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 Previous Article
The Journal of Neuroscience, August 1, 1999, 19(15):6712-6722
Monoamine Control of the Pacemaker Kernel and Cycle Frequency in
the Lobster Pyloric Network
Amir
Ayali and
Ronald M.
Harris-Warrick
Section of Neurobiology and Behavior, Cornell University, Ithaca,
New York 14853
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ABSTRACT |
The monoamines dopamine (DA), serotonin (5HT), and octopamine (Oct)
can each sculpt a unique motor pattern from the pyloric network in the
stomatogastric ganglion (STG) of the spiny lobster Panulirus
interruptus. In this paper we investigate the contribution of
individual network components in determining the specific amine-induced cycle frequency. We used photoinactivation of identified neurons and
pharmacological blockade of synapses to isolate the anterior burster
(AB) and pyloric dilator (PD) neurons. Bath application of DA, 5HT, or
Oct enhanced cycle frequency in an isolated AB neuron, with DA
generating the most rapid oscillations and Oct the slowest. When an
AB-PD or AB-2xPD subnetworks were tested, DA often reduced the
ongoing cycle frequency, whereas 5HT and Oct both evoked similar
accelerations in cycle frequency. However, in the intact pyloric
network, both DA and Oct either reduced or did not alter the cycle
frequency, whereas 5HT continued to enhance the cycle frequency as
before. Our results show that the major target of 5HT in altering the
pyloric cycle frequency is the AB neuron, whereas DA's effects on the
AB-2xPD subnetwork are critical in understanding its modulation of the
cycle frequency. Octopamine's effects on cycle frequency require an
understanding of its modulation of the feedback inhibition to the
AB-PD group from the lateral pyloric neuron, which constrains the
pacemaker group to oscillate more slowly than it would alone. We have
thus demonstrated that the relative importance of the different network components in determining the final cycle frequency is not fixed but
can vary under different modulatory conditions.
Key words:
central pattern generation; neuromodulation; pacemaker
neurons; stomatogastric ganglion; pyloric network; dopamine; serotonin; octopamine
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INTRODUCTION |
Control of cycle frequency is one of
the most important parameters for the actions of neuromodulators on
rhythmic motor patterns such as locomotion, mastication, and
ventilation. Cycle frequency is determined by neuronal interactions
within the central pattern generator (CPG) networks that organize
rhythmic movements (Getting, 1989 ). Two main mechanisms for alteration
of cycle frequency have been described (Stein et al., 1998, Katz,
1999): alteration of intrinsic properties of critical pacemaker neurons
(for review, see Selverston et al., 1998) and modulation of the
strength of synaptic connections between the CPG network neurons
(Sillar et al., 1998). The relative importance of these two mechanisms
in setting the cycle frequency is difficult to determine in complex systems.
The pyloric circuit in the lobster stomatogastric ganglion (STG)
provides a unique opportunity to study how the various targets of a
neuromodulator contribute to the network's final cycle frequency. Traditionally (Miller, 1987; Johnson and Hooper, 1992), the rapidly oscillating anterior burster (AB) interneuron is thought to be the most
important cell for determining the pyloric cycle frequency. However, a
number of other network neurons are known to contribute to the
generation of the final pyloric cycle frequency. It has long been known
from both experimental and theoretical studies that the electrically
coupled pyloric dilator (PD) neurons are instrumental in shaping the
rhythm (Marder, 1984; Eisen and Marder, 1984; Hooper and Marder,
1987; Kepler et al., 1990; Abbott et al., 1991). Hence, the AB-PD
subnetwork is typically referred to as the pacemaker kernel of the
network. This subnetwork receives inhibitory feedback from the lateral
pyloric (LP) neuron (to the PD neurons) (Fig.
1), and Selverston and Miller (1980)
reported that inactivation of the LP neuron results in an increase in
the spontaneous pyloric cycle frequency. Finally, the ventricular dilator (VD) neuron makes rectifying electrical synapses with both the
AB and PD neurons (Fig. 1) (Johnson et al., 1993) and in theory could
function to enhance the repolarization of the pacemaker neurons leading
to the next burst.
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Figure 1.
Schematic diagram of the different preparations
used in this study. A, Isolated AB or PD neurons
(descending modulatory inputs were either blocked by a tetrodotoxin
block on the stomatogastric nerve or kept intact). B, An
AB-PD (1) or AB-2xPD (2)
pacemaker subnetwork (with or without descending inputs).
C, The intact pyloric circuit (modulatory inputs were
kept intact). An example of the method of isolating neurons and
subnetworks is also shown in C. To isolate the AB-PD
subnetwork (shown in B1), the VD neuron and one PD
neuron were photoinactivated, and the LP  PD synapse was
pharmacologically blocked with picrotoxin. All synaptic connections are
either electrical (nonrectifying synapses, resistors; rectifying
synapses, diodes) or chemical inhibitory (small
circles).
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Much is known about the characteristics of the individual component
neurons and synapses of the pyloric network (Eisen and Marder, 1982;
Miller and Selverston, 1982a,b; Hartline and Graubard, 1992; Baro et.
al, 1997) and how they are affected by neuromodulators (Dickinson et
al., 1990; Harris-Warrick and Marder, 1991; Marder et al., 1994;
Harris-Warrick et al., 1995a,b; Johnson and Harris-Warrick, 1997; Ayali
and Harris-Warrick, 1998; Kloppenburg and Harris-Warrick, 1999).
A main advantage of the pyloric network is the ability to study
isolated subsets of neurons, through pharmacological blockade of
synapses (Bidaut, 1980) and photoinactivation to eliminate individual
neurons (Fig. 1) (Miller and Selverston, 1979; Selverston and Miller,
1980). Practically all the cellular and synaptic components of the
pyloric network are targets of monoamine modulation: dopamine (DA),
octopamine (Oct), and serotonin (5HT) have been found to have a
bewildering variety of effects on the intrinsic electrical properties
of all pyloric neurons, as well as on synaptic transmission between
network members (Flamm and Harris-Warrick, 1986a,b; Harris-Warrick and
Flamm, 1986, 1987; Harris-Warrick et al., 1995a,b; Johnson et al.,
1995; Johnson and Harris-Warrick, 1997; Ayali et al., 1998).
Now that amine effects on individual components of the circuit have
been mapped, the next goal is to try to put the system back together.
In this paper we show that the effects of DA, 5HT, and Oct on the
pyloric cycle frequency depend critically on interactions within the
traditional pacemaker group as well as on synaptic interactions in the
pyloric network. Thus, the network components that determine the final
cycle frequency vary depending on the different modulatory conditions.
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MATERIALS AND METHODS |
Animals. Pacific spiny lobsters (Panulirus
interruptus) of both sexes weighing between 0.5 and 1 kg were
purchased from Don and Laurice Tomlinson (San Diego, CA), and
maintained in marine aquaria at 15-16°C until use.
Saline and chemicals. Panulirus saline was
composed of (in mM): NaCl 479, KCl 12.8, CaCl2
13.7, Na2SO4 3.9, MgSO4 10.0, glucose 2.0, Tris base 11.1, maleic acid 5.1, pH 7.4-7.6 (Mulloney and Selverston, 1974). All salts and drugs were obtained from Sigma (St.
Louis, MO).
