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The Journal of Neuroscience, May 1, 2002, 22(9):3776-3787
A Telencephalic Nucleus Essential for Song Learning Contains
Neurons with Physiological Characteristics of Both Striatum and Globus
Pallidus
Michael A.
Farries1 and
David J.
Perkel2
1 Department of Neuroscience, University of
Pennsylvania, Philadelphia, Pennsylvania 19104, and
2 Departments of Zoology and Otolaryngology, University of
Washington Medical Center, Seattle, Washington 98195-6115
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ABSTRACT |
The song system of oscine birds has frequently been presented as a
model system for motor learning in vertebrates. This practice has been
bolstered by the growing recognition that one part of the song system
that is essential for song learning, area X, is a component of the
avian striatum. The mammalian striatum, the input structure of the
basal ganglia, has been implicated in a number of motor-related
functions, including motor learning, suggesting that song learning in
birds and motor learning in mammals may use similar physiological
mechanisms. We studied the intrinsic physiological properties of area X
neurons in brain slices to see how closely they match properties
identified in mammalian striatal neurons and to collect data that are
necessary to understand how area X processes information. We found that
area X contains all four physiological cell types present
in the mammalian striatum and that each is very similar to its
mammalian counterpart. We also found a fifth cell type in area X that
has not been reported in mammalian striatum; instead, this cell
type resembles neurons that have been recorded in the mammalian globus
pallidus. This pallidum-like cell type morphologically resembles the
projection neurons of area X. We suggest that area X contains a pathway
equivalent to the "direct" striatopallidothalamic pathway through
the mammalian basal ganglia, with the striatal and pallidal components
intermingled in one nucleus.
Key words:
songbird; striatum; basal ganglia; motor learning; area
X; song learning
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INTRODUCTION |
Birdsong has emerged as one of the
leading models for studying motor learning in vertebrates, combining an
easily quantified, naturally learned behavior with a circumscribed
neural substrate. That neural substrate consists of a motor pathway
that is required for singing (Nottebohm et al., 1976 ) and an anterior
forebrain pathway (AFP) that is not required for singing per se, but is required for song learning (Fig. 1)
(Bottjer et al., 1984; Sohrabji et al., 1990; Scharff and Nottebohm,
1991). The AFP appears to process song-related auditory feedback (Doupe
and Konishi, 1991; Doupe, 1997) and is hypothesized to calculate some
sort of error signal that guides the motor pathway to produce the
target song (Brainard and Doupe, 2001). Our goal is to understand the
physiological mechanisms by which this signal is generated and
transmitted, focusing on the first nucleus of the AFP, area X.
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Figure 1.
Diagram of the oscine song system in a schematic
parasagittal section of the avian brain. The motor pathway begins with
HVc (used as a proper name, not an abbreviation; Fortune and
Margoliash, 1995), which projects to the nucleus robustus of the
archistriatum (RA) (Nottebohm et al., 1976). RA projects to several
brainstem nuclei concerned with respiration and vocalization (Nottebohm
et al., 1976; Wild, 1993) that are not shown explicitly in this figure.
HVc also projects to the AFP, beginning with area X (Nottebohm et al.,
1976). Area X projects to the medial portion of the dorsolateral
anterior thalamic nucleus (DLM) (Okuhata and Saito,
1987; Bottjer et al., 1989), DLM projects to lateral magnocellular
nucleus of the anterior neostriatum (LMAN) (Bottjer
et al., 1989), and LMAN completes the circuit by projecting to RA
(Nottebohm et al., 1982) and to area X (Nixdorf-Bergweiler et al.,
1995; Vates and Nottebohm, 1995). Most of the forebrain song system
nuclei are in the pallium (HVc, RA, and LMAN) or thalamus (DLM) and
have glutamatergic projection neurons. Area X, however, is a component
of the avian basal ganglia (shown in gray) and has
GABAergic projection neurons.
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Area X is a component of the avian basal ganglia, lying in a region
identified previously as a homolog of the striatum (for review, see
Medina and Reiner, 1995), the input structure of the basal
ganglia. Like the mammalian striatum, area X has GABAergic projection neurons (Luo and Perkel, 1999b) and putative interneuron populations containing choline acetyltransferase (ChAT) (Zuschratter and Scheich, 1990), nitric oxide synthase (Wallhäusser-Franke et
al., 1995), and parvalbumin (Meade et al., 1998). Given these histochemical similarities, area X neurons could also share some of
characteristic physiological properties of the mammalian
striatum. Knowing the intrinsic physiological properties of area
X neurons is essential for understanding how it processes and transmits information, and if they prove to be similar to mammalian striatal neurons, it would suggest that the two structures use comparable mechanisms to carry out their respective functions. Moreover, one
function ascribed to the mammalian striatum is a role in motor learning
(Graybiel et al., 1994; Doya, 2000), so concordant physiological properties in area X and the mammalian striatum offer the possibility that research in the song system will be directly applicable to mammals.
Some problems with this conjecture are apparent at the outset, however.
Area X projects directly to the thalamus (Okuhata and Saito, 1987;
Bottjer et al., 1989), whereas the mammalian striatum communicates with
the thalamus via the globus pallidus (Parent and Hazrati, 1995). The
lack of an intervening pallidal structure between area X and the
thalamus also highlights an apparent inconsistency in how auditory
information is transmitted through area X. Excitatory auditory
responses to the bird's own song have been recorded both upstream
(McCasland and Konishi, 1981; Margoliash, 1983) and downstream (Doupe
and Konishi, 1991) of area X, yet one might naively expect area X to
convert an excitatory response into an inhibitory one via its GABAergic
projection neurons. This sign reversal would be counteracted by a
second GABAergic relay through a pallidal structure, if it existed. To
address questions concerning the organization of area X and its
relationship to the mammalian basal ganglia, and to gain essential
information on the intrinsic physiological properties of its neurons,
we made whole-cell current-clamp recordings from area X in several
songbird species.
Parts of this paper have been published previously in abstract form
(Farries and Perkel, 1998).
