Modulation of neural networks for behavior.

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1991

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MODULATION OF NEURAL

Annu. Rev. Neurosci. 1991.14:39-57. Downloaded from www.annualreviews.org by University of Waikato on 07/10/14. For personal use only.

NETWORKS FOR BEHAVIOR Ronald M. Harris- Warrick

Section of Neurobiology and Behavior, Cornell University, Ithaca, New York 14853 Eve Marder

Department of Biology, Brandeis University, Waltham, Massachusetts 02254 KEY

WORDS:

peptide, neuromodulation, central pattern generator, neural net

work, amine. INTRODUCTION All animals need to shape their behavior to the demands posed by their internal and external environments. Our goal is to understand how modu lation of the neural networks that generate behavior occurs, so that animals can change their behavior when necessary. We discuss recent work showing that anatomical networks in the nervous system provide a physical back bone upon which a large library of modulatory inputs can operate. These allow the networks to produce multiple variations in output under different conditions. In the scope of this review, it is impossible to discuss all the neural circuits in which modulatory processes are now known to shape behavior (for reviews, see Selverston 1985, Harris-Warrick 1988, Kravitz 1988, Getting 1989, Bicker & Menzel 1989, Marder & Altman 1989). Instead, we have chosen examples from the literature to highlight general principles and new findings that have arisen from recent work in this field. We emphasize simple rhythmic behaviors, because more is known concerning their neural circuitry than for complex, nonrepetitive actions. As research continues, we anticipate that ideas first developed in simpler invertebrate nervous systems will be found to apply to more complex vertebrate preparations. 39 0147-006Xj91j0301-00 39$02.00

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HARRIS-WARRICK & MARDER

MULTIPLE FUNCTIONAL CIRCUITS FROM A


SINGLE NETWORK: "POLYMORPHIC NETWORKS" Many behaviors such as walking can be generated with an enormous number of variants (forwards, backwards, upstairs, etc). Other behaviors at first glance appear very different from one another but share common muscles or movement components (for example, walking and scratching). An important question is whether the neural networks that control dif ferent behaviors or variants share many or few neuronal elements. At one end of the spectrum, anatomically separate networks could generate each behavior or variant. At the other end, the animal could produce quite different behaviors by continuous modulation of a single network. Clearly, intermediates involving multiple networks with overlapping elements are likely. Getting & Dekin (1985) first defined the "polymorphic network" as the moment-to-moment reconfiguration of a single neural network to produce several different motor patterns. This idea came from their demonstration in the mollusc, Tritonia, that the same neural network can produce both a defensive withdrawal reflex and escape swimming. The most detailed studies of the mechanisms underlying circuit modulation have been carried out in the stomatogastric ganglion (STG) of decapod crustacea. Here, several small, anatomically defined neural circuits each produce multiple variants of their rhythmic motor patterns (Hooper & Marder 1984, Flamm & Harris-Warrick 1986a,b, Hooper & Marder 1987, Marder 1987, Harris Warrick 1988, Nusbaum & Marder 1988, Turrigiano & Selverston 1 989). The reconfiguration of the circuits results from the actions of neuro modulators such as peptides and monoamines, and can be induced by stimulation of identified modulatory neurons that release these substances. As we describe below, modulatory inputs can change essentially all the functional components of the network, thus building a large number of acting circuits from a single anatomically defined network. Although the network interneurons have not yet been identified, there are suggestions in the vertebrate literature that a single neural network can be shaped by sensory or modulatory inputs to produce multiple behaviors. In the chick, a common generic motor pattern appears to underlie both hatching and walking (Bekoff et al 1987). In the turtle, the central oscillators for three distinct forms of rhythmic scratch are located in overlapping segments of the spinal cord and activate the same motor neurons (Martin & Stein 1989). In the lamprey, behavioral measurements have suggested that a single neural network mediates swimming through water, burrowing in mud and crawling on a surface (Ayers et al 1983). Neuromodulators such as serotonin modulate the lamprey motor pattern

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in similar ways in vitro (Harris-Warrick & Cohen 1985), in part by modu lating a calcium-activated K + current in identified neurons (Wallen et al 1989). Research in a number of systems has shown that neuromodulators can alter the output from neural networks by two major mechanisms: (a) changing the intrinsic properties of the component neurons; (b ) changing the synaptic efficacy in the circuit. These mechanisms are described below.


