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The “basal ganglia” refers to a group of subcortical nuclei responsible primarily for motor
control, as well as other roles such as motor learning, executive functions and behaviors, and
emotions. Proposed more than two decades ago, the classical basal ganglia model shows
how information flows through the basal ganglia back to the cortex through two pathways
with opposing effects for the proper execution of movement. Although much of the model
has remained, the model has been modified and amplified with the emergence of new data.
Furthermore, parallel circuits subserve the other functions of the basal ganglia engaging
associative and limbic territories. Disruption of the basal ganglia network forms the basis
for several movement disorders. This article provides a comprehensive account of basal
ganglia functional anatomy and chemistry and the major pathophysiological changes un-
derlying disorders of movement. We try to answer three key questions related to the basal
ganglia, as follows: What are the basal ganglia? What are they made of? How do they work?
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Some insight on the canonical basal ganglia model is provided, together with a selection of
paradoxes and some views over the horizon in the field.
he basal ganglia and related nuclei consist of century, which showed that lesions of the len-
T a variety of subcortical cell groups engaged
primarily in motor control, together with a
ticular nucleus ( putamen and globus pallidus)
and the subthalamic nucleus (STN) were asso-
wider variety of roles such as motor learning, ciated with parkinsonian signs, dystonia, and
executive functions and behavior, and emo- hemiballismus (Wilson 1925; Purdon-Martin
tions. The term basal ganglia in the strictest 1927). Thus, the terms extra-pyramidal system
sense refers to nuclei embedded deep in the and extra-pyramidal syndrome were frequently
brain hemispheres (striatum or caudate-puta- used in the past to refer to the pathological
men and globus pallidus), whereas related nuclei basis of movement disorders in an attempt to
consist of structures located in the diencephalon make a clear distinction from the pyramidal sys-
(subthalamic nucleus), mesencephalon (sub- tem (corticofugal neurons that give rise to cor-
stantia nigra), and pons ( pedunculopontine nu- ticospinal projections). At present, these terms
cleus). Ideas and concepts regarding the func- and distinctions are considered obsolete and
tions of the basal ganglia were strongly influ- misleading and, therefore, will not be used in
enced by clinical observations during the 20th this article.
1
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The basal ganglia and related nuclei can be BASAL GANGLIA NUCLEI
broadly categorized as (1) input nuclei, (2) out-
Input Nuclei: The Striatum
put nuclei, and (3) intrinsic nuclei. Input nuclei
are those structures receiving incoming infor- The striatum is by far the largest subcortical
mation from different sources, mainly cortical, brain structure in the mammalian brain, with
thalamic, and nigral in origin. The caudate nu- an estimated volume of 10 cm3 in the human
cleus (CN), the putamen (Put), and the accum- brain (Schröeder et al. 1975). It is a heteroge-
bens nucleus (Acb) are all considered input nu- neous structure that receives afferents from sev-
clei. The output nuclei are those structures that eral cortical and subcortical structures and pro-
send basal ganglia information to the thalamus jects to various basal ganglia nuclei.
and consist of the internal segment of the globus
pallidus (GPi) and the substantia nigra pars re-
Striatal Neurons: Projection Neurons
ticulata (SNr). Finally, intrinsic nuclei such as
and Interneurons
the external segment of the globus pallidus
(GPe), the STN and the substantia nigra pars The striatum contains two different types of
compacta (SNc) are located between the input neurons: projection neurons and interneurons
and output nuclei in the relay of information. (90% and 10% of striatal neurons, respective-
Cortical and thalamic efferent information en- ly). Projection or striatofugal neurons are also
ters the striatum (CN, Put, and Acb) to be pro- called medium-sized spiny neurons (MSNs) be-
cessed further within the basal ganglia system. cause these multipolar neurons have small to
The output nuclei (GPi and SNr) project main- medium cellular somata (20 mm in diameter),
ly to the thalamus (ventral nuclei), which, in and their dendritic processes are covered by
turn, project back to the cerebral cortex (mainly postsynaptic specializations called dendritic
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frontal lobe). The appropriate functioning of spines (Fig. 2). All striatal MSNs are inhibitory
the basal ganglia system requires dopamine to neurons that use GABA as the neurotransmitter.
be released at the input nuclei. Dopamine dys- Striatofugal MSNs could be divided further, ac-
function is associated with several basal ganglia cording to their projection targets, into those
movement disorders such as the parkinsonian innervating the GPe nucleus and those pro-
syndrome (i.e., Parkinson’s disease), dystonia, jecting to the output nuclei GPi and SNr. Stria-
chorea, and tics. All major basal ganglia com- tal MSNs innervating the GPe nucleus express
ponents are illustrated in Figure 1. the dopamine receptor subtype 2 (D2R), which
CN
GPe
Put
ac
GPi
Acb STN
SNc
SNr
Figure 1. Basal ganglia nuclei. Parasagittal section through the monkey brain (stained with the acetylcholin-
esterase method) showing the localization and boundaries of all major components of the basal ganglia system.
