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Department of Neuroscience, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104
Submitted 31 July 2003; accepted in final form 22 September 2003
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ABSTRACT |
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30 min. These sensory actions on the pyloric and gastric mill circuits were mimicked by either ventral cardiac nerve or dorsal posterior esophageal nerve stimulation. VCN actions on the STG circuits required the activation of projection neurons in the commissural ganglia. A subset of the VCN actions on these projection neurons appeared to be direct and cholinergic. We propose that the VCN neurons are mechanoreceptors that are activated when food stored in the foregut applies an outward force, leading to the long-lasting activation of projection neurons required to initiate chewing and modify the filtering of chewed food. |
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INTRODUCTION |
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; Marder and Pearson 1998; McCrea 1998; Pearson 1995, 2001; Pearson et al. 1998; Stein et al. 1997). Sensory neurons that are responsible for mechanoreception are sensitive to distortions of the body caused by either internally or externally generated mechanical energy and thus can sense gravity, pressure, touch, stretch, and vibration (McIver 1985). With respect to rhythmically active neural networks [i.e., central pattern generators (CPGs)] such as those responsible for locomotion, respiration, and feeding, mechanoreceptors are classically thought to provide transient feedback, correctional information used to ensure that the network output is appropriate for the current environmental situation (Stein et al. 1997). In this context, mechanoreceptors regulate, on a cycle-to-cycle basis, the frequency of network activity and the intensity/timing of impulse bursts produced by network neurons.
Phasic regulation of pattern-generating circuits has been well studied in a variety of systems, including feeding in Aplysia (Cropper et al. 1996; Evans and Cropper 1998; Evans et al. 1999), flight in locust (Pearson and Wolf 1987, 1988; Pearson et al. 1983; Stein et al. 1997; Wilson 1961; Wolf and Pearson 1987, 1988), swimming in lamprey (Wallen 1982), respiration in rat (Mellen and Feldman 2001), and walking in stick insects (Akay et al. 2001; Hess and Buschges 1999) and cats (Andersson and Grillner 1981; Duysens and Pearson 1980; Duysens et al. 2000; Hiebert et al. 1996; Lam and Pearson 2001; Whelan et al. 1995). Considerable progress has been made in gaining a cellular-level understanding of how these phasic actions are exerted. Work with several systems has established that these types of sensory neurons can also have longer lasting, modulatory actions that reconfigure network dynamics to produce different activity patterns that outlast sensory activation by many cycles (Hooper et al. 1990; Katz and Harris-Warrick 1989; Katz et al. 1989; Sigvardt and Mulloney 1982). In some cases, mechanoreceptor activation can also initiate or terminate network output (Boothby and Roberts 1992; Perrins et al. 2002; Viana di Prisco et al. 1997, 2000).
In this study, we establish the influence of a mechanoreceptive system with both short- and long-lasting actions in the stomatogastric nervous system (STNS) of the crab Cancer borealis. The crustacean STNS is an extensively characterized model system for studying rhythmically active neural circuits at the cellular level (Harris-Warrick et al. 1992; Marder and Calabrese 1996; Nusbaum and Beenhakker 2002). The STNS is an extension of the crustacean CNS that contains motor circuits controlling the movement of food through the crab esophagus and 3-compartment stomach (cardiac sac, gastric mill, pylorus). The STNS consists of 4 ganglia, including the paired commissural ganglia (CoGs: about 500 neurons each), the unpaired esophageal ganglion (OG: 14 neurons), and the stomatogastric ganglion (STG: 26 neurons). Most of the STG neurons participate in one or both of 2 well-characterized CPG circuits that generate the gastric mill (food chewing) and pyloric (food filtering) rhythmic motor patterns (Weimann and Marder 1994). In vivo and in vitro, the pyloric circuit is generally spontaneously active, whereas the gastric mill circuit is inactive except when it receives input from specific CoG projection neurons that are not spontaneously active (Blitz and Nusbaum 1997; Blitz et al. 1999; Clemens et al. 1998). The STG circuits can generate many versions of the pyloric and gastric mill rhythms (Nusbaum and Beenhakker 2002; Nusbaum et al. 2001). This flexibility results from the synaptic and modulatory actions of projection (Nusbaum et al. 2001) and sensory neurons (Combes et al. 1999; Hooper et al. 1990; Katz and Harris-Warrick 1989; Simmers and Moulins 1988a,b). In C. borealis, there are fewer than 20 projection neurons innervating the STG (Coleman et al. 1992).