NEUROMODULATORS ALTER THE INTRINSIC PROPERTIES OF NEURONS Each neuron has characteristic intrinsic response properties that result from the ensemble of ion channels found in its membrane. Modulatory substances can modify the type, number, and/or kinetic properties of these ion channels and thus change the excitability of the cell (Kaczmarek & Levitan 1987). Consequently, a single neuron can display a variety of intrinsic activity patterns and can switch between them, depending on the modulatory environment. Rhythmic Bursting

Many neurons have endogenous oscillatory properties and can generate rhythmic bursts of action potentials in the absence of synaptic input. Rhythmically bursting neurons often act as pacemakers for cyclic behaviors. In such cases, modulators and modulatory neurons that modify the membrane properties of these neurons will have pronounced effects on the circuits in which these neurons act. The ionic mechanisms underlying bursting and its modulation have been extensively studied in neuron R I5 of Aplysia (Adams & Benson 1985). At least eight different conductances contribute to the rhythmic bursts of action potentials endogenously generated by this cell. Bursting in R l5 is modulated by many substances, including serotonin, dopamine, and FMRFamide (Latshaw et a1 1986, Levitan & Levitan 1988 ). Each neuro transmitter affects not one but several different ionic currents that par ticipate in burst generation. Many bursting neurons are "conditional bursters." That is, they only burst in the presence of one of a number of modulatory substances. For example, the AB neuron of the crustacean STG is a conditional oscillator that is strongly activated by a number of modulators, including dopamine, serotonin, octopamine, proctolin, and muscarinic agonists (Flamm & Harris-Warrick 1 986b, Harris-Warrick 1988, Marder & Meyrand 1 989). Interestingly, the character of the AB burst (burst period, amplitude of slow


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wave oscillation, etc) is different with each substance, and pharmacological experiments have shown that the three amines each use different ionic mechanisms to generate bursting (Harris-Warrick & Flamm 1987). For example, bursting induced by dopamine is critically dependent on calcium currents, whereas bursting induced by serotonin and octopamine requires tetrodotoxin-sensitive sodium currents. Models of oscillatory neurons show that even relatively minor changes in the ratio of the conductances controlling bursting can produce significant changes in burst waveform and amplitude (Epstein & Marder 1990). Since AB oscillations are critical in the generation of the pyloric rhythm, modulation of these cellular properties changes the motor patterns produced by the pyloric circuit. Modulation of bursting properties is important in the control of rhyth mic behaviors in all species, including mammals. This is shown by the induction of rhythmic bursting by thyrotropin-releasing hormone in neurons involved in the control of breathing in the guinea pig (Dekin et al 1 985). Plateau Potentials

Many neurons display bistable properties, or plateau potentials. These neurons have two fairly stable resting potentials: a hyperpolarized state with little or no activity, and a depolarized and tonically active plateau state. A brief excitation (either from an electrode or from a synaptic input) can trigger the transition from one state to another (Hartline et al 1 988). When such neurons are part of a network they can be switched between two activity states in a manner that is relatively insensitive to the intensity of synaptic inputs, once a particular threshold is exceeded. In the lobster STG, a single identified neuron, the anterior pyloric modulator (APM), can both enhance and suppress plateau properties in different cells. Stimulation of the APM activates the pyloric motor pattern by enhancing plateau potential capabilities in all of the pyloric neurons (Dickinson & Nagy 1983, F. Nagy, personal communication). However, APM suppresses plateau potential ability in the lateral gastric neuron (LG), resulting in a marked change in the gastric mill motor pattern (Nagy et al 1988). Similar properties have been observed in the vertebrate spinal cord (Sigvardt 1 989). Intracellular recordings from turtle (Hounsgaard & Kiehn 1989) and cat (Conway et al 1 988, Hounsgaard et a1 1988) spinal motor neurons show bistable firing properties in the presence of biogenic amines or their precursors. Under these conditions, a brief sensory input can produce prolonged plateau potentials that outlast the stimulus by many seconds or minutes (Conway et aI 1988). The ionic mechanism underlying the plateau in the isolated turtle spinal cord results at least in part from a prolonged Ca 2+ current. Serotonin uncovers the plateau capability by


