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The basal ganglia downstream control of brainstem motor centres — an evolutionarily conserved strategy
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ScienceDirect The basal ganglia downstream control of brainstem motor centres — an evolutionarily conserved strategy Sten Grillner and Brita Robertson The basal ganglia plays a crucial role in decision-making and control of motion. The output of the basal ganglia consists of tonically active GABAergic neurons, a proportion of which project to different brainstem centres and another part projecting to thalamus and back to cortex. The focus here is on the former part, which keeps the different brainstem motorcentres tonically inhibited under resting conditions. These centres will be disinhibited when called into action. In the control of motion the direct pathway will promote movement and the indirect pathway inhibit competing movement patterns counteracting the motor-command issued. The basal ganglia detailed structure and function are conserved throughout the vertebrate evolution, including the afferent (e.g. habenulae) and efferent control of the dopamine system. Addresses The Nobel Institute for Neurophysiology, Department of Neuroscience, Karolinska Institutet, SE-171 77 Stockholm, Sweden Corresponding author: Grillner, Sten ([email protected])
Current Opinion in Neurobiology 2015, 33:47–52 This review comes from a themed issue on Motor circuits and action Edited by Ole Kiehn and Mark Churchland
http://dx.doi.org/10.1016/j.conb.2015.01.019 0959-4388/# 2015 Elsevier Ltd. All rights reserved.
projections from the basal ganglia output nuclei directly to brainstem motor command centres. Goal-directed movements can be controlled by the basal ganglia in the absence of neocortex
Striatum, the input stage of the basal ganglia, relies for its excitatory input on cortex (pallium in lower vertebrates) to somewhat more than 50% and for the remainder on direct input from thalamus [1]. In addition, a number of modulatory systems, like the dopamine system, determine the properties of striatal neurons and their role in the striatal microcircuits [2,3,4]. What may seem surprising, but is well established, is that when the entire input from neocortex has been abolished experimentally, advanced mammals like cats, rabbits and rodents still move around in a graceful way — and display goal-directed behaviour like searching for food when ‘hungry’, and they eat, drink and groom themselves [5,6] and even show maternal behaviour towards their offspring. Under these conditions, decision-making relies on the basal ganglia and it will depend entirely on the thalamic input to striatum. These coarse experiments are nevertheless important, because they demonstrate that very complex aspects of behaviour can be controlled without the cerebral cortex and will depend entirely on the basal ganglia with its input from thalamus and of course also on downstream brainstem structures. Not only the input from cortex is abolished, but also another crucial circuit that often takes a centre stage position in basal ganglia research, the entire basal ganglia projections via thalamus back to cortex. The basal ganglia provides tonic inhibition of brainstem motor centres at rest
Introduction The basal ganglia is an evolutionarily conserved key structure for the control of action. A dysfunction of the different components within the basal ganglia due to dopamine deficiency can lead to severe neurological consequences like the hypokinesias of Parkinson’s with difficulties to initiate movements and carry out complex movements or conversely the hyperkinesias due to enhanced levels of dopamine or Huntington’s or hemiballismus, in which movements are initiated without the conscious intention of the individual. Also psychiatric symptoms have been described. We will here review how the basal ganglia contribute to the control of action and the selection of different motor programs — but not other important aspects like motor learning. The focus will be on the prominent, but somewhat neglected, direct www.sciencedirect.com
The output of the basal ganglia is from Globus Pallidus interna (GPi) and from Substantia Nigra pars reticulata (SNr; see [7,8]). Neurons in these structures are all inhibitory (GABA) and have a high level of tonic activity under resting conditions [9]. They project to various structures, and also to thalamus brainstem (Figures 1 and 2). SNr thus contains neurons that project to the optic tectum (superior colliculus) for eye and orienting movements, the mesencephalic locomotor command region (MLR) and centres for postural control, to the periaqueductal grey for vocalisation and the thalamus for hand and finger movements. Neurons within SNr that target the different brainstem centres are located in different parts of SNr [10,11,12,13] in both rodents and lamprey, the latter representing the oldest now living group of vertebrates. Many of the brainstem projection Current Opinion in Neurobiology 2015, 33:47–52
48 Motor circuits and action
Figure 1
The indirect and direct pathway are both activated during initiation of a movement
Cortex/Pallium
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red, glutamate blue, GABA green, dopamine (DA) Current Opinion in Neurobiology
The organisation of the basal ganglia is almost identical throughout vertebrate phylogeny — from lamprey to primates. The striatum, globus pallidus externa (GPe), globus pallidus interna (GPi) and substantia nigra pars reticulata (SNr). SNr and GPi represent the output level of the basal ganglia, and it projects via different subpopulations of neurons to optic tectum (superior colliculus), the mesencephalic (MLR) and diencephalic (DLR) locomotor command regions and other brainstem motor centres, and also back to thalamus and cortex (pallium in lower vertebrates). The indirect loop is represented by the GPe, the subthalamic nucleus but is drawn here only as a dotted line to the output level (SNr/GPi) — the net effect being an enhancement of activity in these nuclei. The striatal neurons of the direct pathway to SNr/GPi express the dopamine D1 receptor (D1), while the indirect pathway neurons in striatum express the dopamine D2 receptor (D2). Excitatory glutamatergic neurons are represented by red colour and GABAergic structures in blue. Also indicated is the dopamine supply from the substantia nigra pars compacta (SNc; green).
