- Email: [email protected]
Escape behavior — brainstem and spinal cord circuitry and function
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Escape behavior - brainstem and spinal cord circuitry and function Henri Korn 1 and Donald S Faber 2 Recent work has demonstrated that the neural circuits mediating escape reactions in lower vertebrates and mammals have a common framework, with only two excitatory central synapses in the reflex arc. This relatively direct linkage from sense organs to muscles and the fact that segments of the network also transmit other motor commands help guarantee that escape always has priority over ongoing behaviors. Yet, modulation and plasticity contribute some variability to the expression of escape and, therefore, to the adequacy of its survival function.
Addresses l lnstitut Pasteur, Biologie Cellulaire et Moleculaire du Neurone, INSERM U 261, Departement des Biotechnologies, 25 rue du Dr Roux, 75015 Paris, France; e-mail: [email protected] 2Department of Neurobiology and Anatomy, MCP-Hahnemann University School of Medicine, Allegheny University of the Health Sciences, 3200 Henry Avenue, Philadelphia, Pennsylvania 19129, USA; e-mail: [email protected] Abbreviations C-start C-shaped contraction GABA y-aminobutyric acid LTP long-termpotentiation M-cell Mauthner cell NMDA N-methyl-o-aspartate PnC nucleusreticularis pontis caudalis
Current Opinion in Neurobiology 1996, 6:826-832 © Current Biology Ltd ISSN 0959-4388
Introduction The escape response, which can be observed in many vertebrates and invertebrates, has commonly been viewed as an abrupt and stereotyped reflex, triggered with minimal delay by a sudden, unexpected, and possibly aversive, stimulus. Because the escape response often involves an identifiable giant fiber, especially in invertebrate nervous systems that are accessible for single-cell recordings, it has been used for decades for correlating a behavior with the neural circuits that generate it and hence for analyzing the neural bases of sensorimotor interactions. Diverse escape reactions have been observed throughout the phyla, in species such as sea anemones, annelids, cockroaches, crayfish, rats, cats and humans [1]. As these activities have been dissected, several clarifications leading to new definitions have emerged. First, although speed is obviously required for such an adaptive response, not all escape responses are mediated by giant fiber systems. Further, when they are involved, such fibers may mediate only part of the reflex. Second, escape reactions take
different forms in different species and too often are ambiguously referred to as 'startle responses'. In fact, some startle reactions do not result in a translation of the body away from the threatening stimulus, a good example being that of humans whose response is primarily flexion, whereas in rodents, an initial extension can result in a jump. These differences would seem to distinguish the escape of lower species from that of higher vertebrates, in which the reflex is graded in amplitude and duration [2]. Intuitively, it would be expected that the complexity of the circuitry mediating this function would increase phylogenetically. However, as described in this review, recent progress indicates this is not the case. Furthermore, insights from work on lower vertebrates, namely fish, and from mammals such as rats are complementary, in part, because these species offer different technical advantages. Studies of these diverse systems indicate that these different behaviors all exhibit variability and plasticity, thus providing the basis for a convergent perspective on escape in all species. Neuronal components of escape Although little new information has emerged in the past two years about its circuitry and behavioral features, the escape reaction of goldfish remains one of the main references for studying vertebrate sensorimotor processing, primarily because of the involvement of a large identifiable reticulospinal interneuron, the Mauthner (M)-cell. In a freely swimming fish, activation of its M-cell causes a C-shaped contraction (C-start) of its trunk, which initiates predator avoidance and may be followed by a return flip (Figure la). M-cell activation can be evoked by auditory and possibly visual or lateral line stimuli, with a latency to movement onset as short as 10-15 ms. Invertebrate escape responses produced by different sensory modalities may utilize common central circuits [3]. Recently, it has been shown, through use of chronically implanted electrodes, that the fast body bend triggered by M-cell activation during an escape reaction also occurs during feeding, that is, during prey capture [4]. Thus, the same circuits and motor behavior may serve contrasting vital purposes, such as attack, evasion, and establishment of territorial boundaries.
Comparison of natural escape responses with those produced by direct M-cell stimulation suggested that one population of reticulospinal neurons, including the M-cell, triggers the first stage of the C-start while a second group of neurons may fire later, if the animal needs to correct its orientation [.5]. It was postulated that the second
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taps, but that, contrary to expectations, all motoneurons are synchronously active during escape responses [9°°].
Figure 1
T h e acoustic startle response described in mammals [2] differs from the goldfish escape response in that it is graded in amplitude with stimulus intensity and is bilateral. It consists of a characteristic sequence of movements that in rats includes an extension of the limbs that can cause jumping in non-habituated animals (Figure lb), followed by a generalized flexion that shortens the body. Interestingly, its latency is comparable to that of the C-start in goldfish. Numerous studies have been devoted to characterizing the pharmacological and behavioral mechanisms of control of this reaction, but there have been almost no investigations of its internal circuitry at the synaptic level.