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reducing a Ca2+ -activated K + current responsible for the slow spike afterhyperpolarization (Hounsgaard & Kiehn 1989). These data are in significant contrast to traditional ideas about the passive follower role of vertebrate motor neurons. These neurons, like many invertebrate neurons, respond differently to an identical synaptic input under different conditions and thus actively interpret their synaptic drive. Since the motor neurons are surrounded by serotonergic terminals, it is likely that these effects are behaviorally relevant. Plateau potentials may account for sharp discontinuities in motor neuron firing frequency seen in electromyographic recordings from freely moving rats (Eken & Kiehn 1989). In the lamprey spinal cord, L-glutamate, acting at NMDA receptors, activates rhythmic plateau potentials in both interneurons and motor neurons (Sigvardt 1989). Swimming bouts induced by sensory stimulation are abolished by NMDA antagonists (Alford & Williams 1989), thus suggesting that these modulatory actions are important in the generation of swimming. The widespread occurrence of plateau potential capabilities in neurons throughout the vertebrate central nervous system has recently been reviewed by Llimis (1988). Postinhibitory Rebound

Many neurons respond to strong hyperpolarization with a rebound exci tation, which can trigger action potentials. This process, called post inhibitory rebound, has been invoked as an important mechanism in the generation of rhythmic motor patterns (Calabrese et aI1989). Long-lasting postinhibitory rebound may result from the activation of a sag current, or hyperpolarization-activated inward current (Calabrese et al 1989). The rate of recovery following hyperpolarization can also be affected by the transient K + current, lA, which can delay repolarization. Little is known about the modulation of these currents in a behavioral context, but it is clear that any substance that modulates either of them will dramatically affect rhythm generation. NEUROMODULATORS CAN ALTER SYNAPTIC EFFICACY There are numerous examples showing that neuromodulators can change the amount of transmitter released from presynaptic terminals and/or the postsynaptic responsiveness. Synaptic modulation is an important mechanism underlying simple forms of learning (Kandel et a11987, Byrne 1987). However, changes in synaptic efficacy are equally important in understanding how neural networks are reversibly modulated in an on going manner during the life of an animal.


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Chemical transmission is modulated at numerous sites within vertebrate and intervebrate nervous systems. In some cases the behavioral relevance of these changes are obvious. For example, numerous modulators such as enkephalin and GABA are found in neurons in the spinal cord and decrease the release of substance P from primary sensory pain fibers (Mudge et al 1979). A consequent reduction in pain sensitivity is attributed to a reduction of the voltage-dependent calcium conductance in the presynaptic terminal (Dunlop & Fischbach 1981). Amines such as serotonin modulate the amplitude of junctional poten tials at many crustacean neuromuscular junctions (Glusman & Kravitz 1982, Kravitz 1988, Dixon & Atwood 1989). Since the contraction force of these slow muscles is directly coupled to the amplitude of the junctional depolarization, modulation of synaptic efficacy leads directly to behavioral changes. Central synaptic connections are also sites for modulation. In the lobster STG, graded inhibitory synapses are critically important for the appro priate phasing of neuronal activity during rhythmic stomach movements (Graubard et al 1 98 3). These graded synaptic interactions can be both increased and decreased by serotonin, octopamine, and dopamine (John son & Harris-Warrick 1990), resulting in altered phasing of the STG motor patterns. The peptide red pigment concentrating hormone (RPCH) strongly potentiates synaptic inputs in STG neurons, thus resulting in a major reconfiguration of the neural networks in the STG (Dickinson et al 1990). In Aplysia, an identified histaminergic neuron modulates the efficacy of inputs from the buccal-cerebral interneurons onto cerebral neurons engaged in the organization of feeding behavior (Chiel et al 1988). Electrotonic coupling between neurons is common in many circuits, and this too can be modulated. In the retina, dopaminergic interneurons reduce the strength of electrical coupling between horizontal cells by a cAMP dependent mechanism (Piccolino et al 1 984, Dowling 1989). This reduces the lateral inhibition mediated by these cells, weakening the antagonistic surround response to light. The overall effect of synaptic modulation within a behavioral network is a quantitative "rewiring" of the network interactions. By strengthening some synapses and weakening others, neuromodulatory inputs can, in essence, create new circuits for different behaviors. MODULATION OCCURS AT ALL LEVELS OF THE NERVOUS SYSTEM Most of the work described above focuses on modulation of neurons and connections within the pattern-generating networks themselves. However, neuromodulation occurs at all possible sites in the nervous system, inc1ud-