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MATERIALS AND METHODS |
Preparation of brain slices. The bird species used in
this study were purchased from a local supplier (zebra finches,
Bengalese finches, and canaries), raised in our own breeding colony
(juvenile zebra finches), collected in the wild and hand-reared (one
white-crowned sparrow), or generously provided by Dr. G. Ball (Johns
Hopkins University, Baltimore, MD) (starlings). Adult zebra
finches (Taeniopygia guttata) were housed three to five per
cage, whereas juvenile zebra finches raised in our colony were kept in
cages containing only their parents and siblings. Other avian species
were housed individually until they were used. Birds were kept on a
13/11 hr light/dark cycle, except for starlings, which were kept on an
11/13 hr cycle. Slices were prepared as described by Stark and Perkel
(1999). The procedures were approved by the Institutional Animal Care
and Use Committees at the University of Pennsylvania and the University
of Washington. Briefly, birds were anesthetized with isoflurane or
halothane and killed by decapitation. The brain was quickly removed and
immersed in ice-cold artificial CSF (ACSF) containing (in
mM): 119 NaCl, 2.5 KCl, 1.3 MgSO4, 2.5 CaCl2, 1 NaH2PO4, 26.2 NaHCO3, and 11 D-glucose.
Parasagittal or coronal brain slices, 300-400 µm thick, were cut
using a vibrating microtome and collected in ACSF (usually heated to
30°C, sometimes at room temperature). On occasion, a modified ACSF
was used during slicing (but not during slice storage or recording)
containing 10 mM HEPES and only 16.2 mM
NaHCO3, but which was otherwise identical to ACSF described
above. All solutions were bubbled with a mixture of 95%
O2 and 5% CO2.
Electrophysiological recording. Slices were placed in a
recording chamber and superfused with ACSF at 24-27°C. We recorded using the "blind" (Blanton et al., 1989) or visualized (Edwards et
al., 1989) whole-cell techniques. Recording pipettes had a resistance
of 4-9 M and were filled with a solution containing (in
mM): 120 K gluconate or K methylsulfate, 10 HEPES, 2 EGTA, 8 NaCl, 2 MgATP, and 0.3 MgGTP. The osmolarity and pH of
this solution were adjusted to 275-285 mOsm and 7.2-7.4,
respectively. We did not observe any differences in recordings made
with K gluconate versus those made with K methylsulfate. In
approximately one-half of our recordings, 0.5% neurobiotin (Vector
Laboratories, Burlingame, CA) or biocytin (Sigma, St. Louis, MO) was
included in the pipette solution to permit visualization of the
recorded neuron. Signals were amplified with an Axoclamp 2B (Axon
Instruments, Foster City, CA) followed by a Brownlee model 410 amplifier (Brownlee Precision Co., Santa Clara, CA). They were
low-pass-filtered at 1-3 kHz and digitized at twice (or more) the
filter cutoff frequency using a National Instruments (Austin, TX) data
acquisition board with custom data collection software written in
LabVIEW (National Instruments). Membrane potentials were corrected for
a liquid junction potential of +5 mV. The drugs used in this study,
4-aminopyridine (4-AP; Research Biochemicals, Natick, MA) and cesium
chloride, were bath-applied.
Measurement of electrophysiological parameters. Basic
electrophysiological parameters were measured as described by Farries and Perkel (2000a). Because the membrane resistance of many of our
recorded neurons varied considerably with membrane potential (as
explained by Farries and Perkel, 2000a), the input resistance was not
simply calculated from the response of each neuron to a small
current pulse delivered at rest. Instead, the input resistance was
defined as the maximum slope of the current-voltage curve at
membrane potentials more negative than  50 mV. This provides a measure
of input resistance that does not depend on what the resting membrane
potential of each cell happens to be. The "delay to first action
potential" is defined as the time from the onset of a 500 msec
depolarizing current pulse to the occurrence of the first action
potential (AP) in traces in which only one AP was fired. If no such
traces were available in a recording, we made this measurement on
traces containing the fewest APs. Other electrophysiological parameters
(listed in Table 2) were measured using custom software written in IGOR
(WaveMetrics, Lake Oswego, OR), as detailed by Farries and Perkel
(2000a).
Anomalous spiny neurons in area X. As we describe in
Results, we found a spiny neuron (SN) type in area X of the zebra finch that was very similar to the medium spiny type of the mammalian striatum. However, most (132 of 191) spiny neurons recorded in area X
of zebra finches exhibited "anomalous" firing properties that
distinguished them from mammalian striatal spiny neurons. In
particular, these cells fired spikes at the onset of depolarizing current pulses, could only rarely fire more than one or two spikes during a given pulse, and sometimes had unusually broad APs. We believe
that these neurons were very likely cells that had been damaged during
the slicing process rather than a distinct and novel cell type, because
cells like this have been recorded in the mammalian striatum after
intracellular dialysis (C. Wilson, personal communication) and
because in a few zebra finches almost all recorded cells were of the
"healthy" variety. We reasoned that if these anomalous spiny
neurons recorded in zebra finches were simply sick, area X of other
songbird species might not be as sensitive to the slicing process and
would thus exhibit a lower proportion of such neurons. We tested this
idea by recording from area X in Bengalese finches (Lonchura
striata), canaries (Serinus canaria), starlings
(Sturnus vulgaris), and a white-crowned sparrow (Zonotrichia leucophrys). In all of those species, the
proportion of anomalous spiny neurons was much lower compared with
zebra finches: 0 of 8 in a Bengalese finch (one bird), 2 of 17 in
canaries (two birds), 4 of 12 in starlings (three birds), and 2 of 4 in a white-crowned sparrow (one bird). We concluded that the anomalous spiny neurons are indeed injured or otherwise altered spiny neurons and
excluded them from further analysis. Readers interested in a detailed
description of these cells can consult Farries and Perkel (2000a),
which describes such neurons recorded from the basal ganglia outside of
area X in zebra finches; these neurons are essentially identical to the
ones recorded from area X. A summary of the different cell types
recorded from each songbird species is given in Table
1. We checked for general differences among species by comparing the parameters shown in Table
2 for the SN cell type (the only type
common enough to permit comparison); there were no significant
differences at the p = 0.05 level (one-way ANOVA for
each of the 10 parameters, using the Bonferroni correction because 10 separate ANOVAs were performed), so the data acquired from different
species are combined in all subsequent analyses.