Muscle 1996 Current Opinion in Neurobiology
The reflex arc of fish and rats. (a) Goldfish escape response and its analysis. (i) Silhouettes showing that as a ball is dropped into the water (Stimulus), the animal first turns away from the threat and then initiates a forward propulsion, possibly followed by a counter turn. The last image shows the location of the fish 50 ms after the end of the initial turn. (ii) Vectors designating the fish's midline orientation and position at selected times during the reaction, which are used to quantify the distance moved and the acceleration at successive stages. Adapted from [8]. (b) Acoustic startle response of the rat. Posture (i) at rest and (ii) after a noise burst. The reaction propels the animal off the floor of its cage. Adapted from [2]. (c) Excitatory reflex arc subserving both reactions. Hair cells drive first-order neurons, the axons of which contact reticulospinal neurons: the ipsilateral M-cell in fish, and neurons of the PnC in rats. The descending axons excite cranial and spinal motoneurons (Mns). The dashed lines indicate that the rat startle reaction is bilateral, and the plus (+) signs designate synaptic excitation.
group of neurons includes the Mauthner cell homologues described first in the zebrafish [6] and later in goldfish [7]. These predictions have recently been confirmed through use of in vivo confocal imaging of calcium transients in hindbrain neurons of larval zebrafish during escape responses (JR Fetcho, Y-H Kao, DM O'Malley, Soc Neurosci Abstr 1995, 21:687). This powerful method has further demonstrated that, as predicted [8], these reticulospinal neurons are differentially activated by abrupt head or tail
Initially, the acoustic startle response was thought to include a series of central relays, with the output of the last stage, the caudal pontine reticular formation (PnC), projecting to motoneuron pools [10]. Recent results obtained through use of standard electrophysiological tests [11] are consistent with this scheme. However, a simpler excitatory chain comparable to that already established in teleosts (Figure lc) is now favored. Apparently, a special class of auditory afferents, with their somata in the cochlear nucleus, project monosynaptically to the PnC [12,13°°]. Although the results obtained through use of neurotoxic lesions [14] and intracellular recordings [12] suggest that the postsynaptic targets of these auditory afferents are giant reticulospinal neurons, the results of work using more localized lesions implicate non-giant cells [13°°], leaving this issue unresolved.
Pre-motor processing Escape behaviors necessarily have high thresholds, and their short latencies leave minimal time for complex treatment of sensory information, such as assessing the location of a threatening stimulus relative to environmental parameters. Before initiating an escape response, an animal must decide upon the appropriate direction and magnitude of the movements required. In the cockroach, escape direction appears to be encoded within the brain by a group of giant interneurons that collectively dictate to each thoracic ganglion where to move the pair of legs it innervates [15]. In other species, this information may be specified by the neuron(s) that reach threshold for action potential initiation, such as the left or right M-cell in the case of teleosts. A puzzle is that goldfish escape is directional [16], even though the swim bladder, the main organ for transducing sound pressure, activates both ears simultaneously. An important theoretical controversy has emerged around this issue. Although there ate still questions about which end-organs project to the M-cell [17], one view is that the M-cell can detect small deviations of its excitatory inputs from a perfect interaural correlation [18°], whereas the other
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view assigns a critical role to the inhibitory interneurons that mediate feedforward inhibition of the M-cell [19] and that are postulated to decode phase differences in afferent activity [20°]. In either case, it is clear that central processing is critical for decision-making in the escape response, and the same may be true for the acoustic startle response.
Inhibitory systems Proper execution of an escape response requires that muscles antagonistic to the effectors are not co-activated, and it has been recognized that this is the role of spinal inhibition. Glycinergic inhibition of reticulospinal neurons has been directly demonstrated in the goldfish through use of electrophysiology and immunocytochemistry [19], and it has been recently characterized in the embryonic and adult zebrafish ([21]; H Korn, N Ankri, K Hatta, G Rao, RC Eaton, abstract, Zebrafish Development and Genetics meeting, Cold Spring Harbour, April 1996, page 174). Patch clamp studies in zebrafish embryos [22] have confirmed previous conclusions from adult goldfish [23] that the mean open time of glycine-activated channels increases with depolarization, making inhibition more effective near threshold. In mammals, evidence for a role for glycine in acoustic startle has been obtained in rats after systemic injections of strychnine [24] and, more importantly, through molecular genetics. A mutation in the gene encoding the c~l subunit of the human glycine receptor results in a decreased affinity for glycine, thereby causing an exaggerated startle reflex termed hyperekplexia [25]. This syndrome or 'startle disease' is dominated by sudden jumps and excessive flexions of the neck and trunk in response to acoustic and tactile stimuli. Similar disorders are found in a number of mammals [26"], notably two mutant mouse strains, spasmodic and spastic, which are generated by alterations to the c~l and 13 subunits of the glycine receptor, respectively. In the spastic mouse, receptor number, not sensitivity, is decreased, demonstrating that diverse mutations can produce similar physiological syndromes. Another interesting observation is that the change in the structure of the human c~l subunit disrupts the transduction process [27,28] and may make the glycinc receptor sensitive to GABA [29], which could partially compensate for the deficit in the glycinergic control of startle responses. Recent results from work on inhibitory mechanisms in zebrafish, coupled with the advantages of this species for genetic studies, indicate that the zebrafish is a tractable system for developing new approaches for treating syndromes caused by glycine receptor dysfunction, particularly since both glycine and GABA operate on M-cell circuits [19].
