to local circuit and lower motor neurons that initiate movements. Conversely, an abnormal reduction in the tonic inhibition as a consequence of basal ganglia dysfunction leads to excessive excitability of the upper motor neurons, and thus to the involuntary movement syndromes that are characteristic of basal ganglia disorders such as Huntington’s disease (Box A; see also Figure 17.9A). Evidence from Studies of Eye Movements The permissive role of the basal ganglia in the initiation of movement is perhaps most clearly demonstrated by studies of eye movements carried out by Okihide Hikosaka and Robert Wurtz at the National Institutes of Health (Figure 17.7). As described in the previous section, the substantia nigra pars reticulata is part of the output circuitry of the basal ganglia. Instead of projecting to the cortex, however, it sends axons mainly to the deep layers of the superior colliculus. The upper motor neurons in these layers command the rapid orienting movements of the eyes called saccades (see Chapter 19). When the eyes are not scanning the environment, these upper motor neurons are tonically inhibited by the spontaneously active reticulata cells to prevent unwanted saccades. Shortly before the onset of a saccade, the tonic 423 Chapter Seventeen Figure 17.6 A chain of nerve cells arranged in a disinhibitory circuit. Top: Diagram of the connections between two inhibitory neurons, A and B, and an Transient Excitatory excitatory inputs to C inputs from cortex to A excitatory neuron, C. Bottom: Pattern of the action potential activity of cells A, B, Globus pallidus and C when A is at rest, and when neuron A fires transiently as a result of its excitatory inputs. Such circuits are central to the gating operations of the basal 1 Motor cortex P ganglia. I3 424 VA/VL complex of thalamus To lower motor neurons Striatum Globus pallidus ~ VA/VL complex of thalamus Upper motor neuron in cortex discharge rate of the reticulata neurons is sharply reduced by input from the GABAergic medium spiny neurons of the caudate, which have been activated by signals from the cortex. The subsequent reduction in the tonic discharge from reticulata neurons disinhibits the upper motor neurons of the superior colliculus, allowing them to generate the bursts of action potentials that command the saccade. Thus, the projections from substantia nigra pars reticulata to the upper motor neurons act as a physiological “gate” that must be “opened” to allow either sensory or other, more complicated, signals from cognitive centers to activate the upper motor neurons and initiate a saccade. Upper motor neurons in the cortex are similarly gated by the basal ganglia but, as discussed earlier, the tonic inhibition is mediated mainly by the GABAergic projection from the internal division of the globus pallidus to the relay cells in the ventral lateral and anterior nuclei of the thalamus (see Figures 17.5 and 17.6). Circuits within the Basal Ganglia System The projections from the medium spiny neurons of the caudate and putamen to the internal segment of the globus pallidus and substantia nigra pars Modulation of Movement by the Basal Ganglia Caudate nucleus Caudate nucleus Figure 17.7 425 The role of basal ganglia disinhibition in the generation of saccadic eye movements. (A) Medium spiny cells in the caudate nucleus respond with a transient burst of action potentials to an excitatory input from Substantia nigra pars reticulata the cerebral cortex (1). The spiny cells inhibit the tonically active GABAergic cells in substantia nigra pars reticulata (2). As a result, the upper motor neurons in the deep layers of the superior colliculus are no longer tonically inhibited and can generate the bursts of action potentials that command a saccade (3, 4). (B) The temporal relation- Substantia nigra pars reticulata Superior colliculus _ Eye movement (®) Target onset Horizontal eye position Vertical eye position 100 spikes per second per trial 0 400 800 1200 1600 2000 ship between inhibition in substantia nigra pars reticulata (purple) and disinhibition in the superior colliculus (yellow) preceding a saccade to a visual tar- 8¢t (After Hikosaka and Wurtz, 1989.) 