Trigeminal influences on entopeduncular units

Brain Research, 141 (1978) 227-234 ~f~) Elsevier/North-Holland Biomedical Press

227

T R I G E M I N A L I N F L U E N C E S ON E N T O P E D U N C U L A R UNITS

T. I. LIDSKY, J. H. ROBINSON, F. J. DENARO and P. M. WEINHOLD Department o] Psychology, State University o/ New York, Stony Brook, N.Y. 11794 (U.S.A.)

(Accepted May 25th, 1977)

SUMMARY Because considerable work has implicated the basal ganglia in oral-ingestive behavior, an assessment was made of the effects of trigeminal stimuli upon entopeduncular single units. Units were recorded extracellularly in awake, paralyzed and locally anesthetized cats. The effects of two types of sensory input were tested. Afferents from periodontal mechano-receptors involved in reflex jaw opening were stimulated via electrodes in the inferior dental nerve. Afferents from stretch receptors involved in reflex jaw closure were stimulated via electrodes in the trigeminal mesencephalic nucleus. A significant proportion of cells responded to both types of stimulation. The data were discussed in the context of a basal ganglionic role in oropharyngeal motor processes and a more general role in movement per se.

INTRODUCTION Data from ablation1,11,13 and stimulation',V, 19 studies suggest that the basal ganglia have an important role in oropharyngeal processes. This suggestion was underscored by recent work demonstrating that a large proportion of pallidal and entopeduncular neurons show changes in activity during ingestion12,16. In addition, tactile stimulation of the vibrissa and perioral areas greatly affected ingestion-related neurons in the entopeduncular nucleus r'. The purpose of the work described in this report was to extend previous observations of basal ganglia neuronal concomitants of oropharyngeal processes. In the present research, an assessment was made of the extent to which entopeduncular neurons are affected by sensory stimuli that are involved in the control of jaw movements. Afferents (1 A) from jaw elevator stretch receptors were stimulated via electrodes in the tract of the trigeminal mesencephalic nucleus. Activation of these fibers evokes a monosynaptic jaw closing myotatic reflex (masseteric reflex, MR) 6. In addition, afferents from periodontal mechanoreceptors were stimulated via electrodes in the inferior dental nerve (containing A/3 and A6 axons). Activation of these axons evokes a polysynaptic jaw-opening reflex (digastric reflex,

228 DR) and inhibition of jaw closure motor neurons 6. Thus, via stimulation of these two loci, the neuronal correlates of both jaw opening- and also jaw closing-related stimuli were tested. METHODS

Surgery Experimental subjects were adult cats (2.2-4.2 kg). Surgery was performed with the animal under general anesthesia (sodium thiamylal) delivered through an intravenous cannula in the femoral vein. The trachea was cannulated for artificial respiration and a pneumothorax was performed to minimize respiratory-induced brain movements. Electrodes, constructed from stainless steel screws, were threaded into the ventral surface of the mandible for stimulating the inferior dental nerve (inf. dent. n.). The exposed outer surface of these screws was insulated to prevent current spread to adjacent cutaneous tissue. Afferents from jaw elevator stretch receptors were stimulated by bipolar electrodes (side by side o - o insect pins insulated except for 0.5 m m at the tips) implanted bilaterally into the tract of the trigeminal mesencephalic nucleus (rues. nuc.). Position of the electrode was adjusted so that minimal stimulating currents evoked the MR. The M R and D R were monitored via stainless steel E M G electrodes inserted in the masseter and digastric muscles. A bipolar stimulating electrode was implanted in the caudate nucleus. This electrode was used to observe striato-entopeduncular evoked unit responses. In several animals, a multiple unit recording electrode was stereotaxically positioned in the trigeminal root. Recordings were used to verify the occurrence of reflex activity after paralysis. The tracheal cannula was fixed in place to prevent movement-induced aversive effects, in addition, the animal's head was immobilized with a head holder t2 that obviated use of earbars and eyepieces, thereby eliminating potential sources of noxious pressure. PupiUary indicants showed that animals slept throughout the experiment unless stimulated by touch or loud noises. Following surgery, cats were paralyzed with gallamine triethiodide and artificially ventilated. All wound margins were infiltrated with local anesthetic (xylocaine). Local anesthetic was readministered periodically during the course of the experiment.

Stimulation and recording Electrical stimulation was monophasic square wave pulses (duration 0.5 msec) used either in single pulses or in short trains (within train frequency I00 Hz, train duration 50 msec). Because of the possibility of current spread when stimulating the tract of the trigeminal mesencephatic nucleus and the additional possibility of inducing noxious effects (from activation of high threshold pain fibers) in the inferior dental nerve, stimulation intensities were adjusted (prior to paralysis) to between threshold and never greater than 1.5 times threshold for elicitation of the M R a n d DR. Gustatory responsiveness was also tested in a number o f cells. 0.25 MNaC1 was ejected onto the tongue with a syringe and distilled water was similarly ejected as the wash solution.