neurons in SNr or GPi also send off an axonal branch to thalamus and then upstream to cortex — thus the same information can be transmitted to the brainstem centres and in parallel to cortex [14–16]. The latter may represent an efference copy of the command signal to brainstem centres (with reversed sign due to the inhibitory nature). At rest the net effect is that SNr and GPi keep all the different brainstem centres under tonic inhibition — most likely an important control strategy to ascertain that the different motor programs are not released in a haphazard way. If a brainstem motor centre should be called into action, striatum can via its direct projections inhibit the SNr/GPi neurons, thereby indirectly removing the inhibition from the motor centre (disinhibition) and releasing the motor centre. Such a release has been demonstrated for saccadic movements in primates [17,18] and for the different locomotor command centres, both in mammals and lamprey [7,19,20,21]. Current Opinion in Neurobiology 2015, 33:47–52
Around 95% of neurons in striatum are GABAergic spiny projection neurons while the rest are inhibitory interneurons and some cholinergic neurons (see Bolam and Silberberg, this volume). The projection neurons are of two types (for review see [2]), one projecting directly to the output level, that is SNr/GPi — referred to as the direct pathway, which expresses dopamine receptors of the D1 subtype (D1R; see Figure 1). Dopamine enhances the excitability of these neurons. By contrast, the other subtype of projection neuron expresses D2R, and dopamine has a net depressing effect on these cells. They instead project to the intrinsic basal ganglia nuclei (Globus Pallidus externa (GPe), subthalamic nucleus (STN)), which in turn act on SNr/GPi. The net effect of activating this pathway will be an enhanced activity at the SNr/GPi level and thus an enhanced inhibitory output. This ‘indirect pathway’ can therefore be used to terminate or reduce activity in the different motor centres, while the direct pathway instead can release activity in a given motor centre through disinhibition. The striatal projecting neurons of the direct and indirect pathway both receive converging input from different sensory modalities (e.g. vision and vibrissae) with larger effects on direct pathway neurons [22]. Recent experiments using optogenetics for stimulation or recording have allowed manipulation of the D1R expressing projection neurons of the direct pathway and confirmed that they contribute to initiation of behaviour. The D2R type of the indirect pathway instead has, as anticipated, a depressing effect [19,23,24]. During the initiation of a behaviour, however, both D1R and D2R neurons become activated [25,26]. At first sight this may seem surprising, but it is evident that as one initiates a movement, it is crucial to ascertain that conflicting movements do not occur. If one considers the complex situation in every day life — rapid transitions between one motor pattern and another need to be controlled in a dynamic way as well as the interplay between different types of motor programs. The detailed organisation of the basal ganglia is conserved throughout vertebrate phylogeny
The anatomical and physiological organisation with striatum, GPi/SNr and GPe and STN (see Figure 1), as well as the synaptic interaction between them, is conserved from lamprey to mammals [11,27,28,29,30]. The D1R projection neurons express substance P in addition to GABA and connect directly to SNr/GPi while the D2R projection neurons express enkephalin and terminate on GPe neurons that project to the STN. The striatal neurons have inward rectifier K+-channels, which is a design feature to make them difficult to activate at rest, while the GPi/SNr are spontaneously active at rest [11,27,30]. www.sciencedirect.com
The basal ganglia control of brainstem motor centres Grillner and Robertson 49
Figure 2
pallium thalamus
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thalamus pallium thalamus Current Opinion in Neurobiology
Overview of the basal ganglia/habenular circuits underlying the control of motion and evaluation. The lower part of the diagram shows that the matrix component of striatum projects to both globus pallidus interna and substantia nigra pars reticulata (GPi/SNr) and further to the brainstem motor programs. In addition, it shows the indirect pathway with GPe (globus pallidus externa) and the subthalamic nucleus (STN). The colour code is blue for GABAergic, red for glutamatergic and green for dopaminergic neurons (DA). The evaluation circuit in the upper part of the diagram contains the lateral habenulae (Hab) with its projection to dopamine neurons directly and indirectly via the GABAergic RMTg (Rostro-Medial Tegmental nucleus). The lateral habenulae has input from the glutamatergic habenula-projecting globus pallidus (GPh), which in turn is excited from pallium and thalamus, whereas it receives inhibition from the striosomal compartment of striatum.