426 Chapter Seventeen Box A Huntington’s Disease In 1872, a physician named George dementia, and a rapidly progressive Huntington described a group of patients seen by his father and grandfather in their practice in East Hampton, Long Island. The disease he defined, which became known as Huntington’s. course. A distinctive neuropathology is asso- disease (HD), is characterized by the ciated with these clinical manifestations: a profound but selective atrophy of the caudate and putamen, with some associated degeneration of the frontal and tem- gradual onset of defects in behavior, cog- poral cortices (see Figure 17.9A). This fourth and fifth decades of life. The dis- explain the disorders of movement, cognition, and behavior, as well as the sparing of other neurological functions. The availability of extensive HD pedigrees has allowed geneticists to decipher nition, and movement beginning in the order is inexorably progressive, resulting in death within 10 to 20 years. HD is inherited in an autosomal dominant pattern, a feature that has led to a much bet- ter understanding of its cause in molecu- lar terms. One of the more common inherited neurodegenerative diseases, HD usually presents as an alteration in mood (especially depression) or a change in personality that often takes the form of in- creased irritability, suspiciousness, and impulsive or eccentric behavior. Defects of memory and attention may also occur. The hallmark of the disease, however, is a movement disorder consisting of rapid, jerky motions with no clear purpose; these choreiform movements may be confined to a finger or may involve a pattern of destruction is thought to cade of molecular events culminating in dysfunction and neuronal death. Interestingly, although Huntingtin is ex- which DNA polymorphisms were used to localize the mutant gene, which in 1983 was mapped to the short arm of chromosome 4. This discovery led to an intensive effort to identify the HD gene within this region by positional cloning. Ten years later, these efforts culminated into this and other triplet repeat diseases. the molecular cause of this disease. HD was one of the first human diseases in in identification of the gene (named Huntingtin) responsible for the disease. In contrast to previously recognized forms of mutations such as point muta- tions, deletions, or insertions, the muta- tion of Huntingtin is an unstable triplet repeat. In normal individuals, Huntingtin ments themselves are involuntary, but whereas the gene in HD patients con- contains between 15 and 34 repeats, the patient often incorporates them into tains from 42 to over 66 repeats. apparently deliberate actions, presumably in an effort to obscure the problem. There is no weakness, ataxia, or deficit of sensory function. Occasionally, the disease begins in childhood or adolescence. The clinical manifestations in juveniles HD is one of a growing number of diseases attributed to unstable DNA segments. Other examples are fragile X syndrome, myotonic dystrophy, spinal and bulbar muscular atrophy, and spinocerebellar ataxia type 1. In the latter two and include rigidity, seizures, more marked acid glutamine and is present within the coding region of the gene. The mechanism by which the increased number of polyglutamine repeats injures neurons is not clear. The leading hypothesis is that the increased numbers of glutamines alter protein folding, which somehow triggers a cas- pressed predominantly in the expected neurons in the basal ganglia, it is also present in regions of the brain that are not affected in HD. Indeed, the gene is expressed in many organs outside the nervous system. How and why the mutant Huntingtin uniquely injures striatal neurons is unclear. Continuing to elucidate this molecular pathogenesis will no doubt provide further insight whole extremity, the facial musculature, or even the vocal apparatus. The move- ment (CAG) that codes for the amino References GuseLLa, J. L AND 13 OTHERS (1983) A poly‘morphic DNA marker genetically linked to Huntington'’s disease. Nature 306: 234-236. HUNTINGTON, G. (1872) On chorea. Med. Surg. Reporter 26: 317. HUNTINGTON'S DISEASE COLLABORATIVE ReseARCH GRoUP (1993) A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell 72: 971-983. WEXLER, A. (1995) Mapping Fate: A Memoir of Family, Risk, and Genetic Research. New York: Times Books, YOUNG, A. B. (2003) Huntingtin in health and disease. J. Clin. Invest. 111: 299-302. HD, the repeats consist of a DNA seg- reticulata are part of a “direct pathway” and, as just described, serve to release the upper motor neurons from tonic inhibition. This pathway is summarized in Figure 17.8A. A second pathway serves to increase the level of tonic inhibition and is called the “indirect pathway” (Figure 17.8B). This pathway provides a second route, linking the corpus striatum with the inter- Modulation of Movement by the Basal Ganglia (A) Direct pathway Figure 17.8 [+] l (transient) [+] (transient) Disinhibition in the direct and indirect pathways through the basal ganglia. (A) In the direct pathway, transiently inhibitory projections from the caudate and putamen project to ton- ically active inhibitory