Histology and immunohistochemistry. After recordings
were made using neurobiotin or biocytin, slices were immersion-fixed in
paraformaldehyde (4% in 0.1 M phosphate buffer, for at
least 4 hr) and cryoprotected by immersion in a cold sucrose solution (30% in 0.1 M phosphate buffer, for at least 4 hr). Slices
were resectioned to a 30-60 µm thickness with a freezing microtome. Tracer-filled neurons were visualized using an
avidin-biotin-horseradish peroxidase complex kit (Vector
Laboratories) followed by a reaction with a peroxidase substrate,
either diaminobenzidine or the Vector VIP kit (Vector
Laboratories). To make morphological measurements, images of filled
cells were acquired with a digital camera and measurements were taken
with the assistance of image-analysis software (Global Lab Image; Data
Translation Inc., Marlboro, MA). The photomicrographs shown in the
figures were acquired with a digital camera, except for those acquired
using confocal microscopy (as noted in the figure legends). The images
for each cell are montages of several images of that cell taken at
different focal planes, to show as much of the neuron in focus as
possible. For ChAT immunostaining, sections were incubated
overnight in 1:1000 primary antibody ( ChAT 1465; gift of Dr. M. L. Epstein, University of Wisconsin, Madison, WI) at 4°C,
followed by incubation overnight with Cy5-conjugated secondary
antibody (1:200; Jackson ImmunoResearch, West Grove, PA) at 4°C. In
this ChAT labeling experiment, the intracellular biocytin fill was
visualized for fluorescence by incubating slices with
Cy2-conjugated streptavidin (Jackson ImmunoResearch); images
were acquired with a confocal microscope.
Tracer injection. The medial poriton of the dorsolateral
anterior thalamic nucleus (DLM)-projecting area X neuron shown in Figure 14 was labeled by injecting the bidirectional tracer
tetramethylrhodamine-conjugated dextran (3000 kDa; Molecular Probes,
Eugene, OR) into the DLM of an adult male zebra finch. The surgery was
performed as described by Luo and Perkel (1999b) and tracer was
injected iontophoretically with 5 µA pulses (7 sec on/7 sec off) for
20 min using a Midgard Precision Current Source (Stoelting Co., Wood
Dale, IL). After allowing 5 d for retrograde transport, the
bird was given a lethal overdose of pentobarbital and perfused
transcardially with 0.9% saline followed by 4% paraformaldehyde (in
0.1 M phosphate buffer). The brain was removed and
cryoprotected by immersion in 30% sucrose solution (in 0.1 M phosphate buffer) overnight. Brain sections (30 µm
thick) were cut using a freezing microtome, mounted on glass slides,
and imaged by confocal microscopy.
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RESULTS |
The most common cell type in area X closely resembles the principal
cell type of the mammalian striatum
We identified a total of five cell types in area X. The majority
of cells we recorded (92 of 141) were small (soma diameter, 5-10 µm)
and possessed moderately to densely spiny dendrites (Fig. 2C); accordingly, we
designated this cell type as spiny neuron (SN). On hyperpolarization,
these cells always exhibited fast inward rectification (i.e., a rapid
decrease in membrane resistance) (Fig. 2A,B). We
quantified this inward rectification by calculating the ratio of
minimum membrane resistance achieved during hyperpolarization to the
input resistance; this ratio was 0.21 ± 0.17 (mean ± SD; n = 70). When injected with depolarizing current
pulses, all SNs exhibited a characteristic ramping response (Fig.
2A), ultimately producing APs that were substantially
delayed relative to the onset of the current pulse for sufficiently
large current levels (Fig. 3). As larger
current pulses were delivered, these cells fired at higher rates (Fig.
3B) and with a shorter delay from the onset of the pulse to
the first spike (Fig. 3C); some spike-rate accommodation was
present (Fig. 3D). SNs did not fire spontaneously. Physiological and morphological measurements for SNs and all other cell
types are given in Table 2; Table 3
summarizes the significant differences among them.
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Figure 2.
Intrinsic properties of the SN cell type.
A, Response of a SN to a series of hyperpolarizing and
depolarizing current pulses. The baseline potential was 82 mV.
B, Graph of the steady-state voltage deflection in this
neuron as a function of current pulse amplitude. C,
Photomicrograph of the neuron shown in A and
B, filled with biocytin. This photomicrograph, like all
others in this paper except the confocal images, is a montage of
several images of this cell taken at different focal planes to show as
much of the cell in focus as possible. Scale bar, 10 µm. This cell
was recorded in a canary brain slice.
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Figure 3.
Firing properties of the SN cell type.
A, Sample traces of an SN firing in response to four
successively larger 500 msec current pulses. The baseline potential was
84 mV. B, Firing rate plotted as a function of
injected current for five representative SNs. The firing rate was
defined as the inverse of the average interspike interval, so
that the delay before the first spike is excluded from this
calculation. Each symbol corresponds to a different
neuron, and a given symbol represents the same neuron in
B-D (e.g., the filled circles signify
the same cell in all panels). C, Delay
from the onset of the current pulse to the time of the first spike for
the same five SNs, plotted as a function of current amplitude.
D, Spike rate accommodation for these SNs, illustrated
by plotting the instantaneous firing rate (inverse of the interspike
interval) for each interval during a current pulse that evoked a mean
firing rate of ~20 Hz. Current pulse amplitude for each neuron:
filled circle, 0.12 nA; filled square,
0.12 nA; filled triangle, 0.10 nA; open
circle, 0.16 nA; open square, 0.14 nA. Each
point in these graphs represents the average of two
repetitions of the same current amplitude. All current pulses were 500 msec in duration. The sample traces shown in A were
taken from the neuron denoted by open circles in
B-D. The cells denoted by filled circles
and open squares were recorded in canary brain slices;
the others are from zebra finches.
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The SNs we recorded in area X were remarkably similar to the principal
cell type of the mammalian striatum, the medium spiny neuron (MSN).
They share two characteristic properties: fast inward rectification on
hyperpolarization and a ramping response to depolarizing current (Kita
et al., 1984; Jiang and North, 1991; Nisenbaum and Wilson, 1995). In
mammals, the fast inward rectification is blocked by
Cs+, whereas the ramping response is
eliminated by 4-AP, a blocker of A-type K+
channels (Nisenbaum et al., 1994; Nisenbaum and Wilson, 1995). We
further examined the physiological similarities between area X and the
mammalian striatum by examining the effect of these channel blockers on
area X SNs. Bath application of 100 µM 4-AP eliminated
the ramping response and the delayed spiking in SNs (Fig.
