- Email: [email protected]
Pattern generation
Pattern generation Ronald M Harris-Warrick Cornell
University,
Ithaca, USA
Significant advances have been made in understanding the cellular mechanisms for pattern generation in both invertebrate and vertebrate preparations. In a number of preparations, slow neuromodulators have been shown not only to modify network function, but to be intimately involved in development and/or normal function of the neural network and its associated behavior. The mechanisms underlying coordination between multiple pattern-generating networks, including switching of neurons from one network to another, are now being studied. Several new quantitative models of network function have been developed, and modeling is now an important component of research in this field.
Current Opinion in Neurobiology
Introduction A major goal of neuroethology is to identify and study the neural networks that generate simple behaviors. The networks generating rhythmic motor patterns such as locomotion, scratching and simple autonomic behaviors were the earliest studied and are still the best understood, as a result of the ease of detecting and analyzing the network neurons. In many systems, the neural networks are almost completely defined, and studies are focusing on stimulating and modulatory inputs that alter the properties of the network and its associated behavior. These studies have now matured to the point that realistic computer models are important components of a research strategy to understand how a network functions. In this review, I summarize recent advances in four areas of research on pattern generation: analysis of the components of the networks; the cellular mechanisms that determine network function; modulation of cellular and synaptic properties of neural networks; and mechanisms for interaction between simple patterngenerating networks to create complex movements. Several important reviews on this subject have appeared recently [l-3,4*.,5,61.
Analysis of neural networks Significant advances have been made in understanding a number of simple networks. The gastric mill network in the crustacean stomatogastric ganglion (STG) has been anatomically described, but due to its multi-
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functional properties, it has been difficult to analyze. Elson and Selverston [7**1 isolated the STG and determined the essential components of the network activated by the muscarinic agonist pilocarpine. Four of the eleven component neurons comprise the essential pattern generator under these conditions, due to their induction of conditional plateau potential capability and synaptic interactions; the other neurons are followers. A dynamic connectionist model of the local bending reflex in the leech was derived using a back-propagation algorithm 18*,91. A distributed network of 40 multifunctional interneurons could generate all forms of local bending. Different sets of initial conditions yielded different but equally effective model networks, all of which differed in detail from experimental observations 1101.Thus, the actual neural network cannot be obtained by back-propagation, but the general principles of function in a highly distributed network can be elucidated. Much smaller networks were effective, suggesting that the biological network is redundant and may be involved in other behaviors. In fact, some of the same intemeurons are involved in the shortening reflex and swimming 111,121. Neuroethological analyses of the gill and siphon withdrawal reflexes (GSWR) in Aplysia have revealed the dominant role of polysynaptic network interactions 1131in the reflex and its modulation. Polysynaptic pathways account for about 75% of the compound EPSPs recorded in motoneurons following siphon or gill stimulation 114.1. The mono- and polysynaptic components respond differentially to neuromodulators such as sero-
Abbreviations AMPA-a-amino-3-hydroxy-5-methyl isoxazole4propionic acid; DSI-dorsal swim interneuron; EM-excitatory amino acids; EPSP-excitatory postsynaptic potential; GSWR-gill and siphon withdrawal reflexes; 5HT-5-hydroxytryptamine kerotonin); IA-transient potassium current; Ih-hyperpolarization-activated inward current; IKtc~~--calciumdependent potassium current; Ir--low threshold calcium current; MLR-mesencephalic locomotor region; NMDA-_N-methyl-D-aspartate; STC-stomatogastric ganglion.
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Pattern generation Harris-Warrick
tonin (5hydroxytryptamine: 5HT) and the peptide SCPn. A set of inhibitory interneurons exert activity-dependent negative feedback on the polysynaptic pathway of the reflex 1151.Enhancement of these inhibitory synapses provides a possible mechanism for habituation of the polysynaptic component of the GSWR 1151. When these inhibitory synapses are pharmacologically blocked, the GSWR is dramatically increased, and its facilitation is mostly occluded. This suggests that disinhibition in the polysynaptic pathway may be a major mechanism of sensitization of the GSWR 116.*1. A major barrier in analyzing vertebrate motor networks is the difficulty in identifying the component neurons. Recently, activity-dependent uptake of the fluorescent marker sulforhodamine 117’1 has been used to label active cells in the neonatal rat spinal cord during fictive locomotion (0 Kjaerulff, I Barajon, 0 Kiehn, personal communication). Immunoreacivity to c-fos labels neurons active during fictive scratching in the adult cat 1181. The chemical triggers that evoke locomotion in vertebrates continue to receive considerable attention. Recent results support earlier evidence 119-211 that excitatory amino acids @AA) are involved in activating the pattern generators for locomotion in the spinal cord. In the adult cat, NMDA combined with the EAA uptake inhibitor dihydrokainic acid elicits fictive locomotion similar to that evoked by stimulation of the mesencephalic locomotor region (MLR). Further, glutamate antagonists (both NMDA- and non-NMDA-type) abolish locomotion evoked by MLR stimulation 122’1. Similar results were obtained in the neonatal rat 1231.These experiments do not distinguish among several possible sites of action of EAA, including release from descending tracts or within the spinal pattern generators 122.1. One of the best understood vertebrate motor networks is the part of the lamprey spinal cord which generates swimming 1241.A realistic model of the segmental oscillator has been proposed, which includes NMDA- and kainate-type glutamate receptors on neurons modeled with realistic intrinsic membrane properties 12Y.1, and populations of each interneuron type 126”l. A number of mechanisms contribute to burst termination and control of cycle frequency, including NMDA-evoked oscillatory properties, summation of spike afterhyperpolarization and synaptic inhibition. The population model was more robust and stable over a wide range of cycle frequencies. The ability of 5HT to reduce the cycle frequency 1271 was modeled by reducing the conductance of a calcium-dependent potassium current, Ix(e), underlying the slow afterhyperpolarization 1281. New experiments with the Ix(ca) blocker apamin 129,301 suggest, however, that 5HT acts by other mechanisms in addition to modulation of Ix(ca). Two very interesting papers analyzed the post-embryonic development of the Xenopus swimming pattern generator 131”,32”1. Unlike embryonic neurons, which fire only a single spike per cycle 1201, larval motoneurons fire multiple spikes per cycle. This is due at least in part to an increased complexity of central synaptic drive, suggesting that the development of bursting capability occurs in the pattern-generating interneurons
131**1. Acquisition of multiple spikes per cycle develops in a rostrocaudal wave, and may be due to the development of serotonergic input from the raphe nuclei in the medulla, whose processes grow down the cord during this time 1331. Bath-applied 5HT enhances the complexity of ventral root discharges, and sensitivity to 5HT also develops as a rostrocaudal wave preceding the development of endogenous bursting discharge by about 12 hours. Sillar et al. 132*1 propose that in each spinal sement, neurons begin to express 5HT receptors shortly before the raphe processes arrive. These results suggest that endogenous 5HT evokes the changes in intrinsic properties to allow burst firing in the pattern-generating neurons and motoneurons. Thus, this monoamine, which is normally thought to modulate pre-wired neural networks, may be causally involved in the development of adult neuronal properties and their maintenance in the mature pattern generator. In a number of systems, mechanosensory feedback plays an essential instructive role in determining timing in the motor pattern 1341. In the cat, group Ib afferents from ankle extensor muscles can entrain the locomotor pattern 135’1. Flexor bursts are triggered at a fixed latency after release of ankle extensor stretch. This suggests that during normal locomotion in intact cats, the decline in Ib afferent activity at the end of the stance phase determines the timing of flexor bursting to initiate the swing phase. In the locust oviposition pattern generator, deafferentation reduces the duration of digging episodes, but mechanosensory stimulation can restore the motor pattern. This suggests that sensory feedback is essential for maintaining the motor pattern 1361. Cellular
mechanisms
involved
in network
function A pattern-generating network’s output depends not only on its pattern of synaptic connectivity but also on the unique intrinsic electrophysiological properties of the component neurons that shape their firing patterns during network function 1371. These intrinsic properties can be studied with isolated cells in tissue culture 138,391. In an important technical advance combining modeling with experiment, Sharp et al. [40”1 devised the ‘dynamic clamp’, whereby a computer is used interactively to introduce simulated voltage- and transmitter-activated currents into real cultured neurons. Artificial synapses can also be generated between two real neurons 1411. Most rhythmic motor patterns are generated in part by neurons that show conditional oscillatory or bistable firing patterns. A variety of neurons show bistability 142,431. In the lobster cardiac ganglion, all the motoneurons generate plateau potentials, but with different ionic mechanisms 1441. In the vertebrate heart, the frequency of oscillation in the sino-atria1 node is controlled to a considerable extent by modulation of the hyperpolarization-activated inward current (called If or Ih) 145’1. In the STG, 5HT evokes plateau poten-
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Neural control Cal capability in a motoneuron,
in part by enhancing I,, and decreasing 1~~0) [461. Thalamic yaminobutyric acid (GABA)ergic neurons fire in bursts initiated by a slow T-type calcium channel 1471.
