Trigeminal and pretectal influences upon slow-wave activity of the ventral tegmental area in the cat

EXPERIMENTAL

NEUROLOGY

Trigeminal Activity

and of

the

7,

355-365

Pretectal

(1963)

Influences

Ventral

Tegmental

JOSEPHWELLSANDJEROME Department

of Anatomy, New

upon

Slow-Wave

Area

in the

SUTIN~

Yale University School Haven, Connecticut

Received

January

Cat

of

Medicine,

10, 1963

The influence of the posterior brain stem on the 6 to 10 per set slow-wave rhythm of the ventral tegmental area of Tsai (VTA) associated with barbiturate anesthesia in cats was investigated. The VTA slow-wave activity was augmented by stimulation (6-lO/sec) of the descending trigeminal tract or trigeminal ganglion. Augmentation of the VTA rhythm was also observed during stimulation of the inferior alveolar nerve, the supraorbital nerve and the greater occipital nerve, but not the infraorbital nerve. Lesions in the caudal part of the descending tract of the trigeminal nerve, in the medial forebrain bundle, the lateral habenular nucleus, or brain-stem transection at a rostra1 pontine level had no effect upon the VTA rhythm. Lesions in the pretectal region or centrummedianum-parafascicular nucleus comp!ex markedly diminished or abo!ished the rhythm. Introduction

Six- to twelve-per-second rhythmic electrical activity has been recorded from the ventral tegmental area of Tsai (VTA) in cats anesthetized with barbiturates (15). Slow-wave activity was not observed during normal behavioral sleep, nor in cats anesthetized with agents other than . barbiturates. Low-frequency stimulation of the globus palidus suppressed or abolished this rhythmic activity. Stimulation of the thalamic nucleus ventralis anterior or the habenular nuclei evoked potentials in the VTA, but did not influence the rhythmic activity. The present report deals primarily with the influence of caudal brainstem structures upon the barbiturate-induced slow-wave activity in the VTA. 1 Supported by NSF Grant G-13274 and by U.S.P.H.S. Grant l-GS-58. The authors wish to express their gratitude to Miss Nancy Margiotta and Mrs. Fay Gomes for histological and technical contributions and to Mrs. Mary Spang for secretarial contributions to this work. 35s

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Materials

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Methods

The twenty-four adult cats used were anesthetized with sodium pentobarbital (Nembutal), 30 to 40 mg per kg. When brain-stem or peripheral nerve stimulation was accompanied by reflex movement, the anesthetized animal was given gallamine triethiodide (Flaxedil) and maintained on artificial respiration. In five animals, peripheral branches of the trigeminal nerve, and in one animal, the greater occipital nerve, were exposed for stimulation. Twenty-six gauge’concentric stainless steel bipolar electrodes with a tip separation of 0.5 to 1 mm were used for recording and stimulation. Spontaneous activity or evoked responses were recorded on a Grass polygraph (Model 5) or displayed oscilloscopically for photographic recording. Frozen sections of the formalin-fixed brains of each animal were stained with thionine or the Kliiver technique for verification of electrode placements or lesions. Resdts

Influence of Caudal Brain-Stem Structures upon the VTA Rhythm. A systematic exploration of the brain-stem caudal to the superior colliculus with high (100 per set) and low (S-10 per set) frequency trains of stimuli revealed two modifications of the VTA slow-wave activity. In some regions, low-frequency stimulation increased the amplitude of the VTA rhythm and, for convenience, will be referred to as “augmentation” (Fig. 1). The stimulus frequency that produced augmentation was critical. It varied from one cat to another, but was always between 6 and 10 per sec. In any given animal optimal augmentation was usually obtained when the stimulus frequency matched that of the slow-wave rhythm. Stimulation at frequencies 1 or 2 per set above or below the critical rate usually failed to augment the rhythm. The regions from which augmentation of the VTA rhythm was obtained are represented by open circles in Fig. 2. Each large open circle represents a locus at which augmentation occurred in at least three or four animals. The smaller open circles represent sites where augmentation was obtained in less than 75% of the animals in which the designated area was stimulated. Because many of these points were associated with the medial lemniscus, the medial portion of the contralateral dorsal column was stimulated, but did not effect the VTA rhythm. The structure most consistently producing augmentation of the VTA rhythm was the descending trigeminal tract (Fig. 2C). When it