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ing muscles and neuromuscular junctions (Calabrese 1989), sense organs such as stretch receptors (Pasztor 1 989), motor neurons (Dickinson 1 989, Sigvardt 1989), and neurons of central networks, including those in pattern generating networks (Dickinson 198 9) as well as activating and coor dinating inputs (Mulloney et al 1987). A single neuron can exert modulatory effects on a simple behavior at many levels. For example, the metacerebral giant (MCG ) neuron in mol luscs contains serotonin and innervates the buccal musculature, motor neurons that drive buccal muscle, multiple interneurons of the feeding motor circuit, and putative activating neurons for feeding. The cellular actions of the MCG neuron are coordinated at all levels to modify the properties of all of the components of the system producing consummatory behavior (Kupfermann & Weiss 1 981, Benjamin & Elliott 1989). Some modulatory neurons produce multiple effects by releasing neuro transmitter as a local hormone from nonsynaptic sites, or globally into the circulation. For example, in Aplysia, activity of the bag cells coor dinates egg-laying behavior (Mayeri & Rothman 1985). A number of different behaviors are simultaneously affected, including the cessation of feeding and locomotion, increased respiratory and cardiac motor activity, and complex head-weaving and tamping movements to deposit a chain of extruded eggs. The bag cells release a family of related peptides into the local circulation in the abdominal ganglion, where they diffuse short distances to affect many different neurons involved in these multiple behaviors. Some of the bag cell peptides are rapidly inactivated by extra cellular aminopeptidases and thus act only within the ganglion. However, egg-laying hormone, the major peptide, also diffuses into the circulation where it can travel long distances to distant neuronal, muscular, and glandular targets to coordinate the multiple motor programs involved in egg-laying (Mayeri et al 1985). In the lobster, a single neuron appears to release serotonin both from an important neurosecretory structure and from neuropil sites within the CNS, thus enabling it to have both central transmitter and circulating hormonal effects (Beltz & Kravitz 1 987, Kravitz 1 988). SENSORY NEURONS ARE BOTH TARGETS AND SOURCES OF NEUROMODULATION Although sensory feedback may not be required for rhythm generation, it is nonetheless essential for correctly shaping the final motor patterns. In several cases, sensory neurons pass all the traditional tests for inclusion as components in the pattern generator network (reviewed in Pearson 1987 and Harris-Warrick & Johnson 1989). Sensory neurons can be direct targets of modulatory action (Pasztor