A number of theoretical modeling studies have analyzed bursting mechanisms. A detailed data-based model of bursting in thalamocortical relay neurons [48,49’1 suggests that the low threshold calcium current (IT) and Ih are critically involved in burst foret al. 150.01 used dynamical mation. Guckenheimer systems analysis to map the parameter space of a model of a conditional bursting neuron in the STG. The model’s dynamic response to sequential reduction of the transient potassium current, IA, gave a good match to experimental results. Cobalt evokes classical chaotic oscillatory behavior in a pacemaker neuron in the mollusc Onchidium. A simple model consisting only of rapid and slow sodium and potassium currents can reproduce this behavior 1511.
Modulation of neural network function Pattern-generating networks are not fixed in their cellular and synaptic properties; modulatory inputs can shape the final motor pattern by setting the strength of synaptic interactions and modifying the intrinsic firing properties of the network neurons 137,521. Modulation by amines and peptides of a number of pattern-generating networks has been reported 153-591. In the locust, octopamine appears to act globally as part of a general arousal mechanism to activate the insect for flight [4**1. This amine acts at multiple levels, including regulation of energy metabolism, induction of plateau properties in flight interneurons to activate the flight central pattern generator, modulation of flight muscle contraction, and enhancement of proprioceptor sensitivity. Work continues to identify and map the neurons and transmitters that modulate central pattern generators 160-631. Traditionally, modulatory inputs are thought to be separate from the neural networks they innervate. However, modulatory actions can also be found within a functioning network, generating ‘intrinsic neuromodulation’. The best example of this is in the swimming pattern generator in Tritoniu (PS Katz, PA Getting, WN Frost, personal communication). One network neuron, the dorsal swim interneuron (DSD, uses 5HT as a transmitter, and during a swim episode, DSI activity enhances the strength of synapses made by another network neuron, C2. In another example which blurs the distinction between the cells that form the network and the modulatory inputs that affect them, Nusbaum et al. 164..1 recorded from the axons of descending modulatory neurons near their terminations in the crab STG. These modulatory terminals receive feedback from network neurons in the STG, which causes the terminals to fire bursts of action potentials in phase with the motor patterns. Thus, modulation is a dynamic interaction between the input fibers and STG pattern-generating networks. Modulation of synaptic strength can lead to a quantitative ‘rewiring’ within a neural network. De Schutter et
al. 1651 published a model of graded transmission between heart intemeurons in the leech that should be useful for other networks. In the distributed network model of the leech local bending reflex, the reflex amplitude can be changed by 50% through very mlnor (3-5%) changes at most or all of the synapses, rather than large changes at a few key synapses 166.1. In the pyloric network of the crustacean STG, dopamine and octopamine evoke small changes in efficacy at nearly all the synapses, showing that distributed modulation of synapses in a network actually occurs 1671. Monoamine modulation of electrical coupling between network neurons can change the degree of synchrony between cells 168,691. Modulation of the chemical sensorimotor synapse in the ApZysiu GSWR uses several different mechanisms that are sensitive to different neuromodulators. 5HT enhances presynaptic release through both a spike-broadening mechanism and a spike-duration-independent process; pep tide SCPu only acts by the spike-broadening mechanism 170’1. In the lobster pyloric network, some graded chemical synapses disappear when isolated from modulatory input, and only become active when modulators such as dopamine and 5HT are applied 171”l. This has important consequences for analyses of synapses in preparations, such as brain slices, where the normal modulatory milieu has been removed. Mixed synapses, with both electrotonic and chemical components, are common in the nervous system, and both components can be modulated 1721. The lobster STG has synapses where electrical coupling is mixed with graded chemical inhibition; differential modulation by dopamine can actually reverse the sign of the net synaptic interaction from depolarizing to hyperpolarizing, due to simultaneous reduction of electrical coupling and enhancement of chemical inhibition 171”l. Behavior can also be affected by modulation of the muscles themselves. During ovipositioning in the locust, proctolin appears to be released by motoneurons to enhance muscle tension 173”‘l. In ganglion-muscle preparations, muscle contractions and proctolin release in the muscle both cease after about 20minutes, despite continued production of the ovipositioning central motor pattern. Application of proctolin to the muscle restores rhythmic contractions driven by the central motor pattern. Thus, proctolinergic modulation of the muscle appears to be essential for the behavioral expression of the central motor pattern. In a crab stomatogastric neuron, 5HT evokes a second, peripheral spike initiation zone along its distal axon, and a train of centrally generated spikes can evoke a second train of peripherally generated spikes that propagate both ortho- and antidromically 174’1. The antidromic spikes do not evoke release in the STG, but the orthodromic spikes can prolong the contraction evoked by the centrally generated spike burst. Thus, this neuron can send different S&MIS to its STG and muscle targets, Kepler and Marder 1751 have proposed a model whereby 5HT induces a slow voltage-dependent inward current that is activated by the burst of or-
Pattern generation Harris-Warrick
thodromic initiation.
spikes to create a traveling zone of spike
Coordination between networks Complex behavior requ&es coordination between several pattern-generating networks [76,77**,78,791. The pattern generator for locomotion in the lamprey spinal cord consists of a chain of coupled oscillators whose activity is coordinated with a descending intersegmental phase lag of about 1% per segment during forward swimming at any speed. One computer model [SOI achieves this with a set of equally activated segmental oscillators: the synapses within an oscillator are repeated in neighboring segments with reduced strength and asymmetry in rostra1 and caudal directions. Alternatively, Matsushima and Grillner [81*1 propose that the phase lag is determined by differences in the level of excitability among the spinal segmental oscillators. Cohen and Kiemel [791, however, did not find regional differences in intrinsic frequency in short pieces of the spinal cord. A third possibility is that neuromodulators help determine the phase lag. Local application of 5HT only to caudal segments does not alter the cycle frequency (which is determined by the faster rostra1 segments), but does prolong the intersegmental phase lag. A SHT-uptake blocker has similar effects, suggesting that endogenous 5HT is released locally within the cord to regulate the intersegmental phase lag [82**1. In the crab STG, many neurons can switch their activity patterns from one pattern-generating network to another 177-I. The movements that correlate with each motor pattern were studied in intact crabs by combining intra- and extracellular recordings of the motor pattern with direct endoscope observations of the behavior [SY*l. The behavioral consequences of peptide application and neuron switching between motor patterns were seen as changes in the phasing and intensity of movements of the internal teeth in the foregut. This correlates the modulation of neural motor pattern with changes in real behavior, for the first time, in the STG.
Conclusions It is very satisfying to review our progress in understanding the mechanisms of pattern generation. The structure of many neural networks and the coordination among them are now better understood, especially the role of the unique intrinsic properties of the various component neurons. We now must consider that some synapses within networks use slow neuromodulators to alter network properties during the behavior itself or during development. Neuromodulatory inputs create flexible motor patterns by evoking changes in cellular and synaptic properties at all levels, from the central networks to the muscles. Theoretical modeling of neural networks has come of age, and strong interactions between theory and experiment are essential to analyze the non-linear dynamics of pattern-generating networks. Perhaps accomplishing our goal of understanding how the nervous system generates simple behaviors is not that far off.
Acknowledgements Research in the author’s lab is supported by NIH grants NS17323 and NS259l5, and a grant from the Human Frontiers Science Program.
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DIFRANCESCO D: Pacemaker Mechanisms in Cardiac Tiisue. 45. . Annu Rev Pbysfol 1993, 55:45-72. This is an excellent review of the ionic mecbanfsms underlying pacemaker hmction at the sino-atriai node and their modulation by sympathetic and parasympathetic transmitters. The roie of Ii, is emphasized. KIEHN 0, HARRIS-WARRICK RM: 5HT Modulation of HyperpolariaationActivated Inwanl Current and Calcium-Depen-
dent Outward Current in a Crustacean Motor Neuron. NeuropbVsroll992, 6fk4~5OB. 47.
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I-IAYASHI H, ISHIZUKAS: Chaotic Nature of Bursting Dib charges in the Oncbfdfwn Pacemaker Neuron. J 7kw Bfol 1992, 156:269-291.
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HARRIS-WARRICK RM, MARDERE: ModuIation of NeuraI Nctworks for Behavior. Annu Rev Newvscf 1991, 14339-57.
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RAJASHEKHAR Kp, WILKENSJL: Dopamine and Nicotine, but Not Serotonin, Modulate the Crustacean VentiIatory Pattern Generator. J Netrmbfol1992, 23680-691.
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CASAGRAND JL, RITZMANNRE: BiogenIc AmInes Modulate Synaptic Transmission Between Idcntiiled Giant Intemeu rons and Thoracic Intemcurons in the Escape System of the Cockroach. J Nenrobfol 1992, 23:m55.