In mammals and lamprey, cortex/pallium provides two types of input to striatum (1) one that is a collateral of cortical projections to the brainstem-spinal cord, and (2) intratelencephalic projections, which can originate from the contralateral hemisphere that make synapses within cortex, and also represent a dedicated major projection to striatum [31,32]. In mammals both types originate in layer 5, in the two-layered lamprey pallium the neurons are pyramidal-like with dendrites that extend towards the molecular layer [31]. Since the lamprey belongs to the oldest vertebrate group that diverged some 560 million years ago from the evolutionary line leading to mammals, and since the similarities are so striking with regard to connectivity, ion channels expressed, transmitters and co-transmitters, one can conclude that the design of the basala ganglia was invented very early in vertebrate evolution, and has been maintained throughout vertebrate phylogeny. The dopamine innervation includes not only the basal ganglia but also down-stream motor centres
An increased activity of the dopamine neurons in substantia nigra pars compacta (SNc) will affect striatum and the STN and other basal ganglia structures, but it is important to note that these neurons also project to the optic tectum (superior colliculus) as well as the MLR and other brainstem regions (see Figures 1 and 2; [33,34]). In the optic tectum, dopamine differentially modulates the deep layer premotor cells — increasing the excitability in dopamine D1R-expressing cells and decreasing the www.sciencedirect.com
excitability in those expressing the D2R (Pe´rez-Ferna´ndez et al., abstract in Soc Neurosci Abstr 2014, 541:03). The dopaminergic input from the SNc directly tunes the motor responses elicited by the sensory inputs that come in to the superficial layers of tectum. Moreover, an enhanced dopamine drive will promote the occurrence of locomotor activity driven from MLR [35]. It is remarkable to note that the projection pattern of the dopaminergic system is virtually identical in lamprey and mammals and that this important modulator system has been conserved throughout vertebrate phylogeny [33]. The dopaminergic projections from the mammalian ventral tegmental area (VTA) contain separate sets of dopamine cells, one preferentially projecting to the ventral striatum (accumbens) and another to the frontal lobes in rodents [36]. This would seem to be quite important because the dopaminergic innervation of the two structures can be independent and link to different functional contexts. An enhanced dopamine activity will potentiate synaptic plasticity and enhance the possibilities for motor learning and is also related to the effects of drug abuse. The input to the dopamine system includes neocortex/ pallium and also input from the pedunculopontine nucleus and from the lateral habenula (see Figure 2). The lateral habenula is involved in the mediation of aversive behaviour and negative reward and projects directly to dopamine neurons, but also indirectly via an inhibitory group of GABAergic cells (Rostro-Medial Tegmental Current Opinion in Neurobiology 2015, 33:47–52
50 Motor circuits and action
(RMTg) nucleus) [37,38,39]. It is not yet known whether the two projection patterns (direct or via RMTg) target different dopamine neurons or if the signal can be gated to have opposite effects. An increase of the activity in the dopamine neurons relate to reward, unexpected events and a decrease to not receiving an expected reward (disappointment) [40]. As indicated schematically in Figure 2, the striatum is composed of a mosaic of striosomal and matrisomal patches or compartments. The matrisomes (matrix) are linked to the indirect and direct pathway for the control of motion, as discussed above (lower part of the diagram). The striosomes are instead involved in the control of the activity of dopamine neurons, and can therefore be assumed to be involved in the evaluation of the actions performed (upper part of Figure 2). One input to the lateral habenulae is from a glutamatergic pallidal nucleus (GPh; see Figure 2) with a high level of spontaneous activity, which in turn has input from pallium, but also directly from the striosomal compartment of striatum [39,41]. The striosomes provide direct projections to the dopamine neurons in the SNc (see [42]), but also to the route via GPh and the lateral habenulae [40]. These two different routes can be regarded as serving the function of evaluating the success of a given action, through the modulation of the dopamine activity (see Figure 2). Neurons belonging to the striosomal compartment engaged in the control of dopamine neurons are born earlier than those forming matrisomes and engage in the direct control of the direct and indirect pathways for motor actions [43]. The striatum may thus have two distinct compartments, one for control of movement and the other for evaluation of action (Figure 2). The possible relevance of the down-stream control of brainstem motor centres for Parkinson’s disease
The net effect of the decreased dopamine innervation of striatum in Parkinson’s leads to a decreased excitability in the D1 projection neurons of the direct pathway and a decreased inhibition of the D2 projection neurons of the indirect pathway. These two effects can in themselves explain part of the symptoms in Parkinson’s with regard to the difficulty in initiation of movements. The question that needs to be asked is how much of the symptoms that depend on the basal ganglia projections directly to the brainstem as opposed to those that are channelled back to cortex via thalamus. One important clue can be obtained from the lesions in the thalamic nuclei mediating the basal ganglia signals that were performed to alleviate symptoms in Parkinsonian patients (e.g. [44]). These lesions led to a marked improvement of hand tremor and the arm-hand control, deficits, which can be very handicapping for patients particularly when eating. However, these extensive thalamic lesions did not affect the postural and locomotor deficits. This would indicate that the arm-hand control from, for example, motor cortex is Current Opinion in Neurobiology 2015, 33:47–52
affected by feedback via thalamus and the enhanced oscillatory output from GPi/SNr in Parkinson’s [45]. On the other hand, the control of locomotion, posture and similar motor programs would possibly be channelled via the direct output from the basal ganglia to the brainstem centres (see [46]). The direct dopaminergic modulation from the SNc to the superior colliculus/tectum may thus also be involved in the impairment in performing saccadic eye movement seen in Parkinson’s disease.