4A) (n = 12; delay to first spike went from 421 ± 56 msec to 181 ± 94 msec on application of 4-AP; p < 0.0001, paired
t test), just as it does in mammalian MSNs. Bath application
of 3 mM CsCl abolished the fast inward
rectification (Fig. 4B) (n = 4; the
inward rectification ratio went from 0.18 ± 0.13 to 1.00 ± 0.00 on application of CsCl; p = 0.001, paired
t test) and usually revealed outward rectification in
response to hyperpolarizing current (data not shown), an effect that
has also been observed in mammalian MSNs (Uchimura et al., 1989;
Belleau and Warren, 2000). Our experiments did not find any qualitative
electrophysiological or morphological difference between the spiny
neurons of area X and those of mammalian striatum.
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Figure 4.
4-AP-sensitive and cesium-sensitive conductances
in SNs. A, 4-AP eliminates the ramping response and
delayed spiking in SNs. Left, Response of an SN to three
successively larger depolarizing current pulses before drug
application. Right, Response of this SN to the same
current pulses after bath application of 100 µM 4-AP. The
baseline membrane potential was 80 mV. B, Cesium
blocks the fast inward rectification exhibited by SNs.
Left, Response of an SN to a series of hyperpolarizing
current pulses before drug application. Right, Response
of this SN to the same current pulses after bath application of CsCl.
The baseline membrane potential was 74 mV. Both of these neurons were
recorded in zebra finch brain slices.
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Presumptively cholinergic neurons in area X resemble the
cholinergic interneurons of mammalian striatum
All of the other cell types we found in area X had aspiny or
sparsely spiny dendrites and had substantially larger somata than the
SNs. One such cell type exhibited a characteristically long-duration
afterhyperpolarization (AHP) after each AP and are named
"long-lasting afterhyperpolarization" (LA) neurons (Fig. 5). These cells fired spontaneously at
low rates (five of eight cells at 0.7 ± 0.2 Hz) or exhibited slow
membrane potential fluctuations without spiking (Fig.
6A); they generally did
not rest at a stable membrane potential (the "resting potential"
given in Table 2 was measured at times when these cells were more
quiescent and should be interpreted loosely). These cells often (five
of eight) exhibited time-dependent inward rectification in response to
hyperpolarizing current pulses (seen as a sag in membrane potential
during the pulse), followed by rebound depolarization or spiking (Fig.
6B). When injected with depolarizing current pulses,
they fired repetitively (Fig. 6D), but none of our
recorded LA neurons could sustain firing at rates of >10 Hz. Instead,
a larger depolarizing current would evoke only one or two spikes at the
beginning of the pulse (Fig. 6C).
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Figure 5.
Intrinsic properties of the LA cell type.
A, Response of an LA neuron to a series of
hyperpolarizing and depolarizing current pulses. These current pulses
were delivered from a hyperpolarized potential of 90 mV, maintained
by continuous injection of 0.16 nA. B, Graph of the
steady-state voltage deflections in this neuron as a function of
current pulse amplitude. C, Photomicrograph of the
neuron shown in A and B, filled with
neurobiotin. Scale bar, 10 µm. This neuron was recorded in a zebra
finch brain slice.
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Figure 6.
Firing properties of the cholinergic LA cell type.
A, A spontaneous depolarizing event recorded in an LA
neuron (recorded from a zebra finch); the cell would normally fire a
fast AP at the crest of this event. The membrane potential at the
beginning of the trace was 65 mV. The calibration is shown in
D. B, Response of a different LA neuron
to a hyperpolarizing current pulse during ongoing spontaneous activity,
showing a sagging response. The spontaneous firing rate was momentarily
elevated after the current pulse. The baseline potential was 54 mV.
C, Response of an LA neuron to a +0.3 nA current pulse;
the LA is no longer apparent. (This is the same cell shown in Fig. 7.)
The baseline potential is 61 mV. The calibration is shown in
D. D, Sample traces of an LA neuron
firing in response to three successively larger 500 msec current
pulses. (This is the same cell shown in Fig. 5.) The amplitudes of the
current pulses are indicated to the right of each trace.
These current pulses were delivered from a hyperpolarized potential of
90 mV, maintained by continuous injection of 0.16 nA.
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The LA neurons of area X bear a striking resemblance to a cell type of
the same name identified in the mammalian striatum. Both types have
unusually long afterhyperpolarizations (Kawaguchi, 1992, 1993), can be
spontaneously active in vitro at comparable rates (Bennett
and Wilson, 1999), and show a sagging response to hyperpolarization
that is followed by rebound depolarization (Kawaguchi, 1992, 1993). The
LA neurons of the mammalian striatum contain ChAT, the enzyme that
synthesizes acetylcholine (Kawaguchi, 1993). Naturally, we wondered
whether the LA neurons of area X contain ChAT, and in one case we were
able to process a filled LA neuron for ChAT immunohistochemistry. This
neuron proved to be ChAT-positive (Fig.
7). The LA neurons of area X are
physiologically and histochemically very similar to their counterparts
in the mammalian striatum; the few differences we did observe (lesser capacity for repetitive firing, less prominent time-dependent inward
rectification) could have been attributable to differences in recording
conditions or the state of our brain slices.
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Figure 7.
ChAT immunoreactivity in an LA neuron.
A, Spike evoked in an LA neuron, showing the
characteristic long-lasting afterhyperpolarization. The baseline
potential was 64 mV, maintained by continuous injection of 0.04 nA.
B, Biocytin fill of this neuron, visualized with
Cy2-conjugated streptavidin and acquired with a confocal microscope.
Scale bar, 25 µm. C, ChAT immunostaining in this
neuron visualized with a Cy5-conjugated secondary antibody, suggesting
that it is cholinergic. This neuron was recorded from a zebra finch
brain slice.
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Low-threshold spike cell type in area X
A second large, aspiny cell type we observed in area X fired a
broad, plateau-like AP when injected with a depolarizing current from a
hyperpolarized baseline potential (Fig.
8); we call these neurons
"low-threshold spike" (LTS) cells. LTS cells rested at relatively
depolarized potentials (Table 2) or in some cases spontaneously fired
bursts of APs (three of nine cells) (Fig. 9A). When injected with
hyperpolarizing current pulses, LTS cells displayed a sagging response
indicative of time-dependent inward rectification (Fig.
