Ancestry of Basal Ganglia Circuits:New Evidence in Teleosts
Mario F. Wullimann*
Graduate School of Systemic Neurosciences and Department Biology II, Ludwig-Maximilians-Universit€at (LMU)
Munich D-82152, Planegg, Germany
The elegant and long overdue analysis presented by
Filippi, Mueller, and Driever in this issue of Journal of
Comparative Neurology addresses questions relating to
phyletic origins of basal ganglia circuitry, specifically
whether dopaminergic (and noradrenergic) neurons in
the zebrafish (Danio rerio) brain express molecular fea-
tures characteristic of corelease of glutamate and
GABA. This is important for understanding the evolu-
tionary origins of the direct and indirect pathways for
basal ganglia control of motor function as known in
amniote vertebrates.
A hard road of comparative research led to the cur-
rent evolutionary understanding of vertebrate basal gan-
glia. In mammals, the motor loop of basal ganglia
circuitry starts in the isocortex and activates two differ-
ent striatal inhibitory (GABAergic) neuronal populations,
which give rise to a direct and an indirect pathway (see
Fig. 1). These two pathways form neural circuits running
through internal and external pallidum, reticular portion
of the substantia nigra (SNr), and a dorsal thalamic
nucleus back to premotor–motor cortex. The specific
synaptic interactions of direct and indirect pathways in
these centers and their GABAergic vs. glutamatergic
nature leads to excitatory (direct pathway) and inhibi-
tory (indirect pathway) feedback onto isocortex. In
behaviorally relevant situations, the dopaminergic com-
pact nigral population (SNc) of the basal midbrain has a
pivotal role for triggering the execution of a selected
motor behavior, because the SNc releases dopamine
onto both striatal GABAergic populations. These carry
different dopamine receptors, i.e., direct pathway cells
D1 receptors, indirect pathway cells D2 receptors. As a
consequence, the D1-mediated excitatory intracellular
signal in the striatal, direct pathway cells supports the
excitatory feedback of the direct pathway onto cortex.
In contrast, the D2-mediated inhibitory signal to striatal
indirect pathway cells changes the sign of the neuronal
output and, thus, results also in excitatory cortical feed-
back. In this way, nigral dopamine release leads to exe-
cution of a planned motor behavior through the basal
ganglia motor loop in mammals (Mink, 2008).
Consensus has been reached that in birds (Reiner,
2002; Reiner et al., 2004) homologous basal ganglia
structures and circuitry also occur, including both
descending (towards brainstem) and re-entrant path-
ways (back to dorsal pallium or Wulst). Although the sit-
uation is similar in reptiles (turtles, some lizards;
Medina and Smeets, 1991), their motor loop differs
because the major reptilian basal ganglia output leads
to motor centers of pretectum, midbrain, and brainstem
(descending pathway) and does not lead through thala-
mus back to dorsal cortex (re-entrant pathway). Anam-
niote tetrapods (amphibians) show essentially the
reptilian situation; they lack the re-entrant pathway but
show the other elements of the motor loop described
above, including the descending output pathway (Mar�ın
et al., 1998a,b; Wullimann, 2011; see Fig. 2). Thus, the
re-entrant pathway probably evolved convergently in
birds and mammals.
Exciting reports from Sten Grillner’s laboratory (Ste-
phenson-Jones et al., 2011; Ericsson et al., 2013)
recently demonstrated core elements of basal ganglia
circuitry, neurochemistry, and neurophysiology in the
river lamprey, a representative of an agnathan clade
(Braun, 1996; Fig. 2). Combined tracing and transmitter
studies demonstrate neurochemically different striatal
GABAergic neuron populations and indicate the pres-
ence of direct and indirect pathways converging into a
descending output pathway. However, lampreys lack
the re-entrant pathway (see discussion in Wullimann,
2011; and Fig. 2), consistent with the organizational
pattern of basal tetrapods, i.e., a dominant descending
output and absence of a re-entrant pathway (Medina
and Smeets, 1991; Mar�ın et al. 1998a,b; Reiner, 2002).
Grant sponsor: Graduate School for Systemic Neurosciences (GSN)at LMU-Munich; Grant sponsor: Deutsche Forschungsgemeinschaft(DFG).