229 Extracellular potentials were recorded with glass micropipettes (electrolyte 1.6 M potassium citrate) and amplified by a high input impedance amplifier (frequency 300 Hz-10 kHz). Activity was displayed on a storage oscilloscope and recorded on FM tape for later analysis. Poststimulus histograms were constructed with a raster maker and a laboratory computer. Except in cases in which unit responses were clearly timelocked to consecutive stimulus presentations (Fig. 2D), validity of responses was determined by comparing poststimulus histograms to histograms constructed from control (non-stimulation) periods. Differences of at least 3 standard deviations from the mean control rate were defined as responses. Increases in rate were termed 'excitatory' and decreases were termed 'inhibitory' - - responses thus classified were done so for ease of description with no implication of underlying synaptic mechanisms. Histology

At the completion of the experiment, the animal was again deeply anesthetized. The tip of the recording electrode was broken off and the larger diameter shaft was driven into the brain to make a visible track. The recording electrode was then replaced with a stainless steel electrode and marking lesions were made for histological study. RESULTS Histology

Units were recorded throughout the anatomical extent of the entopeduncular nucleus. All entopeduncular cells (84 units) were localized to the area between AP levels 10.5 and I 1.517. An additional 23 units were localized in the indistinct boundary between the entopeduncular nucleus and internal capsule. These cells were separately classified as 'border units'. The properties of these border units did not differ from those of entopeduncular cells. Mes. nuc. stimulation points were located in the trigeminal mesencephalic nucleus and more posteriorly in the tract of the trigeminal mesencephalic nucleus. These minor AP differences in stimulation loci did not produce differences in the patterns of evoked neuronal responses. Evoked unit responses

Trigeminal stimulation had pronounced effects upon the firing rates of many TABLE | Proportion of entopeduacular cells responsive to trigeminal sthmdation No. units sampled No. ~nits responsive (%)

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84 79 79 79

54 29 24 21

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Fig. 1. The upper histogram shows the distribution of response latencies of 29 cells driven by inf. dent. n. stimulation. The lower histogram shows the distribution of response latencies of 54 cells driven by rues. nuc. stimulation.

entopeduncular neurons (Table I, Figs. 2 and 3). Stimulation of the mes. nuc. evoked responses in more units (64~,,) than did stimulation of the inf. dent. n. (37~). Excitatory responses were observed as frequently as were inhibitory responses. Excitatory responses typically were bursts of action potentials (Fig. 2A and C) although single driven spikes were occasionally recorded (Fig. 2D). Response latencies were usually quite long (median latencies: mes. n uc. 30 msec. inf. dent. n. 50 msec) (Fig. I) although such measures obtained with extracellular recording must be viewed with caution. Responses of very long latency ( > t00 msec) also tended to show considerable trial-to-trial variability of latency ( ± 25 msec). Fig. 2C illustrates the most obvious example of this variability. However, two-thirds of these long latency responses were excitatory and they occurred in units with very slow ( < l/sec) control firing rates. These slow spontaneous activity levels precluded observation of possible earlier occurring periods of inhibition. Therefore, the possibility that these very long and variable latency responses represented postinhibitory rebound firing could not be ruled out. Multiple unit recordings f r o m the trigeminal nerve indicated that most unit responses occurred after the onset and usually well after the cessation of reflex jaw movements. A small population of units showed such short response latencies c.~< 20 msec) (Fig. 2D) so as to preclude the possibility that these responses were conducted via striato-entopeduncular connections (the shortest latencies of trigeminal evoked striatal responses were 20 msec unpublished data). However, since the striatum is the major source of entopeduncular afferents 14, the possibility must be considered that these short-latency responses are artifacts of current spread. There are a number of ways in which current spread could cause short-latency entopeduncular effects. For example,

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Fig. 2. Responses of 4 different units to mes. nuc. or inf. dent. n. stimulation. A and B s h o w successive responses to single pulse inf. dent. n. and mes. nuc. stimulation (arrows indicate stimulus). C s h o w s successive long-latency responses to 50 msec trains of inf. dent. n. stimulation. Note variability of latency. ]'his unit showed no activity in the absence of stimulation. D illustrates short-latency responses (on expanded trace) evoked by rapid mes. nuc. stimulation. Each trace s h o w s s u p e r i m p o s e d responses to 2 stimuli.