Figure 2. Striatal medium-sized spiny neurons (MSNs). Striatal MSNs are the most abundant neuronal phe-
notype in the striatum (representing up to 95% of the total number of striatal neurons). These medium-sized
neurons (20 mm in diameter) are multipolar stellate cells with radially oriented dendrites. These dendrites are
covered by small postsynaptic specializations called dendritic spines. Photomicrograph taken from a striato-
nigral-projecting MSN, retrogradely labeled following the delivery of rabies virus into the substantia nigra pars
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reticulata.
inhibits intracellular adenyl-cyclase trough G- aspiny cholinergic neurons that use acetylcho-
protein signaling, and give rise to the indirect line as neurotransmitter. Electrophysiologically,
pathway (striato-GPe-STN-GPi/SNr). On the these neurons show a rather continuous and
other hand, striatal MSNs projecting directly constant firing pattern of activity and are there-
to GPi and SNr contain dopamine receptor sub- fore also known as tonically active neurons
type 1 receptors (D1R), which activate adenyl- (TANs). Another type of striatal interneuron is
cyclase signaling (D1-containing neurons), and GABAergic and also contains the calcium-bind-
give rise to the direct striatopallidal pathway. ing protein parvalbumin. Based on their electro-
Furthermore, striatal MSNs projecting through physiological fingerprint, these neurons are also
the indirect pathway are known to contain the called fast-spiking interneurons (FSIs). Another
neuropeptide enkephalin, whereas the neuro- group of GABAergic interneurons with a differ-
peptides substance P and dynorphin are ex- ent phenotype is those containing the calcium-
pressed in those MSNs projecting directly to binding protein calretinin. In addition to parval-
the GPi and SNr. bumin and calretinin, a third type of GABAergic
In addition to these spiny projection neu- interneuron, known as nitrergic interneuron,
rons, the striatum also contains several different uses nitric oxide as the neurotransmitter. Both
classes of local-circuit neurons (interneurons), TAN and FSI interneurons modulate the activity
all of which show smooth dendrites. Inter- of striatofugal neurons and are, in turn, under
neurons in the striatum are often classified into dopaminergic control, forming a complex intra-
four groups depending on their neurochemical striatal microcircuit, which is discussed below
profiles and morphological characteristics (for (see section “Classic Basal Ganglia Model”). Cal-
review, see Kawaguchi et al. 1995). The most retinin-positive and nitrergic interneurons in-
abundant group of interneurons consists of large nervate TAN and FSI interneurons.
Striatal Compartments: Striosomes and Matrix substance P, GABA, and neurotensin (Graybiel
et al. 1981; Gerfen 1984), whereas the matrix
The striatum appears as a rather homogeneous compartment is enriched with calcium-binding
structure when viewed with cytoarchitectural proteins such as parvalbumin (Prensa et al.
techniques; however, the use of some specific 1999) and calbindin (Fig. 3) (Gerfen et al. 1985).
immunohistochemical markers highlights two In terms of striatal afferent and efferent sys-
subdivisions: striosomes and matrix compart- tems, striosomes and the matrix could be viewed
ments. The first evidence for these striatal as isolated compartments. Although striatal
compartments, shown using the histochemical MSNs show profuse arborization throughout
detection of the enzyme acetylcholinesterase the striatum (Fig. 2), their dendritic domains
(AChE), was published in the late 1970s by and local axon collaterals remain restricted
Graybiel and Ragsdale (1978). The pattern of within the striatal compartment in which they
AChE staining revealed the presence of several are located. In other words, dendrites from
patchy areas showing weak AChE activity (strio- MSNs located in a striosomal compartment
somes, sometimes also called patches) im- never enter the matrix, and the same holds
mersed within a background of more intense true for matrix MSNs. Such a distinct compart-
AChE staining (matrix). Moreover, the immu- mental segregation of MSNs was first reported
nocytochemical detection of the m opioid re- by Penny et al. (1988) and Kawaguchi et al.
ceptor revealed an enriched expression of this (1989) and more recently confirmed by Fujiya-
receptor within the striosomes, together with a ma et al. (2011). Furthermore, matrix MSNs
weaker expression in the matrix (Perth et al. innervate the GPe, GPi, and SNr, whereas
1976; Desban et al. 1995). From a neurochem- MSNs located in striosomes preferentially pro-
ical perspective, striosomes are characterized by ject to the SNc, also giving rise to axon collat-
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strong immunoreactivity against enkephalin, erals targeting the GPe, GPi, and SNr (Gerfen
Figure 3. Striatal compartments. Although the striatum appears as a rather homogeneous structure, several
histochemical and immunohistochemical stains evidence the presence of two compartments named striosomes
and matrix. The photomicrograph is taken from a parasagittal section through the primate striatum. The
immunohistochemical detection of the calcium-binding protein calbindin reveals the presence of a number
of patchy areas with weak calbindin stain (striosomes) immersed within a background showing higher calbindin
stain (matrix).