Shared spinal cord circuits Given its vital purpose, an escape response must have priority over ongoing activity, once the 'behavioral decision'
is reached. This notion is exemplified in invertebrates such as the sea slug Pleurobranchaea, in which impulses in one neuron both initiate escape swimming and suppress feeding [30]. However, the same cell(s) may actually be integral to multiple movements with different functions, such as in the locust, in which kicking and jumping (which serve escape and repulsion of adversaries, respectively) use similar motor patterns that are generated by common flexible networks [31"]. T h e M-cell system is a good model for analyzing this functional switch (Figure 2), as already shown by simultaneous kinematic and electromyographic evidence that the performance of the escape reaction is unaffected in unrestrained fish, regardless of the swimming phase during which it occurs [32]. In addition, direct intracellular stimulation of the M-cell axon during fictive swimming not only overrides alternating bursts in motor nerves innervating both red and white muscles, but later resets the swimming rhythm [33°]. T h e similarities between the escape and swimming circuits suggest that activation of commissural inhibitory interneurons by the dominant M-cell turns off competing motor commands. It has been proposed that the rapid spread of this inhibition, which synchronously blocks motor units throughout one side of the body, provides a new raison d'~.tre for the large diameter of the M-axon and of other reticulospinal neurons [34].
Plasticity and modulation It is becoming progressively clear that the escape reaction is not stereotyped in all species and that both its threshold and pattern of execution are modified by internal and external signals acting on central circuits (Figure 3). This is apparent in invertebrates, such as the cockroach [35,36] and crayfish [37°',38"]. In the latter, habituation of the tailflip is attributable to activation of a tonic inhibition from higher centers rather than, as previously believed, to intrinsic depression of the synapses in the network [37°°]. More provocative is the fact that a crayfish's social status determines whether serotonin is a positive or negative modulator of its escape circuit [38"]. In fish, serotonergic and dopaminergic terminals have been identified in the vicinity of the M-cell; the corresponding amines increase inhibitory [19] and excitatory [39] transmission onto this neuron, albeit by acting at distinct synaptic sites. T h e most promising advance in the past few years, however, has been the realization that synaptic strength is dependent on previous experience at the level of the initial stages of sensory processing that control the reflex threshold and its directionality [40,41°,42,43",44°]. Both the electrotonic and chemical components of the 'mixed' excitatory connections between primary eighth nerve afferents and the Mcell lateral dendrite undergo tetanus-induced long- and short-term potentiations that have N M D A receptor and calcium dependencies comparable to those reported for
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Spinal circuits shared by different motor behaviors in fish, and reconfiguration of network activity by reticulospinal commands as escape overrides swimming. Fish silhouettes, at the indicated times, (a) during swimming and (b) during the first stage of an escape triggered at 0 ms by an object thrown in the water. Darkened lateral areas represent the dominant red and white muscle activity. Adapted from [32]. Two segments (caudal and rostral, separated by horizontal dashed line) of the network used in each case are shown next to the silhouettes, with the M-cell and its connections superimposed on the right-hand panel (b). Escape priority is imparted by the M-cell's excitation of inhibitory commissural interneurons ((31), which guarantee that only one side of the spinal cord will be activated. Other active neurons and muscles are shaded in light gray. P~us (+) and minus (-) signs indicate the direction of synaptic action, which is chemical or electrical (e), the latter occurring without delay. Shading designates neurons that are activated. DI, descending interneuron; Mn, motoneuron. Adapted from [50].
hippocampal long-term potentiation (LTP) [40,41°]. These effects tend to decrease the threshold for M-cell activation, which can also be upregulated by tetani that trigger both long-term depression of the same junctions [42] and LTP of the glycinergic inhibitory synapses on the cell's soma [43"°]. T h e inhibitory LTP can be induced by tone bursts, indicating it may be functionally relevant (Y Oda, A Morita, K Kawasaki, H Korn, abstract B351, 4th IBRO World Congress, Kyoto, July 1995). Paired pre- and postsynaptic recordings, with reliable identification of the inhibitory interneurons, have revealed that this LTP is, in part, expressed presynaptically, as shown by quantal analysis [43°°], and that there is a reserve pool of latent connections that become effective after the tetanization [44°]. Studies of plasticity in the acoustic startle paradigm have focused on its potentiation by conditioned fear, a
model for associative learning. In this paradigm, a neutral conditioning stimulus, such as a tone, acquires aversive properties and enhances the startle response after it has been associated with an unconditioned electrical shock. Modulation of the startle response occurs in the amygdala [2], which, in turn, regulates transmission in the reflex pathway (Figure 3).