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became apparent that low-frequentcy stimulation of the descending trigeminal tract produced augmentation, peripheral portions of the trigeminal system were stimulated. Low-frequency stimulation of the trigeminal (semilunar) ganglion produced augmentation of the VTA

FIG. 1. Polygraph recordings showing augmentation during low-frequency stimulation (upper tracings) and blocking during high-frequency stimulation (lower tracings) in the medulla. Duration and frequency of the stimulation are shown beneath each set of tracings. Abbreviations: VTA,, bipolar recording from the ventral tegmental area; EEG, electroencephalogram ; EKG, electrocardiogram.

rhythm in twelve of thirteen cats. Augmentation of the slow-wave VTA rhythm was also produced by low-frequency stimulation of the inferior alveolar nerve, supraarbital nerve and greater occipital nerve, but not the infraorbital nerve.

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Single pulse stimulation of the descending trigeminal tract, the trigeminal ganglion, the inferior alveolar nerve and the greater occipital nerve produced similar evoked potentials in the VTA (Fig. 4). These evoked potentials showed a phase-reversal as the recording electrode was lowered through the VTA. The evoked response consisted of a series of low-amplitude spikes varying in latency from 2 to 5 msec, followed by a

FIG. 2. Schematic diagram of brain-stem sites stimulated: A, caudal midbrain; B, rostra1 medulla; C, caudal medulla. Dots: no change in the spontaneous rhythm of the VTA; large open circles: increased amplitude of the VTA rhythm in at least three of four cats; small open circles: increased amplitude in less than three of four cats; X: suppression of the VTA rhythm. Abbreviations: CI, inferior coIliculus; DTN, dorsal tegmental nucleus; IO, inferior olive; LL, lateral lemniscus; LM, medial

lemniscus; MLF, mediallongitudinalfasciculus;P, pyramid; PCI, inferior cerebellar peduncle; PCM, middle cerebellar peduncle; PCS, superior cerebellar peduncle; RG, nucleus reticularis gigantocellularis ; RL, nucleus reticularis lateralis; RPC, nucleus reticularis caudalis pontis ; SO, superior olive; T, trapezoid body; TS, spinothalamic tract; TT, tectospinal tract; V,, descending trigeminal tract; V,, motor nucleus of the trigeminal; V,, pars principalis of the trigeminal nucleus; VII, facial nerve.

15 to 20-mseclatency slow-wave. The evoked potentials usually were not observed at stimulus frequencies above 4 per sec. When simultaneous recordings of the right and left VTA were taken, they showed bilateral changes in electrical activity upon brain-stem or peripheral trigeminal stimulation. Lesions destroying the caudal descending trigeminal tract at the level of the obex did not alter the VTA rhythm or block responsesevoked

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in the VTA by stimulation of the trigeminal ganglion. Pretrigeminal transection of the brain stem in three cats had no effect upon the spontaneous slow-wave rhythm of the VTA. Upon histological examination a small portion of the basal pons at the level of transection was found intact in all of these animals. In some regions of the brain stem, 100 per set or higher stimulation diminished or abolished the rhythmic activity of the VTA and, for convenience, this effect will be referred to as “blocking” (Fig. 1). The sites from which blocking was obtained are designated in Fig. 2 by an X. No consistent relation was found between sites producing blocking and augmentation. Only two of the twelve animals in which low-frequency stimulation of the trigeminal ganglion produced augmentation displayed blocking of the VTA rhythm when the ganglion was stimulated at a high frequency. Influence of Rostra1 and Dorsal Areas on the VTA Rhythm. Low-frequency (2-5 per set) stimulation of the globus pallidus blocked the VTA rhythm ( 15). The augmented VTA activity produced by trigeminal ganglion stimulation was blocked by stimulation of the globus pallidus. Stimulation of the thalamic ventralis anterior (VA) evoked bilateral responses in the VTA after a 6-msec latency (15) _ During paired stimulation of VA and the trigeminal ganglion, the VA evoked-VTA response was reduced following trigeminal activation of the VTA (Fig. 3). When