neurons in the (+] (transient) 427 © | (transient) -} (tonic) internal segment of the globus pallidus, which project in turn to the VA/VL complex of the thalamus. Transiently excitatory inputs to the caudate and putamen from the cortex and substantia nigra are also shown, as is the transiently excitatory input from the thala- mus back to the cortex. (B) In the indi- rect pathway (shaded yellow), (B) Indirect and direct pathways transiently active inhibitory neurons from the caudate and putamen project to tonically active inhibitory neurons of the external segment of the globus pal- lidus. Note that the influence of nigral dopaminergic input to neurons in the indirect pathway is inhibitory. The globus pallidus (external segment) neurons project to the subthalamic nucleus, which also receives a strong excitatory input from the cortex. The subthalamic nucleus in turn projects to the globus pallidus (internal segment), where its transiently excitatory drive acts to oppose the disinhibitory action of the direct pathway. In this way, the indirect pathway modulates the effects of the direct pathway. nal globus pallidus and substantia nigra pars reticulata. In the indirect pathway, a population of medium spiny neurons projects to the lateral or external segment of the globus pallidus. This external division sends projections both to the internal segment of the globus pallidus and to the subthalamic nucleus of the ventral thalamus (see Figure 17.1). But, instead of projecting to structures outside of the basal ganglia, the subthalamic nucleus projects back to the internal segment of the globus pallidus and to the substantia nigra pars reticulata. As already described, these latter two nuclei project out of the basal ganglia, which thus allows the indirect pathway to influence the activity of the upper motor neurons. The indirect pathway through the basal ganglia apparently serves to modulate the disinhibitory actions of the direct pathway. The subthalamic nucleus neurons that project to the internal globus pallidus and substantia 428 Chapter Seventeen nigra pars reticulata are excitatory. Normally, when the indirect pathway is activated by signals from the cortex, the medium spiny neurons discharge and inhibit the tonically active GABAergic neurons of the external globus pallidus. As a result, the subthalamic cells become more active and, by virtue of their excitatory synapses with cells of the internal globus pallidus and reticulata, they increase the inhibitory outflow of the basal ganglia. Thus, in contrast to the direct pathway, which when activated reduces tonic inhibition, the net effect of activity in the indirect pathway is to increase inhibitory influences on the upper motor neurons. The indirect pathway can thus be regarded as a “brake” on the normal function of the direct pathway. Indeed, (A) Huntington's disease many neural systems achieve fine control of their output by a similar interplay between excitation and inhibition. The consequences of imbalances in this fine control mechanism are apparent in diseases that affect the subthalamic nucleus. These disorders remove a source of excitatory input to the internal globus pallidus and reticulata, and thus abnormally reduce the inhibitory outflow of the basal ganglia. A basal ganglia syndrome called hemiballismus, which is characterized by violent, involuntary movements of the limbs, is the result of damage to the subthalamic nucleus. The involuntary movements are initiated by abnormal dis- charges of upper motor neurons that are receiving less tonic inhibition from the basal ganglia. Another circuit within the basal ganglia system entails the dopaminergic cells in the pars compacta subdivision of substantia nigra and modulates the output of the corpus striatum. The medium spiny neurons of the corpus striatum project directly to substantia nigra pars compacta, which in turn (B) Parkinson's disease sends widespread dopaminergic projections back to the spiny neurons. These dopaminergic influences on the spiny neurons are complex: The same nigral neurons can provide excitatory inputs mediated by D1 type dopaminergic receptors on the spiny cells that project to the internal globus pallidus (the direct pathway), and inhibitory inputs mediated by D2 type receptors on the spiny cells that project to the external globus pallidus (the indirect pathway). Since the actions of the direct and indirect pathways on the output of the basal ganglia are antagonistic, these different influences of the nigrostriatal axons produce the same effect, namely a decrease in the inhibitory outflow of the basal ganglia. The modulatory influences of this second internal circuit help explain