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1989). The oval organ is a proprioceptor involved in coordination of the gill ventilatory system in crustaceans. Its sensitivity to stretch is modulated by amines and the peptide proctolin (Pasztor & Bush 1989). It is par ticularly interesting that the dendrites of the sensory neurons innervating the oval organ contain and release proctolin in response to stretch, thus suggesting an automodulation of their own sensitivity (Pasztor 1989). In locusts, stretch receptor organs participate in the pattern generator for flight (Reye & Pearson 1988). The stretch sensitivity of these cells is hor monally regulated by circulating amines (Ramirez & Orchard 1990, Koller et al 1989). During vertebrate locomotion, the efficacy of primary afferent synapses onto central circuits varies with the phase of the ongoing rhythmic motor pattern (Sillar 1989). This phase-dependent reflex reversal depends, at least in part, on rhythmic membrane potential oscillations in primary afferent terminals that are phase-coupled to the motor rhythm (Gossard et aI1989). This may affect the amount of transmitter released by an incoming action potential. Gating of the post-synaptic response also occurs (Sillar 1989). Normally, modulatory inputs to motor circuits are thought to arise from neural centers within the CNS. However, recent work has shown that primary sensory neurons can themselves be sources of slow modulatory input to pattern-generating networks. In the crab, the gastro-pyloric recep tor (GPR) cells are primary mechanoreceptors rhythmically activated by movements of muscles in the gastric mill region of the foregut (Katz et al 1989). These cells contain both serotonin and acetylcholine and make synaptic conncctions with ncurons in thc pattern-generating networks in the STG. The GPR neurons elicit both rapid nicotinic excitatory responses and slow, prolonged modulation of the intrinsic properties of the STG neurons that are mimicked by serotonin (Katz & Harris-Warrick 1989, 1990, Kiehn & Harris-Warrick 1990). These modulatory actions include the induction of rhythmic bursting, plateau potentials, and prolonged excitation and inhibition of different cells, resulting in a functional reor ganization of the neural circuits in the STG. In a semi-intact foregut prep aration, the GPR cells are rhythmically activated by the gastric mill rhythm (Katz ct al 1989). Thus, thcy provide a peripheral feedback loop for the gastric mill to modulate the pyloric rhythm: The GPR cells can induce periodic changes in the rapid pyloric motor pattern phase-coupled with the slower gastric mill rhythm. In Apiysia, a histaminergic neuron, C2, appears to be a primary mech anoafferent activated by touch to the perioral zone (Weiss et al 1986a). Like the GPR cells, this cell is active in phase with the rhythmic feeding program (Weiss et al 1986b) and modulates a variety of feeding-related neurons, including motor neurons (Chiel et al 1986), the modulatory

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serotonergic MCG (Weiss et al 1986c), and synaptic inputs to the MCG (Chiel et al 1988). Thus, this sensory cell plays an important premotor role in the coordination of feeding.

MODULATION OF MUSCLES AND


NEUROMUSCULAR JUNCTIONS Modulation of muscle properties and neuromuscular junctions has been extensively studied in a number of invertebrate preparations (Calabrese 1989). Many circulating amine and peptide hormones affect the efficacy of neuromuscular junctions and muscle contractile responses. This is seen clearly with serotonin, which acts at both pre- and postsynaptic sites on crustacean neuromuscular junctions (Glusman & Kravitz 1982, Kravitz 1988) and involves multiple receptors and several second messenger sys tems (Goy & Kravitz 1989, Dixon & Atwood 1989). Thus a muscle can respond to the identical motor neuron discharge with quite variable move ments. This is also seen in the dilator muscle of the shrimp, where dopamine (Meyrand & Moulins 1986) and FMRFamide-like peptides (Meyrand & Marder 1990) enhance oscillatory contractions of the muscle. This ampli fies the strength of the contraction evoked by motor neuron discharge, and makes it independent of the intensity of the motor neuron burst, so long as it is sufficient to elicit an oscillation. Many motor neurons contain several neurotransmitter substances. Frequently, the co-transmitters have quite different roles. In the leech, the myogenic heart muscle is innervated by heart excitor (HE) motor neu rons and heart accessory (HA) modulatory neurons (Calabrese 1989). The HE neurons release acetylcholine, which evokes rapid excitatory junc tional potentials (EJPs), and FMRFamide, which elicits myogenic cy cling in quiescent hearts. The HA neurons also contain FMRFamide, and assist in increasing the amplitude and duration of heartbeat tension. Here the same modulator is used by motor neurons and modulatory neurons, with subtle differences in its role due to the presence or absence of co transmitters and the endogenous pattern of neuron activity (Calabrese 1989). In Aplysia, the accessory radula closer (ARC) muscle is innervated by several motor neurons, including the well-studied B 15 cell. B15 uses acetylcholine and three peptides, small cardioactive peptide A (SCPA), small cardioactive peptide B (SCPB), and buccalin (Cropper et al 1988). These peptides have opposing effects. SCPA and SCPB act primarily post synaptically to increase the size and relaxation rate of muscle contrac tions evoked by motor neuron stimulation. In contrast, buccalin decreases

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the size of motor neuron-evoked muscle contractions, primarily acting presynaptically. The significance of these: opposing actions is not clear. One possible explanation is that the transmitters might be differentially released under some circumstances (Bartfai et al 19 88, Cropper et al 1990).