8A,B). A depolarizing rebound followed the termination of hyperpolarizing current pulses, which triggered APs in
some cases (Fig. 9B). The plateau-like spike of LTS cells was triggered at a relatively negative threshold potential: 57 ± 5 mV. This plateau-like spike was accompanied by a few conventional fast APs restricted to the early peak of the plateau (Fig.
8A), but in one cell spiking continued at a lower
rate throughout the injected current pulse (Fig. 9C). The
plateau generally could be evoked only if the cell was first
hyperpolarized (Fig. 9D), which is not surprising in light
of the fact that these neurons invariably rested at potentials more
depolarized than the threshold for the plateau-like spike.
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Figure 8.
Intrinsic properties of the LTS cell type.
A, Response of an LTS neuron to a series of
hyperpolarizing and depolarizing current pulses. These current pulses
were delivered from a hyperpolarized potential of 76 mV, maintained
by the continuous injection of 0.06 nA. B, Graph of
the steady-state voltage deflections in this neuron as a function of
current pulse amplitude. Filled circles, Voltage
deflection at the end of the current pulse; open
circles, voltage deflection earlier in the current pulse, near
the bottom of the "sag" (time of measurement indicated by the
position of the circles below the voltage
traces in A). C, Photomicrograph of the
neuron shown in A and B, filled with
neurobiotin. Scale bar, 10 µm. This neuron was recorded in a zebra
finch brain slice.
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Figure 9.
Firing properties of the LTS cell type.
A, Example of spontaneous activity in an LTS neuron;
this neuron exhibited the highest rate of spontaneous activity of any
LTS neuron we recorded. B, Rebound spike fired after a
hyperpolarizing current pulse delivered from rest. The baseline
potential was 60 mV. C, An example of an LTS neuron
that could fire APs throughout a depolarizing current pulse. The
baseline potential was 69 mV, maintained by continuous injection of
0.02 nA. This cell is the same as the one shown in A.
D, APs evoked in an LTS cell by a current pulse
delivered from rest (top, baseline potential of 47 mV)
and a hyperpolarized potential (bottom, baseline
potential of 67 mV maintained by continuous injection of 0.06 nA).
All of the cells in this figure were recorded in zebra finch brain
slices.
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The LTS cell type of area X, like the SN and LA cell types, strongly
resembles its counterpart in the mammalian striatum. This mammalian
cell type, known as the LTS or "persistent low-threshold spike" (PLTS) interneuron class, fires plateau-like spikes, exhibits a sagging response to hyperpolarization that can be followed by rebound
spikes, and fires fast APs near the beginning of the plateau (Kawaguchi, 1993; Kubota and Kawaguchi, 2000), just as in the LTS
neurons of area X. There is some heterogeneity in the firing properties
of the LTS/PLTS cell type in mammals (Koós and Tepper, 1999),
which also appears among our recorded LTS neurons (specifically, the
sustained firing evident in the cell shown in Fig. 9B).
Fast-spiking cell type in area X
Two physiological classes of GABAergic interneuron are known
in the mammalian striatum: the LTS/PLTS class discussed above and a
fast-spiking (FS) class (Kawaguchi, 1993; Kubota and Kawaguchi, 2000).
Area X also has an FS cell type. These cells were significantly larger
than SNs and possessed aspiny or sparsely spiny dendrites (Fig.
10C). They did not fire
spontaneously, and exhibited varying degrees of fast inward
rectification when hyperpolarized (Fig. 10A,D)
(minimum resistance to input resistance ratio, 0.45 ± 0.35; range, 0.12-0.93). When injected with depolarizing current pulses, FS
neurons sometimes gave a ramping response (much briefer than that seen
in SNs; arrow in Fig. 10D) coincident with
or followed by intermittent spiking. FS cells characteristically fired
APs in bursts interspersed with silent intervals containing small oscillations in membrane potential (Fig.
11A,B). With
increasing current injections, each burst contained more APs (Fig.
11A) fired at higher intraburst rates (Fig.
11C, open circles) and with shorter intervals
between bursts, until above a certain current level the neuron fired
continuously at very high rates (Fig. 11A,
bottom). In all these respects, the FS neurons in area X
were virtually identical to mammalian striatal FS cells, save only that
the FS cells we recorded rested at more depolarized membrane potentials (Kawaguchi, 1993; Koós and Tepper, 1999).
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Figure 10.
Intrinsic properties of the FS cell
type. A, Response of an FS neuron to a series of
hyperpolarizing and depolarizing current pulses. The baseline potential
was 55 mV. B, Graph of the steady-state voltage
deflections in this neuron as a function of current pulse amplitude.
C, Confocal image of the neuron shown in
A and B, filled with biocytin. Scale bar,
25 µm. D, Response of a different FS neuron to current
pulses (delivered from a potential of 75 mV maintained by continuous
injection of 0.02 nA). This panel illustrates two
common properties of FS neurons not clearly visible in
A: a brief ramping response to depolarization
(arrow) and fast inward rectification on
hyperpolarization. Both neurons in this figure were recorded in zebra
finch brain slices.
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Figure 11.
Firing properties of the FS cell type. The cell
depicted here is the same as that in Figure
10A-C. A, Sample traces of this
cell firing in response to three successively larger 500 msec current
pulses. The amplitudes of the current pulses are indicated to the
right of each trace. For moderate current amplitudes,
the cell fired intermittently. The baseline potential was 55 mV.
B, Histogram of interspike intervals for this
cell during +0.35 nA current pulses (three repetitions). This shows two
populations of interspike intervals: short (<30 msec) intraburst
intervals and longer (>40 msec) interburst intervals ("pauses").
C, Firing rate of this cell as a function of injected
current. Filled circles show the firing rate averaged
over the entire current pulse; open circles
show the firing rate during current levels that evoked intermittent
firing, excluding the pauses. This rate was defined as the inverse of
the intraburst interspike interval (i.e., excluding intervals that were
>40 msec). These points were an average of one to three repetitions of
each current pulse.
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The aspiny, fast-firing cell type of area X resembles a cell type
found in the mammalian globus pallidus
The four cell types described above account for all of the major
physiological classes identified in the mammalian striatum to date.
However, we did find a fifth physiological cell type in area X that has
never been reported in the mammalian striatum. These neurons are most
clearly distinguished from the other four types by their propensity to
fire APs spontaneously at a relatively high rate (18.4 ± 11.6 Hz)
(Fig. 12A).