many of the manifestations of basal ganglia disorders. For example, Parkinson’s disease is caused by the loss of the nigrostriatal dopaminergic neurons (Figure 17.9B and Box B). As mentioned Figure 17.9 The pathological changes in certain neurological diseases provide insights about the function of the basal ganglia. (A) The size of the caudate and putamen (the striatum) (arrows) is dra- matically reduced in patients with Huntington’s disease. (B) Left: The midbrain from a patient with Parkinson’s disease. The substantia nigra (pigmented area) is largely absent in the region above the cerebral peduncles (arrows). Right: The mesencephalon earlier, the normal effects of the compacta input to the striatum are excitation of the medium spiny neurons that project directly to the internal globus pallidus and inhibition of the spiny neurons that project to the external globus pallidus cells in the indirect pathway. Normally, both of these dopaminergic effects serve to decrease the inhibitory outflow of the basal ganglia and thus to increase the excitability of the upper motor neurons (Figure 17.10A). In contrast, when the compacta cells are destroyed, as occurs in Parkinson’s disease, the inhibitory outflow of the basal ganglia is abnormally high, and thalamic activation of upper motor neurons in the motor cortex is therefore less likely to occur. In fact, many of the symptoms seen in Parkinson’s disease (and in other hypokinetic movement disorders) reflect a failure of the disinhibition nor- mally mediated by the basal ganglia. Thus, Parkinsonian patients tend to from a normal subject, showing intact have diminished facial expressions and lack “associated movements” such etal, 1991) ate and, once initiated, is often difficult to terminate. Disruption of the same substantia nigra (arrows). (From Bradley as arm swinging during walking. Indeed, any movement is difficult to initi- Box B Parkinson’s Disease: An Opportunity for Novel Therapeutic Approaches ease or amyotrophic lateral sclerosis, in Parkinson’s disease the spatial distribution of the degenerating neurons is with broad developmental potential (see Chapters 21 and 24). Instead of isolating ‘mature dopaminergic neurons from the James Parkinson in 1817, this disorder is largely restricted to the substantia nigra pars compacta. This spatial restriction, characterized by tremor at rest, slowness combined with the defined and relatively fetal midbrain for transplantation, this approach isolates neuronal progenitors at earlier stages of development, when Parkinson’s disease is the second most common degenerative disease of the nervous system (Alzheimer’s disease being the leader; see Chapter 30). Described by of movement (bradykinesia), rigidity of the extremities and neck, and minimal facial expressions. Walking entails short steps, stooped posture, and a paucity of associated movements such as arm swinging. To make matters worse, in some patients these abnormalities of motor function are associated with dementia. Following a gradual onset between the ages of 50 and 70, the disease progresses slowly and culminates in death 10 to 20 years later. The defects in motor function are due to the progressive loss of dopaminergic neurons in the substantia nigra pars compacta, a population that projects to and innervates neurons in the caudate and putamen (see text). Although the cause of the progressive deterioration of these dopaminergic neurons is not known, genetic investigations are providing clues to the etiology and pathogenesis. Whereas the majority of cases of Parkinson's disease are sporadic, there may be specific forms of susceptibility genes that confer increased risk of acquiring the discase, just as the apoE4 allele increases the homogeneous phenotype of the degener- ating neurons (i. e, dopaminergic neu- rons), has provided an opportunity for novel therapeutic approaches to this disorder. One strategy is so-called gene therapy. Gene therapy refers to the correction of a disease phenotype through the introduction of new genetic information into the affected organism. Although still in its infancy, this approach promises to revolutionize treatment of human disease. One therapy for Parkinson’s disease would be to enhance release of dopamine in the caudate and putamen. In principle, this could be accomplished by implanting cells genetically modified to express tyrosine hydroxylase, the enzyme that converts tyrosine to L- DOPA, which in turn is converted by a nearly ubiquitous decarboxylase into the neurotransmitter dopamine. The feasibility of this approach has been demonstrated by transplanting tissue derived from the midbrain of human fetuses into risk of