In the current study we examined the actions of the ventral cardiac neurons (VCNs), a population of mechanosensory neurons in C. borealis that modulate the ongoing pyloric rhythm and evoke a long-lasting activation of the gastric mill rhythm. Here, we characterize these events and determine the pathways by which this sensory system activates the gastric mill rhythm. This activation of the gastric mill rhythm by VCN stimulation appears to operate by long-lasting VCN actions on identified projection neurons that are known to activate this motor pattern. Part of this work appeared previously in abstract form (Beenhakker et al. 2000).
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METHODS |
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Jonah crabs (Cancer borealis) were obtained from a commercial supplier (Commercial Lobster and Seafood, Boston, MA) and from the Marine Biological Laboratory (MBL, Woods Hole, MA). Before experimentation, the crabs were housed in commercial tanks containing recirculating, aerated artificial seawater (10–12°C). Before dissection, the crabs were cold-anesthetized by packing them in ice for 30 min. The foregut was then removed and maintained in chilled physiological saline while the STNS was dissected away (Fig. 1A).
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Under most experimental conditions, the STNS was maintained in physiological saline containing (in mM) 440 NaCl, 26 MgCl2, 11 KCl, 13 CaCl2, 10 Trizma base, and 5 maleic acid (pH 7.4–7.6). To limit neuronal interactions to those that were likely to be monosynaptic, in a subset of experiments we superfused the preparation with saline containing 5 times the normal concentration of the divalent salts (i.e., "high-divalent cation saline") (Blitz and Nusbaum 1999). This saline contained (in mM) 439 NaCl, 130 MgCl2, 11 KCl, 64.5 CaCl2, 10 Trizma base, and 5 maleic acid (pH 7.4–7.6). In a few preparations, chemical transmission was eliminated by superfusing the preparation with saline that contained reduced (0.1x normal) concentrations of Ca2+ plus a compensatory concentration of Mn2+ (i.e., "low-calcium saline") (Blitz and Nusbaum 1997) (in mM): 439 NaCl, 26 MgCl2, 11 KCl, 1.3 CaCl2, 11.7 MnCl2, 10 Trizma base, and 5 maleic acid (pH 7.4–7.6).
In some experiments, neurotransmitter receptor antagonists were superfused to characterize the central actions of the VCN neurons in the CoG. Antagonists used included the serotonin receptor antagonists cinanserin (10–4–10–3 M, Tocris Cookson, Ellisville, MO) and atropine (10–4 M, Sigma, St. Louis, MO), the nicotinic acetylcholine receptor antagonist decamethonium bromide (10–3 M, Sigma), and the muscarinic cholinergic receptor antagonists scopolamine (10–4 M, Sigma) and atropine (10–3 M).
Electrophysiology
All experiments were performed using either the completely isolated STNS (Fig. 1B) or a semi-intact preparation consisting of the isolated STNS attached to a small portion of the cardiac sac containing the cardiac gutter. Both preparations were pinned down in a saline-filled silicone elastomer-lined petri dish (Sylgard 184, KR Anderson, Santa Clara, CA) and superfused continuously (7–12 ml/min) with physiological and/or experimental (high-divalent cation or low-calcium) saline (10–12°C). Intracellular and extracellular recordings of the gastric mill and pyloric rhythms were made using routine methods for the STNS (Fig. 1C) (Blitz and Nusbaum 1999). Intracellular recordings were made with Axoclamp 2B amplifiers (Axon Instruments, Foster City, CA) and glass microelectrodes (15–30 M
) filled with 4 M potassium acetate and 20 mM KCl. Intracellular current injections were performed in single electrode discontinuous current clamp mode with sample rates of 2–3 kHz. To facilitate intracellular recordings, the STNS ganglia were desheathed and illuminated with light transmitted through a dark-field condenser (Nikon, Tokyo, Japan). Extracellular recordings were made by placing a reference wire electrode (stainless steel) in the bath and a recording wire alongside an individual nerve and isolated from the bath by petroleum jelly (Vaseline, Chesebrough-Ponds USA, Greenwich, CT). The signal was then amplified with AC (AM Systems, Carlsborg, WA) and DC (Brownlee Precision, Santa Clara, CA) amplifiers. Extracellular nerve stimulation was accomplished by placing the pair of wires used to record nerve activity into a stimulus isolation unit (Astromed/Grass Instruments, West Warwick, RI) that was connected to a S88 stimulator (Astromed/Grass Instruments).