In confirmation of this finding, it has been found that brief trains of stimuli applied to the medial geniculate body, which has a monosynaptic input to the amygdala, result in a long-lasting potentiation of the field potential evoked in the latter by acoustic stimuli [45]. Furthermore, in freely moving rats, fear conditioning significantly increased the responsiveness of neurons in the lateral nucleus of the amygdala to tones and converted unresponsive cells into tone-responsive ones [46]. This last observation underlines
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Figure 3
Sites of synaptic plasticity in the escape networks of (a) fish and (b) rats. In both species, activity-dependent modifications of synaptic efficacy have been demonstrated at the junctions highlighted on the diagrams by thick gray arrows or by bold lettering. The direction (+,-) of synaptic action is as for Figure 2, and e and c designate mixed electrical and chemical contacts, respectively. Only excitatory connections are shown in (b) because the internal circuitry has not been investigated. In fish, plasticity has been found at all levels of its escape circuitry, whereas in mammals, only modulation of the reflex arc that is mediated through the amygdala has been described. CRN, cochlear root neuron; CS, conditioned stimulus; Int, commissural interneurons; M, Mauthner cell; US, unconditioned stimulus; VIII, auditory afferents. See also Figure 1.
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the contribution of silent connections to the expression of LTE
Conclusions The need to quantify motor performance may have obscured the diversity of escape behaviors by restricting the types of behaviors that can be studied, such as the rapid response of a fish to a dropped ball or of a rat to a loud tone. The common definition of escape, also used here, excludes alternative forms of escape, such as the slower and more prolonged reaction of the channel catfish [47], a restriction that may hide the involvement of the same circuit elements. Conversely, the concept of shared networks may need to be refined, because the functional role(s) of some of their components may be specified to a greater extent than assumed.
case, the similarities in the reticulospinal networks of distantly related lower and higher vertebrates underline the relevance of the model systems in fish for further studies of neuronal activity during the control of motor performances. New techniques, such as transneuronal labeling of functionally related circuits of neurons [48"], in vivo imaging of activity-related cell populations [9°°] and genetic manipulations [49], are particularly suited for this type of investigation, especially in zebrafish. Interest in the circuitry of escape behavior has been somewhat restricted, because of the limitations of using electrophysiological techniques alone, but it should be revived by the opportunities provided by these new approaches.
Acknowledgements We thank Robert Eaton and Joe Fetcho for helpful discussions on this topic.
A general feature of the escape and acoustic startle reactions is their variability, which could be explained by numerous factors, including the number of responsive cells, the balance between excitation and inhibition that determines threshold for spike generation, and, although not yet documented, the intensity of the ongoing motor activity that must be superseded. This variability has a clear adaptive advantage, as even predator avoidance (or attack) would be degraded if executed in a predictable manner.
References and recommended reading Papers of particular interest, published within the annual period of review, have been highlighted as: • ••
of special interest of outstanding interest
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The recently discovered activity-dependent plasticity of the inhibitory systems that control the goldfish tailflip [43"°,44 "] raises two questions. One, is habituation the behavioral correlate of the resulting enhanced inhibition? Second, is supraspinal inhibition, which is not yet well documented in mammals, also involved in the graded nature of the acoustic startle reaction? In any
of escape movements evoked by tactile stimulation in the cockroach Periplaneta americana, J Exp Bio/1994,
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Fetcho JR, O'Malley DM: Visualization of active neural circuitry in the spinal cord of intact zebrafish. J Neurophysio/1995, 73:399-406. Introduces an innovative and promising technique that allows the activity of populations of neurons contributing to a motor behavior to be measured noninvasively in embryonic zebrafish. Functional differences between primary and secondary motoneurons, described for behaviors such as swimming, are not observed with escape.
25.
Shiang R, Ryan SG, Zhu Y-Z, Hahn AF, O'Connell P, Wasmuth JJ: Mutations in the (xl subunit of the inhibitory glycine receptor cause the dominant neurologic disorder, hyperekplexia. Nat Genet 1993, 5:351-358.
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9. ••
Lee Y, Lopez DE, Meloni EG, Davis M: A primary acoustic startle pathway: obligatory role of cochlear root neurons and the nucleus reticularis pontis caudalis. J IVeurosci 1996, 16:3775-3789. Electrolytic and NMDA-induced lesions of structures previously implicated in the rat acoustic startle circuit reduce the apparent complexity of the network. The network may involve only three synapses, onto cochlear root neurons, neurons in the nucleus reticularis pontis caudalis (PnC) and spinal motoneutons, in agreement with a model based on intracellular recordings in the PnC [12].
26.
Rajendra S, Schofield PR: Molecular mechanisms of inherited startle syndromes. Trends Neurosci 1995, 18:80-82. comprehensive review that focuses on the molecular pathologies of the glycine receptor and their common motor consequences in various species.
13. ••
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Koch M, Lingenhohl K, Pilz PKD: Loss of the acoustic startle response following neurotoxic lesions of the caudal pontine reticular formation: possible role of giant neurons. Neuroscience 1992, 49:617-625.