Physiology. The stomatogastric nervous system was dissected
as described by Selverston et al. (1976) and placed in a preparation dish filled with Panulirus saline. The STG was desheathed,
enclosed in a small (1 ml) pool of saline walled by Vaseline, and
constantly superfused at 3 ml/min with oxygenated saline at 16-17°C.
The cell bodies of the pyloric neurons were identified by correlation of action potentials recorded intracellularly in the soma and extracellularly on identified motor nerves, and by the characteristic shape and timing of bursts of action potentials in the pyloric rhythm.
Extracellular recordings were made with bipolar stainless-steel pin
electrodes. Standard intracellular techniques were used for voltage
recordings using KCl-filled (3 M, 15-25 M )
microelectrodes. The AB-2xPD subnetwork was isolated by
photoinactivation (Miller and Selverston, 1979) of the VD neuron in
addition to pharmacological blockade (10 5
M picrotoxin) of the LP PD synapse (Fig. 1). Further
inactivation of one PD neuron generated the AB-PD subnetwork. Single
neurons were isolated by additional photoinactivation of the remaining PD or AB neuron. Amine solutions were prepared in normal saline just
before bath application. As in earlier studies (Flamm and Harris-Warrick, 1986a,b; Johnson and Harris-Warrick, 1990), we used
104 M DA, 105
M 5HT, and 104 M to
105 M Oct. When required, inputs to
the STG from higher ganglia were blocked by applying
107 M tetrodotoxin (TTX) saline to a
small pool walled with Vaseline on the desheathed stomatogastric nerve.
This stopped rhythmic activity of the pyloric network (Russell, 1979;
Nagy and Miller, 1987).
Statistical significance was tested and stated when p < 0.05 (two-tailed t test for unpaired or paired variates,
as was appropriate).
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RESULTS |
Amine modulation of the isolated AB or PD neurons
The modulatory effects of the monoamines on isolated pyloric
neurons have been studied previously (Flamm and Harris-Warrick, 1986a,b; Harris-Warrick and Flamm, 1987; Harris-Warrick et al., 1995a,b; Kloppenburg et al., 1999). In these studies, all descending inputs to the pyloric network were blocked to test amine effects on the
isolated neurons in a basal, nonmodulated state. Because the pyloric
pacemaker neurons are conditional oscillators, blocking modulatory
inputs results in a baseline condition of nonoscillating neurons with
no ongoing pyloric rhythm (Nagy and Miller, 1987). In the present
study, we confirmed these previous results, and in addition we studied
amine modulation of the AB and PD neurons when isolated from other
pyloric neurons but with intact descending modulatory inputs.
The two experiments shown in Figure
2A demonstrate the
effects of bath-applied amines on the isolated AB and PD neurons. As described previously (Flamm and Harris-Warrick, 1986b; Harris-Warrick and Flamm, 1987), after blocking descending modulatory inputs the AB
neuron was in a quiescent nonoscillatory state, and all three amines
had excitatory effects to induce AB rhythmic bursting (Fig.
2A1). Dopamine was the most potent excitatory
modulator, inducing the largest oscillations with the most spikes at
the highest cycle frequency; 5HT was intermediate, and Oct had the weakest excitatory effects (Figs. 2A1,
3A).
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Figure 2.
Effects of bath-applied amines on the AB and PD
neurons. Each neuron was isolated from all pyloric synaptic inputs as
described in Materials and Methods. Descending modulatory inputs via
the stomatogastric nerve were either blocked
(A) or kept intact (B).
Both A1 and B1 for the AB neuron, as well
as A2 and B2 for the PD neuron, show
recordings from a single neuron. Dopamine (DA),
serotonin (5HT), and octopamine
(OCT) induced fully reversible changes in the
cellular activity. The control resting membrane potential or potential
at the lowest voltage of oscillations is marked by
arrows.
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Figure 3.
Effects of bath-applied dopamine
(DA), serotonin (5HT), and
octopamine (Oct) on the AB neuron, when isolated from
all pyloric synaptic inputs as described in Materials and Methods, with
descending modulatory inputs in the stomatogastric nerve blocked
(A) or left intact (B).
Filled bars, AB cycle frequency; open
bars, mean spike frequency within the AB burst. The data show
the mean of three (A) or five
(B) different preparations ± SD. In
A, both parameters measured in Oct (*) are significantly
different from DA and 5HT frequencies. Both parameters measured in all
three amines in B (*) are significantly different from
control. In addition, the measurements in Oct are significantly
different from those in DA (**).
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The AB neuron with intact modulatory descending inputs was bursting
rhythmically (Fig. 2B1). The modulatory effects of
the amines under these conditions were qualitatively similar to those seen in the blocked preparation (Fig. 2, compare A,
B). Although not all differences between the effects of the
three amines were statistically significant (mainly because of a large
variation in control cycle frequencies), some trends were very clear.
Dopamine induced the highest AB cycle frequency, number of spikes per
burst, and spike frequency within an AB neuron burst (Fig. 3). Dopamine also generated the largest amplitude oscillations in the AB neuron (Fig. 2). Octopamine had the weakest enhancement of cycle frequency, had very minor effects on the AB neuron's spiking, and generated no
net enhancement of the AB neuron oscillation amplitude (14.7 ± 7.5 and 14.4 ± 4.5 mV in control and Oct conditions,
respectively, compared with 18.7 ± 5.0 mV in DA;
n = 5). Serotonin had intermediate effects on all these parameters.
As shown previously (Flamm and Harris-Warrick, 1986b), the isolated PD
neuron with no modulatory inputs fired tonically and was strongly
inhibited by DA (Fig. 2A2). Dopamine caused a
hyperpolarization of 7.2 ± 1.8 mV (n = 10) and
abolished the PD neuron's tonic firing. Octopamine had a slight but
not statistically significant excitatory effect, whereas 5HT had no
detectable effect on the PD neuron's spontaneous firing properties
(Fig. 2A2). When modulatory inputs from other ganglia
are intact, the isolated PD neurons are sometimes capable of generating
bursting pacemaker potentials (R. Elson, personal
communication). However, in 80% of our experiments with intact
descending modulatory inputs, the isolated PD neuron fired tonically
(Fig. 2B2), with only small and slow membrane
potential oscillations (up to 1 mV, 0.2 Hz), which caused only subtle
changes in tonic spike frequency (data not shown). These slow
oscillations in the PD neuron's membrane potential were never seen
after blocking descending inputs. The PD neuron spike frequency was
higher with intact descending modulatory inputs than in the isolated
state (6.8 ± 1.2 Hz compared with 4.2 ± 0.3 Hz,
respectively; n = 5) (see also Fig. 2). As seen in
Figure 2, the amines' effects on the PD neuron firing properties were
essentially the same in the presence of descending modulatory inputs
(Fig. 2B2) as in the isolated PD neuron (Fig.
2A2): DA abolished PD neuron activity, whereas 5HT
had no effect and Oct weakly enhanced tonic spike activity.