FIG. 3. A. Oscilloscopic recordings of the evoked response in the VTA following single-pulse stimulation of the trigeminal ganglion. Similar evoked responses were observed in the VTA following stimulation of the supraorbital nerve, the inferior alveolar nerve, the greater occipital nerve and the descending trigeminal tract, B. Evoked response in the VTA following single-pulse stimulation of the tha!amic nucleus ventralis anterior. C. Stimulation of the ventralis anterior is preceded by stimulation of the trigeminal ganglion, leading to a reduction in the amplitude of the VA-VTA evoked response. Horizontal bar, 50 msec; vertical bar, SOuv.

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a VA-VTA response preceded the trigeminal-VTA response, there was no depression of the trigeminal evoked-VTA potential (Fig. 4). Latency responses of 3 to 4 msec were evoked bilaterally in the VTA by stimulation of the habenular nuclei, the habenulointerpeduncular tract

FIG. 4. A. Evoked response in VTA following trigeminal ganglion. B. Stimulation of VA prior no effect on the ganglion-VTA evoked response. bar, 50 msec; vertical bar, 50~~.

single shock stimulation of the to stimulation of the ganglion has Compare with Fig. 3. Horizontal

or adjacent pretectal region. In five cats, lessions were placed rostra1 or dorsal to the VTA. In this series, if a lesion did not effect the VTA rhythmic activity, a second lesion was placed in a different region. Lesions in the mamillary peduncle and medial forebrain bundle at the level of the mamillary bodies (Fig. S), in the lateral habenular nucleus or stria medularis thalami did not effect the VTA rhythm (Fig. 6A). Lesions involving the pretectal area, or the centrum medianum, parafascicular nucleus and habenulointerpeduncular tract abolished or markedly diminished the amplitude of the VTA rhythm but other lesions involving the habenulointerpeduncular tract and sparing the pretectal region had no effect on the VTA rhythm (Figs. 6 and 7). Recordings from the pretectal and adjacent regions did not show slow-wave activity. Discussion

The ventral tegmental area of Tsai (VTA) consists of scattered, small neurons in the basal mesencephalon ventral to the red nucleus, and is bounded laterally by the substantia nigra and medially by the interpeduncular nucleus (2, 16). Many afferent fibers to the VTA pass through the mamillary peduncle, and appear to originate chiefly in the dorsal tegmental nucleus of Gudden (5, 10). Other afferent fibers have their

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origin in the subthalmic nucleus (ll), septal nuclei (12), hypothalamic nuclei (7, 12), preoptic area, mamillary bodies (12), and the lenticular nuclei (17). LeGros Clark (9) and Tsai ( 16) have indicated pathways from the pretectal area to the substantia nigra and Tsai ( 16) has described an accessory, optic pathway in the opossum which ends immediately lateral to the VTA in the nucleus opticus tegmenti. Elec-

FIG.

level VTA.

5. Lesion (L) of the mamillary Kliiver stain.

in the mamillary peduncle and medial forebrain bodies. This lesion did not alter the slow-wave

bundle activity

at the of the

trophysiological evidence indicates afferent projections to the VTA from the thalamic nucleus ventralis anterior, the habenula (15), and in the present study the trigeminal nerve. Berry, Anderson, and Brooks (1) described a projection from the contralateral infraorbital nerve to the medial tip of the cerebral peduncle at the level of the VTA. Stimulation of the thalamic nucleus ventralis anterior did not affect the slow-wave rhythm of the VTA. Prior trigeminal stimulation suppressed the

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VTA response to ventralis anterior stimulation, but prior ventralis anterior stimulation did not alter the VTA response to trigeminal stimulation. This, together with the observation that 6 to 10 per set trigeminal stimulation increased the amplitude of VTA slow-wave activity, suggests that the ventralis anterior projection does not directly influence VTA cells producing the slow-wave activity. Trigeminal projections, however, would

FIG. 6. A lesion involving the lateral habenular nucleus and stria medullaris thalami (a) had no effect on the VTA rhythm. A lesion involving the pretectal region and underlying the centrum-medianum-parafascicular nucleus complex (b) markedly diminished the VTA rhythm (Fig. 7). Kliiver stain.

appear to influence both the VTA cells activated by ventralis anterior stimulation and those generating the rhythmic activity. The lesion experiments indicate that the habenular nuclei and the habenulointerpeduncular tract are not required for the maintainance of the rhythmic VTA activity. Destruction of the pretectal region or underlying centrum medianum-parafascicular nucleus complex abolishes

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the slow-wave VTA rhythm, suggesting that descending fibers from the pretectal region may be required for maintenance of the synchronized 6 to 10 per set activity characteristic of the VTA in cats under barbiturate anesthesia.