Anatomy
VCN neurons were localized in the STNS with a methylene blue staining protocol (Alexandrowitcz 1951). Briefly, the STNS, including the cardiac gutter, was dissected from the foregut. The preparation was then pinned out in a silicone elastomer-lined petri dish containing physiological saline. Next, the physiological saline was replaced with a methylene blue solution made with the following specifications: 100 ml cold physiological saline, 15 drops 1% aqueous methylene blue (Sigma), and 10 µL HCl (Sigma). The preparation was incubated in the methylene blue solution overnight at 4°C. The cardiac gutter was then examined for the presence of cell bodies with axons projecting through the vcn. Digital images were taken with the use of a Leica DMRB microscope and Leica DC 350FX digital camera system (Leica Microsystems, Bannockburn, IL). Images were acquired with Image-Pro Express software (Media Cybernetics, Silver Spring, MD).
Sensory stimulation
Semi-intact preparations containing the cardiac gutter were stimulated mechanically. In our semi-intact preparations, the section of stomach wall containing the cardiac gutter was connected to the STNS only by the vcn/dpon. The stimulus was delivered to the region of the cardiac gutter by gently applying pressure with a glass probe ending in a small (0.5 mm) blunt tip, roughly 
the size of the cardiac gutter. The probe was handcrafted by melting/pulling a Pasteur pipette and fire-polishing to remove any sharp edges that could cause tissue damage. In some experiments, the neighboring muscle (posterior inferior cardiac muscle, cv3) was transected to test the possibility that the VCN neurons were muscle stretch receptors.
Data analysis
Individual STNS neurons were identified by their axonal pathways, activity patterns, and interactions with other neurons (Blitz et al. 1999; Wood et al. 2000). Data were collected directly onto a MT-95000 chart recorder (Astromed, West Warwick, RI), and were simultaneously digitized (about 5 KHz) and collected onto a PC computer using data acquisition/analysis tools (Spike2, Cambridge Electronic Design, Cambridge, UK). Figures were made from Spike2 files incorporated into Adobe Photoshop (Adobe, San Jose, CA) and Powerpoint graphics programs (Microsoft, Seattle, WA). Statistical analyses were performed with SigmaStat 3.0 and SigmaPlot 8.0 (SPSS, Chicago, IL). Data are expressed as means ± SD.
Data analysis was facilitated with a custom-written program for Spike2 that determines the activity levels and phase relationships of neurons (freely available at http://www.neurobiologie.de/). Unless otherwise stated, each datum in a data set was derived by determining the average of 10 consecutive impulse bursts. Briefly, burst duration was defined as the duration (s) between the onset of the first and last action potential in an impulse burst. The firing rate of a neuron was defined as the number of action potentials minus 1, divided by the burst duration. The cycle frequency of pyloric and gastric mill rhythms was determined by calculating the inverse of the period between the onset of 2 successive pyloric dilator (PD) neuron bursts and 2 successive lateral gastric (LG) neuron bursts, respectively. The phase relationships among gastric mill neurons were determined relative to gastric mill cycles in which the onset and end of a cycle were designated by the onset of successive LG neuron bursts. Thus the phase onset and offset of each gastric mill neuron burst represented the fraction of a gastric mill cycle during which each neuron was active. Phase relationships were determined exclusively from extracellular recordings.
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RESULTS |
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The VCN neurons innervate a portion of the cardiac sac wall and project to the STNS through the ventral cardiac nerve (vcn) and the dorsal posterior esophageal nerve (dpon) (Fig. 2A). The dpon is a bilaterally symmetric nerve that branches from the superior esophageal nerve (son, Fig. 1, A and B). About 1 cm distal to the son, the dpon turns laterally and ventrally to project toward the ventral portion of the foregut. Near the ventral midline of the foregut, the dpon branches into 3 nerves (Figs. 1B and 2A). One branch (dponAnt) projects anteriorly, one branch (dponLat) projects laterally, and one branch (vcn) projects posteriorly toward the posterior end of the cardiac sac compartment of the foregut (Fig. 2). Ringel (1924) described in detail the anatomical structures, including putative mechanosensory neurons, found in this region of the crustacean foregut.
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). Nerve backfills (n > 10) using fluorescent dyes such as Lucifer yellow (10–20%) and rhodamine dextran (10–20%) were unsuccessful, partly because the portion of the stomach wall innervated by the vcn is autofluorescent (even when cleared with methylsalicylate). The autofluorescence made it impossible to visualize labeled axons projecting into the tissue. Backfills of the vcn using either of the nonfluorescent dyes nickel chloride (5%) or cobalt chloride (3%) (n > 10) also failed to yield labeling of any vcn axons projecting into the stomach wall. The VCN axon diameter at the point where the vcn enters the cardiac gutter was 1.2 ± 0.2 µm (n = 5). Therefore the lack of success with the backfills may have resulted from the small diameter of the vcn axons, perhaps because the small diameter axons did not remain open sufficiently long to enable much dye to diffuse into them. In fact, previous attempts to backfill several other STNS sensory neurons were also unsuccessful (Hooper et al. 1990; Sigvardt and Mulloney 1982).