Conclusion The basal ganglia have been conserved throughout vertebrate evolution, not only in terms of connectivity, but also in great detail with regard to transmitters, synaptic and membrane properties. The focus here has been on a conserved feature of the basal ganglia control — the downstream direct control of brainstem motor centres that most likely are of major importance not only for the control of eye movement. Taken together, old and newer data indicate that a large proportion of the control is exerted directly on different brainstem structures involved in the control of motion. Moreover, the afferent and efferent organisation of the dopamine system is virtually identical in mammals and lamprey. In both cases there are also distinct projections to downstream motor centres that may facilitate their activation.
Conflict of interest statement Nothing declared.
Acknowledgements We thank Dr Peter Walle´n for valuable comments on the manuscript. This work was supported by the Swedish Research Council, grant number: VRM-K2013-62X-03026, VR-NT 621-2007-6049, EU Cortex Training Program FP6 MEST-CT-2005-019729, EU/FP7 Select-and-Act, EU/FP7 no 604102 The Human Brain Project (HBP), and the Karolinska Institutet’s Research Funds.
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13. Takakusaki K, Obara K, Nozu T, Okumura T: Modulatory effects of the GABAergic basal ganglia neurons on the PPN and the muscle tone inhibitory system in cats. Arch Ital Biol 2011, 149:385-405. Shows projection patterns from SNr to different brainstem centres.
30. Stephenson-Jones M, Ericsson J, Robertson B, Grillner S: Evolution of the basal ganglia: dual-output pathways conserved throughout vertebrate phylogeny. J Comp Neurol 2012, 520:2957-2973.
14. Beckstead RM: Long collateral branches of substantia nigra pars reticulata axons to thalamus, superior colliculus and reticular formation in monkey and cat. Multiple retrograde neuronal labeling with fluorescent dyes. Neuroscience 1983, 10:767-779.
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32. Reiner A, Jiao Y, Del Mar N, Laverghetta AV, Lei WL: Differential morphology of pyramidal tract-type and intratelencephalically projecting-type corticostriatal neurons and their intrastriatal terminals in rats. J Comp Neurol 2003, 457:420-440. 33. Pe´rez-Ferna´ndez J, Stephenson-Jones M, Suryanarayana SM, Robertson B, Grillner S: Evolutionarily conserved organization of the dopaminergic system in lamprey: SNc/VTA afferent and efferent connectivity and D2 receptor expression. J Comp Neurol 2014, 522:3775-3794. The detailed organisation of the dopamine system appears to have evolved very early in vertebrate evolution. 34. Campbell KJ, Takada M: Bilateral tectal projection of single nigrostriatal dopamine cells in the rat. Neuroscience 1989, 33:311-321. 35. Ryczko D, Gratsch S, Auclair F, Dube C, Bergeron S, Alpert MH, Cone JJ, Roitman MF, Alford S, Dubuc R: Forebrain dopamine neurons project down to a brainstem region controlling locomotion. Proc Natl Acad Sci U S A 2013, 110:E3235-E3242. Shows that dopamine neurons target brainstem motor centres for locomotion. 36. Lammel S, Lim BK, Ran C, Huang KW, Betley MJ, Tye KM, Deisseroth K, Malenka RC: Input-specific control of reward and aversion in the ventral tegmental area. Nature 2012, 491:212217. Subpopulations of dopamine neurons in VTA project to frontal lobe and accumbens — and have different inputs. 37. Hong S, Jhou TC, Smith M, Saleem KS, Hikosaka O: Negative reward signals from the lateral habenula to dopamine neurons are mediated by rostromedial tegmental nucleus in primates. J Neurosci 2011, 31:11457-11471. The RMTg nucleus is shown to translate lateral habenula reward-prediction errors (negative) into dopamine reward-prediction errors (positive). 38. Stephenson-Jones M, Floros O, Robertson B, Grillner S: Evolutionary conservation of the habenular nuclei and their Current Opinion in Neurobiology 2015, 33:47–52
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circuitry controlling the dopamine and 5-hydroxytryptophan (5-HT) systems. Proc Natl Acad Sci U S A 2012, 109:E164-E173. 39. Stephenson-Jones M, Kardamakis AA, Robertson B, Grillner S: Independent circuits in the basal ganglia for the evaluation and selection of actions. Proc Natl Acad Sci U S A 2013, 110:E3670-E3679. It is shown that the striosomal compartment of striatum targets an excitatory pallidal nucleus that in turn controls the lateral habenula, and thereby dopamine activity. 40. Hikosaka O: The habenula: from stress evasion to value-based decision-making. Nat Rev Neurosci 2010, 11:503-513. 41. Rajakumar N, Elisevich K, Flumerfelt BA: Compartmental origin of the striato-entopeduncular projection in the rat. J Comp Neurol 1993, 331:286-296. 42. Graybiel AM: Habits, rituals, and the evaluative brain. Annu Rev Neurosci 2008, 31:359-387.