1984; Bolam et al. 1988; Kawaguchi et al. 1989; ally (Reiner et al. 2003; for review, see Reiner
Giménez-Amaya and Graybiel 1990; Fujiyama et al. 2010). Furthermore, IT-type neurons
et al. 2011). mainly innervate striatal MSNs giving rise to
Striatal glutamatergic afferents originating the direct pathway, whereas PT-type neurons
from the cerebral cortex, thalamus, and amyg- mainly contact striatal MSNs in the indirect cir-
dala, as well as dopaminergic afferents aris- cuit (Lei et al. 2004). More recently, such
ing from SNc are heterogeneously distributed a selective pattern of striatal innervation from
throughout the striosome/matrix compart- IT-type neurons has been challenged by Baillon
ments. Motor and sensory areas of the cerebral et al. (2008), who show that IT-type neurons
cortex, together with thalamostriatal projec- equally excite striatonigral and striatopallidal
tions and dopaminergic neurons from the SNc, neurons (direct and indirect pathway neurons
mainly innervate the matrix compartment, in rodents). However, this is not completely
whereas cortical limbic areas, the basolateral inconsistent with preferential IT-type input
amygdala, and ventral parts of the SNc prefer- to MSNs of the direct pathway and PT-type in-
entially target striosomes (Graybiel 1984, 1990; nervation of striato-GPe neurons (Lei et al.
Donoghue and Herkenham 1986; Ragsdale 2004).
and Graybiel 1988; Gerfen 1992; Sadikot et al. In addition to the corticostriatal system,
1992a,b; Kincaid and Wilson 1996). At present, thalamostriatal projections are a major source
an accurate explanation of the functional corre- of glutamatergic afferents reaching the stria-
late underlying this striosome/matrix compart- tum. Initial descriptions of the thalamostriatal
mental organization is still lacking. system were made by Vogt and Vogt (1941) as
well as by Powell and Cowan (1956) in the mid-
20th century. Although this pathway has been
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shafts, whereas thalamic inputs arising from nu- mesolimbic dopaminergic projections. At least
clei other than the CM-Pf complex contact den- two different territories have been described
dritic spines (Raju et al. 2006). Furthermore, within the SNc: dorsal and ventral tiers. Dopa-
although the midline and intralaminar thalam- minergic neurons in the ventral tier are orga-
ic nuclei are often considered the main source nized in columns, enter the SNr, and give rise
of the thalamostriatal system (Berendse and to a topographically organized nigrostriatal pro-
Groenewegen 1990; Groenewegen and Berendse jection (Lynd-Balta and Haber 1994a,b; Ha-
1994), it is worth noting that the ventral tha- ber et al. 2000). Dopaminergic terminals densely
lamic motor nuclei also contribute to thala- innervate the striatal matrix compartment,
mostriatal projections (McFarland and Haber whereas striosomes display different densities
2001). of nigrostriatal innervation (Prensa and Parent
The corticostriatal and thalamostriatal pro- 2001). Nigrostriatal axons synapse with both
jections can be differentiated based on the type types of striatal MSNs. It has been generally ac-
of vesicular glutamate transporter expressed. cepted that dopaminergic input exerts a facilita-
The vesicular glutamate transporter isoform 1 tory effect on D1R-containing MSNs (direct
(vGlut1) has been commonly used as a marker pathway neurons) and an inhibitory effect on
for corticostriatal projections, whereas the vesic- D2R-containing MSNs (indirect pathway neu-
ular glutamate transporter isoform 2 (vGlut2) rons). Such a dichotomous effect on striatal
typically characterizes thalamostriatal terminals projection neuron activity represents one of
(Kaneko et al. 2002; Fujiyama et al. 2004, 2006; the foundations of the basal ganglia model,
Raju and Smith 2005; Raju et al. 2006). Despite as explained below; however, it should not be
this apparent segregation of glutamate trans- taken for granted in physiological terms. An
porters, vGlut1 transcripts have been found important morphological feature of the nigro-
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in ventral relay and associative thalamic nuclei striatal projection is the very large number of
(Barroso-Chinea et al. 2007), which contrib- axonal arborizations it expresses. In the rat,
ute substantially to the thalamostriatal system one dopaminergic axon is estimated to inner-
(Beckstead 1984a,b; Smith and Parent 1986; Be- vate some 75,000 MSNs, and one MSN is under
rendse and Groenewegen 1990; Erro et al. 2001, the influence of 95 – 194 dopaminergic neurons
2002; McFarland and Haber 2001; Van der Werf on average (Matsuda et al. 2009). These figures
et al. 2002). In this regard, recent data from our are thought to be much higher in the primate,
group have shown coexpression of vGlut1 and where one dopaminergic neuron may make up
vGlut2 transcripts within single thalamostria- to 1 million synaptic contacts onto striatal neu-
tal-projection neurons located in thalamic ter- rons. This huge profusion of dopaminergic con-
ritories other than the midline and intralaminar nectivity implies a wide modulatory effect of
nuclei (Barroso-Chinea et al. 2008). dopamine by the nigrostriatal projection.
