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In all but the simplest monosynaptic reflex arcs, sensory stimuli are encoded by sensory neurons that transmit a signal via sensory interneurons to downstream partners in order to elicit a response. In the embryonic zebrafish (Danio rerio), cutaneous Rohon-Beard (RB) sensory neurons fire in response to mechanical stimuli and excite downstream glutamatergic CoPA (commissural primary ascending) interneurons to produce a flexion response contralateral to the site of stimulus. In the absence of sensory stimuli, zebrafish spinal locomotor circuits are spontaneously active during development due to pacemaker activity resulting in repetitive coiling of the trunk. Self-generated movement must therefore be distinguishable from external stimuli in order to ensure the appropriate activation of touch reflexes. Here, we recorded from CoPAs during spontaneous and evoked fictive motor behaviors in order to examine how responses to self-movement are gated in sensory interneurons. During spontaneous coiling, CoPAs received glycinergic inputs coincident with contralateral flexions that shunted firing for the duration of the coiling event. Shunting inactivation of CoPAs was caused by a slowly deactivating chloride conductance that resulted in lowered membrane resistance and increased action potential threshold. During spontaneous burst swimming, which develops later, CoPAs received glycinergic inputs that arrived in phase with excitation to ipsilateral motoneurons and provided persistent shunting. During a touch stimulus, short latency glutamatergic inputs produced cationic currents through AMPA receptors that drove a single, large amplitude action potential in the CoPA before shunting inhibition began, providing a brief window for the activation of downstream neurons. We compared the properties of CoPAs to those of other spinal neurons and propose that glycinergic signalling onto CoPAs acts as a corollary discharge signal for reflex inhibition during movement.

1. Overview . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 2. Autonomic visceral afferent neurons . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 3. Divisions of the ANS. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 4. Organ to organ connections, not through the CNS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 5. Local ganglia with possible intrinsic connections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 6. Mixed ganglia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 7. Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

The effects of acoustic stimuli whose onsets and durations were controlled to vary their transient and sustained features on the size of a subsequently elicited blink reflex were examined in humans. Prestimuli both with and without transient features inhibited the reflex when they preceded the eliciting stimulus by brief lead intervals, showing that acoustic transients are sufficient, but not necessary, for reflex inhibition. Inhibition evoked by transient and sustained stimulus features showed partial summation, and inhibition evoked by stimuli with only transient and with transient and sustained features showed similar decay functions with increasing lead intervals. Blink augmentation was found at longer lead intervals early but not late in a session, and was more evident in women than men. Prestimuli with only transient features were more effective than those with both transient and sustained features, showing that sustained stimulus energy at the time of reflex elicitation is not only not necessary for blink augmentation, but also diminishes it.

T his focus article by Gebhart and Randich provides a thorough review of recent experimental findings that support the hypothesis that vagal afferent stimulation (VAS) modulates nociception. In this brief commentary, I address a few of the major issues discussed by the authors and suggest some additional areas that merit investigation. The authors have reviewed the experimental findings that cervical vagal electrostimulation modulates (i.e., either inhibits or facilitates) spinally mediated nociceptive reflexes and the responses of spinal neurons to noxious stimuli in the rat. Although there is general agreement among investigators that cervical vagal electrostimulation produces both inhibitory and facilitatory effects, few studies have investigated the anatomical origin of the vagal afferents that contribute to either the inhibitory or the facilitatory responses produced by cervical vagal electrostimulation. My laboratory has recently addressed this issue. Using a different experimental model and species, we also have demonstrated that cervical vagal electrostimulation produces either facilitation or inhibition of the digastric reflex produced by electrical stimulation of the tooth pulp in anesthetized cats2 Similar to the findings reviewed in this focus article, the modulatory effects are independent of cardiovascular responses produced-by vagal stimulation. 3.9 Reflex facilitation is observed when the interval between vagal conditioning and tooth pulp stimulation is less than 20 ms while reflex inhibition was observed when conditioning test intervals are between 100 ms and 500 ms. Similar findings have been obtained by Chase and co-workers. 4,s We also demon