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43. Newman HLF-C, Graybiel AM: Dynamic ordering of early generated striatal cells destined to form the striosomal compartment of the striatum. J Comp Neurol 2015. Shows that the striosomal compartments of striatum develop before the matrisome compartments involved with the control of action. 44. Duval C, Panisset M, Strafella AP, Sadikot AF: The impact of ventrolateral thalamotomy on tremor and voluntary motor behavior in patients with Parkinson’s disease. Exp Brain Res 2006, 170:160-171. 45. Brazhnik E, Novikov N, McCoy AJ, Cruz AV, Walters JR: Functional correlates of exaggerated oscillatory activity in basal ganglia output in hemiparkinsonian rats. Exp Neurol 2014, 261:563-577. 46. Grillner S, Robertson B, Stephenson-Jones M: The evolutionary origin of the vertebrate basal ganglia and its role in action selection. J Physiol 2013, 591:5425-5431.
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ScienceDirect The basal ganglia downstream control of brainstem motor centres — an evolutionarily conserved strategy Sten Grillner and Brita Robertson The basal ganglia plays a crucial role in decision-making and control of motion. The output of the basal ganglia consists of tonically active GABAergic neurons, a proportion of which project to different brainstem centres and another part projecting to thalamus and back to cortex. The focus here is on the former part, which keeps the different brainstem motorcentres tonically inhibited under resting conditions. These centres will be disinhibited when called into action. In the control of motion the direct pathway will promote movement and the indirect pathway inhibit competing movement patterns counteracting the motor-command issued. The basal ganglia detailed structure and function are conserved throughout the vertebrate evolution, including the afferent (e.g. habenulae) and efferent control of the dopamine system. Addresses The Nobel Institute for Neurophysiology, Department of Neuroscience, Karolinska Institutet, SE-171 77 Stockholm, Sweden Corresponding author: Grillner, Sten ([email protected])
Current Opinion in Neurobiology 2015, 33:47–52 This review comes from a themed issue on Motor circuits and action Edited by Ole Kiehn and Mark Churchland
http://dx.doi.org/10.1016/j.conb.2015.01.019 0959-4388/# 2015 Elsevier Ltd. All rights reserved.