NEUROMODULATORS ACT IN CONCERT In intact animals, neural networks receive simultaneous input from many modulatory neurons. Chemical neuroanatomical studies have shown that all ganglia and brain regions contain many different neurotransmitters and modulators. For example, the crustacean STG contains about 30 neu rons and is innervated by fibers containing at least 13 different neuro transmitters (Marder 19 87, Marder & Nusbaum 19 89). Most of the identified modulatory inputs to the STG contain more than one neuro transmitter, and evoke both rapid PSPs and slow modulatory responses in follower cells. Since it is likely that many of these inputs are active simultaneously, the STG networks are modulated by a continuously vary ing mixture of transmitters. The relative contribution of one substance may be significant under some conditions but only produce subtle effects at other times. The presence of multiple transmitters in single cells suggests that there might be a mechanism for differential release of the transmitters (Bartfai et aI19 88). Indeed, in several preparations, small transmitters and peptides appear to be packaged into different vesicles. As described above, in Aplysia, the bag cells release a large group of peptides that organize a family of behaviors to support egg-laying. These peptides are cleaved from a common precursor protein (Scheller et al 19 83), but they appear to be differentially packaged into two classes of vesicles that are transported to different terminal regions of the cell (Sossin & Scheller 19 89). Differential actions of co-transmitters may also result from differential release as a function of stimulation frequency (Bartfai et al 19 88). While small, rapid transmitters are usually released in high quantities with each impulse, there is accumulating evidence that peptides are only released in physiologically adequate amounts during higher-frequency trains of stimuli. For example, Whim & Lloyd (19 89) showed that the acetyl choline/SCPB motor neuron B15 in Ap/ysia does not release physio logically significant amounts of SCPB unless the cell fires in a high frequency burst, though it releases functional amounts of ACh at all frequencies. Many identified modulatory neurons show patterned activity, with bursts of action potentials at high frequency. This may ensure the release of peptides or other slow transmitters.

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STATE-DEPENDENT EFFECTS OF MODULATORY


INPUTS The behavioral state of an animal can influence its response to stimuli. In recent years, studies of modulator actions in simple systems have provided suggestions of how this may occur. In the crustacean stomatogastric system, stimulation of either the anterior pyloric modulator neuron (APM; Nagy & Dickinson 19 83), the modulatory proctolin-containing neuron (MPN; Nusbaum & Marder 19 89), or the gastro-pyloric receptor neuron (GPR; Katz & Harris-Warrick 1990) increases the cycle frequency of a quiescent or slowly cycling pyloric rhythm up to a ceiling of about 1 Hz, but such stimulation has no effect when the pyloric rhythm is already cycling at or above this frequency. Since each of these neurons has a different mix of transmitters and different target neurons in the STG, this result is unexpected; it argues that the 1 Hz frequency attained by stimulation of each of these neurons is physiologically important to the animal. State-dependent effects on networks may result from voltage-dependent modulator actions on the target neurons. Some modulators affect ion currents that show a marked voltage dcpendence, and the effect will thus only be seen at certain membrane potentials. The voltage-dependent Mg2+ blockade of the NMDA receptor (Nowak et a1 19 84) is an example. Many neuromodulators act by elevating the levels of second messenger molecules inside the cell. The synthetic pathways for second messengers are totally intertwined, and changes in the level of one second messenger may alter the responses mediated by other second messengers. Thus, the response of a neuron to a single modulator will vary depending on previous modulatory actions. NETWORK INTERACTIONS ARE IMPORTANT TO UNDERSTANDING MODULATOR ACTION In addition to direct modulatory actions on target neurons, the effects of neuromodulators on network output are emergent functions of the network. This is illustrated by two examples from the STG. Neurons of the STG release neurotransmitter as a graded function of membrane potential (Graubard et al 19 83, Hartline et aI 19 88). Even when a neuron is oscillating below threshold for spike initiation, it can still release neuro transmitter and shape the final circuit output. Therefore, to understand the network, one must know the relationship between presynaptic mem brane potential and transmitter release. Since modulators such as dopa mine, octopamine, and serotonin can change the threshold for graded