In summary, the thalamostriatal system is Finally, other sources of glutamatergic in-
currently viewed as a dual system, consisting of puts to the striatum arise from the amygdaloid
a projection originating from midline and intra- complex reaching striosomes (Ragsdale and
laminar thalamic nuclei (vGlut2-positive pro- Graybiel 1988) and serotoninergic projections
jections), together with another projection that originating from the raphe nuclei, with a pre-
arises from ventral and associative relay nuclei ponderant role for the dorsal raphe nuclei. The
that uses both isoforms of the vesicular gluta- presence of serotoninergic projections has long
mate transporter. been characterized (Andén et al. 1966; Bobillier
The nigrostriatal system originates from the et al. 1976; Szabo 1980), and its functional cor-
SNc (A9 group from Dahlström and Fuxe 1964) relate remains unknown. More recently, this
and provides the major source of dopaminergic projection has gained increasing attention be-
innervation reaching the striatum. The retroru- cause serotoninergic axons have been suggested
bral field (A8) and the ventral tegmental area to underlie graft-induced dyskinesias and by
(A10) also participate in the mesostriatal and extension levodopa-induced dyskinesias (López
et al. 2001, López-Real et al. 2003; Carta et al. MSNs innervating the GPi and SNr also send
2007, 2008a,b, 2010). axon collaterals to the GPe, whereas most striatal
MSNs were found to innervate GPe directly (Ka-
waguchi et al. 1990; Parent et al. 2000; Wu et al.
Striatal Efferents: Striatum-GPe
2000). It is also worth noting that these types of
and Striatum-GPi/SNr
anatomical data have their own limitations, in-
Two main routes for striatofugal projections cluding a limited number of axons being recon-
have been properly characterized: D2R-express- structed and the lack of information on the rel-
ing striatal MSNs innervating the GPe and D1R- ative importance of each axon collateral when
expressing striatal MSNs projecting down- compared with the main axonal terminal field.
stream to the GPi and SNr. It has been formerly
considered that striatal fibers reaching GPe and
Output Nuclei: Globus Pallidus, Internal
GPi were, in fact, collaterals of striatonigral pro-
Segment, and Substantia Nigra Pars Reticulata
jections (Fox and Rafols 1975), although the
current view of the striatofugal system describes The GPi, also known as the medial division of
three different types of striatofugal MSNs, in- the globus pallidus, and the SNr are often
nervating the GPe, GPi, or SNr (Beckstead and grouped together as basal ganglia output nuclei
Cruz 1986). However, it is well known that ef- because they share a number of cyto- and che-
ferent striatal neurons interact with different moarchitectural characteristics and to some
target structures through axon collaterals (for extent similar types of afferent and efferent sys-
review, see Parent et al. 2000), and, indeed, mod- tems. Both nuclei consist of inhibitory GA-
ern dual retrograde tract-tracing studies have BAergic neurons with a high rate of discharge
shown that a substantial proportion of striato- that fire tonically to inhibit their targets. In
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nigral-projecting MSNs send collaterals to GPe comparison with the striatum, the GPi shows
(Castle et al. 2005). Although much anatomical, a smaller cellular density. This feature, together
neurochemical, and electrophysiological evi- with the presence of a large number of myelin-
dence has supported the complementary distri- ated striatofugal fibers crossing the GPi nucleus,
bution of D1R and D2R within different types of provides the GPi with a paler appearance when
striatofugal neurons (Beckstead et al. 1988; Ger- compared with the striatum.
fen et al. 1990; for review, see Bertrán-González As discussed above, the GPi and SNr receive
et al. 2010), such a sharp degree of D1R/D2R two different types of inputs. D1R-containing
complementary expression still remains contro- striatal MSNs that give rise to the direct pathway
versial. In this regard, two fundamental ques- are a major source of inhibition to the GPi and
tions remain unanswered: whether the segrega- SNr. The STN provides an excitatory glutama-
tion of striatofugal MSNs is matched by the tergic projection to the GPi and SNr, part of the
differential expression of dopamine receptors indirect pathway. The subthalamopallidal and
and whether the two populations of striatofugal subthalamonigral projections are highly collat-
MSNs are fully segregated from each other. The eralized (simultaneously reaching GPi and SNr
recent implementation of BAC-transgenic mice neurons) and can be easily characterized im-
has shown that only a small number of striatal munohistochemically using antibodies against
efferent neurons (,6% in the dorsolateral stria- vGlut2. Both types of afferent systems (GA-
tum) coexpress D1R and D2R (Bertrán-González BAergic and glutamatergic) converge onto basal
et al. 2008). These newly available data challenge ganglia output neurons, which, in turn, inner-
earlier indications that roughly half of striatal vate thalamic targets and brainstem (i.e., supe-
MSNs coexpress both dopamine receptors (for rior colliculus, PPN). Thalamic-recipient areas
review, see Bertrán-González et al. 2010). When of basal ganglia output neurons differ slightly
considering anatomical data gathered from jux- when considering pallidothalamic versus nigro-
tacellular tract-tracing studies and single axon thalamic projections, differences that paved the
reconstruction, approximately half of striatal way for introducing an accurate parcellation of
the ventral thalamic nuclei based on hodologi- projection from D2R-containing striatal MSNs,
cal criteria (Ilinsky and Kultas-Ilinsky 1987; an inhibitory projection that represents the first
Percheron et al. 1996). In this respect, pallid- synaptic relay station of the indirect pathway as is
othalamic projections innervate the densicellu- discussed below. Moreover, striatal projections
lar and parvicellular territories of the ventral innervating GPe neurons also show an enriched
anterior motor thalamus (VAdc and VApc, re- expression of adenosine type 2A receptors (A2A-
spectively), whereas nigrothalamic projections Rs), and thus antibodies against A2A-Rs have
mainly target the magnocellular division of the been used to define the boundaries of the GPe
ventral anterior motor thalamus (VAmc). More- nucleus accurately (Rosin et al. 1988; Bogenpohl
over, thalamic intralaminar nuclei (mainly the et al. 2012). GPe neurons are also reciprocally
CM-Pf complex) are also known to be innervat- connected with STN neurons from which they
ed by basal ganglia output. There are two routes receive strong glutamatergic excitatory projec-
by which pallidothalamic projections can gain tions (vGlut2-positive). The existence of such
access to their respective thalamic targets: (1) a close interrelationship between the GPe and
projections that arise from neurons located in STN has provided the foundation for no longer
lateral GPi territories form the ansa lenticularis considering the GPe as simply a relay station
that course around the internal capsule finally between the striatum and the STN (Shink et al.