*CORRESPONDENCE TO: Mario F. Wullimann, Graduate School of Sys-temic Neurosciences and Department Biology II, Ludwig-Maximilians-Universit€at (LMU) Munich, Grosshadernerstr. 2, D-82152 Planegg,Germany. E-mail: [email protected]
Received November 20, 2013; Revised December 6, 2013; AcceptedDecember 12, 2013.DOI 10.1002/cne.23525Published online December 17, 2013 in Wiley Online Library(wileyonlinelibrary.com)VC 2013 Wiley Periodicals, Inc.
The Journal of Comparative Neurology | Research in Systems Neuroscience 522:2013–2018 (2014) 2013
COMMENTARY
This suggests that lampreys exhibit an ancestral basal
ganglia machinery, including dopaminergic neurons of
the posterior tuberculum (PoTu), but not midbrain, pos-
sibly used in motor learning/performance and homolo-
gous in phylogeny throughout vertebrates. This speaks
for an extended ancestry of this system.
Unfortunately, the picture for basal ganglia in gna-
thostome fishes has remained sketchy in comparison.
Developmental genetic markers clearly delineate sub-
pallial vs. pallial telencephalic regions and furthermore
suggest the presence of separate pallidal and striatal
areas both in teleosts (involving dorsal and central
nuclei of area ventralis, Vd and Vc; Mueller et al.,
2008; Mueller and Wullimann, 2009) and in cartilagi-
nous fishes (Quintana-Urzainqui et al., 2012). Also, both
fish groups have ascending dopaminergic input to the
striatum from either basal midbrain and posterior
tuberculum (sharks; Quintana-Urzainqui et al., 2013) or
only from the posterior tuberculum (teleosts; Rink and
Wullimann, 2001). The term posterior tuberculum
(PoTu) is used here for basal plate portions of proso-
meres 1–3 (Vernier and Wullimann, 2009; see Fig. 3).
What is the developmental and phylogenetic relation-
ship of these diencephalic (posterior tubercular)
dopaminergic striatal projecting cells to the midbrain
nigral cells of other vertebrates?
The current paper sorts out glutamate/dopamine
(DA)-positive from GABA/DA-positive neuronal popula-
tions in the entire teleost (zebrafish) brain. Impor-
tantly, tyrosine hydroxylase-positive neurons of the
posterior tuberculum, among which are long-distance
striatal projection neurons (Rink and Wullimann,
2001), are identified as the only candidate for an
excitatory modulatory DA input to the striatum neces-
sary for basal ganglia function. This is critical
because of the long-known absence of obvious basal
midbrain dopamine cells in teleosts. Furthermore, this
new work establishes that intrinsic telencephalic
GABA/DA-positive cells, which indeed do contain DA
(Yamamoto et al., 2011), do not serve an equivalent
role in basal ganglia function, because these telence-
phalic cells apparently have local inhibitory roles, as
doubly GABA-DAergic cells of the olfactory bulb do in
olfactory processing (Cave and Baker, 2009). The
identification of rare glutamatergic/DAergic neurons
in the zebrafish posterior tuberculum, which includes
the long-distance ascending projection system, is a
main finding of the present JCN paper.
Figure 1. Schematic diagram of the circuitry of the basal ganglia in a mammal showing direct and indirect pathways, dopaminergic striatal input,
dopamine receptors, and transmitters involved. DA, dopamine; GABA, g-aminobutyric acid; Glu, glutamate; GPe, GPi, external and internal parts
of globus pallidus (respectively); SNc, SNr, compact and reticular parts of substantia nigra (respectively); Subthal, subthalamic nucleus.
2014 The Journal of Comparative Neurology |Research in Systems Neuroscience
M.F. Wullimann
Given an impressive projectome analysis of DA cell
populations in 3–4-day zebrafish from the Driever labo-
ratory (Tay et al., 2011), Filippi and colleagues interpret
the fraction of posterior tubercular dopaminergic striatal
projecting cells as homologous to mammalian DA group
A11. The former project to the spinal cord and the tel-
encephalon (Tay et al., 2011) and express the transcrip-
tion factor orthopedia (OTP), as various brain regions
do, for example, some telencephalic, preoptic, and
hypothalamic areas (in particular the nondopaminergic
neurons of the magnocellular preoptic nucleus homolo-
gous to the neuropeptidergic/endocrine paraventricular
nucleus of other vertebrates), as well as hindbrain
areas (Herget et al., 2013). Both otp expression and
spinal projections also apply to the mouse A11 (Ryu
et al., 2007). The interpretation of Ryu and colleagues
and Filippi and colleagues would imply that a dopami-
nergic A11 population evolved in agnathans with this
critical basal ganglia function and changed through phy-
logeny into the mammalian/amniote A11 as we
know it.