In conscious humans, fatiguing muscular contractions are accompanied by a decrease in the discharge rate of alpha motoneurons. The association between alpha motoneuron discharge rate and the generation of force by skeletal muscle has been called “muscle wisdom” (Marsden et al., 1983). Its purpose is believed to ensure that central neural drive to skeletal muscle, which is fatigued, matches that needed to generate the required force. In addition, muscle wisdom may be one mechanism that functions either to decrease or to postpone central neural fatigue (Enoka & Stuart, 1992). Bigland-Ritchie and colleagues (1986) have suggested that a reflex arising from fatigued skeletal muscle is responsible, at least in part, for muscle wisdom. This chapter has two purposes. The first is to evaluate the evidence that a reflex arising from fatigued skeletal muscle causes muscle wisdom, and the second is to examine the discharge properties of muscle afferents to determine which ones are most likely to initiate reflexly this phenomenon.

Reflex modification is a psychophysical technique based on the phenomenon that the response to a reflex-eliciting stimulus is changed in amplitude by the prior presentation of a neutral prestimulus. This technique provides reliable data on hearing thresholds both in quiet and in noise for anuran amphibians. Potential difficulties with the reflex modification technique include variability in the effectiveness of the reflex-eliciting stimulus, individual variability between animals, variability in the slopes of psychometric functions, and the small size of reflex modification effects in anurans.

Crayfish claw proprioceptors and slow closer exciter and opener inhibitor motor neurons were monitored simultaneously during imposed claw displacements. With increasing displacement velocity and decreasing joint angle, the activity of closing sensitive receptors increased, while dynamic-static opening sensitive receptor activity decreased during claw closing. Motor neuron activity evoked by claw opening varied inversely as a function of preceding closing velocity, and directly with preceding pause duration at the closed position. This dependence on closing history cannot be accounted for by changes in opening sensitive receptor activity. Data demonstrate that closing sensitive receptors can suppress excitatory interactions between claw proprioceptors and motor neurons.

Interneurones located in the circumoesophageal commissures were found to control the activity of the cardioinhibitor and cardioaccelerator regularity neurones. These interneurones (cardiac command fibres) fell into three classes: (1) strong inhibitors, which caused cardiac arrest, (2) weak inhibitors, which caused bradycardia, and (3) accelerators, which caused tachycardia. When the positions of interneurones were plotted collectively, they formed distinct clusters, suggesting that each cluster was represented by one command unit in an individual preparation. Twenty strong inhibitor units and 16 accelerator units were found. Weak inhibitors did not form clusters. Stimulus threshold characteristics were as low as 3·0 V and 3 Hz for the strong inhibitor units (mean range 4·7−7·1 and 14−V 30 Hz). Higher values were found for weak inhibitors and accelerators. The strong inhibitor command drives always showed a positive bias toward the contralateral cardioinhibitor neurone, relative to the ipsilateral cardioinhibitor. Plots of command neurone stimulating frequency versus evoked cardioinhibitor activity displayed steep positive slopes for strong inhibitor command units and shallow positive slopes for weak inhibitor units. Reciprocity between the cardioinhibitor and cardioaccelerator neurones occurred during both inhibitory and acceleratory command drives. This is not likely to be a property inherent in the command units themselves because reciprocity was earlier observed during chemical and tactile reflex inhibition of the heart. (Field & Larimer, 1974a).

Reflex inhibition was investigated in young and elderly subjects as a function of prestimulus duration. In Experiment 1, tone prestimuli of 20 and 200 msec duration were presented at ISIs of 60, 120, 240, and 420 msec before the reflex-eliciting, periorbital airpuff. Both age groups evidenced more eyeblink inhibition with the longer prestimulus. The heart rate response was primarily decelerative in both age groups. In young subjects, the initial deceleration was augmented by the prestimulus, particularly for the 200-msec prestimulus, whereas the elderly heart rate response was unaffected. In Experiment 2, a gap in a continuous tone served as the prestimulus. In both young and elderly subjects, eyeblink inhibition increased as gap duration increased from 10 to 80 msec. The longest gap (120 msec) produced the most inhibition in the elderly, while inhibition decreased somewhat in young subjects between the 80 and 120 msec gaps. Heart rate was not affected by the gap prestimuli in either group. It was proposed that reflex inhibition is, in part, a function of the onset and offset transients of the prestimulus. As prestimulus duration is increased and, consequently, the two transients become more separated in time, their effects upon the reflex may become progressively more independent. The discrepancy between the PS effects upon eyeblink and HR in the elderly is probably due to a decline in HR response plasticity rather than central nervous system processes involved in reflex inhibition.