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LINDSAY AD, FELDMAN JL: Modulation of Respiratory Activity of Neonatal Rat Phrenic Motoneurones by Serotonln. / Pbysfol &w&on1 1993, 461:2X&233.
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DI PASQUALE E, MORIND, MONTEAUR, HILA~REG: Seroton ergic Modulation of the Respiratory Rhythm Generator at Birth: an in Vitro Study in the Rat. Neutwzf Left 1992, 143:91-95.
Electrical
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GUCXNHEIMER J, GUERONS, HARRIS-WARRICK RM: Mapping the Dynsmics of a Bursting Neuron. PbuoS Tmnr R Sot Lotld lBfo!l1993, in press. Non-linear dynamical systems analysis was used to create two-d& mensionai maps of parameter space of a model of the conditional bunter anterior burster (AB) neuron in the crustacean SIG. BIrcation analysis was used to identify regions of bursting and tonic activity. The model response to sequential reductions of IA were weII matched to the response of a reai anterior burster neuron during application of increasing concentrations of the IA blocker 4-aminopy50.
”
SHARP AA,
SHARP AA,
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HUGUENARD JR, MCCORMICK DA: SiiuIation of the Currents InvoIved In Rhythmic OsciIlations In Thalamic Relay Ncurons. J Narrqbysfof 1992, 68:137>1383.
Cellular Properties.
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HAIKUS-WARRICK RM, NAGY F, NUSBAUMMP: Ncuromodulation of Stomatogastrk Networks by Identified Neurons and Transmitters. In L+mumfc Bfo&fcaf Netumks. ‘Ihe Stomatogust& Nenous S~tenz. Edited by Harris-War&k RM, Marder E, Selverston AI, Moulins M. Cambridge, USA: MIT Press; 1992:87-138.
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T, MANIRA A EL, GIULLNERS: The WGNBRJ, MATXJSHIMA Spinal GABA System Modulates Burst Frequency and In tcrsegmental Coordination in the Lampreyz Differential Effects of GABA,, and GABAn Receptors. J NmmpbysM 1993, 69647-657.
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TURRIGIANO GG, SEL~R~TONAI: Distribution of Cholecysto ItininLikc Immunoreactivity Within the Stomatogastric Nclr vous Systems of Four Species of Decapod Crustacca. J Comp Neuroi 1991, 305:164-176.
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SCHNUDERH, TRIMMERBA, RAPUSJ, ECKERTM, VALENTINE DE, RRAvITZEA: ‘Mapping of OctopamIne-Immunoreactive Neurons in the Central Nervous System of the Lobster. J Con@ Neund 1993, 329X$‘-142.
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COLEMAN MJ, NUSBAUMMP, COURNILI, CLA~BORNEBJ: Dirt tribution of Modulatory Inputs to the Stomatogastric Gan @on of the Crab, Cancer borualfs. J Camp Netwoi 1992, 325:5Sl-5%.
64. ..
NUSBAUM MP, WEIMANN JM, GOLOWAXHJ, MARDERE: Presynaptic Control of Modulatory Fibers by Their Neural Network Targets. J Newoscf 1992, 12:2706-2714.
49.
MCCORMICK DA, HUGUENARD JR: A Model of the EIectro physiologicsl Properties of ThaIamocorticaI Relay Neurons. J Nenropbysfol 1992, 68:13&l-1400. This paper generates a model of single thalamoconical neurons based on experimental measurements of the voltage dependence, amplitude and kinetic propenies of a number of ionic currents. Tbe
!XHOTLAND JL, GIULLNER S: EBects of Serotonin on Fictive Locomotion Coordinated by a Neural Network Deprived of NMDA Receptor-Mediated
J
HUGUFNARD JR, PRINCEDA: A Novel T-Type Current UndcrLies Prolonged &+-Dependent Burst Fii in GABAergic Neurons of Rat ThaIamic ReticuIar Nucleus. J Netrroscf 1992, 12:~3g17.
calcium current In burst generation
.
988
Neural control Recordiigs were made from axons of modulatory neurons near their terminations in the c~stacean STG. These termit’& receive synaptic feedback from pattern-generating neurons in the STG, which shape theii impulse activity and release of modulator. Thus, modulatory input can be shaped by the pattern-generating network. 65.
DE Scntrrm~ E, ANG~I’ADTJD, CUABRFZTERL: A Model of Graded Synaptic Transmission for Use in Dynamic Network Siiuiations. J Narmphysfol 1993, 4:1225-1235.
66. .
L~CKERY SR, SEJNOWSKITJ: A Lower Bound on the Detectabiiity of No nasscciative Learning in the Locai Bending Refla of the Medicinai Leech. Bebav Netrml Biol 1993,
59208-224. This paper studies models of sensitization
and habituation of the local bending reflex results from distributed changes in synaptic strength. Changes of 50% in reflex strength can be generated by small changes distributed throughout the whole network. These changes may be difficult to detect experimentaiiy.
67.
68.
HARR&WARRKK RM, FLAMMRE, JOHNSONBR, KATZ PS, KIEHN 0, ZHANGB: Neuromoduiation of Smaii Neural Networks in Crustacca. In Neurotar 91: Mokwrhr Basis of Dnrg E pesticide Action. Edited by Duce IR. London: Elsevier; 1992305-322.
70. .
PIERONIJP, BYRNEJH: Differential Effects of Serotonin, FMRPamide, and Smaii Cardioactive Peptidc on Multiple, Dis tributed Processes Modulating Sensorimotor Synaptic Transmission in Ap&skr. J Neuroscf 1992, 12:2633-2647. At least two independent processes am involved in modulation of the monosynaptic component of the giil withdrawal reflex, one that involves presynaptic spike broadening and another that is independent of spike broadening. These are diierentiaily modulated by 5HT, FMRFamide and SCPn. 71. ..
JOHNSONBR, PECKJH,
HARRIS-WARRICK RM: Dopaminc In ducts Sign Reversal at Mixed Chemical-Electrical Synapses. Bdn Res 1993, in press. In the STG, some mixed synapses combine electrical coupling with chemical inhibition. Dopamine has opposite effects on these two components, reducing electrical coupling and enhancing chemical inhibition. In some cells, this results in a reversal of the sign of the net synaptic interaction. 72.
PEREM A, TRUER A, KORN H, FABER DS: Dopaminc En hances Both Eicctrotonic Coupling and Chemical Excitatory Postsynaptic Potentials at Mixed Synapses. Pmc Natl Acad Scf USA 1992, 89:1208812092.
BFLANGERJH, ORCHARDI: The Locust Ovipositor Opener Muscle: Proctoiincrgic Centrai and Peripheral Ncuromodu lation in a Centrally Driven Motor System. J Eap Bfol 1993, 174~343362. The peptide proctolin appears to be released by motoneurons onto a digging muscle. During centraliy patterned ovipositioning, proctolm release onto the muscle declines with time, and the strength of muscle contractions decline and disappear in parallel, even though the central motor pattern is still being generated. Bath application of proctolm restores the rhythmic muscle movements. Thus, peripheral release of proctolin appears to be essential for behavior expression of the ovipositioning motor pattern.
73. ..
of a stomatogastric neuron. This results in differential actions of the motoneuron on the muscle and in the ganglion. 75.
KEPLERTB, MARDER E: Spike Initiation and Propagation on Axons with Slow Inward Currents. Bid C’bern 1993, 68:209-214.
76.
BW(OFFA: Neuroethologicai Approaches to the Study of Mo tot Development in Chicks: Achievements and Chalienges. J NeuroMoll992, 23:1486-1505.
DICKINXIN PS, MOUINS M: Interactions and Combiitions Between Different Networks in the Stomatogastric Nervous System. In +mic Bkhgicul Nettunis. 7be StomatogasEdited by Harris-Warrick RM, Marder MC Nerwtrs Spem. E, Selverston Al, Moulins M. Cambridge, USA: MIT Press, 1992:134L160. An important review of the mechanisms by which neurons switch their activity from one neural network to another within the crustacean STG.
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MARDERE, WEIMANNJM: Modulatory Control of Multiple Task Processing in the Stomatogastric Nervous System In NeuroMdogy of Motor Progmmme Selection. Edited by Kien J, McCrohan CR, Wiiow W. Oxford: Pergammon; 19923-19.
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JANSEC: Serotoncrgic Modulation of Junctionai Conductance in an Identified Pair of Neurons in the Moihtsc Lymnaea stapt.alls. Brain Res 1992, 595343-352.
MEYRAND P, WWMANN JM, MARDERE: Multiple Axonal Spike Initiation Zones in a Motor Neuron: Serotortin Actiiion. J
Neurwsci 1992, 12SO32812. 5HT evokes a new, peripheral spike initiation zone along the axon
JOHNSONBR, PECKJH, HN~RIS-WARRICK RM: Amine Modula-
tion of Elcctricai Coupling in the Pyioric Network of the Lobster Stomatogastric Ganglion. / Camp Pbysfol /Al 1993, 172:715-732. 69.