entering the so-called field H of Forel (also 1996; Joel and Weiner 1997; Nambu 2004). Fur-
known as the prerubral field); and (2) axons thermore, it has long been known that both seg-
from more medially located GPi neurons that ments of the globus pallidus (GPe and GPi) are
course through the internal capsule to form the also reciprocally interconnected. Finally, anoth-
lenticular fasciculus (Forel’s field H2) located er minor source of glutamatergic afferents is rep-
between the STN and the zona incerta. The len- resented by inputs received from the caudal in-
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ticular fasciculus merges with the ansa lenticu- tralaminar nuclei (Kincaid et al. 1991; Marini
laris at the level of field H of Forel to enter the et al. 1999; Yashukawa et al. 2004).
thalamic fasciculus (H1 of Forel), the latter fi-
nally reaching ventral and intralaminar thalam-
Subthalamic Nucleus
ic nuclei.
Extensive research has been performed in the
last few decades focused on the subthalamic
INTRINSIC NUCLEI nucleus of Luys. This small subcortical nucleus,
with densely packed neurons, is located imme-
Globus Pallidus, External Segment
diately ventral to the zona incerta and rostral to
The GPe (also known as the lateral division of the the substantia nigra. It has become very relevant
globus pallidus) is part of the pallidal complex and well known over the last decade because it is
together with GPi and the ventral pallidum. The the best surgical target for electrode placement
GPe is surrounded laterally by the putamen, during deep brain stimulation (STN-DBS). The
from which it is separated by the lateral medul- canonical basal ganglia model (Albin et al. 1989;
larly lamina. The boundary between the GPe and DeLong 1990) provided an oversimplified view
GPi is made of another thin layer of myelinated of afferent and efferent STN connectivity. This
fibers named the medial medullarly lamina. The simplistic view, which only considered GA-
GPe shares with the GPi several cyto- and che- BAergic input from the GPe and STN efferents
moarchitectural features, because both nuclei are targeting basal ganglia output nuclei, has been
made of sparsely distributed GABAergic neu- superseded by much experimental evidence
rons with large somas. All GPi and GPe neurons that emerged shortly after the model was first
are also characterized by an enriched expression introduced (see section, “Pathophysiology: A
of the calcium-binding protein parvalbumin. Summary,” below). Besides the classical GA-
Two principal afferent systems innervate BAergic projection from GPe neurons (second
GPe neurons. The GPe receives a GABAergic relay station of the indirect pathway), the STN
also receives glutamatergic projections from the tion or inhibition of the caudal intralaminar
cerebral cortex (known as the hyperdirect path- nuclei (Mouroux et al. 1995).
way) (see Nambu et al. 2002; Nambu 2004, The bulk of STN efferent projections are
2005) and the ipsilateral thalamic caudal intra- directed toward the basal ganglia nuclei, a
laminar nuclei (Sugimoto and Hattori 1983; projection typically characterized by highly
Sugimoto et al. 1983; Royce and Mourey 1985; branched neuronal processes. It has been pos-
Sadikot et al. 1992a,b; Sidibé and Smith 1996; tulated that most STN efferent neurons send
Marini et al. 1999; Gonzalo et al. 2002; Lanciego axons that simultaneously innervate the GPi,
et al. 2004, 2009; Castle et al. 2005), as well as a GPe, and SNr (Van der Kooy and Hattori
minor projection from the contralateral caudal 1980; Kita et al. 1983; Kita and Kitai 1987; Plenz
intralaminar nuclei (Gerfen et al. 1982; Castle and Kitai 1999; Castle et al. 2005). The pattern
et al. 2005). Finally, it is also worth noting that of axonal collateralization has served to identify
the STNalso receives a sparse dopaminergic pro- up to five distinct types of STN efferent neurons
jection from the SNc, as a part of the so-called (Parent et al. 2000; Sato et al. 2000). In addition
nigro-extrastriatal projection system (for review, to STN projections to the GPi, GPe, and SNr,
see Rommelfanger and Wichmann 2010). efferent STN neurons also innervate thalamic
The cerebral cortex sends direct projections targets: those projecting ipsilaterally to ventral
to the STN, which, in turn, innervates the out- thalamic motor nuclei (Nauta and Cole 1978;
put nuclei, thus providing a way for motor-re- Rico et al. 2010) and a smaller contralateral
lated cortical areas to access the output nuclei projection linking the STN with the parafascic-
directly, bypassing the input nuclei. This path- ular nucleus (Gerfen et al. 1982; Castle et al.