Amine modulation of the AB-PD and AB-2xPD subnetworks
When isolated from all descending inputs, the AB-PD subnetwork
did not show oscillatory behavior; the PD neuron fired tonically, whereas the AB neuron was silent. Because DA, Oct, and 5HT all evoke
rhythmic oscillations in an isolated AB neuron, we expected the amines
to activate synchronized cycling in the AB-PD subnetwork, and this was
indeed observed. The DA-evoked cycling in the AB-PD subnetwork
(0.9 ± 0.4 Hz; n = 8) was significantly slower
then DA-evoked cycling in the isolated AB neuron (1.8 ± 0.6 Hz;
n = 5). 5HT-evoked cycling was similar in both cases
(0.9 ± 0.4 Hz for AB-PD vs 1.1 ± 0.5 Hz for AB;
n = 5), whereas Oct-evoked cycling was significantly
faster in the AB-PD subnetwork (0.9 ± 0.3 Hz; n = 5) than in the isolated AB neuron (0.6 ± 0.3 Hz;
n = 5).
In an AB-PD subnetwork with intact modulatory inputs, both neurons
oscillate synchronously without amine addition, reflecting the strong
electrical coupling between them (Fig.
4A,
Control) (Miller, 1987). Figure 4A
shows an example of the modulatory effects of the three amines on an
AB-PD subnetwork with intact descending inputs. Some of the amine
modulatory effects on the AB and PD neurons' firing properties were
qualitatively similar to the effects on the isolated neurons (Figs.
2B, 3B). For example, DA inhibited PD
neuron spiking while generating higher amplitude oscillations in the AB
neuron. The amplitude of the AB neuron oscillations as well as other AB
firing characteristics were intermediate in 5HT and smallest in Oct
(data not shown). However, looking at the amine effects on cycle
frequency of the two-cell subnetwork reveals a different picture. The
major result is that although the order of cycle frequencies in the
isolated AB neuron was DA > 5HT > Oct (Fig. 3) (Flamm and
Harris-Warrick, 1986b), this order changes in the AB-PD subnetwork
with descending modulatory inputs to Oct = 5HT > DA (Fig.
4A). Thus, DA switched position from evoking the
fastest cycle frequency in the isolated AB neuron to the slowest cycle
frequency in the AB-PD subnetwork.
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Figure 4.
A, Effects of bath-applied amines
on an AB-PD subnetwork isolated from all pyloric synaptic inputs.
Descending modulatory inputs were kept intact. A1,
Simultaneous recordings from the AB and PD neurons. The recordings
shown in all panels are from a single preparation. Dopamine
(DA), octopamine (Oct), and serotonin
(5HT) induced fully reversible and reproducible
changes in the subnetwork activity. The control oscillation trough
membrane potential of both neurons is marked by arrows
in all panels. A2, Effects of the bath-applied amines on
cycle frequency in the AB-PD subnetwork. Open bars,
Control; filled bars, amine bath application.
B, Effects of bath-applied amines on cycle frequency in
an AB-2xPD subnetwork, with descending modulatory inputs intact. In
A2 and B, data show the mean of five to
eight different preparations ± SD. Cycle frequencies in 5HT and
Oct (*) are significantly different from control and DA but not from
each other.
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The basic features of the AB-PD subnetwork amine-induced rhythms are
also seen in a pacemaker subnetwork with two PD neurons (Fig.
4B). Two major differences are seen. First, the
control cycle frequency (without amines) is somewhat lower with two PD neurons, reflecting the electrical drag the PD neurons exert on the AB
oscillator (Kepler et al., 1990; Sharp et al., 1992). Second, the
effect of DA is changed from a modest enhancement of cycle frequency in
the AB-PD subnetwork to a consistent although small reduction in cycle
frequency of the AB-2xPD subnetwork. Thus, as we add to the AB neuron
the first and then the second PD neuron, the opposing effects of DA on
the two cell types add up to change the DA modulatory effect from
strong excitation to slight inhibition. This point will be further
dealt with below. The enhancement of cycle frequency by 5HT and Oct is
essentially the same in AB-PD and AB-2xPD subnetworks (Fig. 4,
compare A, B).
Amine modulation of the intact pyloric network with descending
modulatory inputs
Having established how the amines determine the cycle frequency of
the AB-PD pacemaker subnetworks, we wished to compare these results
with the intact pyloric network to investigate whether the AB-PD
pacemaker group alone performs the final determination of the pyloric
cycle frequency. Figure 5A
shows a simultaneous recording from four of the pyloric cell types in
an intact pyloric network with descending modulatory inputs. This
figure shows a typical example of the nature of the amine effects.
Dopamine somewhat reduced the pyloric cycle frequency, 5HT had a strong
excitatory effect, and Oct slightly decreased the ongoing cycle
frequency. In other examples where the pyloric constrictor (PY)
neurons fired less strongly during Oct superfusion and thus did not
confine the Oct-induced prolongation of the LP burst, the inhibitory
effect of Oct was even stronger. On averaging the responses in six
intact preparations (Fig. 5B), 5HT evoked a significant
increase in cycle frequency, to essentially the same extent as its
effects in the AB neuron and the AB-PD subnetworks. Dopamine's slight
reduction of cycle frequency in the intact network also resembles its
effects on the AB-2xPD subnetwork (Fig. 4B).
However, the effects of Oct on the intact network are very different
from its effects on the more reduced subnetworks: instead of enhancing
the cycle frequency, Oct caused the cycle frequency to be virtually
unchanged or even decreased.
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Figure 5.
Effects of bath-applied dopamine
(DA), serotonin (5HT), and
octopamine (Oct) on the intact pyloric network with
descending modulatory inputs. A, Simultaneous recordings
from four of the six pyloric neuron classes. All of the recordings are
from a single preparation. All amine effects were reversible after wash
with normal saline. B, Effects of bath-applied amines on
the pyloric cycle frequency in the intact pyloric network with
descending modulatory inputs. Open bars, Control;
filled bars, amine bath application. Data show the mean
of six different preparations ± SD. Cycle frequency in 5HT (*) is
significantly different from control, Oct, and DA frequencies.
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Figure 6 summarizes all the amine effects
on cycle frequency as we advance from the single AB neuron up to the
intact pyloric network. Dopamine evoked the highest change in cycle
frequency in the isolated AB neuron but the lowest change in the AB-PD
subnetworks and the intact network. Octopamine and 5HT evoked similar
changes in cycle frequencies in the isolated AB neuron and had
practically identical effects in the AB-PD as well as AB-2xPD
subnetworks. However, these amines' effects on the full circuit were
quite different: 5HT continued to enhance cycle frequency to the same extent as in the simpler preparations, whereas Oct did not
significantly alter cycle frequency above control values.
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Figure 6.
Summary of amine effects on the cycle frequency of
an isolated AB neuron, an AB-PD subnetwork, an AB-2xPD subnetwork,
and an intact pyloric circuit, all with intact descending modulatory
inputs. Data shown as percentage relative to control frequencies in
each condition. Means of five to eight different preparations ± SEM are shown. An asterisk signifies a
significant difference between amines within the same type of
preparation. For each amine, bars marked by a
different letter show statistically significant
difference between a single amine-induced change in the different types
of preparations; the same letter indicates no
significant difference between the different types of
preparations.
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These changes in Oct's effects in the intact pyloric network must
reflect different contributions of other members of the pyloric circuit
that provide feedback to the AB-PD group. The two inputs to the
pyloric pacemaker neuron group from the rest of the network are the
chemical inhibitory synapse from the LP neuron to the PD neurons, and
the VD neuron's rectifying electrical coupling to the AB and PD
neurons (Fig. 1). A close look at the traces in Figure 5A
suggests that the differences in Oct's effects on cycle frequency in
the pacemaker and intact networks (Fig. 6) are attributable primarily
to the LP neuron's inhibition of the PD neurons in the intact circuit.