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Intersegmentai Coordination: Lessons from Modciing Systems of Coupled Non-Linear Osciilators.
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WIUIAMSTL: Phase Coupling by Synaptic Spread in Chains of Coupled Ncuronai Oscillators. Science 1992, 258662-665.
81. .
MATSUSHIMA T, GRILLNER S: Neural
Mechanisms of Intersegmental Coordination in Lamprey: Local Excitability Changes Modify the Phase Coupling Along the Spinai Cord. J Neuropbvsiol 1992, 67:373388. Application of different concentrations of NMDA or 5HT in a multicompartment bath along the lamprey spinal cord can alter the intersegmentai phase iag smoothiy from forward to backward. Thii suggests that local differences in excitability of segmental oscillators determines the phase lag in the intact animal. 82. MAT~USHIMA T, GRLLNERS: Lccai Serotoncrgic Modulation .. of Calcium-Dependent Potassium Channels Controls In tcrsegmentai Coordination in the Lamprey Spinai Cord. J NeumpbysfolW92,
67:X&31690.
Local application of 5HT to part of the lamprey spinai cord can alter the intersegmental phase iag without changing the cycle ftequency. Locai application of a SHT-uptake inhibitor had the same effects, suggesting that endogenously released 5HT helps to determine the phase lag in the intact animal.
HEINZEE H-G, WEIMANN JM, MARDER E: Tbc Behavioral Repertoire of the Gastric MiU in the Crab, Cancerpagu*us: An In Situ Endoscopic and Electrophysioiogical Examination. J Neunxci 1993, 13:17931803. Simukaneous electrophysiologicai and endoscopic measurements were made of the gastric mill motor pattern in intact crabs. The movements corresponding to peptide-evoked motor patterns were visuaiized. Some pyloric neurons can switch to fire in time with the slower gastric mili rhythm, the changes in gastric tooth movement during these switches were observed and mapped. 83.
..
R Harris-Warrick, Section of Neurobiology and Behavior, Seeley G. Mudd Haii, Cornell University, Ithaca, New York 14853, USA.
University,
Ithaca, USA
Significant advances have been made in understanding the cellular mechanisms for pattern generation in both invertebrate and vertebrate preparations. In a number of preparations, slow neuromodulators have been shown not only to modify network function, but to be intimately involved in development and/or normal function of the neural network and its associated behavior. The mechanisms underlying coordination between multiple pattern-generating networks, including switching of neurons from one network to another, are now being studied. Several new quantitative models of network function have been developed, and modeling is now an important component of research in this field.
Current Opinion in Neurobiology
Introduction A major goal of neuroethology is to identify and study the neural networks that generate simple behaviors. The networks generating rhythmic motor patterns such as locomotion, scratching and simple autonomic behaviors were the earliest studied and are still the best understood, as a result of the ease of detecting and analyzing the network neurons. In many systems, the neural networks are almost completely defined, and studies are focusing on stimulating and modulatory inputs that alter the properties of the network and its associated behavior. These studies have now matured to the point that realistic computer models are important components of a research strategy to understand how a network functions. In this review, I summarize recent advances in four areas of research on pattern generation: analysis of the components of the networks; the cellular mechanisms that determine network function; modulation of cellular and synaptic properties of neural networks; and mechanisms for interaction between simple patterngenerating networks to create complex movements. Several important reviews on this subject have appeared recently [l-3,4*.,5,61.
Analysis of neural networks Significant advances have been made in understanding a number of simple networks. The gastric mill network in the crustacean stomatogastric ganglion (STG) has been anatomically described, but due to its multi-
1993,
3:982-988
functional properties, it has been difficult to analyze. Elson and Selverston [7**1 isolated the STG and determined the essential components of the network activated by the muscarinic agonist pilocarpine. Four of the eleven component neurons comprise the essential pattern generator under these conditions, due to their induction of conditional plateau potential capability and synaptic interactions; the other neurons are followers. A dynamic connectionist model of the local bending reflex in the leech was derived using a back-propagation algorithm 18*,91. A distributed network of 40 multifunctional interneurons could generate all forms of local bending. Different sets of initial conditions yielded different but equally effective model networks, all of which differed in detail from experimental observations 1101.Thus, the actual neural network cannot be obtained by back-propagation, but the general principles of function in a highly distributed network can be elucidated. Much smaller networks were effective, suggesting that the biological network is redundant and may be involved in other behaviors. In fact, some of the same intemeurons are involved in the shortening reflex and swimming 111,121. Neuroethological analyses of the gill and siphon withdrawal reflexes (GSWR) in Aplysia have revealed the dominant role of polysynaptic network interactions 1131in the reflex and its modulation. Polysynaptic pathways account for about 75% of the compound EPSPs recorded in motoneurons following siphon or gill stimulation 114.1. The mono- and polysynaptic components respond differentially to neuromodulators such as sero-
Abbreviations AMPA-a-amino-3-hydroxy-5-methyl isoxazole4propionic acid; DSI-dorsal swim interneuron; EM-excitatory amino acids; EPSP-excitatory postsynaptic potential; GSWR-gill and siphon withdrawal reflexes; 5HT-5-hydroxytryptamine kerotonin); IA-transient potassium current; Ih-hyperpolarization-activated inward current; IKtc~~--calciumdependent potassium current; Ir--low threshold calcium current; MLR-mesencephalic locomotor region; NMDA-_N-methyl-D-aspartate; STC-stomatogastric ganglion.
982
@ Current Biology Ltd ISSN 0959-4388
Pattern generation Harris-Warrick
tonin (5hydroxytryptamine: 5HT) and the peptide SCPn. A set of inhibitory interneurons exert activity-dependent negative feedback on the polysynaptic pathway of the reflex 1151.Enhancement of these inhibitory synapses provides a possible mechanism for habituation of the polysynaptic component of the GSWR 1151. When these inhibitory synapses are pharmacologically blocked, the GSWR is dramatically increased, and its facilitation is mostly occluded. This suggests that disinhibition in the polysynaptic pathway may be a major mechanism of sensitization of the GSWR 116.*1. A major barrier in analyzing vertebrate motor networks is the difficulty in identifying the component neurons. Recently, activity-dependent uptake of the fluorescent marker sulforhodamine 117’1 has been used to label active cells in the neonatal rat spinal cord during fictive locomotion (0 Kjaerulff, I Barajon, 0 Kiehn, personal communication). Immunoreacivity to c-fos labels neurons active during fictive scratching in the adult cat 1181. The chemical triggers that evoke locomotion in vertebrates continue to receive considerable attention. Recent results support earlier evidence 119-211 that excitatory amino acids @AA) are involved in activating the pattern generators for locomotion in the spinal cord. In the adult cat, NMDA combined with the EAA uptake inhibitor dihydrokainic acid elicits fictive locomotion similar to that evoked by stimulation of the mesencephalic locomotor region (MLR). Further, glutamate antagonists (both NMDA- and non-NMDA-type) abolish locomotion evoked by MLR stimulation 122’1. Similar results were obtained in the neonatal rat 1231.These experiments do not distinguish among several possible sites of action of EAA, including release from descending tracts or within the spinal pattern generators 122.1. One of the best understood vertebrate motor networks is the part of the lamprey spinal cord which generates swimming 1241.A realistic model of the segmental oscillator has been proposed, which includes NMDA- and kainate-type glutamate receptors on neurons modeled with realistic intrinsic membrane properties 12Y.1, and populations of each interneuron type 126”l. A number of mechanisms contribute to burst termination and control of cycle frequency, including NMDA-evoked oscillatory properties, summation of spike afterhyperpolarization and synaptic inhibition. The population model was more robust and stable over a wide range of cycle frequencies. The ability of 5HT to reduce the cycle frequency 1271 was modeled by reducing the conductance of a calcium-dependent potassium current, Ix(e), underlying the slow afterhyperpolarization 1281. New experiments with the Ix(ca) blocker apamin 129,301 suggest, however, that 5HT acts by other mechanisms in addition to modulation of Ix(ca). Two very interesting papers analyzed the post-embryonic development of the Xenopus swimming pattern generator 131”,32”1. Unlike embryonic neurons, which fire only a single spike per cycle 1201, larval motoneurons fire multiple spikes per cycle. This is due at least in part to an increased complexity of central synaptic drive, suggesting that the development of bursting capability occurs in the pattern-generating interneurons
131**1. Acquisition of multiple spikes per cycle develops in a rostrocaudal wave, and may be due to the development of serotonergic input from the raphe nuclei in the medulla, whose processes grow down the cord during this time 1331. Bath-applied 5HT enhances the complexity of ventral root discharges, and sensitivity to 5HT also develops as a rostrocaudal wave preceding the development of endogenous bursting discharge by about 12 hours. Sillar et al. 132*1 propose that in each spinal sement, neurons begin to express 5HT receptors shortly before the raphe processes arrive. These results suggest that endogenous 5HT evokes the changes in intrinsic properties to allow burst firing in the pattern-generating neurons and motoneurons. Thus, this monoamine, which is normally thought to modulate pre-wired neural networks, may be causally involved in the development of adult neuronal properties and their maintenance in the mature pattern generator. In a number of systems, mechanosensory feedback plays an essential instructive role in determining timing in the motor pattern 1341. In the cat, group Ib afferents from ankle extensor muscles can entrain the locomotor pattern 135’1. Flexor bursts are triggered at a fixed latency after release of ankle extensor stretch. This suggests that during normal locomotion in intact cats, the decline in Ib afferent activity at the end of the stance phase determines the timing of flexor bursting to initiate the swing phase. In the locust oviposition pattern generator, deafferentation reduces the duration of digging episodes, but mechanosensory stimulation can restore the motor pattern. This suggests that sensory feedback is essential for maintaining the motor pattern 1361. Cellular
mechanisms
involved
in network
function A pattern-generating network’s output depends not only on its pattern of synaptic connectivity but also on the unique intrinsic electrophysiological properties of the component neurons that shape their firing patterns during network function 1371. These intrinsic properties can be studied with isolated cells in tissue culture 138,391. In an important technical advance combining modeling with experiment, Sharp et al. [40”1 devised the ‘dynamic clamp’, whereby a computer is used interactively to introduce simulated voltage- and transmitter-activated currents into real cultured neurons. Artificial synapses can also be generated between two real neurons 1411. Most rhythmic motor patterns are generated in part by neurons that show conditional oscillatory or bistable firing patterns. A variety of neurons show bistability 142,431. In the lobster cardiac ganglion, all the motoneurons generate plateau potentials, but with different ionic mechanisms 1441. In the vertebrate heart, the frequency of oscillation in the sino-atria1 node is controlled to a considerable extent by modulation of the hyperpolarization-activated inward current (called If or Ih) 145’1. In the STG, 5HT evokes plateau poten-
983
984
Neural control Cal capability in a motoneuron,
in part by enhancing I,, and decreasing 1~~0) [461. Thalamic yaminobutyric acid (GABA)ergic neurons fire in bursts initiated by a slow T-type calcium channel 1471.