In a paper on “Antagonism between Reflex Inhibition and Reflex Excitation,” Sherrington has shown that the combined effects of excitatory and inhibitory stimuli produce a response intermediate between those of the two stimuli acting singly. Prof. Cannon, of Harvard, called my attention to certain minute oscillations which occur in Sherrington’s myograph line where it represents the response of muscle to the combined effects of the opposed stimuli, and suggested that these might have an important significance. They might mean that the nerve impulses in breaking through the opposition imposed by inhibition were subjected to a condition analogous to a stream of air passing out from a tube under water. It seemed possible that just as the air bubbles will be larger and more infrequent if the opening of the tube be deeply submerged than if near the surface, so the nerve impulses might be rendered more intense and more infrequent in overcoming the opposing influence of inhibition. On account of the impossibility of recording nerve impulses with the myograph I have planned to investigate the question by electrical methods. But in the course of another series of experiments I have obtained records whose bearing on the problem renders them of interest.

In freely-moving cats stimulation of the orbital gyrus of the cerebral cortex induced jaw activity which was analyzed on a behavioral and neurophysiologic basis. Repetitive orbital cortical stimulation led to sequential cycles of jaw opening and jaw closure. The frequency of this cycle was not time-locked to the frequency of stimulation, but was within the range of normal masticatory movements. The masseteric and digastric reflexes were monitored during orbital stimulation; their amplitude varied according to the cycle of masticatory activity. During jaw opening the masseteric reflex was inhibited and the digastric reflex was facilitated. Reciprocal changes took place during the jaw-closing phase. In conjunction with single pulse train stimulation of the orbital cortex, masseteric reflex inhibition was observed at cortical conditioning-test response intervals of approximately 8–20 msec, and was followed by a facilitatory phase lasting for about 60 msec. During these time periods the digastric reflex showed reciprocal changes, i. e. initial facilitation followed by long-lasting inhibition. Orbital cortical stimulation evoked activity in the muscle at a latency of approximately 10 msec. The effects of cortical stimulation were compared with masseteric reflex inhibition induced by stimulation of the inferior dental nerve before and after anesthetization with sodium pentobarbital. Anesthetization abolished the cortical effects but had relatively little effect on the inhibition of the masseteric reflex induced by inferior dental nerve stimulation. Digastric and masseter responses to orbital stimulation in the freely-moving cat were compared with previous descriptions of intra- and extracellular responses in the immobilized preparation.

Experiments were performed on cats. It was established that when evipan-sodium (arpal) acts on intestinal interoceptors there is usually a reflex inhibition of the cortical motor effects and “spontaneous” motor activity of the animal (in 22 cases out of 38). The dependence of this effect on the initial functional condition of the central nervous system and the dose of narcotic introduced was studied.