way is characterized by shorter conduction 2005). Furthermore, dual retrograde tract-trac-
times than those funneled through direct and ing studies have shown that subthalamic projec-
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indirect basal ganglia pathways and therefore tions reaching the GPi and ventral thalamic nu-
exerts powerful excitation onto basal ganglia clei largely arise from different subpopulations
output. Furthermore, cortical inputs arising of STN neurons (Rico et al. 2010).
from the primary motor cortex, the supplemen-
tary motor area, premotor cortices, frontal eye
Substantia Nigra Pars Compacta
field area, and supplementary eye field area are
conveyed through the cortico-subthalamic hy- Deep in the ventral midbrain, several groups of
perdirect pathway, somatotopically organized at tyrosine-positive neurons supplying the basal
the level of the STN (Nambu et al. 1996, 2002). ganglia nuclei with dopamine can be found.
The direct projection arising from the caudal According to Dahlström and Fuxe (1964), these
intralaminar nuclei is another important source dopaminergic neurons could be classified in up
of glutamatergic activation, described in ro- to three main groups: A10 neurons (ventral teg-
dents, cats, and primates (Sugimoto and Hat- mental area), A9 neurons (SNc), and A8 neu-
tori 1983; Sugimoto et al. 1983; Royce and rons (retrorubral field). Neurons from the A10
Mourey 1985; Sadikot et al. 1992; Sidibé and field mainly innervate the accumbens nucleus as
Smith 1996; Marini et al. 1999; Gonzalo et al. well as several limbic-related areas, whereas the
2002; Lanciego et al. 2004, 2009; Castle et al. nigrostriatal projection mainly arises from the
2005). Thalamo-subthalamic projections are A9 and A8 dopaminergic groups. In the past
topographically organized (Sadikot et al. 1992; few years, efforts were made to subdivide the
Lanciego et al. 2004), reaching STN efferent SNc into several clusters or cell groups. Because
neurons innervating the GPe and SNr/GPi this issue is beyond the scope of this article, this
(Castle et al. 2005). Furthermore, thalamo-sub- will not be addressed here. However, more
thalamic projections are bilateral, albeit with an information can be found elsewhere (Gonzá-
ipsilateral predominance (Castle et al. 2005). lez-Hernández and Rodrı́guez 2000; Fu et al.
Indeed, opposite changes in STN activity have 2012). In humans, dopaminergic neurons locat-
been found following drug-induced stimula- ed in the SNc contain the dopamine precursor
neuromelanin, a pigment that produces the physiology of movement, the existence of par-
black color inherent to SNc territories as seen allel circuits subserving oculo-motor control,
in freshly extracted brains in human necropsies. executive functions, and emotions was also rec-
Interestingly, this black pigment of the SNc is ognized.
still maintained in human albinism, because The basis of the model resides in the stria-
the gene coding cutaneous melanin is different topallidal connections via the direct and the
from the one coding neuromelanin. Dopami- indirect projections (Fig. 5), which have an op-
nergic neurons in the SNc degenerate progres- posite functional effect on basal ganglia output
sively in Parkinson’s disease (PD), leading to (Albin et al 1989; DeLong 1990). Activation of
severe dopamine deficiency and the appearance GABAergic MSNs that give rise to the direct
of the cardinal features of the disease. Neurons pathway inhibits GPi/SNr tonic activity, induc-
still alive often display intracellular aggregates ing a pause of neuronal firing. At the same time,
of misfolded proteins, from which a-synuclein activation of MSNs of the indirect pathway first
is the most prominent, giving rise to circular inhibits GPe neurons, followed by disinhibition
shape aggregates known as Lewy bodies (Fig. of the STN, which then excites GPi/SNr neu-
4), which represent the histopathological hall- rons. Because pauses of neuronal firing in the
mark of PD. basal ganglia output are associated with the
occurrence of an action (e.g., an eye movement
saccade), and discharges are associated with
FUNCTIONAL ORGANIZATION OF THE stopping or halting movement, the direct and
BASAL GANGLIA: THE CANONICAL MODEL indirect pathways are viewed as opposite func-
tional projection systems that facilitate and in-
Classic Basal Ganglia Model
hibit movements and behaviors, respectively. As
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The functional organization of the basal ganglia previously mentioned, the nigrostriatal projec-
formulated in the 1980s was based on the con- tion exerts a differential effect on D1R/D2R
cept that neuronal signals from the cortex flow MSNs, facilitating and inhibiting the direct and
to the striatum, through the GPi and SNr, and indirect circuits, respectively (Gerfen et al.
project back to the cortex via the thalamus, 1990). Accordingly, dopaminergic depletion
forming parallel cortico – basal ganglia – tha- reduces the facilitation of MSNs in the direct
lamo – cortical loops. Although the model was pathway and increases the activation of indi-
primarily formulated to understand the patho- rect circuit neurons, which leads to increased
Figure 4. Lewy bodies in dopaminergic neurons from the substantia nigra pars compacta. In humans suffering
from Parkinson’s disease, dopaminergic neurons accumulate intracytoplasmatic aggregates of misfolded a-
synuclein. These aggregates often adopt a circular shape and form the so-called Lewy bodies, which represent
the pathological hallmark of this disease. Dual immunofluorescent detection of tyrosine hydroxylase (red
channel) and a-synuclein (green channel), identifying two dopaminergic neurons from a PD patient, one of
them showing a typical intracytoplasmic Lewy body.