A number of theoretical modeling studies have analyzed bursting mechanisms. A detailed data-based model of bursting in thalamocortical relay neurons [48,49’1 suggests that the low threshold calcium current (IT) and Ih are critically involved in burst foret al. 150.01 used dynamical mation. Guckenheimer systems analysis to map the parameter space of a model of a conditional bursting neuron in the STG. The model’s dynamic response to sequential reduction of the transient potassium current, IA, gave a good match to experimental results. Cobalt evokes classical chaotic oscillatory behavior in a pacemaker neuron in the mollusc Onchidium. A simple model consisting only of rapid and slow sodium and potassium currents can reproduce this behavior 1511.
Modulation of neural network function Pattern-generating networks are not fixed in their cellular and synaptic properties; modulatory inputs can shape the final motor pattern by setting the strength of synaptic interactions and modifying the intrinsic firing properties of the network neurons 137,521. Modulation by amines and peptides of a number of pattern-generating networks has been reported 153-591. In the locust, octopamine appears to act globally as part of a general arousal mechanism to activate the insect for flight [4**1. This amine acts at multiple levels, including regulation of energy metabolism, induction of plateau properties in flight interneurons to activate the flight central pattern generator, modulation of flight muscle contraction, and enhancement of proprioceptor sensitivity. Work continues to identify and map the neurons and transmitters that modulate central pattern generators 160-631. Traditionally, modulatory inputs are thought to be separate from the neural networks they innervate. However, modulatory actions can also be found within a functioning network, generating ‘intrinsic neuromodulation’. The best example of this is in the swimming pattern generator in Tritoniu (PS Katz, PA Getting, WN Frost, personal communication). One network neuron, the dorsal swim interneuron (DSD, uses 5HT as a transmitter, and during a swim episode, DSI activity enhances the strength of synapses made by another network neuron, C2. In another example which blurs the distinction between the cells that form the network and the modulatory inputs that affect them, Nusbaum et al. 164..1 recorded from the axons of descending modulatory neurons near their terminations in the crab STG. These modulatory terminals receive feedback from network neurons in the STG, which causes the terminals to fire bursts of action potentials in phase with the motor patterns. Thus, modulation is a dynamic interaction between the input fibers and STG pattern-generating networks. Modulation of synaptic strength can lead to a quantitative ‘rewiring’ within a neural network. De Schutter et
al. 1651 published a model of graded transmission between heart intemeurons in the leech that should be useful for other networks. In the distributed network model of the leech local bending reflex, the reflex amplitude can be changed by 50% through very mlnor (3-5%) changes at most or all of the synapses, rather than large changes at a few key synapses 166.1. In the pyloric network of the crustacean STG, dopamine and octopamine evoke small changes in efficacy at nearly all the synapses, showing that distributed modulation of synapses in a network actually occurs 1671. Monoamine modulation of electrical coupling between network neurons can change the degree of synchrony between cells 168,691. Modulation of the chemical sensorimotor synapse in the ApZysiu GSWR uses several different mechanisms that are sensitive to different neuromodulators. 5HT enhances presynaptic release through both a spike-broadening mechanism and a spike-duration-independent process; pep tide SCPu only acts by the spike-broadening mechanism 170’1. In the lobster pyloric network, some graded chemical synapses disappear when isolated from modulatory input, and only become active when modulators such as dopamine and 5HT are applied 171”l. This has important consequences for analyses of synapses in preparations, such as brain slices, where the normal modulatory milieu has been removed. Mixed synapses, with both electrotonic and chemical components, are common in the nervous system, and both components can be modulated 1721. The lobster STG has synapses where electrical coupling is mixed with graded chemical inhibition; differential modulation by dopamine can actually reverse the sign of the net synaptic interaction from depolarizing to hyperpolarizing, due to simultaneous reduction of electrical coupling and enhancement of chemical inhibition 171”l. Behavior can also be affected by modulation of the muscles themselves. During ovipositioning in the locust, proctolin appears to be released by motoneurons to enhance muscle tension 173”‘l. In ganglion-muscle preparations, muscle contractions and proctolin release in the muscle both cease after about 20minutes, despite continued production of the ovipositioning central motor pattern. Application of proctolin to the muscle restores rhythmic contractions driven by the central motor pattern. Thus, proctolinergic modulation of the muscle appears to be essential for the behavioral expression of the central motor pattern. In a crab stomatogastric neuron, 5HT evokes a second, peripheral spike initiation zone along its distal axon, and a train of centrally generated spikes can evoke a second train of peripherally generated spikes that propagate both ortho- and antidromically 174’1. The antidromic spikes do not evoke release in the STG, but the orthodromic spikes can prolong the contraction evoked by the centrally generated spike burst. Thus, this neuron can send different S&MIS to its STG and muscle targets, Kepler and Marder 1751 have proposed a model whereby 5HT induces a slow voltage-dependent inward current that is activated by the burst of or-
Pattern generation Harris-Warrick
thodromic initiation.
spikes to create a traveling zone of spike
Coordination between networks Complex behavior requ&es coordination between several pattern-generating networks [76,77**,78,791. The pattern generator for locomotion in the lamprey spinal cord consists of a chain of coupled oscillators whose activity is coordinated with a descending intersegmental phase lag of about 1% per segment during forward swimming at any speed. One computer model [SOI achieves this with a set of equally activated segmental oscillators: the synapses within an oscillator are repeated in neighboring segments with reduced strength and asymmetry in rostra1 and caudal directions. Alternatively, Matsushima and Grillner [81*1 propose that the phase lag is determined by differences in the level of excitability among the spinal segmental oscillators. Cohen and Kiemel [791, however, did not find regional differences in intrinsic frequency in short pieces of the spinal cord. A third possibility is that neuromodulators help determine the phase lag. Local application of 5HT only to caudal segments does not alter the cycle frequency (which is determined by the faster rostra1 segments), but does prolong the intersegmental phase lag. A SHT-uptake blocker has similar effects, suggesting that endogenous 5HT is released locally within the cord to regulate the intersegmental phase lag [82**1. In the crab STG, many neurons can switch their activity patterns from one pattern-generating network to another 177-I. The movements that correlate with each motor pattern were studied in intact crabs by combining intra- and extracellular recordings of the motor pattern with direct endoscope observations of the behavior [SY*l. The behavioral consequences of peptide application and neuron switching between motor patterns were seen as changes in the phasing and intensity of movements of the internal teeth in the foregut. This correlates the modulation of neural motor pattern with changes in real behavior, for the first time, in the STG.
Conclusions It is very satisfying to review our progress in understanding the mechanisms of pattern generation. The structure of many neural networks and the coordination among them are now better understood, especially the role of the unique intrinsic properties of the various component neurons. We now must consider that some synapses within networks use slow neuromodulators to alter network properties during the behavior itself or during development. Neuromodulatory inputs create flexible motor patterns by evoking changes in cellular and synaptic properties at all levels, from the central networks to the muscles. Theoretical modeling of neural networks has come of age, and strong interactions between theory and experiment are essential to analyze the non-linear dynamics of pattern-generating networks. Perhaps accomplishing our goal of understanding how the nervous system generates simple behaviors is not that far off.