projections from the basal ganglia output nuclei directly to brainstem motor command centres. Goal-directed movements can be controlled by the basal ganglia in the absence of neocortex
Striatum, the input stage of the basal ganglia, relies for its excitatory input on cortex (pallium in lower vertebrates) to somewhat more than 50% and for the remainder on direct input from thalamus [1]. In addition, a number of modulatory systems, like the dopamine system, determine the properties of striatal neurons and their role in the striatal microcircuits [2,3,4]. What may seem surprising, but is well established, is that when the entire input from neocortex has been abolished experimentally, advanced mammals like cats, rabbits and rodents still move around in a graceful way — and display goal-directed behaviour like searching for food when ‘hungry’, and they eat, drink and groom themselves [5,6] and even show maternal behaviour towards their offspring. Under these conditions, decision-making relies on the basal ganglia and it will depend entirely on the thalamic input to striatum. These coarse experiments are nevertheless important, because they demonstrate that very complex aspects of behaviour can be controlled without the cerebral cortex and will depend entirely on the basal ganglia with its input from thalamus and of course also on downstream brainstem structures. Not only the input from cortex is abolished, but also another crucial circuit that often takes a centre stage position in basal ganglia research, the entire basal ganglia projections via thalamus back to cortex. The basal ganglia provides tonic inhibition of brainstem motor centres at rest
Introduction The basal ganglia is an evolutionarily conserved key structure for the control of action. A dysfunction of the different components within the basal ganglia due to dopamine deficiency can lead to severe neurological consequences like the hypokinesias of Parkinson’s with difficulties to initiate movements and carry out complex movements or conversely the hyperkinesias due to enhanced levels of dopamine or Huntington’s or hemiballismus, in which movements are initiated without the conscious intention of the individual. Also psychiatric symptoms have been described. We will here review how the basal ganglia contribute to the control of action and the selection of different motor programs — but not other important aspects like motor learning. The focus will be on the prominent, but somewhat neglected, direct www.sciencedirect.com
The output of the basal ganglia is from Globus Pallidus interna (GPi) and from Substantia Nigra pars reticulata (SNr; see [7,8]). Neurons in these structures are all inhibitory (GABA) and have a high level of tonic activity under resting conditions [9]. They project to various structures, and also to thalamus brainstem (Figures 1 and 2). SNr thus contains neurons that project to the optic tectum (superior colliculus) for eye and orienting movements, the mesencephalic locomotor command region (MLR) and centres for postural control, to the periaqueductal grey for vocalisation and the thalamus for hand and finger movements. Neurons within SNr that target the different brainstem centres are located in different parts of SNr [10,11,12,13] in both rodents and lamprey, the latter representing the oldest now living group of vertebrates. Many of the brainstem projection Current Opinion in Neurobiology 2015, 33:47–52
48 Motor circuits and action
Figure 1
The indirect and direct pathway are both activated during initiation of a movement
Cortex/Pallium
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Tectum/MLR/DLR Motor Programs
red, glutamate blue, GABA green, dopamine (DA) Current Opinion in Neurobiology
The organisation of the basal ganglia is almost identical throughout vertebrate phylogeny — from lamprey to primates. The striatum, globus pallidus externa (GPe), globus pallidus interna (GPi) and substantia nigra pars reticulata (SNr). SNr and GPi represent the output level of the basal ganglia, and it projects via different subpopulations of neurons to optic tectum (superior colliculus), the mesencephalic (MLR) and diencephalic (DLR) locomotor command regions and other brainstem motor centres, and also back to thalamus and cortex (pallium in lower vertebrates). The indirect loop is represented by the GPe, the subthalamic nucleus but is drawn here only as a dotted line to the output level (SNr/GPi) — the net effect being an enhancement of activity in these nuclei. The striatal neurons of the direct pathway to SNr/GPi express the dopamine D1 receptor (D1), while the indirect pathway neurons in striatum express the dopamine D2 receptor (D2). Excitatory glutamatergic neurons are represented by red colour and GABAergic structures in blue. Also indicated is the dopamine supply from the substantia nigra pars compacta (SNc; green).
neurons in SNr or GPi also send off an axonal branch to thalamus and then upstream to cortex — thus the same information can be transmitted to the brainstem centres and in parallel to cortex [14–16]. The latter may represent an efference copy of the command signal to brainstem centres (with reversed sign due to the inhibitory nature). At rest the net effect is that SNr and GPi keep all the different brainstem centres under tonic inhibition — most likely an important control strategy to ascertain that the different motor programs are not released in a haphazard way. If a brainstem motor centre should be called into action, striatum can via its direct projections inhibit the SNr/GPi neurons, thereby indirectly removing the inhibition from the motor centre (disinhibition) and releasing the motor centre. Such a release has been demonstrated for saccadic movements in primates [17,18] and for the different locomotor command centres, both in mammals and lamprey [7,19,20,21]. Current Opinion in Neurobiology 2015, 33:47–52