Striatum Striatum
Excitatory
Inhibitory
STN STN
Modulatory
Normal state Parkinsonian state
Figure 5. Schematic summary of the original basal ganglia model. The motor circuit is composed of a cortico-
striatal ( putaminal) projection, two major striatofugal projection systems giving rise to the direct and indirect
pathways, and the efferent pallido –thalamo –cortical projections to close the motor loop. The thickness of
arrows represents the functional state of a given circuit. Thicker arrows illustrate hyperactive pathways, whereas
thinner arrows represent hypoactive circuits.
activity of the STN, which, in turn, overactivates and therefore facilitate or disinhibit movements.
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inhibitory output neurons in the GPi/SNr, such However, in monkeys and patients, pallidotomy
that the reduction of GABAergic inhibition of does not induce involuntary movements, but
direct MSNs combined with an increased glu- on the contrary, it abolishes dyskinesias (Car-
tamatergic driving force from the disinhibited penter et al. 1950; Lozano et al. 1995). (2) Lesion
STN increases activity in the GPi/SNr. This ef- of the STN, GPi, or motor thalamus singly or in
fectively reduces the likelihood of phasic inhib- combination does not deteriorate motor func-
itory activity in these output neurons, thus tion (Marsden and Obeso 1994), but it is actu-
impeding movement initiation and execution. ally associated with marked improvement in PD
Seminal studies in the monkey by Crossman patients (Obeso et al. 2009).
(1987) led to a similar understanding of the Nevertheless, the model served to stimulate
dyskinetic state (i.e., hemichorea-ballism and considerable advances in the understanding of
levodopa-induced dyskinesias), essentially con- basal ganglia organization and, importantly,
sidered to result from decreased GPi output paved the way for the resurgence of functional
and, therefore, functionally opposed to the par- neurosurgery for Parkinson’s disease (see be-
kinsonian state (Obeso et al. 2000, 2008). low). Interestingly, two recent studies in the
This dual concept of the classic basal gan- rat using optogenetics have provided strong
glia model gained considerable support from support for the classical model. Kravitz et al.
many different experimental and clinical sources. (2010) showed that selective stimulation of
Over the years, quite a few difficulties were en- MSNs expressing D2R (indirect circuit) pro-
countered in trying to fit together new findings voked movement arrest, whereas activation
with the classical model, creating paradoxes of MSNs expressing D1R led to movement acti-
that have been hotly discussed. Among these, vation. This essentially confirmed the notion
the two best recognized and puzzling paradoxes that the indirect and direct circuits are in func-
are the following: (1) Lesion of the basal ganglia tional equilibrium, inhibiting and facilitating
output should provoke a marked reduction in movement, respectively. Bateup et al. (2010)
inhibition of the thalamocortical projection found that the loss of DARPP-32 in the “direct”
teract with internal reentry loops (Fig. 6) form- In monkeys, bicuculline injections in the
ing a complex network, ideally designed for se- motor putamen elicited focal, brief muscle jerks
Excitatory
Cerebral cortex
Inhibitory
Dopaminergic
SNc
GPe
STN
Thalamus
GPi-SNr
Normal state
Figure 6. Basal ganglia circuits. Cartoon showing the main circuits linking the basal ganglia nuclei. Besides
traditional cortico-basal ganglia-thalamocortical circuits, several transverse loops have been described in the last
few years, most of them with a putative modulatory role.
(tic-like) that were accompanied by increased project to each striatal MSN, and 100 MSNs
neuronal activity in the GPe, marked reduction project onto each pallidal neuron. This arrange-
in the GPi, and increased firing in the primary ment is probably the anatomical basis for fun-
motor cortex (M1) time-locked to the jerks damental striatal function, that is, selection and
(McCairn et al. 2009). This is a firm indication filtering of incoming/outgoing signals. The ca-
that movement release is punctually associated pacity of the striatum to filter massive incoming
with a reduction of GPi output activity. More- signals is facilitated by several mechanisms,
over, focal bicuculline injections, to block spe- among which the nigrostriatal dopaminergic
cific subregions of the striatum, GPe, and STN projection plays a paramount role. Thus, do-
produced dyskinesias, stereotopies, and hyper- pamine exerts a dual effect on MSNs (Onn et al.