Morphologically, these cells were not unlike the FS cell type,
possessing a relatively large soma surrounded by thin, beaded, highly
branched neurites (Fig. 12D). We call this the
aspiny, fast-firing (AF) cell type.
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Figure 12.
Intrinsic properties of the AF cell type.
A, Spontaneous activity recorded in an AF neuron;
calibration is the same as in B. B,
Response of this neuron to a series of hyperpolarizing and depolarizing
current pulses. These current pulses were delivered from a
hyperpolarized potential of 75 mV, maintained by the continuous
injection of 0.06 nA. C, Graph of the steady-state
voltage deflections in this neuron as a function of current pulse
amplitude. Filled circles, Voltage deflection at the end
of the current pulse; open circles, voltage deflection
earlier in the current pulse, near the bottom of the sag (time of
measurement indicated by the position of the circles
below the voltage traces in A).
D, Photomicrograph of the neuron shown in
A-C, filled with neurobiotin. Scale bar, 10 µm. This
neuron was recorded in a zebra finch brain slice.
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To study the current-voltage relationship in these neurons, we
silenced their spontaneous activity by continuously injecting hyperpolarizing current, holding them at a baseline potential of
approximately 75 mV. Hyperpolarizing current pulses evoked a sagging
response, followed by a depolarizing rebound after the pulse, whereas
subthreshold depolarizing pulses produced a depolarizing hump near the
onset of the pulse followed by a small hyperpolarization after its
termination (Fig. 12B,C). Hyperpolarizing pulses
could trigger a rebound burst (Fig.
13C) and hyperpolarizing
pulses delivered during spontaneous firing were succeeded by a
transient increase in the firing rate relative to baseline (Fig.
13D). When depolarizing pulses (delivered from a
hyperpolarized baseline) were large enough to trigger APs, the spike
rate was typically highest early in the pulse and declined to a slower,
steady rate thereafter (Figs. 12A, 13). The firing
rate increased roughly linearly with current amplitude (Fig.
13B) and AF cells could sustain firing at very high rates,
sometimes exceeding 100 Hz (Fig. 13A).
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Figure 13.
Firing properties of the AF cell type.
A, Sample traces of this cell spiking in response to
three successively larger 500 msec current pulses. The amplitudes of
the current pulses are indicated to the right of each
trace. Spontaneous activity was silenced by the continuous injection of
0.19 nA. The baseline potential was 75 mV. B, Firing
rate plotted as a function of injected current for five representative
AF cells. The sample traces shown in A were taken from
the neuron denoted by a filled square. C,
Rebound firing evoked in an AF cell by a hyperpolarizing current pulse.
Spontaneous activity was silenced by the continuous injection of 0.06
nA; the baseline potential was 70 mV. D, Response of
an AF cell to a hyperpolarizing current pulse delivered during ongoing
spontaneous activity. The spontaneous firing rate was briefly elevated
immediately after the termination of the pulse.
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Although AF neurons did not resemble any cell type identified in the
mammalian striatum, they closely resemble some neurons recorded from
the mammalian globus pallidus. One cell type identified in the rat
entopeduncular nucleus (equivalent to the internal segment of the
globus pallidus of primates) shares all of the major physiological
features of AF cells: They fire spontaneously in vitro,
exhibit time-dependent inward rectification, produce depolarizing
"bumps" near the onset of depolarizing current pulses, are capable
of sustained firing at high rates, and display rebound firing after
hyperpolarizing current pulses (Nakanishi et al., 1990). A cell type
recorded from the rat ventral pallidum in vitro also shares
most of these features (Bengtson and Osborne, 2000).
Because both the entopeduncular nucleus (internal globus pallidus) and
ventral pallidum project to the thalamus in mammals (Zahm et al., 1987;
Parent and Hazrati, 1995), we suspect that the AF cells are the
projection neurons of area X, which innervate the thalamic nucleus DLM.
Unfortunately, we did not observe an axon leaving area X in any of our
tracer-filled neurons, so we have no direct evidence that identifies
the projection neurons. Nevertheless, circumstantial evidence based on
cell morphology strongly suggests that the projection neurons of area X
belong to the AF class. From retrograde tracing experiments, we know that the neurons projecting to DLM are larger than the majority of area
X neurons, contain glutamic acid decarboxylase (the enzyme that
synthesizes GABA), and possess thin, beaded neurites with few if any
dendritic spines (Luo and Perkel, 1999b). SNs cannot be the projection
neurons because they have densely spiny dendrites and have the smallest
somata of the neurons we recorded. The LA neurons also appear
morphologically distinct from the projection neurons; although we
recovered only two tracer-filled LA cells, they were markedly larger
than the projection neurons described by Luo and Perkel (1999b) and
have thicker, unbeaded dendrites. The LTS cells are unlikely to be the
projection neurons because their dendrites are unbeaded and relatively
unbranching, although again we have only two filled LTS cells on which
to base this observation. Only the FS and AF cell types morphologically
resemble the DLM-projecting neurons of area X (Fig.
14 shows a comparison of an AF cell
with a DLM-projecting neuron). Because FS cells closely resemble a
mammalian striatal cell type believed to be interneuronal, we think
that the AF cells are most likely to be the projection neurons of area
X.
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Figure 14.
The morphological similarity between
AF cells and the DLM-projecting cells of area X. The AF cell was
recorded via the whole-cell method from a zebra finch brain slice and
filled with biocytin; the area X projection neuron was labeled by
injection of a retrogradely transported tracer
(tetramethylrhodamine-conjugated dextran) into the DLM of a different
male zebra finch. Both images were acquired with a confocal microscope
(the biocytin fill was visualized using Cy2-conjugated streptavidin)
and are shown at the same scale. Scale bar, 10 µm.
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Unclassified cells recorded in area X
We recorded seven neurons in area X that could not be clearly
classified into one of the above cell types (<5% of all stable recordings). All of these recordings exhibited similarities to one or
another of the basic cell types but did not last long enough to be
fully tested or differed from their apparent cell type in an
important respect. Three of these neurons resembled the FS type in that
they had short AP durations (0.52, 0.47, and 0.58 msec) and were not
spontaneously active, but their firing properties were not explored
sufficiently to permit confident identification. Three other neurons
resembled the LTS cell type but had recordings that were too brief to
examine their properties fully or were obscured by massive spontaneous
synaptic input. A seventh cell closely resembled the LA type but
exhibited the characteristic long-lasting AHP only on the first AP of
spike trains evoked by depolarizing current injection. The subsequent
APs consistently lacked this long-lasting AHP; consequently, this cell
cannot be unambiguously classified as LA.