In further prosecution of observations made in Ludwig’s laboratory by Schmiedeberg and by Bowditch, N. Baxt in 1875 carried out in that laboratory a prolonged enquiry into the effect produced on the heart’s frequence by combined stimulation of the inhibitory ( vagus ) and accelerator ( accelerans ) nerves going to that organ. His observations were made on large dogs; the two nerves were faradised simultaneously. In most of his experiments, stimulation of accelerans preceded that of vagus by a few seconds, to allow for the well-known longer latency of the former’s reaction; the precurrent stimulation of accelerans alone was immediately followed by stimulation of both nerves simultaneously. Baxt found the rate of heart-beat under the combined stimulation slowed as though the vagus only and no accelerator was in operation; but, immediately following on cessation of the combined stimulation, a full accelerator effect appeared, as though no stimulation of the vagus had taken place. Baxt employed usually minimal stimulation of vagus and maximal of accelerans , for he found minimal excitation of vagus suffice to set aside completely, for the time being, maximal excitation of accelerans . In his hands, the result of the combined stimulation was vagus action, even when weakest, completely obscuring accelerans action even at strongest; but although the accelerans action showed no trace of its existence during the vagus stimulation, it appeared in full force after the vagus action had passed off. The vagus action, therefore, did not destroy it, but merely postponed its appearing. Baxt drew the conclusion that the inhibitory nerve and the excitatory nerve must act on separate points in the heart’s mechanism and are not true antagonists. This view has since been endorsed by many, but is not that of v. Cyon, the discoverer of the accelerator . Another field for examination of the same problem was chosen by v. Frey. He investigated the effect on the venous flow from the sub-maxillary gland of simultaneous stimulation of the vaso-constrictor ( cervical sympathetic ) and the vaso-dilatator ( chorda tympani ) nerves. The dilatating influence of the chorda proved to be completely overpowered by the constricting effect of the sympathetic during combined stimulation of the two. But on discontinuing the combined stimulation there ensued from the vein a markedly excessive blood-flow, i. e ., a marked chorda action ensued as an after-effect. The action of the sympathetic had, therefore, not destroyed the action of the concurrently excited chorda, it had only postponed its appearing, v. Frey, with his customary clearness, wrote: “the antagonism between constrictor and dilatator has not as its basis a simple summing of two forces which act in opposite direction at the same point of application.” The sympathetic prevails entirely for the time being as regards the surface effect, but the chorda nevertheless develops with regular course the change characteristic of its action, and does so “in some part of the excitable apparatus protected from the attack of the sympathetic: only in some other place do the actions of the two collide.”

Stimulation of an afferent limb-nerve in the decerebrate or decapitate mammal (cat, dog) gives as its reflex result flexion of that limb; during this flexion the pure extensor muscles of the limb relax under central inhibition. In the hind limb this reflex effect is observable in the isolated vasto-crureus, the main extensor muscle of the knee; that muscle if engaged in contraction relaxes when the afferent nerve is stimulated. Its elongation is the sign of the central inhibition which takes place. If the reflex stimulation be strong the muscle relaxes quickly and greatly; if the stimulation be weak the relaxation is slower and less ample. These results are easily demonstrable by using as a stimulus either faradism or mechanical stimulation such as ligation of the central stump of the afferent nerve. Usual and uniform as this result is, we find it possible in the decerebrate preparation under certain conditions to obtain reflex contraction of vastocrureus as well as reflex inhibition, and to elicit the contraction through the same afferent nerves as under other conditions so regularly elicit inhibition. The condition influencing the nature of the reflex result in this respect are (1) the strength and (2) the form of the electrical stimulus applied to the afferent nerve, and (3) the reflex state obtaining in the preparation at the time.

It was shown in previous notes of this series that in the “flexion-reflex” of the limb the reflex inhibition of the extensor muscles is frequently followed by contraction of them. This contraction ensues immediately on cessation of the inhibitory stimulus, and is often more accentuated than was the contraction originally inhibited. The phenomenon was ascribed to a process of rebound in the central of the nervous are inhibited, and this process, on account of its seeming analogy with certain visual phenomena often called “inductive,” was termed “successive induction.” The occurrence of this “successive induction” made it seem probable that under favourable conditions the reflex evoked in the limb by a single stimulus would be diphasic with a first phase of flexion followed by a subsequent phase of extension. The following observations show that this is in fact the case, and under appropriate conditions regularly so.

If we attempt to decipher the biological meaning of reciprocal innervation its various instances when marshalled together say plainly that one of the functional problems which it meets and solves is mechanical antagonism. Where two muscles have directly opposed effect on the same lever, “reciprocal innervation” is the general rule observed by the nervous system in dealing with them, and this holds whether the reciprocal innervation is peripheral as with the antagonists of the arthropod claw, or is central as with vertebrate skeletal muscles. Also where one and the same muscle is governed by two nerves influencing it oppositely, reciprocal innervation seems again the principle followed in the co-ordination of the two opponent centres, as has been shown by Bayliss in his observations on vasomotor reflexes. But the distribution and occurrence of reciprocal innervation extend beyond cases of mere mechanical antagonism. The reflex influence exerted by the limb-afferents on symmetrical muscle-pairs such as right knee-extensor and left is reciprocal. Thus right peroneal nerve excites the motoneurones of left vastocrureus, and concomitantly inhibits those of the right. The reflex inhibition of the one is concurrent with, increases with increase, and decreases with decrease of, the excitatory effect on the other. Here the muscles are not in any ordinary sense antagonistic; not only do they not operate on the same lever, but they are not even members of the same limb, nor do they belong even to the same half of the body. They are, however, actuated conversely in the most usual modes of progression—the walking and the running step—though not always in galloping.