The LP neuron burst duration is extended during Oct application (Fig.
5) (Flamm and Harris-Warrick, 1986a). Octopamine also enhances synaptic
transmission in the LP PD inhibitory synapse (Johnson et al.,
1995). The LP neuron's graded inhibition and spike-evoked inhibitory
postsynaptic potentials can be seen in the PD neuron traces.
On the basis of these results, we hypothesized that in the presence of
Oct, LP inhibition of the PD neuron delays the rise of the next burst
in the pacemaker neurons, thus slowing the rhythm. We tested the role
of LP neuron inputs in shaping the amine-induced rhythms by temporarily
removing LP inhibition of the PD neurons during amine bath application.
This was done by strongly hyperpolarizing the LP neuron to
approximately  100 mV by current injection. Figure 7 shows that Oct enhanced the burst
duration of the LP neuron, but the Oct-evoked cycle frequency (Fig.
7B1) (1.24 Hz) did not change from its control value (Fig.
7A) (1.20 Hz). When the LP neuron was hyperpolarized to
remove its inhibition of the pacemaker neuron group (via the PD
neurons), a significant enhancement of the cycle frequency occurred
(Fig. 7B2) (1.50 Hz; on average 15.1 ± 3.3% change
from before LP hyperpolarization; n = 7). This suggests that LP inhibition constrains the AB-PD group to oscillate at a lower
frequency than it would without the LP input during Oct superfusion.
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Figure 7.
The effect of the LP neuron on octopamine
(Oct) and dopamine (DA) induced rhythms
in an intact pyloric network with descending modulatory inputs.
Simultaneous recordings from the LP and a PD neuron in control
conditions (A), during Oct bath application
(B), and during DA bath application
(C) are shown. In both Oct and DA, the traces
shown in 1 demonstrate the final and stable
amine-induced rhythm (~5 min of bath application). The traces in
2 show the effect of strongly hyperpolarizing the LP
neuron by current injection on the amine-induced rhythm. The traces
shown in 2 were recorded a few seconds after the
recordings shown in 1. The amine effects and effects of
hyperpolarizing the LP neuron were fully reversible.
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We repeated this test with all three amines in the same preparation. LP
neuron hyperpolarization had practically no effect on the 5HT-induced
cycle frequency (data not shown) (1.5 ± 0.8% change from control
frequency; n = 3). In contrast to Oct, 5HT directly
inhibits the LP neuron (Fig. 5A)(Flamm and Harris-Warrick, 1986a,b); it also weakens LP output synapses (Johnson et al., 1995),
thus reducing the impact of the LP neuron's inhibition of the
pacemaker group. As a result, 5HT modulation of cycle frequency in the
AB-2xPD subnetwork and the intact circuit is very similar (Fig. 6).
Dopamine very strongly excites the LP neuron even more than Oct (Figs.
5A, 7C) (Harris-Warrick et al., 1995b) and also strengthens LP output synapses (Johnson et al., 1995), and we would
thus expect the removal of the LP inhibition by hyperpolarization to
speed up the cycle frequency during DA. However, as seen in Figure
7C, LP neuron hyperpolarization had no effect on the
DA-induced rhythm (Fig. 7C2) (1.1 ± 2.3% change from
control frequency; n = 7), and the LP neuron does not
seem to play a significant role in determining the pyloric cycle
frequency during DA application.
Careful examination of Figure 5 suggests that the effectiveness of LP
feedback inhibition of the AB-PD group depends not only on the
amplitude of the inhibition but also on its phasing; that is, exactly
when in the cycle the LP neuron inhibition of the PD neuron (and thus
AB) occurs (Flamm and Harris-Warrick, 1986a; Ayali and Harris-Warrick,
1998). Under control conditions, the LP neuron delivers a moderate but
brief (~200 msec at 1 Hz cycle frequency) inhibition starting shortly
after the middle of the cycle between AB-PD bursts. In the presence of
DA, the LP neuron is highly excited to deliver a much stronger
inhibition of similar duration (~200 msec), but at an earlier phase
(~0.35) in the cycle. In contrast, during Oct application, the LP
neuron is excited to an intermediate level but fires a much longer
burst (~400 msec), starting at a phase similar to control (~0.5)
and lasting much longer.
To study these parameters further, we eliminated the inhibitory LP PD synapse by pharmacological blockade and mimicked it by intracellular
hyperpolarizing current injections to one of the PD neurons while
monitoring its membrane potential with a second electrode (Fig.
8). We used three different current
injection protocols to hyperpolarize the PD neuron: a short mild
inhibition (200 msec, 0.2 nA) to mimic LP inhibition in control
conditions, a long, slightly stronger injection (400 msec, 0.4 nA) to
mimic Oct conditions, and a short but strong inhibition (200 msec, 0.6 nA) to mimic DA conditions. In this experiment we did not add the
amines, so that we could isolate the effects of the three different
inhibitory inputs to the PD neuron on the cycle frequency. Figure
8A demonstrates the effects of the current injections
mimicking the LP inhibition during DA and Oct. Although the DA-like
inhibition is stronger, it has no effect on the cycle frequency,
whereas the longer-lasting although weaker Oct-like inhibition causes a
significant prolongation of the cycle period. To determine whether the
major difference between the LP inputs in DA and Oct conditions is the
phase of the inhibition, we tested the effect of the three types of
stimuli at different stimulus phases. Figure 8B shows these results. The y-axis shows the period of the cycle that
included current injection as a percentage of the cycle preceding it,
which had no injection (as seen in Fig. 8A), and the
x-axis gives the phase of the end of the current injection
pulse, again as a fraction of the preceding cycle, which had no current
injection (thus the end phase could be greater than one, as for example
in the sweep marked Oct in Fig. 8A).
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Figure 8.
The effect of hyperpolarizing current injections
to the PD neurons in an intact pyloric network with the LP PD
synapse pharmacologically blocked. In all the experiments shown,
hyperpolarizing current pulses were intracellularly injected to a PD
neuron while the neuron's membrane potential was recorded with
a second electrode. A, Simultaneous recording from PD
and AB neurons. Two sweeps (from the same preparation) are overlaid. In
both, a cycle with no current injection is followed by one with an
inhibitory stimulus mimicking the LP inhibition of PD during DA
(black) or Oct (gray) (for
details, see Results). The time of current injection is shown by the
black and gray bars, and the phase of two
cycles is shown based on the prestimulation cycle (the first spike in
the AB neuron is defined as phase 0). B, The effect of
inhibitory stimulation of PD on the pyloric cycle period. Single
stimuli (three different stimulus protocols as shown in the graph's
legend) were given at different phases along the PD bursting cycle. The
stimuli duration and intensity correspond to those generated by the LP
neuron in a fully intact network in control (open
squares), DA (black squares), or Oct
(gray squares) conditions. The phase of the end
of the inhibitory stimulus (calculated relative to the preceding cycle
with no stimulus as shown in A) is plotted against the
change in cycle period generated by the inhibition (period with
inhibition/period in previous cycle with no inhibition × 100).
The end phase could exceed 1.0, as for example in the sweep
marked Oct in A. Data points from four different
preparations are shown. The dashed line is a linear fit
calculated for all the data points shown (pooled together). The
oval marked Control refers to the open
data points, corresponding to LP inhibition of PD in a fully intact
network in control conditions. Similarly, the areas marked
DA and Oct refer to the filled
black and filled gray data points, respectively,
and represent LP inhibition of PD during DA or Oct bath application.