The basic properties of area X neurons do not change during the
period of song development
Neurons in some regions of the song system undergo changes in
their physiological properties during the period of song development (Livingston and Mooney, 1997; Boettiger and Doupe, 1998; Bottjer et
al., 1998; Stark and Perkel, 1999; White et al., 1999). Because we
recorded from area X neurons of the zebra finch at a variety of ages,
we were able to look for such developmental changes in area X. We did
not observe any qualitative changes in any of the cell types we
identified, so we looked for quantitative changes in a variety of
parameters (all of the measurements listed in Table 2). We focused on
SN and AF cells recorded from zebra finches, because all of our
juvenile recordings were from zebra finches, and only SN and AF cells
were common enough to permit a meaningful comparison. We checked for
age-related changes in two ways. First, we divided our zebra finch
recordings into two groups, juveniles (<65 d old) and adults ( 80 d
old), and tested for significant differences between the two groups in
any of the parameters listed in Table 2. In the juvenile group there
were 23 SNs (from birds aged 30-57 d; mean, 45) and 10 AF cells (from
birds aged 31-61 d; mean, 51). Among adults, there were 30 SNs and 9 AF cells. We found no significant differences at the p = 0.05 level (t test with the Bonferroni correction for
multiple comparisons). We also tried to detect age-related changes by
performing a linear regression on age for each measured parameter,
using only cells recorded from birds raised in our colony (the only
birds for which we have precise knowledge of age; this includes all
birds in the aforementioned juvenile group plus some older birds). For
all parameters, the regression slopes were not significantly different
from zero. In summary, we did not observe any physiological or
morphological changes in area X neurons over the age range during which
song normally develops in zebra finches. This is consistent with the electrophysiological maturation process observed in the mammalian striatum, which in rats and cats is generally complete by postnatal day
30 (Cepeda et al., 1991; Belleau and Warren, 2000). However, it is
important to note that many developmental neurophysiological changes
reported in the song system concern synaptic properties (Livingston and
Mooney, 1997; Stark and Perkel, 1999; White et al., 1999), which were
not examined in this study.
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DISCUSSION |
The basal ganglia of birds and mammals share a remarkable number
of anatomical (Medina and Reiner, 1995) and electrophysiological (Farries and Perkel, 2000a) traits, despite the apparent differences in
the organization of their telencephala. Here, we have shown that the
electrophysiological similarities extend to area X, a nucleus embedded
within the songbird striatum that is specialized for song-related
functions. All of the major physiological cell types (SN, LA, LTS, and
FS) identified in the mammalian striatum are present in area X. These
neurons are surprisingly similar to their mammalian counterparts, given
that the last common ancestor of mammals and birds lived at least 290 million years ago (Kardong, 1998), not to mention the fact that song
system nuclei are often assumed to be highly specialized within the
avian brain. We did not directly test the neurochemical phenotype of
our recorded neurons, except in the case of the single ChAT-positive LA
cell, but we have reason to believe that the close resemblance to
mammals applies here as well. The SNs of area X are very likely to be GABAergic, like their mammalian counterparts, because area X neurons of
the same size range as our recorded SNs are known to contain glutamic
acid decarboxylase (Luo and Perkel, 1999b). Mammalian striatal LTS and
FS cell types contain nitric oxide synthase and parvalbumin,
respectively (Kawaguchi, 1993); their counterparts in area X may
contain these proteins as well, given that both are present in area X
(Wallhäusser-Franke et al., 1995; Meade et al., 1998).
Although we found no qualitative differences between the cell types of
the mammalian striatum and their counterparts in area X, there are some
quantitative differences that merit discussion. One such difference is
the smaller soma size of all area X cell types relative to their
analogs in the mammalian striatum. It is not clear what (if any)
functional significance this distinction may have, but it is worth
noting that the relative sizes among cell types are roughly the same;
for example, SNs have the smallest somata and LA cells have the
largest. Another apparent difference is a substantially higher input
resistance of area X SNs relative to mammalian MSNs; we report SN
resistances that are three to five times higher than those for MSNs
studied using the whole-cell technique. Naturally, the smaller size of
area X SNs could explain some of this difference, but there are also
methodological differences that might artificially inflate the apparent
disparity. Specifically, our input resistance is roughly the maximum
subthreshold membrane resistance, whereas measurements in mammals were
often made at potentials in which the inward rectification is active,
thereby reducing membrane resistance. The mean resistance of our SNs in the "fully rectified" (hyperpolarized) state is 141 M, which is
actually lower than at least some values reported for mammalian MSNs
recorded using the whole-cell method (e.g., Kawaguchi, 1993). One last
discrepancy that deserves comment is the relatively low proportion of
SNs in our recordings (approximately two-thirds of the total); in
mammals, SNs constitute at least 80% of the total neural population in
the striatum and can constitute 90-95% of striatal neurons (Gerfen,
1992; Parent and Hazrati, 1995). However, our recordings do not
sample the cell types proportionately; our visually guided recordings
targeted the larger interneurons, and SNs seemed more sensitive to the
slicing process than the other cell types.
The overall quantitative differences between mammalian striatal neurons
and the corresponding cell types in area X are minor and might be
explained primarily by differences in experimental conditions such as
temperature (24-27°C in the present study vs 34-37°C in most
mammalian studies) or recording configuration (intracellular vs
whole-cell). Nevertheless, there are two major differences between
these structures: Area X has a fifth physiological cell type not found
in the mammalian striatum (present results) and projects directly to
the thalamus (Okuhata and Saito, 1987; Bottjer et al., 1989).
Ironically, these two differences in effect cancel each other out. Area
X appears to be a mixture of striatum and globus pallidus and we
hypothesize that the "pallidal" cell type projects to the thalamus.
We suggest that area X and its thalamic target may constitute a circuit
that is equivalent to the "direct pathway" through the mammalian
basal ganglia, with the striatal SNs receiving a glutamatergic
"corticostriatal" input and making GABAergic synaptic contacts with
pallidum-like neurons projecting to the thalamic nucleus DLM (Fig.