Alzheimer’s disease. Familial the caudate and putamen, which produces long-lasting symptomatic improvement in a majority of grafted forms of the disease caused by single gene mutations account for less than 10% Parkinson’s patients. (The fetal midbrain is enriched in developing neurons that of all cases, However, identification of these rare genes is likely give some insight into molecular pathways that may underlie the disease. Mutations of three distinct genes—or-synuclein, Parkin, and DJ-1—have been implicated in rare forms of this disease. Identification of these genes provides an opportunity to generate mutant mice carrying the express tyrosine hyroxylase and synthesize and release dopamine.) To date, however, ethical, practical, and political considerations have limited use of fetal transplanted tissue. The effects of trans- planting non-neuronal cells genetically modified in vitro to express tyrosine hydroxylase are also being studied in mutant form of the human gene, poten- patients with Parkinson’s disease, an approach that avoids some of these problems. which the pathogenesis can be elucidated and therapies can be tested. In contrast to other neurodegenerative diseases, such as Alzheimer’s dis- Parkinsonian patients involves “neural grafts” using stem cells. Stem cells are tially providing a useful animal model in An alternative strategy to treating self-renewing, multipotent progenitors these cells are actively proliferating. Critical to this approach is to prospectively identify and isolate stem cells that are multipotent and self-renewing, and to identify the growth factors needed to promote differentiation into the desired phenotype (e.g., dopaminergic neurons). ‘The prospective identification and isolation of multipotent mammalian stem cells has already been accomplished, and several factors likely to be important in differentiation of midbrain precursors into dopamine neurons have been identi- fied. Establishing the efficacy of this approach for Parkinson’s patients would increase the possibility of its application to other neurodegenerative diseases. Although therapeutic strategies like these remain experimental, it is likely that some of them will succeed. References BIORKLUND, A. AND U. STENEVI (1979) Recon- struction of the nigrostriatal dopamine path- way by intracerebral nigral transplants. Brain Res. 177: 555-560. DAUER, W. AND S. PRZEDBORSKI (2003) Parkin- son’s disease: Mechanisms and models. Neuron 39: 889-909. DAWSON, T. M. AND V. L. DAWSON (2003) Rare genetic mutations shed light on the pathogenesis of Parkinson disease. J. Clin. Invest. 111: 145-151. MORRISON,. J., P. M. WHITE, C. ZOCK AND D. J. ANDERSON (1999) Prospective identification, isolation by flow cytometry, and in vivo selfrenewal of multipotent mammalian neural crest stem cells. Cell 96: 737-749. YE, W,, K. SHIMAMURA, J. L. RUBENSTEIN, M. A. HYNES AND A. ROSENTHAL (1998) FGF and Shh signals control dopaminergic and serotonergic cell fate in the anterior neural plate. Cell 93: 755-766. ZABNER, J. AND 5 OTHERS (1993) Adenovirusmediated gene transfer transiently corrects the chloride transport defect in nasal epithelia of patients with cystic fibrosis. Cell 75: 207-216. 430 Chapter Seventeen circuits also increases the discharge rate of the inhibitory cells in substantia nigra pars reticulata. The resulting increase in tonic inhibition reduces the excitability of the upper motor neurons in the superior colliculus and causes saccades to be reduced in both frequency and amplitude. Support for this explanation of hypokinetic movement disorders like Parkinson’s disease comes from studies of monkeys in which degeneration of the dopaminergic cells of substantia nigra has been induced by the neuro- toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Monkeys (or humans) exposed to MPTP develop symptoms that are very similar to those of patients with Parkinson’s disease. Furthermore, a second lesion placed in the subthalamic nucleus results in significant improvement in the ability of these animals to initiate movements, as would be expected based on the circuitry of the indirect pathway (see Figure 17.8B). (A) Parkinson’s disease (hypokinetic) Degenerated Decreased excitation Q sylvius Figure 17.10 Summary explanation of hypokinetic disorders such as Parkinson’s disease and hyperkinetic disorders like Huntington’s disease. In both cases, the balance of inhibitory signals in the direct and indirect pathways is altered, leading to a diminished ability Increased — More tonic inhibition of the basal ganglia to control the thalamic output to the cortex. (A) In Parkin- son’s disease, the inputs provided by (+] the substantia nigra