Afferent inhibition in the cuneate nucleus of the rhesus monkey

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Afferent inhibition in the cuneate nucleus of the rhesus monkey Afferent inhibition has been identified at several levels of the somatosensory system1.2,8,11-1z, although in the spinocervical system it does not 'surround' the excitatory receptive field4,L It is most clearly seen as a loss of responsiveness to a normally efficacious stimulus for a tenth of a second following stimulation of a nearby skin site, and is most powerful when touch or pressure input is used to condition a hair-sensitive unit. (This latter interaction is readily demonstrated in the human as a loss of sensation of hair-bending when pressure is applied near the hairs being bent.) In its weaker form, the afferent inhibition can be seen as a decreased responsiveness - reflected in a decreased number of spikes per discharge, an increased interspike interval, and an increased response latency - - for 0.1-0.2 sec following a conditioning input 1,11,~z. The time course of afferent inhibition suggests that presynaptic 2 as well as postsynaptic3, 6 inhibition may be involved in the phenomenon. The spatial extent of afferent inhibition has received scanty attention. Towe 13 showed how inhibition diminishes as the conditioning stimulus is moved away from the neuron's excitatory receptive field, but did not determine the limits of a measurable effect. Mountcastle and Powel112 showed sharp borders for the 'inhibitory surround' without clarifying how those borders were obtained. Jabbur and Banna s,9 have recently shown that afferent inhibition, ascribable to a presynaptic inhibitory mechanism, can be found in the dorsal column nuclei of the cat by stimulation anywhere over the body surface, both ipsilaterally and contralaterally. Further, it persists in decerebrate preparations 9, thus precluding involvement of more rostral portio nsofthe brain 15. In the present study, we obtained similar observations in the macaque monkey. Single neurons were isolated in the cuneate nuclei of 5 dial-urethane-anesthetized rhesus monkeys (M. mulatta). The dorsal column nuclei were exposed via the atlanto-occipital membrane, some occipital bone being nibbled away to increase the exposure. The pericentral region of the cerebral cortex opposite to the cuneate nucleus under study was exposed and bipolar stimulating electrodes were placed on 'palm' cortex on both sides of the central fissure. Pairs of needle electrodes were inserted into the skin of the palms (IFP and CFP) and the soles (IHP and CHP) and also into the distal phalanx of each digit of the ipsilateral forepaw (IFP). Finally, a bipolar stimulating electrode was driven under stereotaxic control into nucleus ventralis posterolateralis of the thalamus opposite to the cuneate nucleus under study. With the animal thus equipped, NaC1 micropipettes were advanced into the cuneate nucleus. A cube of tissue 2.5 mm on a side was examined; it was centered a! the level of the obex and 2.5 mm from the midline. IFP shock at 1/sec served as the 'hunting' stimulus. Upon extracellular isolation of an evokable unit, conditioningtesting (C-T) stimulation was instituted to detect any afferent inhibition. The 3 'off-focus' paws (IHP, CFP and CHP) and the two cerebral sites (PreC and PostC paw foci) served as conditioning inputs, and their effects on a subsequent IFPevoked discharge were determined. The thalamic electrode was used to identify cuneo-thalamic projection (CTR) neurons. Of the 68 neurons adequately tested, 41 showed measurable afferent inhibition,

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Fig. 1. Effects of conditioning-testing interaction on cuneo-thalamic projection neuron. Unit normally responds with two spikes to IFP shock (a and c); prior condition train to IHP (b), CHP (d) and precentral forepaw cortex (e) either blocks (b) or reduces (d and e) response to IFP shock. A train of shocks to postcentral forepaw cortex (f) excites the neuron. Arrows point to IFP stimulus artifact.

6 showed excitatory interactions, and 21 showed no effects. A train of conditioning shocks was usually required to yield clear inhibition, the train occasionally becoming as long as 10 shocks spaced 3.2 msec apart. Of the 41 neurons showing unequivocal inhibition, 31 showed it to all 5 conditioning inputs (IHP, CFP, CHP, PreC paw and PostC paw); of the remainder, some showed inhibition to fewer than the 5 inputs and some showed mixed effects. For example, the CTR neuron shown in Fig. 1 was inhibited from 4 of the 5 conditioning sites and was fired from PostC paw cortex. It was isolated 1185 # m below the pial surface, 2 m m lateral to the midline and 2 m m caudal to the obex. It fired with a 2.0 msec latency to thalamic stimulation, faithfully responding to iterative shocks in excess of 400/sec. It fired to supramaximal IFP shocks with two spikes at 7.8 and 10.9 msec latency (Fig. la and c), and faithfully responded to iterative shocks in excess of 200/sec. Fig. lb shows failure of response when the I F P shock is preceded by a train of shocks to I H P 42 msec earlier. The C H P train in Fig. ld hardly affected the first spike to I F P shock (7.9 msec), but eliminated the second spike. The train of shocks to PreC paw cortex shown in Fig. le lengthened the first spike latency to IFP shock to 15.9 msec (see ref. 13). However, the neuron fired 14.6 and 16.7 msec after the start of a train to PostC paw cortex, as shown in Fig. If. The natural sensitivity of the neuron was to light touch on all the digits of I F P and to the skin of the hand, wrist, and lbrearm to the elbow. Inhibition was evident on neurons with small receptive fields as well as on those with large fields. As shown in the left column of Fig. 2, the inhibitory influence acted oo the 'spontaneous' as well as the evoked discharge of the neurons. The 'spontaneous' discharge of the neuron shown in Fig. 2a was suppressed for 150-200 msec following Brain Research, 27 (1971) 179-183