We did successfully label the VCNs by staining the relevant region of the stomach wall with methylene blue, a neuronal stain used previously in the STNS (Dando and Maynard 1974; Wales et al. 1970). Methylene blue consistently stained a population of about 60 somata (range: 14–58; mean: 29.6 ± 18.4, n = 5) on each side of the midline region of the cardiac gutter innervated by the vcn (Fig. 2, C and D). The cardiac gutter is a bilaterally symmetrical invagination of the stomach wall near the cardiac sac–gastric mill boundary (see Fig. 2, A and B). Higher-magnification analysis revealed that these stained somata were bipolar (soma length: 24.7 ± 6.8 µm; soma width: 8.5 ± 1.6 µm, n = 5), with an apparently unbranched dendrite (about 60 µm long) and no evident associated specialization of the surrounding tissue (Fig. 2E). One process of each cell projected through the vcn, whereas the presumed dendrite of the cell appeared to be imbedded within the stomach wall. These somata were not visible in unstained preparations and attempts to find them for intracellular recording were unsuccessful.
We used vcn stimulation to gain further evidence that the VCN system corresponds to a population of neurons, rather than a single sensory neuron. To this end, we used an identified motor neuron of the esophageal motor system [esophageal motor neuron (OMN)] as an assay for VCN neuron action. The OMN occurs as a single copy in each CoG and has the largest amplitude spontaneously active action potential in extracellular ion recordings (data not shown). Its soma (diameter about 50 µm) is located near those of modulatory commissural neuron 1 (MCN1) and MCN5 (see Coleman and Nusbaum 1994; Norris et al. 1996). Stimulating the vcn evoked a constant-latency excitatory postsynaptic potential (EPSP) in the ipsilateral OMN. This PSP persisted in the presence of high-divalent cation saline (n = 6) (Fig. 3), indicating that the influence of the VCN neurons on the OMN is likely to be monosynaptic. Gradually increasing the vcn stimulus strength resulted in several stepwise increases in the amplitude of the PSP evoked in the OMN (n = 6) (Fig. 3). One plausible explanation for this effect is that with each step increase in the vcn stimulus voltage, an additional subset of VCN axons was activated, resulting in the recorded increase in PSP amplitude in the OMN. However, an alternate hypothesis is that each increase in PSP amplitude reflects the addition of a single VCN neuron and that a relatively small number of VCN neurons were recruited by vcn stimulation (e.g., 12 VCN neurons in Fig. 3).
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To determine the nature of the stimulus required to activate the VCN neurons, we subjected the relevant region of stomach wall to different types of sensory stimuli. First, we tested the hypothesis that the VCN neurons are chemoreceptors by determining whether exposing the relevant stomach region to 2 diet staples, macerated clams and squid, had any effect on the STNS. Similar food extracts were successfully used to activate esophageal chemoreceptors in the lobster (Robertson and Laverack 1979). When introduced to the cardiac gutter, however, no effect on either the pyloric or the gastric mill rhythm was ever observed (n = 5). Next, we tested the hypothesis that the VCN neurons are proprioceptive because intrinsic muscles occur in the region where the VCN somata are located. However, artificially stretching these muscles with a glass probe had no effect (n = 6). Furthermore, evoking muscle contractions by activating the motor neuron (IC neuron) innervating these muscles also had no effect (n = 2). Moreover, as discussed in the following text, transecting these muscles did not alter the mechanoreceptive function of the VCNs. Finally, we examined whether gently pressing portions of the relevant stomach region with a blunt glass probe (diameter = 0.5 mm) elicited a response. This stimulus did reliably evoke STNS responses when gentle pressure was exerted on a specific area of the stomach wall, that is, the cardiac gutter (n > 15). Specifically, during single, brief (3–5 s) applications of pressure, the pyloric rhythm consistently responded with an increased cycle frequency for the duration that pressure was applied. In response to repetitive probing, a long-lasting gastric mill rhythm was activated. These effects are explored below.
We also tested the hypothesis that the VCN neurons receive a chemical synapse in the stomach lining from a primary transducing element. To this end, we placed the patch containing the VCN neurons in a Vaseline well and replaced the normal saline in the well with low Ca2+ (0.1x normal/added Mn2+) saline to block transmitter release. In 3 out of 3 experiments, pressure applied to the cardiac gutter when bathed in low Ca2+ saline still excited the pyloric rhythm and activated the gastric mill rhythm.