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Levi R, Camhi JM: Distributing coordinated motor outputs to several body segments: escape movements in the cockroach. J Comp Physio/[A] 1995, 177:427-437.
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Eaton RC, Emberley DS: How stimulus direction determines the trajectory of the Mauthner-initiated escape response in a teleost fish. J Exp Bio11991, 161:469-487.
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18. •
Fay RR: Physiology of primary saccular afferents of goldfish: implications for Mauthner cell response. Brain Behav Evol 1995, 46:141-150. A review of studies demonstrating that sound transduced by the swim bladder produces equal stimulation of both sacculi in the goldfish. This suggests that initiation of the M-cell response requires a powerful input from the swim bladder, with directionality derived from smaller, disparate responses to particle motion. 19.
Kern H, Faber DS, Triller A: Convergence of morphological, physiological, and immunocytochemical techniques for the study of single Mauthner cells. In Handbook of Chemica/Neuroanatomy, vol 8. Edited by Bjorklund A, Hokfelt 1", Wouterlood FG, Van den Pol AN. Amsterdam: Elsevier; 1990:403-480.
20. •
Eaton RC, Canfield JG, Guzik AL: Left-right discrimination of sound onset by the Mauthner system. Brain Behav Evo11995, 46:165-179. Proposes the phase model for the goldfish escape, in which directionality is achieved by central processing of signals conveying information about the phase of the particle motion of a stimulus, as detected by hair cells of opposing orientations. In this model, inhibitory interneurons involved in feedfor'ward control of M-cell excitability have a critical role, as they decipher the phase difference and preferentially inhibit the 'wrong' M-cell. 21.
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Burrows M: Motor patterns during kicking movements in the locust J Comp Physiol [A] 1995, 176:289-305. S;mult~.neous in vivo recordings of movements from motoneurons controlling the hindlimb muscles producing the escape jump and kicks in locust. Variability of movements is related to the range of timing and the magnitude of de- and hyperpolarization of antagonistic motoneurons. 32.
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33. •
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Yeh S-R, Fricke RA, Edwards DH: The effect of social experience on serotonergic modulation of the escape circuit of crayfish. Science 1996, 271:366-369. Serotonin enhances responses at an identified synapse in dominant crayfish and reduces them in subordinate ones. First evidence that a neuromodulatot not only adjusts the gain of synapses in escape circuits but can have opposing effects depending on the animal's social experience. 39.
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Escape behavior - brainstem and spinal cord circuitry and function Henri Korn 1 and Donald S Faber 2 Recent work has demonstrated that the neural circuits mediating escape reactions in lower vertebrates and mammals have a common framework, with only two excitatory central synapses in the reflex arc. This relatively direct linkage from sense organs to muscles and the fact that segments of the network also transmit other motor commands help guarantee that escape always has priority over ongoing behaviors. Yet, modulation and plasticity contribute some variability to the expression of escape and, therefore, to the adequacy of its survival function.
Addresses l lnstitut Pasteur, Biologie Cellulaire et Moleculaire du Neurone, INSERM U 261, Departement des Biotechnologies, 25 rue du Dr Roux, 75015 Paris, France; e-mail: [email protected] 2Department of Neurobiology and Anatomy, MCP-Hahnemann University School of Medicine, Allegheny University of the Health Sciences, 3200 Henry Avenue, Philadelphia, Pennsylvania 19129, USA; e-mail: [email protected] Abbreviations C-start C-shaped contraction GABA y-aminobutyric acid LTP long-termpotentiation M-cell Mauthner cell NMDA N-methyl-o-aspartate PnC nucleusreticularis pontis caudalis
Current Opinion in Neurobiology 1996, 6:826-832 © Current Biology Ltd ISSN 0959-4388
Introduction The escape response, which can be observed in many vertebrates and invertebrates, has commonly been viewed as an abrupt and stereotyped reflex, triggered with minimal delay by a sudden, unexpected, and possibly aversive, stimulus. Because the escape response often involves an identifiable giant fiber, especially in invertebrate nervous systems that are accessible for single-cell recordings, it has been used for decades for correlating a behavior with the neural circuits that generate it and hence for analyzing the neural bases of sensorimotor interactions. Diverse escape reactions have been observed throughout the phyla, in species such as sea anemones, annelids, cockroaches, crayfish, rats, cats and humans [1]. As these activities have been dissected, several clarifications leading to new definitions have emerged. First, although speed is obviously required for such an adaptive response, not all escape responses are mediated by giant fiber systems. Further, when they are involved, such fibers may mediate only part of the reflex. Second, escape reactions take
different forms in different species and too often are ambiguously referred to as 'startle responses'. In fact, some startle reactions do not result in a translation of the body away from the threatening stimulus, a good example being that of humans whose response is primarily flexion, whereas in rodents, an initial extension can result in a jump. These differences would seem to distinguish the escape of lower species from that of higher vertebrates, in which the reflex is graded in amplitude and duration [2]. Intuitively, it would be expected that the complexity of the circuitry mediating this function would increase phylogenetically. However, as described in this review, recent progress indicates this is not the case. Furthermore, insights from work on lower vertebrates, namely fish, and from mammals such as rats are complementary, in part, because these species offer different technical advantages. Studies of these diverse systems indicate that these different behaviors all exhibit variability and plasticity, thus providing the basis for a convergent perspective on escape in all species. Neuronal components of escape Although little new information has emerged in the past two years about its circuitry and behavioral features, the escape reaction of goldfish remains one of the main references for studying vertebrate sensorimotor processing, primarily because of the involvement of a large identifiable reticulospinal interneuron, the Mauthner (M)-cell. In a freely swimming fish, activation of its M-cell causes a C-shaped contraction (C-start) of its trunk, which initiates predator avoidance and may be followed by a return flip (Figure la). M-cell activation can be evoked by auditory and possibly visual or lateral line stimuli, with a latency to movement onset as short as 10-15 ms. Invertebrate escape responses produced by different sensory modalities may utilize common central circuits [3]. Recently, it has been shown, through use of chronically implanted electrodes, that the fast body bend triggered by M-cell activation during an escape reaction also occurs during feeding, that is, during prey capture [4]. Thus, the same circuits and motor behavior may serve contrasting vital purposes, such as attack, evasion, and establishment of territorial boundaries.