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Fig. 2. Inhibitory (left) and excitatory (right) effects on 'spontaneous' discharge of cuneate neuron. 'Spontaneous' activity (a) is suppressed by train of shocks to CHP (b) or precentral forepaw cortex (c). Two neurons with low 'spontaneous' rates (d) have those rates mildly (e) or strongly (f) increased by IHP (e) or CHP (f) shocks. a train of stimuli to C H P (Fig. 2b), IHP, CFP, or PostC paw cortex; the PreC paw cortex was less effective (Fig. 2c). Six of the neurons studied showed some degree of excitation or facilitation from the conditioning inputs. To the 'off-focus' cutaneous inputs, this effect appeared as a mild increase in the 'spontaneous' discharge of the neuron. The two neurons shown in Fig. 2d had low 'spontaneous' discharge. A single shock to I H P had a mild facilitatory effect on the small unit (Fig. 2e) whereas a single shock to C H P had a more prominent excitatory effect on both units (Fig. 2f). In the absence of sufficient information, the possibility of'disinhibition' should be mentioned in connection with this phenomenon. On the other hand, the cerebral excitatory effect was usually one of frank evoked discharge, as illustrated in Fig. lf. The monkey cuneate nucleus is different from that of the cat in its pattern of cerebral influencesV,10,14. Thus, it is not too surprising that 38 of the 41 neurons showing inhibition and 5 of the 6 neurons showing excitation were C T R neurons, whereas only 3 of the 21 neurons showing no interaction effects were C T R neurons. Andersen et al. 2 reported that 59 of 69 presumed interneurons (non-CTR neurons) in the cat were excited by cerebral cortex, whereas none of the 78 C T R neurons was so activated. They propose that these interneurons directly inhibit the C T R neurons. We are left with the implication that all 78 C T R neurons were inhibited by cerebral stimulation. On the other hand, many known C T R neurons in the monkey are not only excited by cerebral cortex, but may be driven at latencies so short that a monosynaptic route is implied 7. Wiesendanger and Felix le found many neurons in the nucleus oralis of the trigeminal complex driven from cerebral cortex, and some of these projected to the ventroposterior thalamus. Brain Research, 27 (1971) 179-183

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Thus, although the widespread c h a r a c t e r o f afferent inhibition found in thc cat by J a b b u r a n d BannaS, 9 is clearly present in the rhesus monkey, the o r g a n i z a t i o n o f the cuneate nucleus m a y differ between the two species. T h a t the effect in the m o n k e y may be ascribed p r i m a r i l y to a p r e s y n a p t i c inhibitory m e c h a n i s m seems likely, for the time course o f the interaction was consistent with such a mechanism. F u r t h e r , the P wave o f the N I - N 2 - P c o m p l e x revealed such an effect3,9,15; the a m p l i t u d e o f the I F P - e v o k e d P wave was a t t e n u a t e d along the typical time course for p r e s y n a p t i c inhibition following a train o f c o n d i t i o n i n g shocks to C F P , I H P or C H P . The two h i n d p a w inputs only b r o u g h t the P wave d o w n to 85 % o f its u n c o n d i t i o n e d amplitude, whereas the C F P train reduced it to 6 0 - 7 0 % for 140 msec. This observation enhances the suggestion that the w i d e s p r e a d afferent inhibition observed in the rhesus m o n k e y acts t h r o u g h an axo-axonic, p r e s y n a p t i c mechanism. This w o r k was s u p p o r t e d by G r a n t s NS00396 and NS05136 f r o m the N a t i o n a l Institute o f N e u r o l o g i c a l Diseases a n d Stroke, U.S. D e p a r t m e n t o f Health, E d u c a t i o n a n d Welfare. Facilities for this w o r k were p r o v i d e d by the Regional Primate Research Center o f the University o f W a s h i n g t o n . Department of Physiology and Biophysics, University of Washington School of Medicine, Seattle, Wash. 98105 (U.S.A.)