Physiological activity patterns of VCN neurons
We sought to characterize the response of the VCN neurons to pressure applied to the cardiac gutter. However, we failed to record VCN activity either intracellularly or extracellularly. As indicated above, we were unable to localize the VCN somata in physiological preparations, making intracellular recordings impractical. Furthermore, we were not able to record extracellular VCN activity in either the vcn or the dpon in response to pressure applied to the cardiac gutter. Similarly, no time-locked events were recorded in the dpon in response to extracellular vcn stimulation (0/10), despite this stimulus having actions within the STNS. Averaging the responses of many (50–150) individual vcn stimulations also failed to unmask the VCN action potential, despite recording the desheathed dpon nerve where axonal activity is not muted by the presence of a connective tissue sheath surrounding the nerve (n = 4). Because the amplitude of an extracellularly recorded action potential is related to the axon diameter of the active neuron, we hypothesize that the relatively small axon diameter of the VCN neurons produces action potentials that are lost in the noise of the extracellular recording.
VCN alteration of the pyloric rhythm
Briefly (2–5 s) applying pressure to the cardiac gutter with a glass probe had several effects on the pyloric rhythm (Fig. 4). The most dramatic effects included an increase in the cycle frequency of the pyloric rhythm and decrease in lateral pyloric (LP) neuron activity. The pyloric cycle frequency increased from 1.17 ± 0.11 Hz before stimulation to 1.30 ± 0.13 Hz during stimulation (11% increase, P < 0.05, n = 6), and returned to 1.23 ± 0.09 Hz during the first 5 cycles after stimulation. LP neuron activity, as determined by the number of action potentials it fired per impulse burst, decreased from 5.2 ± 2.3 spikes/burst before stimulation to 2.9 ± 2.2 spikes/burst during stimulation (45% decrease, P < 0.05, n = 6), and increased back to 4.2 ± 1.9 spikes/burst after stimulation. These actions on the pyloric neurons were strongest during the application of pressure and waned within a few seconds after the application (Fig. 4).
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Whereas single applications of pressure to the cardiac gutter influenced the pyloric rhythm, multiple pressure applications in succession also activated the gastric mill rhythm. Using a glass probe, we applied rhythmic pressure to the cardiac gutter, delivering between 5 and 10 stimuli at a rate of one stimulus (duration: 3–4 s) per 10–15 s. During the delivery of such stimuli, uncoordinated bursting in gastric mill neurons was observed. Within 10–20 s after the delivery of the last in a succession of pressure applications, the bursting among gastric mill neurons became more regular and coordinated and a long-lasting gastric mill rhythm commenced (Figs. 6 and 7A, n > 15). The gastric mill rhythm elicited with 10 rhythmic presses was often strongest during the first 5 min after the rhythmic stimulation, and would gradually wane until the rhythm would terminate. This rhythm persisted for as long as 30 min, with its termination occurring on average 14 min after stimulation (Fig. 7B).
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Rhythmically stimulating either the dpon or the vcn routinely activated a gastric mill rhythm that was indistinguishable from the mechanically evoked rhythm on nearly all tested parameters. Thus stimulating either nerve (rhythmic stimulus train: 10 x 6 s burst delivered at 0.06 Hz; 15 Hz intraburst stimulation rate) produced a long-lasting (dpon: 1043 ± 947.5 s, n = 6; vcn: 1131.7 ± 902.9 s, n = 6) gastric mill rhythm in which the impulse bursts of all involved neurons had burst durations, activity levels, burst onsets, and burst offsets that were identical to those derived from the mechanical stimulus except DG firing frequency (Table 1, Fig. 7). Furthermore, the evolution of the gastric mill rhythm was reminiscent of those evoked mechanically in that regular, coordinated gastric mill neuron bursting activity commenced within 10–20 s after the stimulus train. This finding provided us the confidence to proceed with the characterization of this sensory pathway using more detailed intracellular analyses that were afforded by nerve stimulation protocols.