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transmitter release (Johnson & Harris-Warrick 1990), network function can be influenced without obvious changes in the spike activity of many of the components. As a consequence of network interactions, neurons that are not them selves direct targets for modulators can nonetheless shape the overall network response. For example, the peptide proctolin induces a slower cycle frequency in the intact pyloric network than in the isolated pacemaker AB neuron (Hooper & Marder 19 87). This is a consequence of electrical coupling between the AB neuron (a direct target of proctolin action) and several other neurons (not themselves targets) that impose an electrical "drag" on the oscillating AB neuron. Modelling studies have shown that the consequence of this electrical drag depends critically on the exact shape of the bursting pacemaker potential in the AB cell and on the strength of the electrical connections between the cells (Kepler et al 1990).

VARIABLE INTERACTIONS AMONG COUPLED OSCILLATORS Complex behaviors such as locomotion require efficient coordination between multiple oscillators that may be found in different ganglia or segments of the spinal cord (Rand et al 19 88). For example, a quadruped can walk with alternation of opposing limbs, or gallop with synchronous activation of opposing limbs. It is not clear how these switches occur. In the lamprey spinal cord, pharmacologically decreasing the strength of crossed synaptic inhibition can change the left-right intrasegmental coor dination from alternation to synchrony (Cohen & Harris-Warrick 19 84). Modulatory substances that alter synaptic strength across the spinal cord would thus be expected to alter the coordination between the limb oscillators. In crayfish, sensory inputs play an important role in co ordinating the central oscillators controlling adjacent ipsilateral legs, pro ducing either walking (with a metachronal wave of limb movement) or "waving" (with synchronous limb movement; Sillar et al 19 87). The mechanisms underlying these changes in oscillator coordination are not known. Oscillators are distributed at many different levels of motor organ ization. For example, in the stomatogastric system, endogenous oscillatory properties are found in neurons that project to the STG (Nagy & Moulins 19 87), in neurons within the STG (Bal et al 19 88), in foregut muscles (Meyrand & Moulins 19 86), and in sensory neurons that provide rhythmic feedback to the whole system (Katz et al 19 89). These oscillators can be coupled with varying strength, and modulatory substances are likely to

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influence not only the expression of oscillatory properties at each level, but also the strength of the coupling between them. SWITCHING OF NEURONAL ELEMENTS


BETWEEN NEURAL NETWORKS Classically, workers have assigned neurons to a certain network based on their activity under defined conditions. The polymorphic network concept suggests that neurons may be active in one functional circuit under one set of circumstances, but switch to another functional circuit when the conditions change. Evidence to support this has been obtained in the STG. Here, the 30 neurons are usually assigned to one of three different networks of neurons controlling the pylorus, gastric mill, and cardiac sac. However, many if not most of these neurons can be active in time with more than one of the motor rhythms. In the lobster, Palinurus, Hooper & Moulins (19 89) showed that stimulation of a sensory nerve causes the VD neuron to drop out of the rapid pyloric rhythm and become active in time with the slow cardiac sac rhythm. This was due to the loss of intrinsic plateau properties of this neuron, combined with strong synaptic drive from a modulatory neuron active with thc cardiac sac rhythm. In this case, both rhythms were simultaneously active and the cell freely switched between the two. In the crab Cancer, the gastric mill rhythm is frequently inactive. Under these conditions, neurons innervating the gastric mill muscles often oscillate in time with the faster pyloric rhythm (Weimann et aI1990), and they can be recruited to fire action potentials in pyloric time by stimulation of the serotonergic sensory neuron, GPR (Katz & Harris-Warrick 1990). The gastric mill rhythm can be activated by bath application of the peptide SDRNFLRFamide (Weimann et al 1990); the gastric mill cells then fire in the slower gastric mill rhythm, and some neurons of the pyloric group switch to fire in gastric mill time. These motor neurons have a dual function: they are both the messengers sending signals to the muscles and active members in the pattern-generating circuit. Indeed, the motor pattern can be reset by stimulation of neurons that have previously switched allegiance from another circuit (J. M. Weimann, unpublished). In all of the preceding examples, neurons switched from one well defined motor pattern to another. Modulators can also combine previously separate circuits into a new composite circuit. Dickinson & Marder (19 89) showed that RPCH strongly activates the slow cardiac sac rhythm in Panulirus. When the gastric mill rhythm is weak or silent, RPCH evokes a novel conjoint rhythm in which elements of both the cardiac sac and gastric mill circuits participate, due to a strong potentiation of synapses that coordinate these elements (Dickinson et al 1990).