However, looking at comparative data, an alternative
scenario can be envisioned (see Fig. 3). Particularly
enlightening is the situation in amphibians, which display
dopaminergic PoTu cells in addition to midbrain DA
cells (Gonz�alez et al. 1994), with both populations hav-
ing long ascending projections to the striatum (Mar�ın
et al., 1995, 1998a,b). Furthermore, in the PoTu region
of both adult amphibians (S�anchez-Camacho et al.,
2001) and teleosts (Becker et al., 1997), a fraction of
all dopaminergic ToPu cells projects to the spinal cord,
with many more having ascending striatal projections.
Thus, although it is defensible to interpret these spinal
descending DA PoTu cells as A11, the case is different
for the DA cells with an ascending projection to the
striatum. Furthermore, embryonic mammals have DA
cells situated directly anterior to the midbrain ones, in
a region that may be considered to be posterior tuber-
cular (basal diencephalon; Puelles and Verney, 1998;
Vitalis et al., 2000; Smeets and Gonz�alez, 2000; Verney
et al., 2001; Bj€orklund and Dunnett, 2007), comparable
to the situation for amphibians (see above). Thus, basal
diencephalic DA cells anterior to the DAergic midbrain
complex apparently also exist in embryonic mammals
and are interpreted as being integrated into the mam-
malian adult basal midbrain A8/A9/A10 groups.
Clearly, the situation in amphibians and embryonic
mammals, as well as data from reptiles and birds (see
Figure 2. Simplified cladogram of extant craniates with some adult basal ganglia features. SNc, compact substantia nigra; PoTu, posterior
tuberculum. See text for details.
Basal ganglia circuitry
The Journal of Comparative Neurology | Research in Systems Neuroscience 2015
Fig. 3), indicates that a posterior tubercular component
of ascending DA cells does exist in addition to the mid-
brain nigral system in all tetrapods. As similarly dis-
cussed earlier by Smeets and Reiner (1994), the
comparative data suggest that the DAergic PoTu cells
in lampreys and teleosts are homologous to these
ascending PoTu (but not to the midbrain) DA cells in
tetrapods and that they serve basal ganglia function in
lampreys and teleosts, which is also suggested by the
current Filippi et al. contribution. As previously noted
Figure 3. Phylogeny of basal mesencephalic and diencephalic (PoTu) basal ganglia-related dopaminergic cell groups. Shown are schematic
lateral views of early developmental stages. Note that all cell groups both show dopaminergic phenotype and ascending striatal projections
in adults and that similar circuitry and neurophysiology are established at least for mammals, birds/reptiles, and lampreys. Dependence
on OTP in development has been demonstrated in mammals and teleosts for diencephalic groups. See text for details. A8–11, dopaminer-
gic groups; Hy, hypothalamus; Ist, isthmus; P1, P2, P3, prosomeres 1, 2, 3; M, mesencephalon; Oc, optic chiasm; PoTu, posterior tubercu-
lum. Dashed line indicates anteroposterior axis and basal–alar plate boundary. Redrawn after Mar�ın et al. (1998a,b) and extended for
teleosts (after Rink and Wullimann, 2002), sharks (after Carrera et al., 2005), and lampreys (after Barreiro-Iglesias et al., 2010).
M.F. Wullimann
2016 The Journal of Comparative Neurology |Research in Systems Neuroscience
(Wullimann, 2011), both A11 and the diencephalic com-
ponent of ascending DA cells apparently originate in
PoTu in vertebrates. In summary, the following phyloge-
netic scenario seems likely. Starting with agnathans,
both descending and ascending long projection DAergic
systems exist in the vertebrate PoTu. In gnathostomes,
a large additional DAergic midbrain fraction of striatal
ascending cells evolves (present in cartilaginous fishes),
which likely is lost in teleosts. The mammalian A11
cells develop in the alar plate of P1–P2 (Puelles and
Verney, 1998; Vitalis et al., 2000; Smeets and
Gonz�alez, 2000; Verney et al. 2001; Bj€orklund and Dun-
nett, 2007) but may have an earlier developmental ori-
gin in basal plate posterior tuberculum. Diencephalic,
but not mesencephalic, ascending (and descending) DA
projection neurons are likely all OTP dependent and
apparently have an uninterrupted phylogenetic history
from agnathans to mammals (see Fig. 3).
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M.F. Wullimann
2018 The Journal of Comparative Neurology |Research in Systems Neuroscience