Different dpon nerve stimulation protocols evoke similar gastric mill rhythms
Without the ability to record VCN activity, we were unable to characterize the response of the VCN neurons to mechanical stimulation. Therefore we could not apply the behaviorally relevant stimulation pattern to the vcn or dpon. To circumvent this problem, we examined the response of the gastric mill circuit to 3 different dpon nerve stimulation protocols. Because the VCN neurons are sensitive to mechanical movements, we activated the VCN neurons with stimulus patterns that mimic the possible biomechanical movements these neurons may encounter. These include foregut movements produced in response to motor patterns generated by the STNS (e.g., pyloric, gastric mill, and cardiac sac rhythms), and pressure on the stomach wall produced by the constant presence of stored food (e.g., tonic activity). Thus we stimulated the dpon in rhythmic patterns reminiscent of either a slow gastric mill rhythm and fast cardiac sac motor pattern ("gastric mill/cardiac sac" stimulation protocol) or a pyloric rhythm ("pyloric" stimulation protocol), or stimulated the dpon tonically ("tonic" stimulation protocol). From these experiments, the parameter most influential for the activation and maintenance of a robust gastric mill rhythm was the absolute duration of stimulation. Short-duration stimulation protocols, such as those that selectively influenced the pyloric rhythm (see Fig. 5), were not sufficient to elicit the gastric mill rhythm, regardless of the stimulation pattern. Generally, only stimulations in excess of about 1 min activated robust, long-lasting gastric mill rhythms (data not shown). Furthermore, during these longer-duration stimulus protocols, when the stimulus frequency was decreased below 5 Hz the resulting gastric mill rhythm became less robust (data not shown). Thus we compared different stimulation protocols (i.e., gastric mill/cardiac sac, pyloric, and tonic) with stimulus frequencies in the moderate range (15 Hz). With respect to the parameters analyzed (i.e., gastric mill cycle period and LG neuron duty cycle), the rhythms produced by long-duration rhythmic (either gastric mill/cardiac sac or pyloric protocol) and tonic dpon stimulation were the same (Fig. 8). This conclusion was also supported by a qualitative assessment of the other aspects of these rhythms. Thus although we cannot be sure that we are reproducing the physiological response profile of the VCN neurons when we stimulate the vcn or dpon nerves, we are confident that the gastric mill rhythm produced by our stimulation protocols is likely to be a close approximation to the rhythm produced under normal behavioral conditions.
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The production of the gastric mill rhythm requires the activation of particular projection neurons in the commissural ganglia (CoGs; see Fig. 1) that are normally not spontaneously active in C. borealis (Nusbaum and Beenhakker 2002; Nusbaum et al. 2001). Therefore we predicted that the VCN neurons would not activate the gastric mill rhythm after the CoGs were removed from the STNS. To test this hypothesis, we transected the ions and sons. We transected each son between the CoG and dpon, thereby enabling the VCN neurons to still have potential access to the STG by the son and stn (see Fig. 1). When the CoGs were removed, stimulating the VCN neurons, either mechanically (n > 10) or by stimulating the dpon/vcn nerves (n > 10), never elicited a gastric mill rhythm from the STG (Fig. 9). Nonetheless, activating modulatory commissural neuron 1 (MCN1; see following text) in these same preparations by extracellular ion stimulation activated a gastric mill rhythm, indicating that the gastric mill circuit was not compromised by removing the CoGs (Fig. 9C). We therefore determined which identified CoG projection neurons were activated by VCN stimulation and so might contribute to activation of the gastric mill rhythm in the STG.
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; Norris et al. 1994, 1996; Wood and Nusbaum 2002). MCN1 and MCN5 activity is readily recorded extracellularly in the ion (Coleman and Nusbaum 1994; Norris et al. 1996), which enabled us to determine directly that they were activated by mechanically activating the VCN neurons (n = 6). MCN5 was consistently activated quickly, whereas repeated probes gradually activated MCN1 (n = 6). We used an indirect monitor to determine whether CPN2 was also activated by mechanical activation of this sensory pathway. Specifically, CPN2 appears to be the only projection neuron that activates the gastric mill GM neurons (Norris et al. 1994). Thus because the GM neurons actively participate in the mechanically activated gastric mill rhythm (see Fig. 7), it appeared likely that CPN2 was also activated by such stimulation.
Activating the VCN pathway by vcn or dpon stimulation influenced all 4 of the CoG projection neurons in ways that were comparable to mechanical stimulation. Specifically, MCN5 was excited during dpon stimulation (firing frequency: 16.2 ± 1.7 Hz, n = 5) but its activity waned within seconds (14.5 ± 2.0 s, n = 5) after stimulation and remained tonically active at a slower firing frequency (3.0 ± 1.4 Hz, n = 5) for 1–2 min. Previous work demonstrated that MCN5 must be firing in excess of 20 Hz to strongly influence the STG circuits (Norris et al. 1996). MCN1 (n > 10) and CPN2 (n = 8) were initially inhibited during VCN stimulation but exhibited strong activity for tens of minutes after VCN stimulation (Fig. 10). The MCN7 response to VCN stimulation was similar to the MCN1/CPN2 response but much weaker (n = 4) (Fig. 10). In some preparations, the inhibition of MCN1/CPN2 exhibited during VCN stimulation was overcome by the longer-lasting excitation provided by this pathway and, consequently, these projection neurons occasionally became active toward the end of the stimulus delivery (see Fig. 10).