activity among other behavioral abnormalities 2000), inhibiting striatal D2R-containing neu-
when injected into the postero– lateral (motor) rons and exciting striatal neurons that express
segment, associative and limbic regions (Fran- D1Rs through L-type calcium channels. Activa-
çois et al. 2004; Karachi et al. 2009). Injections tion of selected nigrostriatal projections leads
in the ventral striatum also elicited sexual be- to dopamine elevation in innervated striatal re-
haviors (erection and ejaculation) and vomiting gions in parallel with a marked dopamine re-
(Worbe et al. 2009). duction in adjacent zones. This is supported
Human activation studies using functional by experimental evidence indicating that dopa-
magnetic resonance imaging (fMRI) and posi- mine enhances synchronous corticostriatal af-
tron emission tomography (15-0 H2O-PET) ferent volleys while simultaneously inhibiting
showed topographical segregation according to other inputs (Bamford et al. 2004). The crea-
the requested task and underlying functions. tion of a gradient or salient pattern of activity
Thus, activation in the posterior (i.e., sensori- is thought to govern dopaminergic signaling,
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motor) putamen was consistently encountered probably underlying the responses to reward
for movements and presented a somatotopical (and addiction), habit formation, and motor
organization, with the leg lying dorsal, face ven- learning. Another important component of
tral, and arm in between, as expected (Lehéricy striatal internal functioning is provided by stria-
et al. 2005). Preparatory activation as well as tal cholinergic TANs and GABAergic FISs inter-
finger movement sequencing was located more neurons. Phasic release of dopamine induces
rostrally in the anterior putamen, whereas acti- firing pauses in TANs that facilitate cortico-
vation of the associative territory was observed striatal transmission (Bonsi et al. 2011). GA-
during tasks such as motor internal representa- BAergic interneurons, which are also modulat-
tion selection and planning of sequential ac- ed by dopamine, along with axon collaterals
tions (Monchi et al. 2006), whereas tasks evok- from MSNs, mediate a powerful intrastriatal in-
ing emotional responses typically activate the hibition (Tepper et al. 2004). Together, inter-
region of the ventral striatum, where the accum- neurons modulate striatal excitability providing
bens nucleus is recognized. a mechanism to facilitate a given pool of MSNs
excited from the cortex, while competing stim-
Functional Anatomy uli are canceled.
Initial studies recording STN activity in and are caused by pathophysiological mecha-
awake monkeys performing a task indicated nisms directly involving the basal ganglia are
that neuronal firing occurred after or coinciding the following: (1) the parkinsonian syndrome
with movement initiation (DeLong et al. 1985). composed of rigidity, akinesia/bradykinesia,
This suggested that the STN was not involved and resting tremor; (2) dystonia characterized
with signals associated with movement onset, in by prolonged muscle spasms and abnormal
keeping with the prevailing idea that the STN postures; and (3) chorea-ballism, in which frag-
was mainly related to movement inhibition. ments of movements flow irregularly from one
However, recent studies recording single cell ac- body segment to another, to cause a dance-like
tivity and local field potentials in patients with appearance. When the amplitude of the move-
Parkinson’s disease have shown clear evidence ment is very large, the term ballism is applied.
of activation up to 1 sec before initiation of From a practical point of view, levodopa-in-
movement (Rodriguez-Oroz et al. 2001; Alegre duced dyskinesias in PD patients, which are by
et al. 2005). Thus, when a voluntary movement and large choreic in nature, represent the most
is going to be performed, the same cortical vol- frequent cause of choreic dyskinesias in the ge-
ley that arrives to the putamen is dispatched to neral population.
the STN. Indeed, studies in monkeys have
shown that the cortico-STN-GPe/GPi projec-
The Parkinsonian Syndrome
tion is a fast-conducting system, well placed to
modulate basal ganglia output (Nambu 2004). The best known cause and example of the
parkinsonian syndrome is Parkinson’s disease,
Subcortical Connections. Thalamo-Basal Gan- which is mainly characterized by poverty of
glia Loops and Brainstem Circuits. The role and spontaneous movements (hypokinesia) and
www.perspectivesinmedicine.org
excitability in the direct cortico-putaminal-GPi 2000). The initial evidence, therefore, support-
projection (Obeso et al. 2008). ed a major role for the indirect pathway for the
Remarkably, our current understanding of induction of dyskinesias. Subsequently, record-
basal ganglia pathophysiology does not provide ing of neuronal activity in the GPe and GPi in
an adequate explanation for the two other car- MPTP-treated monkeys and PD patients during
dinal features of Parkinson’s disease, namely, surgery, although showing levodopa-induced
rigidity and tremor. Regarding the latter, studies dyskinesias, further showed the increase and re-
in PD patients during surgery and in the mon- duction of GPe and GPi neuronal activity, re-
key MPTP model have started to unravel some spectively, as a basic pathophysiological feature
interesting features (Heimer et al. 2002). Never- of choreic dyskinesias (Papa et al. 1999). More
theless, it is fascinating to realize that when recently, evidence has accumulated for in-
nearly reaching 200 years after James Parkinson creased and extra-synaptic shifting of NMDA
described the “Shaking Palsy,” and therefore, glutamatertic receptors (Gardoni et al. 2006)
the parkinsonian tremor, its origin remains a and abnormal D1R receptor activation in the
mystery. striatum of dyskinetic animals (Berthet et al.
2009), suggesting a paramount role of the direct
circuit as a mediator of levodopa-induced dys-
Pathophysiology of Dyskinesias
kinesias (Bateup et al. 2010).
Chorea-ballism is the abnormal release of frag-
ments of normal movement. In simple terms,
the pathophysiology of dyskinetic movements CONCLUSIONS
may be seen as the opposite of parkinsonism. The basal ganglia network may be viewed as
Chorea is mainly caused by drugs, such as levo-
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Cold Spring Harb Perspect Med 2012; doi: 10.1101/cshperspect.a009621 originally published online
October 15, 2012
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