Comparison of natural escape responses with those produced by direct M-cell stimulation suggested that one population of reticulospinal neurons, including the M-cell, triggers the first stage of the C-start while a second group of neurons may fire later, if the animal needs to correct its orientation [.5]. It was postulated that the second
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taps, but that, contrary to expectations, all motoneurons are synchronously active during escape responses [9°°].
Figure 1
T h e acoustic startle response described in mammals [2] differs from the goldfish escape response in that it is graded in amplitude with stimulus intensity and is bilateral. It consists of a characteristic sequence of movements that in rats includes an extension of the limbs that can cause jumping in non-habituated animals (Figure lb), followed by a generalized flexion that shortens the body. Interestingly, its latency is comparable to that of the C-start in goldfish. Numerous studies have been devoted to characterizing the pharmacological and behavioral mechanisms of control of this reaction, but there have been almost no investigations of its internal circuitry at the synaptic level.
Muscle 1996 Current Opinion in Neurobiology
The reflex arc of fish and rats. (a) Goldfish escape response and its analysis. (i) Silhouettes showing that as a ball is dropped into the water (Stimulus), the animal first turns away from the threat and then initiates a forward propulsion, possibly followed by a counter turn. The last image shows the location of the fish 50 ms after the end of the initial turn. (ii) Vectors designating the fish's midline orientation and position at selected times during the reaction, which are used to quantify the distance moved and the acceleration at successive stages. Adapted from [8]. (b) Acoustic startle response of the rat. Posture (i) at rest and (ii) after a noise burst. The reaction propels the animal off the floor of its cage. Adapted from [2]. (c) Excitatory reflex arc subserving both reactions. Hair cells drive first-order neurons, the axons of which contact reticulospinal neurons: the ipsilateral M-cell in fish, and neurons of the PnC in rats. The descending axons excite cranial and spinal motoneurons (Mns). The dashed lines indicate that the rat startle reaction is bilateral, and the plus (+) signs designate synaptic excitation.
group of neurons includes the Mauthner cell homologues described first in the zebrafish [6] and later in goldfish [7]. These predictions have recently been confirmed through use of in vivo confocal imaging of calcium transients in hindbrain neurons of larval zebrafish during escape responses (JR Fetcho, Y-H Kao, DM O'Malley, Soc Neurosci Abstr 1995, 21:687). This powerful method has further demonstrated that, as predicted [8], these reticulospinal neurons are differentially activated by abrupt head or tail
Initially, the acoustic startle response was thought to include a series of central relays, with the output of the last stage, the caudal pontine reticular formation (PnC), projecting to motoneuron pools [10]. Recent results obtained through use of standard electrophysiological tests [11] are consistent with this scheme. However, a simpler excitatory chain comparable to that already established in teleosts (Figure lc) is now favored. Apparently, a special class of auditory afferents, with their somata in the cochlear nucleus, project monosynaptically to the PnC [12,13°°]. Although the results obtained through use of neurotoxic lesions [14] and intracellular recordings [12] suggest that the postsynaptic targets of these auditory afferents are giant reticulospinal neurons, the results of work using more localized lesions implicate non-giant cells [13°°], leaving this issue unresolved.