C, The effect of repetitive inhibitory inputs to the PD
neuron on the pyloric rhythm. The three PD traces (from the same
neuron) show the effect of control- (cont.), DA-, and
Oct-like repetitive inhibitory stimulation using stimulus parameters
and phasing indicated by the ovals in B.
The time of current injection is shown by the
bars.
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Figure 8B shows two major findings. First, all
three stimulus protocols were capable of generating a significant
change in cycle period (up to 25%). The most important parameter was
indeed phase of the stimulus, specifically the end of the stimulus. As shown by the linear fit, terminating the inhibition at a phase later
then 0.8 caused a delay in the rise of the next pacemaker burst and a
prolongation of the period. The second point is that the combination of
stimulus intensity, duration, and phase that best mimicked the LP
inhibition under control, DA, or Oct conditions also generated an
effect or lack of effect on cycle period similar to that shown in the
corresponding experimental conditions. Control-like injections (Fig.
8B, open squares) with normal termination
phases of 0.75-0.85 (Ayali and Harris-Warrick, 1998) did not greatly alter the pyloric cycle period. Stronger, DA-like injections (Fig. 8B, black squares) that mimic the LP phase
advance to terminate at phases of 0.55-0.65 (Harris Warrick et al.,
1995a; Ayali and Harris-Warrick, 1998) also had little effect on the
cycle period or caused a slight shortening, consistent with the
slightly higher DA-induced cycle frequency of the intact pyloric
network relative to the AB-2xPD subnetwork (Fig. 6). Longer lasting,
Oct-like injections (Fig. 8B, gray
squares) with delayed termination phases of 1.05-1.15 (Flamm and
Harris-Warrick, 1986a) caused a significant prolongation of the cycle.
Again, this mimics Oct's reduction of cycle frequency of the intact
network compared with the AB-2xPD subnetwork (Fig. 6). Finally, it was
possible to entrain an ongoing pyloric rhythm to the cycle frequencies
corresponding to the control, DA, or Oct conditions by repetitive
stimulation, using the specific control-, DA-, or Oct-like current
injection parameters (Fig. 8C). Strong repetitive
stimulation at an early phase (mimicking DA conditions) had a very
minor or no effect on cycle frequency compared with the control,
whereas prolonged weaker inhibition at a later phase (mimicking Oct
conditions) caused significant reduction in cycle frequency.
Our results suggest that the VD neuron plays little if any role in the
amine modulation of pyloric cycle frequency. Octopamine exerts a weak
excitatory effect on the isolated VD neuron (Flamm and Harris-Warrick,
1986b). However, Oct enhances synaptic inhibition at the LP VD
synapse (Johnson et al., 1995), and the inhibition from the LP neuron
was usually strong enough to significantly reduce or eliminate the VD
neuron spiking altogether (Fig. 5A), suggesting a minor role
for the VD neuron in shaping the Oct-induced cycle frequency. The VD
neuron is directly inhibited by both DA and 5HT (Flamm and
Harris-Warrick, 1986b), and it fired weakly or not at all during
application of these amines (Fig. 5A). Hyperpolarization of
the VD neuron did not change the cycle frequency in the presence of DA,
5HT, or Oct (data not shown).
Time and concentration dependence of DA effect on
cycle frequency
As described above, DA's effect on the pyloric cycle frequency
reflects a compromise between its opposing effects on the AB and PD
neurons. We conducted a number of experiments to further characterize
how the individual effects of DA on the properties of the AB and PD
neurons contribute to the overall modulatory effects of DA as described
in the previous sections. We again tested the isolated AB-PD
subnetwork with blocked descending inputs (Fig.
9). Under these conditions there is no
cycling, and the PD neuron fires tonically, generating EPSPs in
the AB neuron. Figure 9A shows that during the initial entry
of DA into the bath, the PD neuron responds earlier than the AB neuron.
Approximately 15 sec passed after the beginning of the
hyperpolarization of the PD neuron, before any sign of depolarization
of the AB neuron was seen, and altogether 35 sec passed before the AB
neuron was excited enough to fire its first action potential. Thus,
DA's inhibition of the PD neuron has a significantly more rapid onset than DA's excitation of the AB neuron, and there is a definite time
window when only the PD neuron inhibition is apparent, with no AB
excitation. Similar results are seen with isolated AB and PD neurons:
the onset of the PD response to DA is significantly more rapid than the
AB response (data not shown). In the AB-PD subnetwork, can we also
obtain DA excitation of the AB neuron with no PD neuron inhibition?
Flamm and Harris-Warrick (1986b) showed that higher concentrations of
DA (threshold 105 M) were needed to
inhibit the PD neuron than to excite the AB neuron
(106 M). As seen in Figure
9B, confirming these earlier findings, in the AB-PD
subnetwork, 5 × 106 M DA was not
sufficient to inhibit the PD neuron, but it did excite the AB neuron
and generate rhythmic cycling. The lower DA concentration eventually
produced a unique pattern, with no PD inhibition (Fig. 9B2).
Thus by selecting time and dose combinations, we can isolate the
inhibitory or the excitatory components of DA's effect on the AB-PD
pacemaker subnetwork.
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Figure 9.
The onset of the effect of
104 M (A) or
5 × 106 M
(B) dopamine bath application on an AB-PD
subnetwork isolated from all pyloric and descending inputs. In both
A and B, panel 1 shows a 1 min period around the onset of dopamine's effect on the two neurons
(the first AB spike is marked by an arrow). Panel
2 shows the final and stable dopamine-induced rhythm (~5 min
of bath application).
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The experiment shown in Figure 10
further supports the idea of a balance between DA's two opposing
effects on the AB and PD neurons, yielding a complex response at the
subnetwork level. In this experiment, the PD neurons were eliminated
one by one from an AB-2xPD network with intact descending inputs. DA
was repeatedly bath-applied and washed out to test its effect on the 3, 2, and 1 pacemaker neuron group. When DA was applied to the AB-2xPD
subnetwork, the major response was a transient reduction in cycle
frequency, beginning at 1.5 min, which reversed by 4.5 min but did not
exceed the initial cycle frequency. After photoinactivating one PD
neuron, DA was applied to the AB-PD subnetwork; now the initial
reduction in cycle frequency was only half as large and was shorter,
replaced at 3.5 min by a marked 50% increase in cycle frequency.
Finally, elimination of the second PD neuron yielded an isolated AB
neuron, which responded to DA as usual with a delayed (3 min) twofold
increase in cycle frequency. Thus, both the magnitude and duration of
the inhibitory response to DA depends on the number of PD neurons
electrically coupled to the AB pacemaker.
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Figure 10.
A, The biphasic effect of dopamine
bath application (104 M) on the
pyloric pacemaker subnetwork isolated from all pyloric synaptic inputs
and with intact descending inputs. All the data were collected from a
single preparation. Dopamine was bath-applied and washed before and
after photoinactivation to sequentially remove the first and then the
second PD neuron (AB-2xPD, AB-PD, and isolated AB). The three
panels in B show simultaneous recording from the AB (top
traces) and PD (bottom traces) neurons in the
AB-PD subnetwork, at the time data points marked in A
by corresponding letters.