The eyeblink reflex to a corneal airpuff was elicited on 10 occasions: 5 times preceded by a light flash at an interval of 100 msec and 5 times by itself. The amplitude of the reflex was inhibited by the light flash, an effect which was evident on the very first trial but increased in strength with further testing. That inhibition was obtained prior to the subject’s having had any experimental experience with the stimulus conditions indicates that inhibition does not depend on an associative conditioning process. The subsequent enhancement of the effect, which has been seen previously with rats, may reflect the modulation of inhibition by the subject’s state of alertness or arousal.

An acoustic stimulus (S1) presented just before reflex elicitation inhibits reflex expression. The present studies questioned whether inhibition provided by initial stimuli of various durations conforms to established temporal integration functions. Initial stimuli were noise bursts varying in duration (2, 20, or 200 msec) and intensity (55 or 85 dB). Eliciting stimuli (S2) for rats were intense tone bursts, which elicited the acoustic startle reflex, and for humans electrotactile stimuli to the forehead, which elicited the eye blink. Findings revealed that inhibition was greater with the 85-dB S1 stimulus and increased linearly with log increases in duration. These latter data suggest that the acoustic substrate for reflex inhibition has a long-time constant. There was one exception to this general finding. For seven (of nine) human subjects, inhibition declined when the duration of the 85-dB S1 was increased from 20 to 200 msec. Postexperimental questioning and video monitoring suggest that this anomaly resulted from a reflex enhancing arousal process.

The “size principle” is known to dictate the sequence of recruitment of motor neurons during voluntary or reflex activation of muscles. The present study sought to determine whether the size principle also determined the sequence of reflexly-elicited inhibition of motor neurones. It was found that all masseter motor units were about equally inhibited by a mildly-noxious stimulus to the lip, providing that they were tested at the same level of pre-stimulus excitability, i.e., firing frequency. At higher prestimulus firing frequencies, more intense stimuli were required to inhibit motor unit activity. Thus it is the firing frequency of individual motor neurones, rather than their size, which determines their susceptibility to inhibition.

Publisher Summary The orbital surface of the frontal lobe appears to be unique in its capacity for inhibiting both somatomotor and visceromotor activities. Electrical stimulation of the orbital surface of the frontal lobe can induce states of behavioral inhibition and the onset of sleep. Electrical stimulation of the orbital-frontal cortex inhibits a brain-stem monosynaptic reflex as well as spinal reflexes. Both pre- and postsynaptic inhibitory processes play a role in cortically produced reflex inhibition. This chapter illustrates the role of the brain stem in orbital cortically evoked changes of somatic reflexes in the cat. Orbital cortically induced inhibition of the monosynaptic masseteric reflex depends upon the integrity of the ventromedial bulbar reticular formation.

The startle reflex to intense acoustic stimuli and its inhibition by light and sound prepulses was examined before and after septal, amygdaloid or hippocampal lesions or control procedures. There was no effect of limbic damage on acoustic startle or its inhibition. Lesions which included damage to the optic tracts or lateral geniculate nucleus abolished the light prepulse produced inhibition of startle but left auditory prepulse produced inhibition unaffected.

The eyeblink reflex to a corneal airpuff was elicited on 10 occasions: 5 times preceded by a light flash at an interval of 100 msec and 5 times by itself. The amplitude of the reflex was inhibited by the light flash, an effect which was evident on the very first trial but increased in strength with further testing. That inhibition was obtained prior to the subject’s having had any experimental experience with the stimulus conditions indicates that inhibition does not depend on an associative conditioning process. The subsequent enhancement of the effect, which has been seen previously with rats, may reflect the modulation of inhibition by the subject’s state of alertness or arousal.