M. A. BIEDENBACH S. J. JABBUR* A. L. TOWE

1 AMASStAN,V. E., Studies on organization of a somesthetic association area, including a single unit analysis, J. Neurophysiol., 17 (1954) 39-58. 2 ANDERSEN,P., ECCLES,J. C., SCHMtDT, R. F., AND YOKOTA,T., Identification of relay cells and interneurons in the cuneate nucleus, J. NeurophysioL, 27 (1964) 1080-1095. 3 ANDERSEN,P., ECCL~S,J. C., OSmMA, T., AND SCmaIDT, R. F., Mechanisms of synaptic transmission in the cuneate nucleus, J. Neurophysiol., 27 (1964) 1096-1116. 4 BROWN,A. G., ANO FRANZ, D. N., Responses of spinocervical tract neurons to natural stimulation of identified cutaneous receptors, Exp. Brain Res., 7 (1969) 231-249. 5 FEOINA,L., GORDON, G., AND LUNDBERG, A., The source and mechanisms of inhibition in the lateral cervical nucleus of the cat, Brain Research, 11 (1968) 694-696. 6 GORDON, G., AND JOKES, M. G. M., Dual organization of the exteroceptive components of the cat's gracile nucleus, J. Physiol. (Lond.), 173 (1964) 263-290. 7 HARRIS,F., JABaUR, S. J., MORSE,R. W., ANDTOWE, A. L., Influence of the cerebral cortex on the cuneate nucleus of the monkey, Nature (Lond.), 208 (1965) 1215-1216. 8 JABnUR, S. J., AND BANNA,N. R., Presynaptic inhibition of cuneate transmission by widespread cutaneous inputs, Brain Research, 10 (1968) 273-276. 9 JABnUR, S. J., AND BANtqA,N. R., Widespread cutaneous inhibition in dorsal column nuclei, J. Neurophysiol., 33 (1970) 616-624. 10 JABatm, S. J., ANO TOWE, A. L., Cortical excitation of neurons in dorsal column nuclei of cat, including an analysis of pathways, J. Neurophysiol., 24 (1961) 499-509. 11 MOtrNTCASTLE,V. B., Modality and topographic properties of single neurons of cat's somatic sensory cortex, J. NeurophysioL, 20 (1957) 408-434. 12 MOUNTCASTLE,V. B., AND POWELL, T. P. S., Neural mechanisms subserving cutaneous sensibility, with special reference to the role of afferent inhibition in sensory perception and discrimination, Bull. Johns Hopk. Hosp., 105 (1959) 201-232. * Present address: Department of Physiology, School of Medicine, American University of Beirut, Beirut. Lebanon. Brain Research, 27 (1971) 179-183

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13 TOWE,A. L., Inhibition and occlusion in cortical neurons. In E. FLOREY(Ed.), Nervous Inhibition:

Proceedings of the 2nd Friday Harbor Symposium, Pergamon, New York, 1961, pp. 410-418. 14 TOWE,A. L., ANDJABBUR,S. J., Cortical inhibition of neurons in dorsal column nucleiof cat,J. Neurophysiol., 24 (1961) 488-498. 15 TowE, A. L., ANDZI~RMAN, I. D., Peripherally evoked cortical reflex in the cuneate nucleus, Nature (Lond.), 194 (1962) 1250-1251. 16 WI~ENDANGER,M., ANDFELIX,D., Pyramidal excitation of lemniscal neurons and facilitation of sensory transmission in the spinal trigeminal nucleus of the cat, Exp. Neurol., 25 (1969) 1-17.

(Accepted January 4th, 1971) Brain Research, 27 (1971) 179-183

Tremor at rest following cerebellar lesions in monkeys: effect of L-DOPA administration The current rationale for treatment of Parkinsonian tremor and rigidity by L-DOPA is based upon the following observations1,9,10: due to loss of a nigrostriatal dopaminergic pathway in Parkinson's disease the normal dopamine le~,els in the striatum fall, thus upsetting a circuit involving the nigra, caudate, thalamus and globus pallidus which normally inhibits synchronous activity presumably at the thalamic or pallidal level. The tremor thus represents a 'beating' of neurons made manifest in the absence of other, supervening motor activity. L-DOPA is used as 'replacement' therapy, restoring the fallen dopamine levels in the striatum to more normal values after decarboxylation. Cerebellar tremor is thought to result from disorder of a different mechanism which is subserved by different pathways. The 'loop' is supposed to depend upon projections from the cerebellar nuclei to the thalamus (with a non-obligatory synapse in the red nucleus), especially its ventrolateral nucleus which, when disrupted, produces abnormal modulation of cortical activity expressed over pyramidal and cortical extrapyramidal pathways4,t3,15. Cerebellar tremor is presumably provoked by motor activity rather than by the absence of it. This view has already been challenged 3 and our own observations on resting tremor following cerebeilar lesions suggest that such a division of tremors, their respective mechanisms and their anatomic substrata is, at best, oversimplified. During the course of investigations into the role of the cerebral cortex in restitution of function following cerebellar lesions 5, we have found that a tremor at rest develops in some monkeys (Macaca mulatta) following bilateral electrolytic lesions limited to the dentate and interpositus nuclei of the cerebellum (Fig. 1). The only distinction between those monkeys that show resting tremor in addition to intention tremor and those that show only the latter is that the former group exhibits flexor hypero Brain Research, 27 (1971) 183-187