15). In this way, area X may retain the
same functional organization as the mammalian basal ganglia while
diverging from it in anatomical organization.
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Figure 15.
Our working hypothesis. Area X appears to be a
mixture of striatum and globus pallidus. An excitatory response in the
HVc may be transmitted to the DLM by two successive inhibitory
synapses. Excitation of SNs by glutamatergic HVc input could inhibit
the AF cells, briefly reducing their spontaneous activity. This would
transiently reduce tonic inhibition in DLM neurons, allowing them to
fire. In this manner, the AFP could act as a functional analog of the
mammalian direct pathway through the basal ganglia. The projection from
LMAN to area X is omitted for the sake of simplicity.
VA, Ventral anterior; VL, ventral
lateral.
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This arrangement could help to resolve the paradox concerning the
transmission of auditory information through area X. Excitatory auditory responses to playback of the bird's own song have been recorded both upstream (HVc) and downstream [DLM and lateral
magnocellular nucleus of the anterior neostriatum (LMAN)] of area X
(McCasland and Konishi, 1981; Margoliash, 1983, 1986; Doupe and
Konishi, 1991; Doupe, 1997), contradicting the perhaps simplistic
expectation that the inhibitory projection of area X would convert an
excitatory response into an inhibitory one. Our working hypothesis
includes two successive inhibitory synapses on the pathway through area X, so that an excitatory input would evoke APs in the striatal SNs,
inhibiting tonic activity in the DLM-projecting AF cells, thereby
transiently reducing inhibition in DLM neurons and allowing them to
fire (Fig. 15). This process is enhanced by the intrinsic properties of
DLM neurons; these neurons exhibit postinhibitory rebound and can fire
simply on termination of a train of IPSPs (Luo and Perkel, 1999a).
Postinhibitory rebound in the AF cells would help terminate this
response quickly after inhibition from SNs ceases.
Our working hypothesis is consistent with what is known about area X,
but it is only a conjecture at this point. We make three key
assumptions about the anatomical organization within area X that are as
yet unproven: that HVc afferents innervate the SNs but not the AF
cells, that the SNs directly inhibit the AF cells, and that the AF
cells are in fact the projection neurons of area X. The second
assumption seems quite reasonable given the large numbers of SNs in
area X and the rarity of interneurons through which indirect
communication between SNs and AF cells would have to occur. However,
the first assumption is more questionable; in fact, we have some
preliminary evidence of pallial (cortex-like) glutamatergic innervation
of both SN and AF neurons (Farries and Perkel, 2000b). This may explain
why tonically active, fast-firing neurons recorded from area X in
vivo generally show an overall increase in firing rate during
singing and playback of the bird's own song, interspersed with pauses
in activity (Doupe, 1997; Hessler and Doupe, 1999; Solis and Doupe,
1999). Our working hypothesis probably represents only one of several
possible routes through area X, and more studies of anatomy and
synaptic physiology will be necessary to answer the many questions
about the organization of circuits within it.
Once one considers circuits through area X that differ from the simple
one shown in Figure 15, one must also reconsider how closely area X
matches the circuits known in the mammalian basal ganglia. First, a
direct cortical projection to the globus pallidus is not a part of the
classic direct pathway, although cortical projections to the
mammalian pallidum do exist (Sesack et al., 1989; Naito and Kita,
1994). Furthermore, the known anatomy of area X does not seem to
accommodate an "indirect pathway" that includes the external
segment of the globus pallidus and the subthalamic nucleus, even if
such a pathway exists in other parts of the avian basal ganglia (Jiao
et al., 2000). Finally, it is not clear that area X and much of the
rest of the avian basal ganglia are homologous to the parts of the
mammalian basal ganglia that are most intimately connected with the
isocortex, that is, the caudate, putamen, "dorsal" pallidum
(internal and external segments of the globus pallidus, substantia nigra pars reticulata), and ventral tier nuclei of the
thalamus. Much of the avian pallium, including the song system nuclei,
may be homologous to the mammalian piriform cortex, claustrum, and
pallial amygdala, but not to the isocortex (Striedter, 1997; Puelles et
al., 2000). By the same token, avian subpallial structures, including
area X, might be more like mammalian ventral basal ganglia structures
such as the nucleus accumbens, ventral pallidum, and extended amygdala
(Farries and Perkel, 2000a).
Whatever organizational differences there may be, the fact remains that
area X contains all of the basic components of the mammalian
sensorimotor basal ganglia with virtually identical physiological and
histochemical properties. If area X is phylogenetically more closely
related to ventral "limbic" basal ganglia than to dorsal
sensorimotor regions, this may only imply that similar physiological
mechanisms are used throughout the basal ganglia, and that its
different regions differ primarily in their inputs and outputs, not in
how those inputs are processed. In any case, the role of area X in
birdsong appears to be sensorimotor, its phylogenetic affinities
notwithstanding. Area X performs functions in birdsong that the
mammalian basal ganglia are thought to perform in other behaviors,
using very similar cell types. Moreover, the principal physiological
cell types of area X (SN and AF) are also found in the avian basal
ganglia outside of the song system (Farries and Perkel, 2000a). Our
work suggests that the study of song learning will be more directly
applicable to other forms of motor learning, in other vertebrate taxa,
than even optimistic researchers had believed previously.
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FOOTNOTES |
Received Oct. 2, 2001; revised Jan. 23, 2002; accepted Jan. 25, 2002.
This work was supported by a National Science Foundation Graduate
Research Fellowship to M.A.F., a predoctoral National Research Service
Award awarded by the National Institute of Mental Health to M.A.F.,
National Institutes of Health (NIH) Grant RO1 MH56646 to D.J.P.,
National Science Foundation Grant IBN 0196104 to D.J.P., and
NIH/National Institute on Deafness and Other Communication Disorders
Core Grant DC04661. We thank Dr. G. Ball for generously providing the
starlings used in this study. We also thank Dr. M. Solis for helpful
comments on early drafts of this paper.
Correspondence should be addressed to Dr. David J. Perkel,
Departments of Zoology and Otolaryngology, University of Washington Medical Center, Box 356515, 1959 Northeast Pacific Street, Seattle, WA
98195-6115. E-mail: perkel{at}u.washington.edu.
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ABSTRACT
INTRODUCTION