are diminished (thinner arrow), making it more difficult to generate the transient inhibition from the caudate and putamen. The result of this change in the direct pathway is to Increased (B) Huntington’s disease (hyperkinetic) sustain the tonic inhibition from the globus pallidus (internal segment) to the thalamus, making thalamic excitation of the motor cortex less likely (thinner arrow from thalamus to cortex). (B) In hyperkinetic diseases such as Huntington’s, the projection from the caudate and putamen to the globus pallidus (external segment) is diminished (+] Degenerated = Increased excitation -} [} (thinner arrow). This effect increases the tonic inhibition from the globus pal- ) lidus to the subthalamic nucleus (larger arrow), making the excitatory subthala- mic nucleus less effective in opposing the action of the direct pathway (thinner arrow). Thus, thalamic excitation of the cortex is increased (larger arrow), lead- ing to greater and often inappropriate ‘motor activity. (After DeLong, 1990.) ] Incre’ased © e Diminished Less tonic inhibition Modulation of Movement by the Basal Ganglia Similarly, knowledge about the indirect pathway within the basal ganglia helps explain the motor abnormalities seen in Huntington’s disease (see Box A). In patients with Huntington’s disease, medium spiny neurons that project to the external segment of the globus pallidus degenerate (see Figure 17.9A). In the absence of their normal inhibitory input from the spiny neurons, the external globus pallidus cells become abnormally active; this activ- ity reduces in turn the excitatory output of the subthalamic nucleus to the internal globus pallidus (Figure 17.10B). In consequence, the inhibitory outflow of the basal ganglia is reduced. Without the restraining influence of the basal ganglia, upper motor neurons can be activated by inappropriate sig- nals, resulting in the undesired ballistic and choreic (dancelike) movements that characterize Huntington’s disease. Importantly, the basal ganglia may exert a similar influence on other non-motor systems with equally significant clinical implications (Box C). As predicted by this account, GABA agonists and antagonists applied to substantia nigra pars reticulata of monkeys produce symptoms similar to those seen in human basal ganglia disease. For example, intranigral injection of bicuculline, which blocks the GABAergic inputs from the striatal medium spiny neurons to the reticulata cells, increases the amount of tonic inhibition on the upper motor neurons in the deep collicular layers. These animals exhibit fewer, slower saccades, reminiscent of patients with Parkinson’s dis- ease. In contrast, injections of the GABA agonist muscimol into substantia nigra pars reticulata decrease the tonic GABAergic inhibition of the upper motor neurons in the superior colliculus, with the result that the injected monkeys generate spontaneous, irrepressible saccades that resemble the involuntary movements characteristic of basal ganglia diseases such as hemiballismus and Huntington’s disease (Figure 17.11). (A) (B) Left visual field Right visual field Substantia nigra pars reticulata Muscimol injection Figure 17.11 After the tonically active cells of substantia nigra pars reticulata are inactivated by an intranigral injection of muscimol (A), the upper motor neurons in the deep layers of the superior colliculus are disinhibited and the monkey generates spontaneous irrepressible saccades (B). The cells in both substantia nigra pars reticulata and the deep layers of the superior colliculus are arranged in spatially organized motor maps of saccade vectors (see Chapter 19), and so the direction of the involuntary saccades—in this case toward the upper left quadrant of the visual field—depends on the precise location of the injection site in the substantia nigra. 431 432 Chapter Seventeen Box C Basal Ganglia Loops and Non-Motor Brain Functions Traditionally, the basal ganglia have been regarded as motor structures that regulate the initiation of movements. However, the basal ganglia are also central structures in anatomical circuits or loops that are involved in modulating non-motor aspects of behavior. These parallel loops originate in broad regions of the cortex, engage specific subdivisions of the basal ganglia and thalamus, and ultimately terminate in areas of the frontal lobe outside of the primary motor and premotor cortices. These Motor loop non-motor loops (see figure) include a “prefrontal” loop involving the dorsolateral prefrontal cortex and part of the caudate (see Chapter 25), a “limbic” loop involving the cingulate cortex and the ventral striatum (see Chapter 28), and an “oculomotor” loop that modulates the activity of the frontal eye fields (see Chapter 19). The anatomical similarity of these loops to the traditional motor loop suggests that the non-motor regulatory functions of the basal ganglia may be gener- Prefrontal loop Oculomotor loop Cortical targets H Thalamus Pallidum Striatum k] g 8 £5 5] Comparison of the motor and three non-motor basal ganglia loops. ally the same as what the basal ganglia do in regulating the initiation of movement. For example, the prefrontal loop may regulate the initiation and termination of cognitive processes such as planning, working memory, and attention. By the same token, the limbic loop may regulate emotional behavior and motivation. Indeed, the deterioration of cognitive and emotional function in both Huntington’s disease (see Box A) and Parkinson’s disease (see Box B) could be the result of disruption of these non-motor loops. Limbic loop Modulation of Movement by the Basal Ganglia In fact, a variety of other disorders are now thought to be caused, at least in part, by damage to non-motor compo- nents of the basal ganglia. For example, patients with Tourette’s syndrome produce inappropriate utterances and obscenities as well as unwanted vocalmotor “tics” and repetitive grunts. These manifestations may be a result of excessive activity in basal ganglia loops that regulate the cognitive circuitry of the prefrontal speech areas. Another example is schizophrenia, which some investigators have argued is associated with aberrant activity within the limbic and prefrontal loops, resulting in hallucinations, delusions, disordered thoughts, and loss of emotional expression. In sup- port of the argument for a basal ganglia contribution to schizophrenia, antipsy- chotic drugs are known to act on dopaminergic receptors, which are found in high concentrations in the striatum. Still other psychiatric disorders, including obsessive-compulsive disorder, depression, and chronic anxiety, may also involve dysfunctions of the limbic loop. A challenge for future research is therefore to understand more fully the relationships between the clinical problems and other largely unexplored functions of the basal ganglia. References ALEXANDER, G. E., M. R. DELONG AND P. L. STRICK (1986) Parallel organization of functionally segregated circuits linking basal ganglia and cortex. Annu. Rev. Neurosci. 9: 357-381. BHatia, K. P AND C. D. MARSDEN (1994) The behavioral and motor consequences of focal lesions of the basal ganglia in man. Brain 117: 859-876. BLUMENFELD, H. (2002) Neuroanatonty through Clinical Cases. Sunderland, MA: Sinauer Associates. DREVETS, W. C. AND 6 OTHERS (1997) Subgenual prefrontal cortex abnormalities in mood disorders. Nature 386: 824-827. Summary The contribution of the basal ganglia to motor control is apparent from the deficits that result from damage to the component nuclei. Such lesions compromise the initiation and performance of voluntary movements, as exemplified by the paucity of movement in Parkinson’s disease and in the inappropriate “release” of movements in Huntington’s disease. The organization of the basic circuitry of the basal ganglia indicates how this constellation of nuclei modulates movement. With respect to motor function, the system forms a loop that originates in almost every area of the cerebral cortex and eventually terminates, after enormous convergence within the basal ganglia, on the upper motor neurons in the motor and premotor areas of the frontal lobe and in the superior colliculus. The efferent neurons of the basal ganglia influence the upper motor neurons in the cortex by gating the flow of information through relays in the ventral nuclei of the thalamus. The upper motor neurons in the superior colliculus that initiate saccadic eye movements are controlled by monosynaptic projections from substantia nigra pars reticulata. In each case, the basal ganglia loop regulates movement by a process of disinhibition that results from the serial interaction within the basal ganglia circuitry of two GABAergic neurons. Internal circuits within the basal ganglia system modulate the amplification of the signals that are transmitted through the loop. 433 GRAYBIEL, A. M. (1997) The basal ganglia and cognitive pattern generators. Schiz. Bull. 23: 459-469. JENIKE, M. A, L. BAER AND W. E. MINICHIELLO (1990) Obsessive Compulsive Disorders: Theory and Management. Chicago: Year Book Medical Publishers, Inc. MARTIN, J. H. (1996) Neuroanatomy: Text and Atlas. New York: McGraw-Hill. MIDDLETON, F. A. AND P. L. STRICK (2000) Basal ganglia output and cognition: Evidence from anatomical, behavioral, and clinical studies. Brain Cogn. 42: 183-200.