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: wullimann@bio.lmu.de

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