Pre-motor processing Escape behaviors necessarily have high thresholds, and their short latencies leave minimal time for complex treatment of sensory information, such as assessing the location of a threatening stimulus relative to environmental parameters. Before initiating an escape response, an animal must decide upon the appropriate direction and magnitude of the movements required. In the cockroach, escape direction appears to be encoded within the brain by a group of giant interneurons that collectively dictate to each thoracic ganglion where to move the pair of legs it innervates [15]. In other species, this information may be specified by the neuron(s) that reach threshold for action potential initiation, such as the left or right M-cell in the case of teleosts. A puzzle is that goldfish escape is directional [16], even though the swim bladder, the main organ for transducing sound pressure, activates both ears simultaneously. An important theoretical controversy has emerged around this issue. Although there ate still questions about which end-organs project to the M-cell [17], one view is that the M-cell can detect small deviations of its excitatory inputs from a perfect interaural correlation [18°], whereas the other
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view assigns a critical role to the inhibitory interneurons that mediate feedforward inhibition of the M-cell [19] and that are postulated to decode phase differences in afferent activity [20°]. In either case, it is clear that central processing is critical for decision-making in the escape response, and the same may be true for the acoustic startle response.
Inhibitory systems Proper execution of an escape response requires that muscles antagonistic to the effectors are not co-activated, and it has been recognized that this is the role of spinal inhibition. Glycinergic inhibition of reticulospinal neurons has been directly demonstrated in the goldfish through use of electrophysiology and immunocytochemistry [19], and it has been recently characterized in the embryonic and adult zebrafish ([21]; H Korn, N Ankri, K Hatta, G Rao, RC Eaton, abstract, Zebrafish Development and Genetics meeting, Cold Spring Harbour, April 1996, page 174). Patch clamp studies in zebrafish embryos [22] have confirmed previous conclusions from adult goldfish [23] that the mean open time of glycine-activated channels increases with depolarization, making inhibition more effective near threshold. In mammals, evidence for a role for glycine in acoustic startle has been obtained in rats after systemic injections of strychnine [24] and, more importantly, through molecular genetics. A mutation in the gene encoding the c~l subunit of the human glycine receptor results in a decreased affinity for glycine, thereby causing an exaggerated startle reflex termed hyperekplexia [25]. This syndrome or 'startle disease' is dominated by sudden jumps and excessive flexions of the neck and trunk in response to acoustic and tactile stimuli. Similar disorders are found in a number of mammals [26"], notably two mutant mouse strains, spasmodic and spastic, which are generated by alterations to the c~l and 13 subunits of the glycine receptor, respectively. In the spastic mouse, receptor number, not sensitivity, is decreased, demonstrating that diverse mutations can produce similar physiological syndromes. Another interesting observation is that the change in the structure of the human c~l subunit disrupts the transduction process [27,28] and may make the glycinc receptor sensitive to GABA [29], which could partially compensate for the deficit in the glycinergic control of startle responses. Recent results from work on inhibitory mechanisms in zebrafish, coupled with the advantages of this species for genetic studies, indicate that the zebrafish is a tractable system for developing new approaches for treating syndromes caused by glycine receptor dysfunction, particularly since both glycine and GABA operate on M-cell circuits [19].
Shared spinal cord circuits Given its vital purpose, an escape response must have priority over ongoing activity, once the 'behavioral decision'
is reached. This notion is exemplified in invertebrates such as the sea slug Pleurobranchaea, in which impulses in one neuron both initiate escape swimming and suppress feeding [30]. However, the same cell(s) may actually be integral to multiple movements with different functions, such as in the locust, in which kicking and jumping (which serve escape and repulsion of adversaries, respectively) use similar motor patterns that are generated by common flexible networks [31"]. T h e M-cell system is a good model for analyzing this functional switch (Figure 2), as already shown by simultaneous kinematic and electromyographic evidence that the performance of the escape reaction is unaffected in unrestrained fish, regardless of the swimming phase during which it occurs [32]. In addition, direct intracellular stimulation of the M-cell axon during fictive swimming not only overrides alternating bursts in motor nerves innervating both red and white muscles, but later resets the swimming rhythm [33°]. T h e similarities between the escape and swimming circuits suggest that activation of commissural inhibitory interneurons by the dominant M-cell turns off competing motor commands. It has been proposed that the rapid spread of this inhibition, which synchronously blocks motor units throughout one side of the body, provides a new raison d'~.tre for the large diameter of the M-axon and of other reticulospinal neurons [34].