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DISCUSSION |
Effects of dopamine, serotonin, and octopamine on the pyloric
cycle frequency
In this paper we demonstrate that the relative importance of each
of the cellular components of the pyloric pacemaker in determining the
final cycle frequency is not fixed but can vary under different modulatory conditions. Our approach has been to work our way up from
single isolated AB and PD neurons to the isolated AB-PD and AB-2xPD
subnetworks and finally to the intact network, determining the
amine-induced cycle frequency at each step. To a first approximation, the effects of the three amines on the isolated AB, PD, and AB-PD groups were the same in the presence and absence of modulatory inputs
from higher ganglia; thus, there are no obvious nonlinear interactions
between the effects of each bath-applied amine and the descending
modulatory inputs. Our comparison of amine effects on the components of
the pyloric pacemaker group has illuminated our interpretation of how
each amine determines the cycle frequency in the intact pyloric network.
One striking point that can be clearly seen in Figure 6 is that the
order of amine efficacy in enhancing cycle frequency changes markedly
with each level of complexity, from the isolated AB neuron to the
intact network. Dopamine induces the highest cycle frequency in the
isolated AB neuron, whereas 5HT and Oct equally generate the highest
frequencies in the AB-PD and AB-2xPD subnetworks, and 5HT alone
increases the cycle frequency in the intact network. These differences
must reflect differing contributions of the different neurons and
synapses to the final cycle frequency for each amine at each level of complexity.
In the presence of DA, the cycle frequency is strongly enhanced with
the isolated AB neuron, weakly enhanced with the AB-PD subnetwork, and
reduced below the control frequency with the AB-2xPD subnetwork and in
the intact network. These results arise from the opposing effects of DA
on the pacemaker AB and PD neurons (Fig. 2) (Eisen and Marder, 1984;
Flamm and Harris-Warrick, 1986b). Recent work has shown that the PD
neuron inhibition is accompanied by a conductance increase attributable
to enhancement of IA and IK(Ca) (Kloppenburg et al., 1999). The leaky,
hyperpolarized PD neurons impose a marked electrical drag on the
excited AB neuron, and this drag is greater when two PD neurons are
present. Hooper and Marder (1987) observed a similar effect of
proctolin on pyloric cycle frequency that varied with the number of PD
neurons present. In their study, proctolin directly accelerated the AB
neuron, whereas the PD neurons were unaffected by proctolin. In the
presence of DA, it appears that the synaptic input to the AB-PD
pacemaker kernel from the LP and VD neurons plays no significant role
in determining the final DA-induced cycle frequency. This is despite the fact that DA strongly excites the LP neuron (Flamm and
Harris-Warrick, 1986b; Harris-Warrick et al., 1995a) and enhances LP
inhibition of the PD neurons (Johnson et al., 1995). The quantitative
effect of DA on LP activity provides an explanation for this result. In
addition to exciting the LP neuron, DA evokes a significant phase
advance of the onset of the LP burst, attributable to a reduction in
IA and an enhancement of
Ih (Harris-Warrick et al., 1995a). The LP burst
duration is not prolonged because DA also excites and phase advances
the PY neurons, which inhibit and terminate the LP burst
(Harris-Warrick et al., 1995b). The phase of LP inhibition of PD is
therefore advanced into a "refractory" region of the oscillatory
cycle where the AB and PD neurons are just beginning to recover from
their own burst-induced hyperpolarization. As we have shown (Figs. 7,
8), the additional LP inhibition at this phase has no net effect on the
time for AB-PD repolarization to resume firing. The VD neuron is
inhibited and hyperpolarized by DA, in part because of an increase in
IA (J. Peck and R. Harris-Warrick, unpublished
data). The electrical synapses between the VD neuron and the pacemaker
neurons are weakened by DA, and in addition they rectify such that
hyperpolarization of the inhibited VD does not effectively
hyperpolarize the AB or PD neurons (Fig. 1) (Johnson et al., 1993). In
conclusion, the DA-evoked cycle frequency is dominated by DA's
opposing effects on the pacemaker AB and PD neurons, with no
contribution from the follower cells.
The cycle enhancement seen with 5HT results primarily from its direct
effects on the AB pacemaker, with little contribution from either the
PD or the follower neurons. 5HT enhances bursting in the isolated AB
neuron [by a different ionic mechanism than DA (Harris-Warrick and
Flamm, 1987)] but has no detectable effect on the PD neurons (Fig. 2)
(Eisen and Marder, 1984; Flamm and Harris-Warrick, 1986b). Thus,
the effects of 5HT on the cycle frequency of the isolated AB neuron,
the AB-PD, and AB-2xPD subnetworks are virtually identical (Fig. 6).
As with DA, the VD and LP neurons appear to play no role in 5HT's
effects on the cycle frequency. The VD neuron is inhibited by 5HT and
usually is silent; its hyperpolarization is not passed electrotonically
to the AB/PD neurons because of the rectifying nature of these
electrical synapses (Johnson et al., 1993). 5HT also directly inhibits
the LP and weakens the synapses between the LP and the PD neurons
(Johnson et al., 1995). As a consequence, LP inhibits the PD neurons to
a lesser degree. Thus, the effect of 5HT on the cycle frequency of the
intact pyloric network is the same as that seen in the isolated AB
neuron and AB-PD pacemaker neurons.
An opposite conclusion can be drawn for Oct's control of cycle
frequency, where feedback from the follower cells, in particular the LP
neuron, plays a dominant role in determining the final cycle frequency
of the intact pyloric network. Octopamine's enhancement of the cycle
frequency of the isolated, cycling AB neuron is relatively modest (Fig.
3B) (Flamm and Harris-Warrick, 1986b) and is caused by a
different ionic mechanism for burst enhancement than either DA or 5HT
(Harris-Warrick and Flamm, 1987). However, Oct also slightly excites
the isolated PD neuron (Fig. 2) (Flamm and Harris-Warrick, 1986b),
which the other amines do not do. This is sufficient to make the
Oct-induced AB-PD and AB-2xPD subnetworks' cycle frequencies comparable to or even slightly higher than the 5HT-evoked frequencies (Figs. 4, 6) and significantly greater than the DA-evoked frequency. However, when we progress to the intact pyloric network, this accelerating effect of Oct is lost, and Oct has virtually no effect on
the cycle frequency (Figs. 5, 6). As we have shown [see also Flamm and
Harris-Warrick (1986a,b)], Oct prolongs and enhances spike activity of
the LP neuron but does not enhance PY activity in the intact network as
DA does. Thus, the LP neuron fires for a much longer fraction of the
cycle than under control conditions. During this time, LP is inhibiting
the PD neuron (and thus, electrotonically, the AB neuron); in addition,
the strength of the LP PD inhibitory synapse is also enhanced by
Oct (Johnson et al., 1995). This prolonged and strengthened inhibition
delays the pacemaker group from repolarizing to fire their next burst.
As a consequence, the overall cycle frequency is not accelerated and
sometimes even slowed (Fig. 5A) despite Oct's excitation of
both the AB and PD neurons in the pacemaker subnetwork. The VD neuron
is directly but weakly excited by Oct (Flamm and Harris-Warrick,
1986b). However, it does not become active during Oct application in
the intact network because of strong inhibition by the activated LP
neuron, so it does not contribute to setting the cycle frequency.