Around 95% of neurons in striatum are GABAergic spiny projection neurons while the rest are inhibitory interneurons and some cholinergic neurons (see Bolam and Silberberg, this volume). The projection neurons are of two types (for review see [2]), one projecting directly to the output level, that is SNr/GPi — referred to as the direct pathway, which expresses dopamine receptors of the D1 subtype (D1R; see Figure 1). Dopamine enhances the excitability of these neurons. By contrast, the other subtype of projection neuron expresses D2R, and dopamine has a net depressing effect on these cells. They instead project to the intrinsic basal ganglia nuclei (Globus Pallidus externa (GPe), subthalamic nucleus (STN)), which in turn act on SNr/GPi. The net effect of activating this pathway will be an enhanced activity at the SNr/GPi level and thus an enhanced inhibitory output. This ‘indirect pathway’ can therefore be used to terminate or reduce activity in the different motor centres, while the direct pathway instead can release activity in a given motor centre through disinhibition. The striatal projecting neurons of the direct and indirect pathway both receive converging input from different sensory modalities (e.g. vision and vibrissae) with larger effects on direct pathway neurons [22]. Recent experiments using optogenetics for stimulation or recording have allowed manipulation of the D1R expressing projection neurons of the direct pathway and confirmed that they contribute to initiation of behaviour. The D2R type of the indirect pathway instead has, as anticipated, a depressing effect [19,23,24]. During the initiation of a behaviour, however, both D1R and D2R neurons become activated [25,26]. At first sight this may seem surprising, but it is evident that as one initiates a movement, it is crucial to ascertain that conflicting movements do not occur. If one considers the complex situation in every day life — rapid transitions between one motor pattern and another need to be controlled in a dynamic way as well as the interplay between different types of motor programs. The detailed organisation of the basal ganglia is conserved throughout vertebrate phylogeny
The anatomical and physiological organisation with striatum, GPi/SNr and GPe and STN (see Figure 1), as well as the synaptic interaction between them, is conserved from lamprey to mammals [11,27,28,29,30]. The D1R projection neurons express substance P in addition to GABA and connect directly to SNr/GPi while the D2R projection neurons express enkephalin and terminate on GPe neurons that project to the STN. The striatal neurons have inward rectifier K+-channels, which is a design feature to make them difficult to activate at rest, while the GPi/SNr are spontaneously active at rest [11,27,30]. www.sciencedirect.com
The basal ganglia control of brainstem motor centres Grillner and Robertson 49
Figure 2
pallium thalamus
GPh
striosomes
Hab
evaluation pallium thalamus
RMTg DA
STRIATUM
GPi DP D P SNr
MLR tectum
motion
matrix GPe
STN
thalamus pallium thalamus Current Opinion in Neurobiology
Overview of the basal ganglia/habenular circuits underlying the control of motion and evaluation. The lower part of the diagram shows that the matrix component of striatum projects to both globus pallidus interna and substantia nigra pars reticulata (GPi/SNr) and further to the brainstem motor programs. In addition, it shows the indirect pathway with GPe (globus pallidus externa) and the subthalamic nucleus (STN). The colour code is blue for GABAergic, red for glutamatergic and green for dopaminergic neurons (DA). The evaluation circuit in the upper part of the diagram contains the lateral habenulae (Hab) with its projection to dopamine neurons directly and indirectly via the GABAergic RMTg (Rostro-Medial Tegmental nucleus). The lateral habenulae has input from the glutamatergic habenula-projecting globus pallidus (GPh), which in turn is excited from pallium and thalamus, whereas it receives inhibition from the striosomal compartment of striatum.
In mammals and lamprey, cortex/pallium provides two types of input to striatum (1) one that is a collateral of cortical projections to the brainstem-spinal cord, and (2) intratelencephalic projections, which can originate from the contralateral hemisphere that make synapses within cortex, and also represent a dedicated major projection to striatum [31,32]. In mammals both types originate in layer 5, in the two-layered lamprey pallium the neurons are pyramidal-like with dendrites that extend towards the molecular layer [31]. Since the lamprey belongs to the oldest vertebrate group that diverged some 560 million years ago from the evolutionary line leading to mammals, and since the similarities are so striking with regard to connectivity, ion channels expressed, transmitters and co-transmitters, one can conclude that the design of the basala ganglia was invented very early in vertebrate evolution, and has been maintained throughout vertebrate phylogeny. The dopamine innervation includes not only the basal ganglia but also down-stream motor centres
An increased activity of the dopamine neurons in substantia nigra pars compacta (SNc) will affect striatum and the STN and other basal ganglia structures, but it is important to note that these neurons also project to the optic tectum (superior colliculus) as well as the MLR and other brainstem regions (see Figures 1 and 2; [33,34]). In the optic tectum, dopamine differentially modulates the deep layer premotor cells — increasing the excitability in dopamine D1R-expressing cells and decreasing the www.sciencedirect.com