Acknowledgements Research in the author’s lab is supported by NIH grants NS17323 and NS259l5, and a grant from the Human Frontiers Science Program.
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SR: NeuronaI Control of Swimming Locomotion: Analysis of the Pteropod MoIlusc CIIone and Embryos of the Amphibian Xenopu~. Trends Newos~i 1993, 16:227-233. ORCHARDI, RAMIRFZJ-M, LANGEAEi: A Multifunctional Role for Octopamine in Locust FIight. Annrr Rev Entomol 1993, 38:227-249. An impressive review of the multiple actions of octopamine in preparing the locust for flight, including adipokiietic activity, modulation of central intemeuronal properties and peripheral modulation of muscle contraction. The authors argue that octopamine is part of a general arousal system for flight. 4. ..
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HARRIS-WARRICK RM, MARDER E, SELVER~T~NAI, MOUL~NS M (Ed& l?vnamic Biobgtcul Networks. 7be Stomatogastdc Nenous @stem. Cambridge: MIT Press; 1992.
7. ..
ELSON RC, SELVER~TONAI: Mechanisms of Gastric Rhythm Generation in the Isolated Stomatogastric Ganglion of Spiny Lobsters: Bursting Pacemaker Potentials, Synaptic lntclr actions, and MuscarInic Modulation. / Netrropbysiol 1992, 68:890-907. This paper analyzes the pilocarpine-induced gastric mill network. Using photoinactivation and synaptic blockade, four isolated neurons show bursting pacemaker potentials under these conditions, and they drive the network. The authors suggests that rhythmicity normally depends on the induction of bursty membrane properties in at least some component neurons, and that different subcircuits can be induced by different neuromodulators to evoke unique rhythmic patterns. 8. .
L~CKERYSR, SEJNOWSKITJ: Distributed Processing of Se* sory Information in the Leech. III. A DynamicaI NeuraI Network Model of the Local Bending Reflex. / Netrt-osci 1992, 123877-3895. A back-propagation algorithm was used to set synaptic weights of network interactions for a model of the local bending reflex. Many different networks (derived from different initial parameters) performed equally well, suggesting that the biological network is highly redundant and may be involved in other behaviors as well. 9.
LO~KERY SR, SEJNOWSKI rJ: The Trends Netrmsct 1993, 16283-290.
ComputationaI
Leech.
10.
MOCKERY SR, KRISTANWB JR: Distributed Processing of Serr soty Information in the Leech. II. Identification of Intemeurolls Contributing to the Local Bending Reflex. J Neurasct 1990, 10:1816-1829.
11.
WI’ITENBERCG, KRISTANWB JR: Analysis and Modeling of the MultIsegmental Coordination of Shortening Behavior in the Medicinal Leech. I. Motor Output Pattern. J Newopkysfol 1992,68:168+1692.
985
986
Neural control 12.
WIT~FNBERG G, KRISTAN WB JR: AnaIysis and Modeling of the MuItiscgmcntaI Coordination of Shortening Behavior in the Medicinal Leech. II. Role of Identified Intemeurons. / Neumpbysiol 1992, 68:169+1707.
13.
FROSTWN, CLARKGA, MNDEL ER: ParaIIel Processing of Short-TermMemory for Sensitization in ApIysia. J Newobtol l!m, 19297-334.
TRUDEAUL-E, CAS~FLLIJCCI VF: Contribution of PoIysynaptic Pathways in the Mediation and Plasticity of Aplysia GIII and Siphon Withdrawal Reflex: Evidence for DiffcrcntiaI Mode lation. J Netrrosci 1992, 12:383&3848. The authors used a hi calcium/high magnesium saline to selectively elimiite polysynaptic pathways in the GSWR, and showed that this removes about 75% of input to motoneurons. The polysynaptic pathway is selectively activated by SCPB, whereas the monosynaptic pathway is selectively enhanced by 5HT. 14. .
15.
FISCHER TM, CAREWTJ: Activity-Dcpcndent Potentiation of Rccurrcnt Inhibition: a Mechanism for Dynamic Gain Control in the Siphon Withdrawal Reflex of Aplys~. J Neumcf 1993, 13:1302-1314.
16.
..
TRUDEAU L-E, CASTELLUCCI VF: Functional Uncoupling of Inhibitory Intcmeurons Plays an Important Role in Short-Term Sensitiaation of Aplysiu GiII and Siphon Withdrawal Reflex.
J Neumxi 1993, 13:212&2135. The drug d-Tubocurarine (dTC> was used to selectively eliminate
cholinergic Inhibitory transmission within the polysynaptic pathway of the GSWR. This greatly enhanced the amplitude of the reflex and significantly reduced the total extent of facilitation without affecting the small monosynaptic component of facilitation. These results suggest that disinhibition within polysynaptic pathways is quantitatively the major mechanism of facilitation in this reflex. KEIFERJ, VYAS D, HOUKJC: SuIforhodamIne Labeling of Neural Circuits Engaged in Motor Pattern Generation in the In V&u Turtle BrainstcmCerebcIIum. J Nezrnasct 1992, 12:3187-3199. The fluorescent probe sulforhodamine is selectively taken up by endocytosis into cells that have been very active over a prolonged period of time. This dye was used to label cells in the turtle brainstem-cerebeIIum network during stimulation from the dorsal quadrant of the spinal cord. 17. .
18.
BARAJON I, GOSSARD J-P, HULTBORN H: Induction of Fos Expression by Activity in the SpInaI Rhythm Generator for Scratching. Bmfn Res 1992, 588:1*172.
19.
BRODIN L, GIULLNER S: The Role of Putative Excitatory Amino Acid Neurotransmitters in the Initiation of Locomotion in the Lamprey SpinaI Cord. I. The meets of Excitatory Amino Acid Antagonists. Bmin Res 1985, 360:139-148.
20.
ROBER‘IS A: How Does a Nervous System Produce Behavior? A Case Study in Neurobiology. Sci pros Oxfwd 1990, 74:31-51.
21.
KUDON, YAMADA T: N-Methyl-D,L-Asparatc-Induced Locomcl tor Activity in a SpinaI Cord-HIndIimb Muscles Preparation of the Newborn Rat Studied in Vittv. Newvscf Len 1987, 75:43-48.
22. .
DOUGLAS JR, NCK~ABR, DAI X, JORDANLM: The EtTects of IntrathccaI Administration of Excitatory Amino Acid Agonists and Antagonists on the Initiation of Locomotion in the Adult Cat. J Neurosci 1993, 13:990-1ooO. The adult cat seems to be similar to lower vertebrate I191 and immature preparations [20,211 in using EA4s to initiate locomotion motor patterns in the spinal cord. Rhythmic motor patterns evoked by stimulation of the MLRare simii to those evoked by Intrathecal application of NMDA, and both are blocked by EAA antagonists. 23.
24.
CAZALETS JR, SQUALLI-HOUS~AINI Y, CLARACF: Activation of the CentraI Pattern Generators for Locomotion by Semtonin and Excitatoty Amino Acids in Neonatal Rat. J Pbysid 1992, 455:187-204. GRKLNER S, WALL P, BRODINL: NeuronaI Network Gcncrating Locomotor Behavior in ~amprcy: Ciiuitry, Transmitters,
Membrane Properties 1991, 14:16+199.
and Simulation. Anntr Reu Newwcf
A, BRODINL, TRAV& H, WA&N P, EKEBERG6, LANSNER GRILLNERS: A Computer-Based Model for Realistic Sii uIations of Neural Networks. Il. The SegmcntaI Network Generating Locomotor Rhythmicity in the Lamprey. J Neumpbysti 1992, &193~1950. This is an improved model of the lamprey swim segmental oscillator. The neurons are modeled on experimentally established membrane properties and strengths of synaptic connections. Fictive locomotion can be evoked by simulating opening of AMPMcaIIte- or NMDAtype glutamate receptors. A thorough analysis of factors contributing to burst termination and the effects of 5HT 1271are presented.
25. ..
26.
HELLCREN J, GRILLNER S, LANSNER A: Computer SimuIation of the ScgmcntaI NcuraI Network Gcncrating Locomotion in Lamprey by Using Populations of Nctwqrk Intemcurons. BIol cybern 1992, 68:1-13. The model in I25”l is extended by modeling populations of each network interneuron type rather than single cells. The populations have cellular properties randomly distributed around experimentally measured means. The population model is much more robust over a wider frequency range than single neuron models. The cellular factors leading to burst termination are somewhat different from those analyzed in single cell models. ..
27.
HARRIS-WARRICK RM, COHENAH: Scrotonin ModuIates the Central Pattern Gcncrator for Locomotion in the Isolated Lamprey Spinal Cord. J Eap Btol 1985, 116:27-46.