Time and concentration dependence of DA effect on
cycle frequency
Our work also shows that DA has a complex time- and
concentration-dependent effect on the AB-PD subnetwork cycle
frequency. At high concentrations (104
M), DA evokes a transient reduction in cycle frequency
followed by a recovery to near control cycle frequency under
steady-state conditions (Figs. 6, 9, 10). The early deceleration is
caused by DA inhibition of the PD neuron, whereas the later
acceleration is caused by the DA's delayed enhancement of AB bursting.
It was been shown previously (Flamm and Harris-Warrick, 1986b), and
confirmed here (Fig. 9), that the threshold for PD inhibition by DA
(105 M) is higher than for AB
excitation (106 M), so the observed
results cannot be caused by the slowly rising concentration of DA in
our bath. Indeed, this would have led to an early enhancement of
cycling followed by a later reduction, the opposite of what is seen. We
are left with several hypotheses to explain this result. First, the
second messenger mechanisms leading to PD inhibition could be activated
more rapidly than those leading to AB excitation. Alternatively, there
could be a difference in the DA receptor level between the AB and PD
neurons; more receptors in the PD neurons could facilitate a more rapid response. Finally, the DA receptors on the PD neurons might be localized to be more readily accessible to bath-applied DA than those
on the AB neuron. Unfortunately, no evidence is available to
distinguish between these mechanisms.
There are several possible consequences of these different time- and
concentration-dependent effects of DA. If the modulatory neurons
providing DA to the STG were to fire weakly, only a low concentration
of DA would be seen in the ganglion, and this could evoke an
acceleration in AB cycle frequency without inhibition of the PD
neurons, as seen in Figure 9B. Brief higher firing rates might evoke just the PD-dependent reduction in firing frequency seen
early during bath application of DA. Finally, prolonged high firing
rates would lead to the biphasic effect seen in Figure 9A,
with the PD neurons inhibited throughout. All of these responses can be
seen in the dish with local pressure ejection of pulses of DA from a
pipette (data not shown). Because the PD neurons are motoneurons
controlling dilation of the pyloric valve, the ability to independently
affect the cycle frequency and the spike frequency of the PD neurons
(and thus activation of the dilator muscles) will allow greater
flexibility in motor output.
Conclusion
Our results show the complexity of the neuronal interactions that
lead to the modulatory control of cycle frequency in the pyloric
network. As summarized in Figure 11,
the major circuit components that are instrumental in setting the cycle
frequency vary depending on the modulatory conditions, from the
predominant role of the single AB neuron in 5HT to the AB-PD pacemaker
subnetwork in DA and the AB-PD-LP subnetwork in Oct. Although the AB
neuron is universally believed to be the most important pacemaker in the pyloric network, we cannot predict the monoamine effects on the
pyloric network frequency based solely on their effects on the isolated
AB neuron. By having contrasting effects on the PD neurons (DA
inhibits, 5HT has no effect, and Oct excites), the amines can
dramatically modify their net effects on the AB-PD group. In addition,
the pacemaker group does not exist in a vacuum; the amines' different
effects on both the LP neuron and its synapse onto the PD neurons shape
the extent to which this input is relevant in controlling the pacemaker
group's cycle frequency. Finally, by differentially modulating the PY
neurons' inhibition of the LP neuron, DA and Oct impart very different
roles to the LP neuron in the control of cycle frequency.
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Figure 11.
The pyloric network components that are the major
targets of monoamine modulation of cycle frequency. Schematic diagrams
of the intact pyloric network are shown. In each panel
(5HT, DA, and Oct) the
circuit components that are instrumental in determining the specific
amine-induced cycle frequency are highlighted.
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These results emphasize that the effects of a neuromodulator on a
network cannot be predicted simply from the sum of the modulator effects on each of the component neurons in isolation: the network generates complex and nonlinear interactions that must be taken into
account as well. However, by carefully studying the different components both alone and in varying combinations, the general mechanisms of frequency control can be determined.
| |
FOOTNOTES |
Received Jan. 12, 1999; revised April 28, 1999; accepted May 3, 1999.
This work was supported by National Institutes of Health Grant NS17323.
We thank Dr. P. Meyrand for his valuable comments on an early version
of this manuscript.
Correspondence should be addressed to Amir Ayali at his present
address: Department of Zoology, Faculty of Life Sciences, Tel-Aviv
University, Ramat-Aviv, Tel-Aviv, Israel 69978.
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J Neurophysiol,
June 1, 2008;
99(6):
2844 - 2863.
[Abstract]
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K. Sasaki, J. Jing, M. R. Due, and K. R. Weiss
An Input-Representing Interneuron Regulates Spike Timing and Thereby Phase Switching in a Motor Network
J. Neurosci.,
February 20, 2008;
28(8):
1916 - 1928.
[Abstract]
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M. S. Kirby and M. P. Nusbaum
Peptide Hormone Modulation of a Neuronally Modulated Motor Circuit
J Neurophysiol,
December 1, 2007;
98(6):
3206 - 3220.
[Abstract]
[Full Text]
[PDF]
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P. Kloppenburg, W. R. Zipfel, W. W. Webb, and R. M. Harris-Warrick
Heterogeneous Effects of Dopamine on Highly Localized, Voltage-Induced Ca2+ Accumulation in Identified Motoneurons
J Neurophysiol,
November 1, 2007;
98(5):
2910 - 2917.
[Abstract]
[Full Text]
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S. R. Saideman, D. M. Blitz, and M. P. Nusbaum
Convergent Motor Patterns from Divergent Circuits
J. Neurosci.,
June 20, 2007;
27(25):
6664 - 6674.
[Abstract]
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P. Rabbah and F. Nadim
Distinct Synaptic Dynamics of Heterogeneous Pacemaker Neurons in an Oscillatory Network
J Neurophysiol,
March 1, 2007;
97(3):
2239 - 2253.
[Abstract]
[Full Text]
[PDF]
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J. H. Peck, E. Gaier, E. Stevens, S. Repicky, and R. M. Harris-Warrick
Amine Modulation of Ih in a Small Neural Network
J Neurophysiol,
December 1, 2006;
96(6):
2931 - 2940.
[Abstract]
[Full Text]
[PDF]
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S. R. Saideman, A. E. Christie, P. Torfs, J. Huybrechts, L. Schoofs, and M. P. Nusbaum
Actions of kinin peptides in the stomatogastric ganglion of the crab Cancer borealis
J. Exp. Biol.,
September 15, 2006;
209(18):
3664 - 3676.
[Abstract]
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[PDF]
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J.-C. Viemari and J.-M. Ramirez
Norepinephrine Differentially Modulates Different Types of Respiratory Pacemaker and Nonpacemaker Neurons
J Neurophysiol,
April 1, 2006;
95(4):
2070 - 2082.
[Abstract]
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[PDF]
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V. Thirumalai, A. A. Prinz, C. D. Johnson, and E. Marder
Red Pigment Concentrating Hormone Strongly Enhances the Strength of the Feedback to the Pyloric Rhythm Oscillator But Has Little Effect on Pyloric Rhythm Period
J Neurophysiol,
March 1, 2006;
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1762 - 1770.
[Abstract]
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[PDF]
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G. Zhong, M. Diaz-Rios, and R. M. Harris-Warrick
Serotonin Modulates the Properties of Ascending Commissural Interneurons in the Neonatal Mouse Spinal Cord
J Neurophysiol,
March 1, 2006;
95(3):
1545 - 1555.