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In an effort to understand which neurotransmitter(s) underlie these EPSPs, we used pharmacological agents that block the actions of various neurotransmitters. We examined whether the VCN neurons were serotonergic, given that one set of identified STNS muscle stretch receptor neurons use serotonin as a cotransmitter (Katz and Harris-Warrick 1990). However, 2 antagonists that block serotonergic actions in the crustacean STNS, atropine (10–4 M) and cinanserin (10–4 M), did not suppress the dpon-evoked EPSPs in the OMN and MCN1 (n > 3, data not shown). Because many mechanoreceptors in arthropods use acetylcholine as a neurotransmitter (Katz et al. 1989; Miller et al. 1992), we investigated whether the VCN neurons used this transmitter to influence the OMN and MCN1. The direct EPSPs in the OMN and MCN1 were indeed partially suppressed by the nicotinic acetylcholine receptor antagonist, decamethonium bromide (10–3 M). This antagonist, superfused in high-divalent cation saline, reversibly reduced the amplitude of the dpon-evoked EPSPs in these neurons by about 40% (n = 3) (Fig. 12). Additionally, we attempted to block the long-lasting component of the EPSPs in the OMN and MCN1 using the muscarinic cholinergic antagonists scopolamine (10–4 M) and atropine (10–3 M). These antagonists were previously used in the STNS to block muscarinic actions (Katz and Harris-Warrick 1989; Marder and Paupardin-Tritsch 1978). However, neither antagonist attenuated the VCN-evoked response in either the OMN or MCN1 (n = 3).
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DISCUSSION |
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) initially identified anatomically in this region of the crayfish, Astacus fluviatilis, and Dando and Maynard (1974) later identified anatomically in crab (Callinectes sapidus) and lobster (Panuliris argus). These neurons do not appear to have chemoreceptive properties. Rather, they are activated by pressure applied to the cardiac gutter. When activated for short durations (5–10 s), the VCNs modulated the pyloric rhythm, and when activated for longer durations (>1 min) they evoked a long-lasting activation of CoG projection neurons that in turn elicited a long-lasting activation of the gastric mill rhythm. Here, we have focused primarily on these latter actions. Behavioral model for VCN neurons
Because of a limited understanding of the biomechanical underpinnings of the foregut during food processing, we can only speculate as to the behavioral function of the VCN neurons. However, based on findings described in other sensory systems, we hypothesize that the VCNs sense movements within the foregut. Functionally analogous sensory neurons have been described in the foregut of insects (Gelperin 1967; Orlov 1924, 1925; Rice 1970). For example, the proper coordination of foregut movements produced by the stomatogastric nervous system of the European house cricket, Acheta domesticus, is thought to involve the interaction between a population of foregut body wall mechanoreceptors and esophageal motor neurons (Mohl 1972). Functionally similar stomach-distention receptors in the blood-feeding insect, Rhodnius prolixus (Bennet-Clark 1966; Chiang and Davey 1988; Chiang et al. 1990) are thought to initiate endocrinological processes underlying molting and egg production (Chiang and Davey 1988). Compartment distention-sensitive mechanoreceptor neurons also innervate the cricket (Teleogryllus commodus) genital chamber, a compartment transiently housing the egg during oviposition behavior (Sugawara and Loher 1986). These neurons sense the distention of the genital chamber produced by the egg in the ovipositing female and are responsible for the rest phase in the egg-laying behavior (Sugawara 1993, 1996).
In line with these previous studies, our current hypothesis regarding the VCN neurons is that they function as mechanoreceptor neurons that are activated during stomach distention resulting from food intake, thereby providing a trigger for the activation of food chewing when the food is subsequently moved to the gastric mill compartment (Fig. 13). Our finding that the gastric mill circuit is primarily activated for long durations after VCN stimulation supports this hypothesis. Rigorously testing this hypothesis, however, will require both a more detailed anatomical description of the VCN neurons and a detailed characterization of how food intake influences the morphology of the crab foregut.
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Relatively brief VCN activation leads to a prolonged activation of rhythmic motor activity. This persistent activation of the gastric mill rhythm appears to result from the long-lasting activation of CoG projection neurons, including MCN1 and CPN2. The extended activation of projection neurons by the VCNs is likely to result from a modulatory action, but it is unresolved whether that action comes directly from the VCN neurons. However, consistent with this possibility is the presence of a long-lasting component to the apparently monosynaptic EPSPs from VCN to MCN1, MCN7, and CPN2. Several other identified sensory neurons in the STNS have actions that are likely to be modulatory in nature (Combes et al. 1999; Hooper et al. 1990; Katz and Harris-Warrick 1989, 1990; Meyrand et al. 1994; Robertson and Laverack 1979; Sigvardt and Mulloney 1982; Simmers and Moulins 1988a,b). The modulatory actions of the VCNs are particularly reminiscent of those of a population of about 180 mechanoreceptive neurons, documented in the lobster (Homarus americanus, Palinurus vulgaris, Jasus lalandii), called the posterior stomach receptors (PSRs) (Nagy and Moulins 1981; Selverston and Moulins 1987). The PSRs have long-lasting actions on a subset of pyloric neurons and can activate the gastric mill circuit by exciting CoG projection neurons. Despite having very similar actions, the VCNs and PSRs reside in different regions of the foregut (Dando and Laverack 1969).