Plasticity and modulation It is becoming progressively clear that the escape reaction is not stereotyped in all species and that both its threshold and pattern of execution are modified by internal and external signals acting on central circuits (Figure 3). This is apparent in invertebrates, such as the cockroach [35,36] and crayfish [37°',38"]. In the latter, habituation of the tailflip is attributable to activation of a tonic inhibition from higher centers rather than, as previously believed, to intrinsic depression of the synapses in the network [37°°]. More provocative is the fact that a crayfish's social status determines whether serotonin is a positive or negative modulator of its escape circuit [38"]. In fish, serotonergic and dopaminergic terminals have been identified in the vicinity of the M-cell; the corresponding amines increase inhibitory [19] and excitatory [39] transmission onto this neuron, albeit by acting at distinct synaptic sites. T h e most promising advance in the past few years, however, has been the realization that synaptic strength is dependent on previous experience at the level of the initial stages of sensory processing that control the reflex threshold and its directionality [40,41°,42,43",44°]. Both the electrotonic and chemical components of the 'mixed' excitatory connections between primary eighth nerve afferents and the Mcell lateral dendrite undergo tetanus-induced long- and short-term potentiations that have N M D A receptor and calcium dependencies comparable to those reported for
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Spinal circuits shared by different motor behaviors in fish, and reconfiguration of network activity by reticulospinal commands as escape overrides swimming. Fish silhouettes, at the indicated times, (a) during swimming and (b) during the first stage of an escape triggered at 0 ms by an object thrown in the water. Darkened lateral areas represent the dominant red and white muscle activity. Adapted from [32]. Two segments (caudal and rostral, separated by horizontal dashed line) of the network used in each case are shown next to the silhouettes, with the M-cell and its connections superimposed on the right-hand panel (b). Escape priority is imparted by the M-cell's excitation of inhibitory commissural interneurons ((31), which guarantee that only one side of the spinal cord will be activated. Other active neurons and muscles are shaded in light gray. P~us (+) and minus (-) signs indicate the direction of synaptic action, which is chemical or electrical (e), the latter occurring without delay. Shading designates neurons that are activated. DI, descending interneuron; Mn, motoneuron. Adapted from [50].
hippocampal long-term potentiation (LTP) [40,41°]. These effects tend to decrease the threshold for M-cell activation, which can also be upregulated by tetani that trigger both long-term depression of the same junctions [42] and LTP of the glycinergic inhibitory synapses on the cell's soma [43"°]. T h e inhibitory LTP can be induced by tone bursts, indicating it may be functionally relevant (Y Oda, A Morita, K Kawasaki, H Korn, abstract B351, 4th IBRO World Congress, Kyoto, July 1995). Paired pre- and postsynaptic recordings, with reliable identification of the inhibitory interneurons, have revealed that this LTP is, in part, expressed presynaptically, as shown by quantal analysis [43°°], and that there is a reserve pool of latent connections that become effective after the tetanization [44°]. Studies of plasticity in the acoustic startle paradigm have focused on its potentiation by conditioned fear, a
model for associative learning. In this paradigm, a neutral conditioning stimulus, such as a tone, acquires aversive properties and enhances the startle response after it has been associated with an unconditioned electrical shock. Modulation of the startle response occurs in the amygdala [2], which, in turn, regulates transmission in the reflex pathway (Figure 3).
In confirmation of this finding, it has been found that brief trains of stimuli applied to the medial geniculate body, which has a monosynaptic input to the amygdala, result in a long-lasting potentiation of the field potential evoked in the latter by acoustic stimuli [45]. Furthermore, in freely moving rats, fear conditioning significantly increased the responsiveness of neurons in the lateral nucleus of the amygdala to tones and converted unresponsive cells into tone-responsive ones [46]. This last observation underlines
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Figure 3
Sites of synaptic plasticity in the escape networks of (a) fish and (b) rats. In both species, activity-dependent modifications of synaptic efficacy have been demonstrated at the junctions highlighted on the diagrams by thick gray arrows or by bold lettering. The direction (+,-) of synaptic action is as for Figure 2, and e and c designate mixed electrical and chemical contacts, respectively. Only excitatory connections are shown in (b) because the internal circuitry has not been investigated. In fish, plasticity has been found at all levels of its escape circuitry, whereas in mammals, only modulation of the reflex arc that is mediated through the amygdala has been described. CRN, cochlear root neuron; CS, conditioned stimulus; Int, commissural interneurons; M, Mauthner cell; US, unconditioned stimulus; VIII, auditory afferents. See also Figure 1.
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the contribution of silent connections to the expression of LTE
Conclusions The need to quantify motor performance may have obscured the diversity of escape behaviors by restricting the types of behaviors that can be studied, such as the rapid response of a fish to a dropped ball or of a rat to a loud tone. The common definition of escape, also used here, excludes alternative forms of escape, such as the slower and more prolonged reaction of the channel catfish [47], a restriction that may hide the involvement of the same circuit elements. Conversely, the concept of shared networks may need to be refined, because the functional role(s) of some of their components may be specified to a greater extent than assumed.
case, the similarities in the reticulospinal networks of distantly related lower and higher vertebrates underline the relevance of the model systems in fish for further studies of neuronal activity during the control of motor performances. New techniques, such as transneuronal labeling of functionally related circuits of neurons [48"], in vivo imaging of activity-related cell populations [9°°] and genetic manipulations [49], are particularly suited for this type of investigation, especially in zebrafish. Interest in the circuitry of escape behavior has been somewhat restricted, because of the limitations of using electrophysiological techniques alone, but it should be revived by the opportunities provided by these new approaches.
Acknowledgements We thank Robert Eaton and Joe Fetcho for helpful discussions on this topic.
A general feature of the escape and acoustic startle reactions is their variability, which could be explained by numerous factors, including the number of responsive cells, the balance between excitation and inhibition that determines threshold for spike generation, and, although not yet documented, the intensity of the ongoing motor activity that must be superseded. This variability has a clear adaptive advantage, as even predator avoidance (or attack) would be degraded if executed in a predictable manner.
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