[Abstract]
[Full Text]
[PDF]
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B. R. Johnson, L. R. Schneider, F. Nadim, and R. M. Harris-Warrick
Dopamine Modulation of Phasing of Activity in a Rhythmic Motor Network: Contribution of Synaptic and Intrinsic Modulatory Actions
J Neurophysiol,
November 1, 2005;
94(5):
3101 - 3111.
[Abstract]
[Full Text]
[PDF]
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M. Gruhn, J. Guckenheimer, B. Land, and R. M. Harris-Warrick
Dopamine Modulation of Two Delayed Rectifier Potassium Currents in a Small Neural Network
J Neurophysiol,
October 1, 2005;
94(4):
2888 - 2900.
[Abstract]
[Full Text]
[PDF]
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P. Rabbah, J. Golowasch, and F. Nadim
Effect of Electrical Coupling on Ionic Current and Synaptic Potential Measurements
J Neurophysiol,
July 1, 2005;
94(1):
519 - 530.
[Abstract]
[Full Text]
[PDF]
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C. Soto-Trevino, P. Rabbah, E. Marder, and F. Nadim
Computational Model of Electrically Coupled, Intrinsically Distinct Pacemaker Neurons
J Neurophysiol,
July 1, 2005;
94(1):
590 - 604.
[Abstract]
[Full Text]
[PDF]
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J.-M. Goaillard, D. J. Schulz, V. L. Kilman, and E. Marder
Octopamine Modulates the Axons of Modulatory Projection Neurons
J. Neurosci.,
August 11, 2004;
24(32):
7063 - 7073.
[Abstract]
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[PDF]
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M. C. Clark, T. E. Dever, J. J. Dever, P. Xu, V. Rehder, M. A. Sosa, and D. J. Baro
Arthropod 5-HT2 Receptors: A Neurohormonal Receptor in Decapod Crustaceans That Displays Agonist Independent Activity Resulting from an Evolutionary Alteration to the DRY Motif
J. Neurosci.,
March 31, 2004;
24(13):
3421 - 3435.
[Abstract]
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[PDF]
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A. L. Weaver and S. L. Hooper
Relating Network Synaptic Connectivity and Network Activity in the Lobster (Panulirus interruptus) Pyloric Network
J Neurophysiol,
October 1, 2003;
90(4):
2378 - 2386.
[Abstract]
[Full Text]
[PDF]
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B. R. Johnson, P. Kloppenburg, and R. M. Harris-Warrick
Dopamine Modulation of Calcium Currents in Pyloric Neurons of the Lobster Stomatogastric Ganglion
J Neurophysiol,
August 1, 2003;
90(2):
631 - 643.
[Abstract]
[Full Text]
[PDF]
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D. Bucher, V. Thirumalai, and E. Marder
Axonal Dopamine Receptors Activate Peripheral Spike Initiation in a Stomatogastric Motor Neuron
J. Neurosci.,
July 30, 2003;
23(17):
6866 - 6875.
[Abstract]
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J. Jing, F. S. Vilim, J.-S. Wu, J.-H. Park, and K. R. Weiss
Concerted GABAergic Actions of Aplysia Feeding Interneurons in Motor Program Specification
J. Neurosci.,
June 15, 2003;
23(12):
5283 - 5294.
[Abstract]
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[PDF]
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A. Szucs, R. D. Pinto, M. I. Rabinovich, H. D. I. Abarbanel, and A. I. Selverston
Synaptic Modulation of the Interspike Interval Signatures of Bursting Pyloric Neurons
J Neurophysiol,
March 1, 2003;
89(3):
1363 - 1377.
[Abstract]
[Full Text]
[PDF]
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A. L. Weaver and S. L. Hooper
Follower Neurons in Lobster (Panulirus interruptus) Pyloric Network Regulate Pacemaker Period in Complementary Ways
J Neurophysiol,
March 1, 2003;
89(3):
1327 - 1338.
[Abstract]
[Full Text]
[PDF]
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A. A. Prinz, V. Thirumalai, and E. Marder
The Functional Consequences of Changes in the Strength and Duration of Synaptic Inputs to Oscillatory Neurons
J. Neurosci.,
February 1, 2003;
23(3):
943 - 954.
[Abstract]
[Full Text]
[PDF]
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A. Ayali, Y. Zilberstein, and N. Cohen
The locust frontal ganglion: a central pattern generator network controlling foregut rhythmic motor patterns
J. Exp. Biol.,
September 15, 2002;
205(18):
2825 - 2832.
[Abstract]
[Full Text]
[PDF]
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P. Telgkamp, Y. Q. Cao, A. I. Basbaum, and J.-M. Ramirez
Long-Term Deprivation of Substance P in PPT-A Mutant Mice Alters the Anoxic Response of the Isolated Respiratory Network
J Neurophysiol,
July 1, 2002;
88(1):
206 - 213.
[Abstract]
[Full Text]
[PDF]
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V. Thirumalai and E. Marder
Colocalized Neuropeptides Activate a Central Pattern Generator by Acting on Different Circuit Targets
J. Neurosci.,
March 1, 2002;
22(5):
1874 - 1882.
[Abstract]
[Full Text]
[PDF]
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K. Mizutani, H. Ogawa, J. Saito, and K. Oka
Fictive locomotion induced by octopamine in the earthworm
J. Exp. Biol.,
January 15, 2002;
205(2):
265 - 271.
[Abstract]
[Full Text]
[PDF]
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J. H. Peck, S. T. Nakanishi, R. Yaple, and R. M. Harris-Warrick
Amine Modulation of the Transient Potassium Current in Identified Cells of the Lobster Stomatogastric Ganglion
J Neurophysiol,
December 1, 2001;
86(6):
2957 - 2965.
[Abstract]
[Full Text]
[PDF]
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M. Thoby-Brisson and J.-M. Ramirez
Identification of Two Types of Inspiratory Pacemaker Neurons in the Isolated Respiratory Neural Network of Mice
J Neurophysiol,
July 1, 2001;
86(1):
104 - 112.
[Abstract]
[Full Text]
[PDF]
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D. E. Wood, W. Stein, and M. P. Nusbaum
Projection Neurons with Shared Cotransmitters Elicit Different Motor Patterns from the Same Neural Circuit
J. Neurosci.,
December 1, 2000;
20(23):
8943 - 8953.
[Abstract]
[Full Text]
[PDF]
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D. J. Baro, A. Ayali, L. French, N. L. Scholz, J. Labenia, C. C. Lanning, K. Graubard, and R. M. Harris-Warrick
Molecular Underpinnings of Motor Pattern Generation: Differential Targeting of Shal and Shaker in the Pyloric Motor System
J. Neurosci.,
September 1, 2000;
20(17):
6619 - 6630.
[Abstract]
[Full Text]
[PDF]
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P. Kloppenburg, W. R. Zipfel, W. W. Webb, and R. M. Harris-Warrick
Highly Localized Ca2+ Accumulation Revealed by Multiphoton Microscopy in an Identified Motoneuron and Its Modulation by Dopamine
J. Neurosci.,
April 1, 2000;
20(7):
2523 - 2533.
[Abstract]
[Full Text]
[PDF]
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TOP
ABSTRACT
INTRODUCTION