28.
WALLS P, BUCHANAN JT, GRILLNER S, HILLRI-I, CHRIS?ENSON J, H~KFELTT: Effects of 5-Hydroxytryptaminc on the Afterhypcrpolariution, Spike Frequency ReguIation, and OsciIIatory Membrane Propcrtics in Lamprey Spinal Cord Neurons. J Neuropbysiol 1989, 61:759-768.
29.
MEER DP, BUCHANAN JT: Apamin Reduces the Late Afterhyperpolarization of Lamprcy SpinaI Neurons, with Little EIfect on Fictive SwimmIng. Nacrosct Letl 1992, 143:1-i.
30.
HIL.LR, M~;~~LJSHIMA T, SCHOTLAND J, GRILLNER S: Apamin Blocks the Slow AHP In Lamprey and DeIays Termination of Locomotor Bursts. Nerrrorepori 1992, 3:%3-945.
SILLAR KT, SIMMERS AJ, WEDDERBURN JFS: The Post-Embryonic Development of CcII Propcrtics and Synaptic Drive Under@ ing Locomotor Rhythm Generation in Xempus Larvae. Proc R Sot Lond lBioU 1992, 249:6%70. . This paper analyzes the development of the motor rhythm undedying swimming during the first post-embryonic day. The motoneurons acquire the ability to fire multiple spikes per cycle, resuItIng in large part from the increased complexity of centraI synaptic drive. This paper shows that the Intrinsic properties of spinal cord neurons change significantly during this developmental window. 31. ..
SILLAI?KT, WEDDERBURN JFS, SIMMERS AJ: Modulation of Swimming RhythmIcity by 5-Hydroxytryptamine During Post-EmbryonicDcvrlopment in Xetwpus kaevis. Pmc R Sot Land /Boll 1992, 250:107-114. This paper continues the studies begun in Ul**l. The ability to fire multiple spikes per cycle develops as a rostrocaudal wave, suggesting that descending developing pathways from the brain cause this change. Bath-applied 5HT can evoke multiple spiking capability, and this develops as a rostrocaudal wave preceding the endogenous multiple spiking ability, and development of serotonergic raphe processes, by about 12 hours. The authors suggest that raphe processes are In part responsible for changing the Intrinsic electrophysiological properties of spinal cord neurons from an embryonic form to the mature form. 32. ..
33.
VANMIERP, JOOSTENHWJ, VANRHEDEN R, TENDONKELMR HJ: The Development of Scrotoncrgic Raphc Spinal Projcctions in Xeno@s kae&. Int J L%v Netrmsct 1986,4:465-476.
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P-N KG: CcntraI Pattern Generation: a Concept Under Scrutiny. In Aahmces in Pbysiokq$al Restnrcb. Edited by McLennan H, Ledsome JR, McIntosh CHS, Jones DR. New York: Plenum Press; 1987:167-185.
Pattern generation Harris-Warrick 35.
role of Ii, and a low-threshold
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PEARSON KG, hhm~2 JM,JIANGw: Entrainment of the Loco motor Rhythm by Group Ib ABcrents Born Ankk Extensor Muscks in SpinaI Cats. &J Emfn Res 1992, 90:557-566. The central pattern generator for locomotion In the cat can be entraIned by rhythmic ankle extension. Flexor bursts were initiated at a fixed latency after release from ankle stretch, and this latency was in-
are described.
dependent of cycle frequency. The authors suggest that, In vtyo, the flexor burst is normally triggered by release from afferentevoked in-
hibition, and that the group Ib aRerents thus play an instructive role in generation of the locomotor pattern.
36.
BELANGER JH, ORCHARDI: The Role of Sensory Input in Main taining Output from the Locust Oviposition Dii CentraI Pattern Generator. J Comp Pbysfol [RI 1992, 171:49%503.
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I-IARR&WARRICK RM: Chemical ModuIation of CentraI Pattern Generators. In Netrml Control of Rbytbmtc Movemenfs fn Vettebmres. Edited by Cohen AH, Rossignol S, GrilIner S. New York: Wiley & Sons: 19SSz28~332.
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TLJRR~GIANO GG, MARDFXE: McduIation of Identified Stomatogastric GangEon Neurons in Primary Cell Culture. J New tqbysfol 1993, 69:1993-2002.
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PANCHINYV, AR~HAVSKY YI, SELWR~TON Al: Lobster Stomato J Nezcropbysfol. 1993,
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O’NEIL MB, ABBOTTLF, MARDER E: Dynamic Ckunp: ComputcrGencratcd Conductances in Real Neurons. J Neuropbyfol1993, 69992-995. A computer is used to monitor the voltage of a cultured neuron and to inject currents calculated from Hodgkin-Huxley-type equations correspondiig to any voltage- or transmitter-activated current of interest. This is a novel approach to direct Interaction between computer models of ionic currents and the responses of real neurons to changes in those currents.
40. ..
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Synapses in 67:1691-K@. 42.
ABE
LP, MARDER E: Oscillatory Networks. J
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HANCOXJC, PITMANRM: PIatcau Potentials in an Insect Mo toneurone Can be Driven by Synaptic Stimulation. J Exp Bid 1993, 176:307-310. HOUNSGMRDJ, RIEHN 0: Cakium Spikes and Cakium PIateaux Evoked by DilferentiaI Polariaation in Dendrites of ‘Butk Motoncurones. J Pbysfol 1993, 468:245-259.
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BERLINDA: Heterogeneity of Motomcuron Driver Potential Properties AIong the Anterior-Posterior Axis of the Lobster Cardiac GangIion. B?nfn Res 1993, 609~51-58.
DIFRANCESCO D: Pacemaker Mechanisms in Cardiac Tiisue. 45. . Annu Rev Pbysfol 1993, 55:45-72. This is an excellent review of the ionic mecbanfsms underlying pacemaker hmction at the sino-atriai node and their modulation by sympathetic and parasympathetic transmitters. The roie of Ii, is emphasized. KIEHN 0, HARRIS-WARRICK RM: 5HT Modulation of HyperpolariaationActivated Inwanl Current and Calcium-Depen-
dent Outward Current in a Crustacean Motor Neuron. NeuropbVsroll992, 6fk4~5OB. 47.
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ridiie.
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I-IAYASHI H, ISHIZUKAS: Chaotic Nature of Bursting Dib charges in the Oncbfdfwn Pacemaker Neuron. J 7kw Bfol 1992, 156:269-291.
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HARRIS-WARRICK RM, MARDERE: ModuIation of NeuraI Nctworks for Behavior. Annu Rev Newvscf 1991, 14339-57.
53.
RAJASHEKHAR Kp, WILKENSJL: Dopamine and Nicotine, but Not Serotonin, Modulate the Crustacean VentiIatory Pattern Generator. J Netrmbfol1992, 23680-691.
54.
CASAGRAND JL, RITZMANNRE: BiogenIc AmInes Modulate Synaptic Transmission Between Idcntiiled Giant Intemeu rons and Thoracic Intemcurons in the Escape System of the Cockroach. J Nenrobfol 1992, 23:m55.
55.
LINDSAY AD, FELDMAN JL: Modulation of Respiratory Activity of Neonatal Rat Phrenic Motoneurones by Serotonln. / Pbysfol &w&on1 1993, 461:2X&233.
56.
DI PASQUALE E, MORIND, MONTEAUR, HILA~REG: Seroton ergic Modulation of the Respiratory Rhythm Generator at Birth: an in Vitro Study in the Rat. Neutwzf Left 1992, 143:91-95.
Electrical
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46.
GUCXNHEIMER J, GUERONS, HARRIS-WARRICK RM: Mapping the Dynsmics of a Bursting Neuron. PbuoS Tmnr R Sot Lotld lBfo!l1993, in press. Non-linear dynamical systems analysis was used to create two-d& mensionai maps of parameter space of a model of the conditional bunter anterior burster (AB) neuron in the crustacean SIG. BIrcation analysis was used to identify regions of bursting and tonic activity. The model response to sequential reductions of IA were weII matched to the response of a reai anterior burster neuron during application of increasing concentrations of the IA blocker 4-aminopy50.
”
SHARP AA,
SHARP AA,
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HUGUENARD JR, MCCORMICK DA: SiiuIation of the Currents InvoIved In Rhythmic OsciIlations In Thalamic Relay Ncurons. J Narrqbysfof 1992, 68:137>1383.
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HAIKUS-WARRICK RM, NAGY F, NUSBAUMMP: Ncuromodulation of Stomatogastrk Networks by Identified Neurons and Transmitters. In L+mumfc Bfo&fcaf Netumks. ‘Ihe Stomatogust& Nenous S~tenz. Edited by Harris-War&k RM, Marder E, Selverston AI, Moulins M. Cambridge, USA: MIT Press; 1992:87-138.
59.