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BEHAVIORAL STUDIES OF MODULATOR


ACTION Most of what we know of modulator action comes from in vitro experi ments. However, correlative modulator-induced changes in the behavior of intact animals have been observed. Kravitz and colleagues (Kravitz 1988, Harris-Warrick & Kravitz 1 984 ) showed that monoamines modulate central postural motor programs in the ventral nerve cord of the lobster, Homarus; this correlates with amine-induced changes in posture in the intact animal. Heinzel & Selverston (HeinzeI19 88a,b, Heinzel & Selverston 1988) correlated proctolin-induced changes in the gastric mill motor pat terns in the STG with alterations in stomach movements observed with an endoscope in intact lobsters. Turrigiano & Selverston (1989,1990) showed that a cholecystokinin (CCK )-like peptide enhances the gastric mill rhythm in vitro in the STG; CCK-like levels rise in the blood of intact lobsters during feeding, when the gastric mill is active, and a CCK antagonist can block gastric mill activity during feeding. These results suggest that the CCK-like peptide may be an important driver of gastric mill activity during feeding. In a different approach, Glanzman et al (19 89) selectively depleted serotonin from the CNS of Ap/ysia with 5,7-dihydroxytryptamine, and showed a corresponding reduction in behavioral dishabituation and sen sitization to tail shock. Clearly, further work is needed to correlate modu lator actions with behavioral change in intact animals. CONCLUSIONS AND FUTURE DIRECTIONS This review has demonstrated the generality of the hypothesis that single anatomically defined neural networks can be reconfigured in many ways by modulatory inputs to generate a family of related behaviors. Although most of the examples have been taken from simpler invertebrate prep arations, in which identified neurons can be repeatedly studied, it is clear that similar rules apply to vertebrate systems. Vertebrate neurons show the same complexity in intrinsic properties and synaptic plasticity as inver tebrate cells (Llinas 1988). Growing evidence suggests that single vertebrate networks underlie multiple behaviors. The major problem facing ver tebrate researchers in this field is the unambiguous identification of neuronal components in behavioral networks. This problem is now cxacer bated by the finding that the same neuron can participate in several circuits at different times. Nonetheless, spinal cord and brainstem slice prep arations and improved anatomical and immunohistochemical techniques are helping workers to make giant strides to overcome these problems. The enormous diversity of modulatory actions at every level of neural


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networks poses two important questions. I. How d o networks retain their essential characteristics and continue t.o operate stably despite all this modulation? 2. Of the many changes induced in a network by a neuromodulator, which are the most important in determining the final motor pattern, and which provide only subtle alterations? Answers to these questions will require a combination of experimental and theoretical approaches, now made possible by recent advances in computational techniques. Ideally, one would like to correlate changes at the biophysical level with changes at the network level. Unfortunately, the preparations best suited for network analysis are less amenable to detailed studies of modulation of single currents and channels. Further work, including tissue culturing of identified neurons, may help alleviate this problem. New preparations that offer promise for improved combined biophysical and network studies are actively being sought (Watson et al 1989). Most invertebrate preparations have suffered from a lack of linkage of cellular and network studies to real behaviors in intact animals. Thus, it is critical now to determine the extent to which the network plasticity observed in vitro is actually used in a behavioral context. By correlating changes at the behavioral and network levels, we can start to approach an understanding of the functional roles of neuromodulators in the living animal. ACKNOWLEDGMENTS

We are indebted to all our colleagues who helped in the development of the ideas discussed in this paper. Supported by NS17323 and Hatch Act grant NYC-191410 (R. H.-W.) and NS17813 (E. M.).

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