entopeduncular neurons project to an area of the reticular formation 14 located just ventral to the mes. nuc. stimulating electrodes. Current spread could activate these fibers and result in short-latency antidromic responses in the entopeduncular nucleus. This first alternative seems unlikely since stimulation-driven spikes showed variability of latency incompatible with antidromic activation (Fig. 2D). A second possibility is that mes. nuc. stimulation activated the closely adjacent pontine taste area'-'. Axons from the pontine taste area in the rat pass through the entopeduncular nucleus en route to the amygdala 1,5. The possibility of current spread to this taste nucleus also receives little support since none of the 12 short-latency units tested with 0.25 M NaC1 showed gustatory responses. The likelihood that recordings from fibers of passage from any system contributed significantly to the short-latency population is not compatible with the data. Most units were affected at short latency by caudate stimulation in a manner similar to previous descriptions of striatopallidal responses 14. In addition, many of these cells also showed an A-B break (when firing rapidly) indicative of recording from a neuronal soma. Perhaps the strongest evidence against the artifactual nature of the short-latency responses is that they were also evoked by inf. dent. n. stimulation at threshold for the DR. Since the inf. dent. n. is located in the

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Fig. 3. A: peristimulus histograms from art entopeduncular neuron showing quantitatively similar response patterns to mes. nuc. (upper histogram) and inf. dent. n. stimulation (lower histogram), B : peristimulus histograms from a n entopeduncular neuron showing qualitatively different response patterns to rues. nuc. (upper histogram) and inf. dent. n, stimulation (lower histogram). Each histogram shows the summed number of action potentials from 20 stimulus presentationsl The bin widths are 100 msec. Arrows indicate stimulation.

periphery, there is minimal possibility of significant current spread to central nervous system structures.

Convergence The effects of stimulation ipsilateral and contratateral to the recording site were tested in 35 cells. For either mes. nuc. or inf. dent. n., stimulation of either side was equally effective. Response patterns to ipsilateral and contralateral stimulation were similar. The effects of mes. nuc. and inf. dent. n. stimulation converged in many cells (42 ~ of the 57 responsive neurons tested with both inputs). Units affected by b o t h inputs tended to show qualitatively similar response patterns with mainly quantitative differences serving to differentiate stimulation loci (58 ~ of units responsive to both rues. nuc. and inf. dent. n.) (Fig. 3A). The remaining cells showed qualitatively different response patterns to different stimulation loci (Fig. 3B). DISCUSSION

The present findings of trigeminal influences on entopeduncular neurons are in accord with similar findings concerning sensory inputs in general and the oropharyngeal system in particular. Intracellular recordings in acute preparations reveated potent effects of somatosensory and auditory stimuli upon pallidal and entopeduncular neurons 1°. In behaving monkeys, a high proportion of pallidal neurons responded to a visual cue. In this same experiment, many pallidal neurons were also shown to change firing rate duringingestion of grape juice 16. Further analysis in cats indicated that ingestion-related firing rate changes may have been due t o sensory aspects of the consummatory act, S~cifically, many entopenduncular a n d pallidal

233 neurons were influenced by tactile stimulation of the perioral tissue and vibrissa r'. The present work extends these observations to show that sensory information, important in the control of jaw movement, also has a potent effect upon entopeduncular neurons. Judging by the high proportion of cells affected by trigeminal stimulation, it appears likely that the basal ganglia have an important role in oropharyngeal motor functions. This assumption is borne out by the findings that pallidal lesions in rats and drug-induced basal ganglia pathology in humans both result in obvious oral-lingual movement disorders 11,1s. However, while the basal ganglia clearly play a major role in suprasegmental control of trigeminal systems, the nature of its influence is unclear. Many of the basic reflex mechanisms involving the oropharyngeal musculature are organized in the brain stem. The central timing generator for masticatory movement and monosynaptic load compensation mechanisms are all located in the pons and medulla3, 9. Indeed, movements similar to normal licking and chewing can be evoked in the absence of the entire forebrain (including the basal ganglia) 4. Recent evidence implicates the basal ganglia in higher order control of basic oral-ingestive movements. Although masticatory behavior can be elicited in cerveau isol6 rats, these movements lack goal-directedness 4. A similar lack of goal-direction results from nigrostriatal lesions in the otherwise intact rat 1. Other work indicates that pallidal damage results in an inability to coordinate head position and oropharyngeal movements to insure efficient ingestion of food H. These findings are compatible with theoretical speculations suggesting that the basal ganglia are preferentially involved in the sensory motor integration necessary for the control of feedback-modulated movements s. The present findings concerning trigeminal entopeduncular influences are in accord with these speculations. Such sensory information, important for monitoring parameters of movement and position, could eventually modify oropharyngeal activity via basal ganglia thalamocortical relays or direct connections to the brain stem. in this context it is interesting to note that stimulation of the caudate modifies jaw opening and jaw closing reflexes evoked by either cortical or brain stem stimulation 5,v,~9. Caudate stimulation per se does not evoke jaw movements 19. In any case, this research demonstrates that sensory information has a potent effect upon basal ganglia neuronal activity and underscores the importance of this neural system in oropharyngeal motor processes. Future work should be addressed to delineating the parameters of trigeminal information reaching the basal ganglia. For this research, more natural stimulation (e.g. tooth taps, torque pulses etc.) will have to be employed. ACKNOWLEDGEMENTS