T, MANIRA A EL, GIULLNERS: The WGNBRJ, MATXJSHIMA Spinal GABA System Modulates Burst Frequency and In tcrsegmental Coordination in the Lampreyz Differential Effects of GABA,, and GABAn Receptors. J NmmpbysM 1993, 69647-657.
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TURRIGIANO GG, SEL~R~TONAI: Distribution of Cholecysto ItininLikc Immunoreactivity Within the Stomatogastric Nclr vous Systems of Four Species of Decapod Crustacca. J Comp Neuroi 1991, 305:164-176.
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SCHNUDERH, TRIMMERBA, RAPUSJ, ECKERTM, VALENTINE DE, RRAvITZEA: ‘Mapping of OctopamIne-Immunoreactive Neurons in the Central Nervous System of the Lobster. J Con@ Neund 1993, 329X$‘-142.
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RJEHN0, ROSTRUPE, MP)UERM: Monoamincrgk Systems in the Brainstem and Spinal Cord of the ‘Dude Pseude mys scrfpta efegans as Revealed by Antibodies Against Serotomn and TyrosIne 325~527-547.
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COLEMAN MJ, NUSBAUMMP, COURNILI, CLA~BORNEBJ: Dirt tribution of Modulatory Inputs to the Stomatogastric Gan @on of the Crab, Cancer borualfs. J Camp Netwoi 1992, 325:5Sl-5%.
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NUSBAUM MP, WEIMANN JM, GOLOWAXHJ, MARDERE: Presynaptic Control of Modulatory Fibers by Their Neural Network Targets. J Newoscf 1992, 12:2706-2714.
49.
MCCORMICK DA, HUGUENARD JR: A Model of the EIectro physiologicsl Properties of ThaIamocorticaI Relay Neurons. J Nenropbysfol 1992, 68:13&l-1400. This paper generates a model of single thalamoconical neurons based on experimental measurements of the voltage dependence, amplitude and kinetic propenies of a number of ionic currents. Tbe
!XHOTLAND JL, GIULLNER S: EBects of Serotonin on Fictive Locomotion Coordinated by a Neural Network Deprived of NMDA Receptor-Mediated
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HUGUFNARD JR, PRINCEDA: A Novel T-Type Current UndcrLies Prolonged &+-Dependent Burst Fii in GABAergic Neurons of Rat ThaIamic ReticuIar Nucleus. J Netrroscf 1992, 12:~3g17.
calcium current In burst generation
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988
Neural control Recordiigs were made from axons of modulatory neurons near their terminations in the c~stacean STG. These termit’& receive synaptic feedback from pattern-generating neurons in the STG, which shape theii impulse activity and release of modulator. Thus, modulatory input can be shaped by the pattern-generating network. 65.
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L~CKERY SR, SEJNOWSKITJ: A Lower Bound on the Detectabiiity of No nasscciative Learning in the Locai Bending Refla of the Medicinai Leech. Bebav Netrml Biol 1993,
59208-224. This paper studies models of sensitization
and habituation of the local bending reflex results from distributed changes in synaptic strength. Changes of 50% in reflex strength can be generated by small changes distributed throughout the whole network. These changes may be difficult to detect experimentaiiy.
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68.
HARR&WARRKK RM, FLAMMRE, JOHNSONBR, KATZ PS, KIEHN 0, ZHANGB: Neuromoduiation of Smaii Neural Networks in Crustacca. In Neurotar 91: Mokwrhr Basis of Dnrg E pesticide Action. Edited by Duce IR. London: Elsevier; 1992305-322.
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PIERONIJP, BYRNEJH: Differential Effects of Serotonin, FMRPamide, and Smaii Cardioactive Peptidc on Multiple, Dis tributed Processes Modulating Sensorimotor Synaptic Transmission in Ap&skr. J Neuroscf 1992, 12:2633-2647. At least two independent processes am involved in modulation of the monosynaptic component of the giil withdrawal reflex, one that involves presynaptic spike broadening and another that is independent of spike broadening. These are diierentiaily modulated by 5HT, FMRFamide and SCPn. 71. ..
JOHNSONBR, PECKJH,
HARRIS-WARRICK RM: Dopaminc In ducts Sign Reversal at Mixed Chemical-Electrical Synapses. Bdn Res 1993, in press. In the STG, some mixed synapses combine electrical coupling with chemical inhibition. Dopamine has opposite effects on these two components, reducing electrical coupling and enhancing chemical inhibition. In some cells, this results in a reversal of the sign of the net synaptic interaction. 72.
PEREM A, TRUER A, KORN H, FABER DS: Dopaminc En hances Both Eicctrotonic Coupling and Chemical Excitatory Postsynaptic Potentials at Mixed Synapses. Pmc Natl Acad Scf USA 1992, 89:1208812092.
BFLANGERJH, ORCHARDI: The Locust Ovipositor Opener Muscle: Proctoiincrgic Centrai and Peripheral Ncuromodu lation in a Centrally Driven Motor System. J Eap Bfol 1993, 174~343362. The peptide proctolin appears to be released by motoneurons onto a digging muscle. During centraliy patterned ovipositioning, proctolm release onto the muscle declines with time, and the strength of muscle contractions decline and disappear in parallel, even though the central motor pattern is still being generated. Bath application of proctolm restores the rhythmic muscle movements. Thus, peripheral release of proctolin appears to be essential for behavior expression of the ovipositioning motor pattern.
73. ..
of a stomatogastric neuron. This results in differential actions of the motoneuron on the muscle and in the ganglion. 75.
KEPLERTB, MARDER E: Spike Initiation and Propagation on Axons with Slow Inward Currents. Bid C’bern 1993, 68:209-214.
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BW(OFFA: Neuroethologicai Approaches to the Study of Mo tot Development in Chicks: Achievements and Chalienges. J NeuroMoll992, 23:1486-1505.
DICKINXIN PS, MOUINS M: Interactions and Combiitions Between Different Networks in the Stomatogastric Nervous System. In +mic Bkhgicul Nettunis. 7be StomatogasEdited by Harris-Warrick RM, Marder MC Nerwtrs Spem. E, Selverston Al, Moulins M. Cambridge, USA: MIT Press, 1992:134L160. An important review of the mechanisms by which neurons switch their activity from one neural network to another within the crustacean STG.
77. ..
78.
MARDERE, WEIMANNJM: Modulatory Control of Multiple Task Processing in the Stomatogastric Nervous System In NeuroMdogy of Motor Progmmme Selection. Edited by Kien J, McCrohan CR, Wiiow W. Oxford: Pergammon; 19923-19.
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JANSEC: Serotoncrgic Modulation of Junctionai Conductance in an Identified Pair of Neurons in the Moihtsc Lymnaea stapt.alls. Brain Res 1992, 595343-352.
MEYRAND P, WWMANN JM, MARDERE: Multiple Axonal Spike Initiation Zones in a Motor Neuron: Serotortin Actiiion. J
Neurwsci 1992, 12SO32812. 5HT evokes a new, peripheral spike initiation zone along the axon
JOHNSONBR, PECKJH, HN~RIS-WARRICK RM: Amine Modula-
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74. .
Intersegmentai Coordination: Lessons from Modciing Systems of Coupled Non-Linear Osciilators.
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81. .
MATSUSHIMA T, GRILLNER S: Neural
Mechanisms of Intersegmental Coordination in Lamprey: Local Excitability Changes Modify the Phase Coupling Along the Spinai Cord. J Neuropbvsiol 1992, 67:373388. Application of different concentrations of NMDA or 5HT in a multicompartment bath along the lamprey spinal cord can alter the intersegmentai phase iag smoothiy from forward to backward. Thii suggests that local differences in excitability of segmental oscillators determines the phase lag in the intact animal. 82. MAT~USHIMA T, GRLLNERS: Lccai Serotoncrgic Modulation .. of Calcium-Dependent Potassium Channels Controls In tcrsegmentai Coordination in the Lamprey Spinai Cord. J NeumpbysfolW92,
67:X&31690.
Local application of 5HT to part of the lamprey spinai cord can alter the intersegmental phase iag without changing the cycle ftequency. Locai application of a SHT-uptake inhibitor had the same effects, suggesting that endogenously released 5HT helps to determine the phase lag in the intact animal.
HEINZEE H-G, WEIMANN JM, MARDER E: Tbc Behavioral Repertoire of the Gastric MiU in the Crab, Cancerpagu*us: An In Situ Endoscopic and Electrophysioiogical Examination. J Neunxci 1993, 13:17931803. Simukaneous electrophysiologicai and endoscopic measurements were made of the gastric mill motor pattern in intact crabs. The movements corresponding to peptide-evoked motor patterns were visuaiized. Some pyloric neurons can switch to fire in time with the slower gastric mili rhythm, the changes in gastric tooth movement during these switches were observed and mapped. 83.
..
R Harris-Warrick, Section of Neurobiology and Behavior, Seeley G. Mudd Haii, Cornell University, Ithaca, New York 14853, USA.