The STNS sensory neurons with the most extensively documented modulatory actions are the gastropyloric receptor neurons (GPRs) (Katz and Harris-Warrick 1989, 1990; Katz et al. 1989). One such GPR-elicited action is its modulation of the dorsal gastric (DG) neuron, by its influence on a hyperpolarization-activated inward current (Ih) and a calcium-dependent current, thereby enabling the expression of plateau properties in the DG neuron (Kiehn and Harris-Warrick 1992a,b). Similarly, the transformation of a cutaneous sensory signal into a swim command is also accompanied by the expression of plateau properties in reticulospinal (RS) neurons in the lamprey (Viana di Prisco et al. 1997, 2000). Thus future studies may reveal that VCN activation of the gastric mill circuit is also mediated by the induction of particular membrane properties in upstream CoG projection neurons.
VCN actions on higher-order neurons
The VCN sensory system belongs to a growing list of examples of mechanosensory neurons that have network-configuring properties in addition to the correctional, feedback-providing properties classically ascribed to such neurons. Of particular interest to this study is the recent focus on work aimed at achieving a cellular-level understanding of how sensory inputs can initiate and/or terminate entire motor programs. Several examples of sensory activation of motor programs exist. In the leech Hirudo medicinalis, for example, activation of pressure and nociception-sensitive sensory neurons excite subesophageal trigger neurons that drive swim-initiating interneurons that, in turn, activate the swim CPG and initiate swimming (Brodfuehrer et al. 1995; Weeks and Kristan 1978). In Aplysia, cerebral-to-buccal interneurons (CBIs) are activated by salient sensory stimuli and initiate/drive buccal motor programs underlying feeding behaviors (Rosen et al. 1991, 2000a,b). Primary afferent activation of a command-like interneuron that activates the swim CPG has also been documented in the marine mollusc Tritonia diomedea (Frost and Katz 1996). As mentioned above, RS neurons mediate the ability of sensory systems to influence spinal locomotor circuits. One such neuron is the Mauthner cell, the RS neuron in fish and amphibians that elicits an escape swim in response to tactile stimulation (Eaton et al. 2001; Liu and Fetcho 1999; O'Malley et al. 1996). In the lamprey, cutaneous inputs activate long-lasting, Ca2+-sensitive plateau potentials in RS neurons that are accompanied by escape swimming activity (Viana di Prisco et al. 1997, 2000). Afferent activation can also have long-term negative effects on rhythmic behaviors. For example, pressure applied to a cement gland on the head of Xenopus laevis activates inhibitory mid-hindbrain RS neurons that in turn inhibit the swim CPG and terminate swimming behavior (Perrins et al. 2002).
Many issues regarding sensory activation of rhythmic motor activity remain unresolved. One such issue involves whether the transformation of a relatively short-duration sensory stimulus into long-lasting motor output commonly results from direct modulatory actions of the sensory neuron(s). In cases where the long-lasting actions do indeed result from direct, sensory-mediated modulation, the range of underlying cellular mechanisms remains to be determined. It is also unclear how incoming sensory information is represented across a population of projection neurons (for review, see Lewis 1999). These and related issues are now amenable to a detailed cellular analysis using the VCN sensory system, given its ability to activate identified projection neurons that initiate the gastric mill motor program, and because of the accessibility and resulting available characterization of many STNS projection and circuit neurons.
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ACKNOWLEDGMENTS |
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GRANTS
This work was supported by National Institute of Neurological Disorders and Stroke Grants NS-42813 and NS-29436 to M. P. Nusbaum and F31-NS-41894 to M. P. Beenhakker.
Present address of D. M. Blitz: Department of Neurobiology, Harvard Medical School, Boston, MA 02115.
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FOOTNOTES |
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Address for reprint requests and other correspondence: M. P. Nusbaum, Department of Neuroscience, University of Pennsylvania School of Medicine, 215 Stemmler Hall, Philadelphia, PA 19104-6074 (E-mail: nusbaum{at}mail.med.upenn.edu).
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