excitability in those expressing the D2R (Pe´rez-Ferna´ndez et al., abstract in Soc Neurosci Abstr 2014, 541:03). The dopaminergic input from the SNc directly tunes the motor responses elicited by the sensory inputs that come in to the superficial layers of tectum. Moreover, an enhanced dopamine drive will promote the occurrence of locomotor activity driven from MLR [35]. It is remarkable to note that the projection pattern of the dopaminergic system is virtually identical in lamprey and mammals and that this important modulator system has been conserved throughout vertebrate phylogeny [33]. The dopaminergic projections from the mammalian ventral tegmental area (VTA) contain separate sets of dopamine cells, one preferentially projecting to the ventral striatum (accumbens) and another to the frontal lobes in rodents [36]. This would seem to be quite important because the dopaminergic innervation of the two structures can be independent and link to different functional contexts. An enhanced dopamine activity will potentiate synaptic plasticity and enhance the possibilities for motor learning and is also related to the effects of drug abuse. The input to the dopamine system includes neocortex/ pallium and also input from the pedunculopontine nucleus and from the lateral habenula (see Figure 2). The lateral habenula is involved in the mediation of aversive behaviour and negative reward and projects directly to dopamine neurons, but also indirectly via an inhibitory group of GABAergic cells (Rostro-Medial Tegmental Current Opinion in Neurobiology 2015, 33:47–52
50 Motor circuits and action
(RMTg) nucleus) [37,38,39]. It is not yet known whether the two projection patterns (direct or via RMTg) target different dopamine neurons or if the signal can be gated to have opposite effects. An increase of the activity in the dopamine neurons relate to reward, unexpected events and a decrease to not receiving an expected reward (disappointment) [40]. As indicated schematically in Figure 2, the striatum is composed of a mosaic of striosomal and matrisomal patches or compartments. The matrisomes (matrix) are linked to the indirect and direct pathway for the control of motion, as discussed above (lower part of the diagram). The striosomes are instead involved in the control of the activity of dopamine neurons, and can therefore be assumed to be involved in the evaluation of the actions performed (upper part of Figure 2). One input to the lateral habenulae is from a glutamatergic pallidal nucleus (GPh; see Figure 2) with a high level of spontaneous activity, which in turn has input from pallium, but also directly from the striosomal compartment of striatum [39,41]. The striosomes provide direct projections to the dopamine neurons in the SNc (see [42]), but also to the route via GPh and the lateral habenulae [40]. These two different routes can be regarded as serving the function of evaluating the success of a given action, through the modulation of the dopamine activity (see Figure 2). Neurons belonging to the striosomal compartment engaged in the control of dopamine neurons are born earlier than those forming matrisomes and engage in the direct control of the direct and indirect pathways for motor actions [43]. The striatum may thus have two distinct compartments, one for control of movement and the other for evaluation of action (Figure 2). The possible relevance of the down-stream control of brainstem motor centres for Parkinson’s disease
The net effect of the decreased dopamine innervation of striatum in Parkinson’s leads to a decreased excitability in the D1 projection neurons of the direct pathway and a decreased inhibition of the D2 projection neurons of the indirect pathway. These two effects can in themselves explain part of the symptoms in Parkinson’s with regard to the difficulty in initiation of movements. The question that needs to be asked is how much of the symptoms that depend on the basal ganglia projections directly to the brainstem as opposed to those that are channelled back to cortex via thalamus. One important clue can be obtained from the lesions in the thalamic nuclei mediating the basal ganglia signals that were performed to alleviate symptoms in Parkinsonian patients (e.g. [44]). These lesions led to a marked improvement of hand tremor and the arm-hand control, deficits, which can be very handicapping for patients particularly when eating. However, these extensive thalamic lesions did not affect the postural and locomotor deficits. This would indicate that the arm-hand control from, for example, motor cortex is Current Opinion in Neurobiology 2015, 33:47–52
affected by feedback via thalamus and the enhanced oscillatory output from GPi/SNr in Parkinson’s [45]. On the other hand, the control of locomotion, posture and similar motor programs would possibly be channelled via the direct output from the basal ganglia to the brainstem centres (see [46]). The direct dopaminergic modulation from the SNc to the superior colliculus/tectum may thus also be involved in the impairment in performing saccadic eye movement seen in Parkinson’s disease.
Conclusion The basal ganglia have been conserved throughout vertebrate evolution, not only in terms of connectivity, but also in great detail with regard to transmitters, synaptic and membrane properties. The focus here has been on a conserved feature of the basal ganglia control — the downstream direct control of brainstem motor centres that most likely are of major importance not only for the control of eye movement. Taken together, old and newer data indicate that a large proportion of the control is exerted directly on different brainstem structures involved in the control of motion. Moreover, the afferent and efferent organisation of the dopamine system is virtually identical in mammals and lamprey. In both cases there are also distinct projections to downstream motor centres that may facilitate their activation.
Conflict of interest statement Nothing declared.
Acknowledgements We thank Dr Peter Walle´n for valuable comments on the manuscript. This work was supported by the Swedish Research Council, grant number: VRM-K2013-62X-03026, VR-NT 621-2007-6049, EU Cortex Training Program FP6 MEST-CT-2005-019729, EU/FP7 Select-and-Act, EU/FP7 no 604102 The Human Brain Project (HBP), and the Karolinska Institutet’s Research Funds.
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