The helpful suggestions of M. S. Levine, J. S. Stamm and R. Norgren are gratefully acknowledged. This investigation was supported by U.S.P.H.S. Biomedical Sciences Support Grant 5 So5 RR07067 - 10 to S.U.N.Y. at Stony Brook.

234 REFERENCES 1 Antelman, S. M., Szechtman, H., Chin, P. and Fisher, A. E.. Tail pinch-induced eating, gnawing and licking behavior m rats: dependence on the nigrostriatal dopamine system. Bra#l Research. 99 (1975) 319--337. 2 Bernard, R. A. and Nord, S. G . A first order synaptic relay for taste fibers in the pontine brain stem of the cat, Brain Research. 30 (1971) 349 356. 3 Dellow, P. G. and Lund, J. P., Evidence for central timing of rhythmical masticatioll_ ,1. Physiol. (Lond.), 215 (1971) 1-13. 4 Grill, H. J. and Norgren, R., Pain elicited ingestive sequences from chronic decerebrate rats. Soe. Neurosci., 6 (1976) 288. 5 Kawamura, Y., Recent concepts of the physiology of mastication. In P. H. Staple (lEd.). Advances in Oral Biology, Vol. I, Academic Press, New York. 1964. pp. 77-109. 6 Kidokoro, Y., Kubota, K.. Shuto. S. and Sumino. R.. Reflex organization of cat masticatory muscles, J. Neurophysiol., 31 (1968) 695-708. 7 King, E. E., Minz, B. and Unna. K. R., The effect of the brainstem reticular lormation on the lingulomandibular reflex, J. comp. Neurol.. 102 (1955) 565-596. 8 Kornhuber, H. H., Cerebral cortex, cerebellum and basal ganglia: an introduction to their motor functions. In F. O. Schmidt and F. G. Worden rEds.), The Neurosciences: Third Study Program M.I.T. Press, Massachusetts. 1974. pp. 267 280. 9 Lamarre, Y. and Lund, J. P.. Load compensation in human masseter muscles. J. PhysioL I Lond.., 253 (1975) 21-35. 10 Levine, M. S., Hull, C. D. and Buchwald, N. A., Pallidal and entopeduncular intracellular responses to striatal, cortical, thalamic and sensory inputs, Exp. Neurol., 44 (1974) 448-460. 1 l Levine, M. S. and Schwartzbaum, J. S., Sensorimotor functions of the striatopallidal system and lateral hypothalamus and consummatory behavior in rats, J. comp. physiol. Psychol.. 85 (1973) 615-635. 12 Lidsky, T. [., Buchwald, N. A., Hull, C. D. and Levine. M. S., Pallidal and entopeduncular single unit activity in cats during drinking, Electroeneeph. clin. Nearophysiol., 39 (1975"1 79-84. 13 Morgane, P. J., Alterations in feeding and drinking behavior of rats with lesions in globi pallidi. Amer. J. PhysioL, 201 (1961) 420-428. 14 Nauta, W. J. H. and Mehler. W. R.. Projections of the lentiform nucleus in the monkey, Brain Research, 1 (1966) 3-42. 15 Norgren, R., Taste pathways to hypothalamus and amygdala. J. comp. Neurol., 166 (1976) 17-30. 16 Soltsysik, S., Hull. C. D.. Buchwald. N. A. and Fekete, T., Single unit activity in basal ganglia of monkeys during performance of a delayed response task. Electroeneeph. olin. NeurophysioL, 39 (1975) 65 78. 17 Snider, R. A. and Niemer. W. T.. A stereotaxic Atlas ot the Cat Brain, University of Chicago Press, Chicago, 1961. 18 Stimmel, G. L,. Neuroleptics and the corpus striatum: clinical implications, Div. ~zerv. ~'st.. 37 (1976) 219-224. 19 Weinhold, P. M., Gustafson, J. W. and Lidsky, I". 1.. The eft'ecl of caudate nucleus stimulation on jaw movements, Soc. Neurosci., 6 (1976) 70.