FIG. 7. Recording from VTA ipsilateral to lesion b, Fig. prior to lesion. B. After lesion. Rhythm was also diminished to the lesion. Horizontal bar, 100 msec; vertical bar, 501.~~.

6. A. Rhythmic activity in the VTA contralateral

The region of the mesencephalon encompassing the VTA has been implicated in several functions, but as yet there is no clear relationship between these functions and the slow-wave rhythm. Thompson (14) described loss of avoidance behavior in rats with lesions that destroyed

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the interpeduncular nucleus and encroached upon the VTA. Hayhow (8) and Giolli (6) demonstrated an accessory optic pathway that ends very close to the VTA in the cat. We have not observed any change in the slowwave rhythm in our preparations with changes in background illumination. Cragg (3) has reported panting in rabbits following stimulation of the habenula, interpeduncular nucleus and the dorsal tegmental nucleus, areas which are closely related to the VTA. Critchlow (4) and Slusher and Critchlow (13) found that ovulation was blocked by large lesions in the basal mesencephalon that included the VTA, interpeduncular nucleus and the mamillary peduncle. References 1. 2. 3. 4. 5. 6.

7. 8. 9. 10. 11.

12. 13.

14.

C. M., F. D. ANDERSON, and D. C. BROOKS. 1956. Ascending pathways of the trigeminal nerve in the cat. J. Neuuophysiol. 19: 144-153. BROWN, J. 0. 1943. The nuclear pattern of the non-tectal portions of the midbrain and isthmus in the dog and cat. J. Camp. Neurol. 37: 36.5-406. CRAGG, B. G. 1959. A heat loss mechanism involving the habenula, interpeduncular, and dorsal tegmental nuclei. Nature 184: 1724. CRITCHLOW, V. 1958. Blockade of ovulation in the rat by mesencephalic lesions. Endocrinology 63: 596-610. Fox, C. A. 1941. The mammillary peduncle and ventral tegmental nucleus in the cat. J. Comp. Neurol. 75: 411-425. GIOLLI, R. A. 1961. An experimental study of the accessory optic tracts (transpeduncular tracts and anterior accessory optic tracts) in the rabbit. J. Comp. Neurol. 117: 77-96. GUILLERY, R. W. 1957. Degeneration in the hypothalamic connexions of the albino rat. J. Anat. 91: 91-11.5. HAYHOW, W. R. 1959. An experimenta study of the accessory optic Aber system in the cat. J. Comp. Neural. 113: 281-313. LEGROS CLARK, W. E. 1932. The structure and connections of the thalamus. Brain 55: 406-470. MOREST, D. K. 1961. Connexions of the dorsal tegmental nucleus in rat and rabbit. J. Anat. 95: 229-246. MORGAN, L. D. 1927. Symptoms and fiber degeneration following experimental lesions in the subthalamic nucleus of Luys in the dog. J. Comp. Neural. 44: 379-397. NAUTA, W. J. H. 1958. Hippocampal projections and reIated neural pathways to the midbrain in the cat. Bruin 81: 319-340. SLUSRER, M. A., and V. CRITCHLOW. 1959. Effect of midbrain lesions on ovulation and adrenal respcnse to stress in female rats. Proc. Sot. Exptl. Biol. Med. 101: 497-499. THOMPSON, R. 1960. Interpeduncular nucleus and avoidance conditioning id the rat. Science 132: 1551-1553. BERRY,

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B., and J. SUTIN. 1962. Slow-wave activity in the ventral tegmental area of Tsai related to barbiturate anesthesia. Exptl. Neural. 5: 120-130. TSAI, C. 1925. The optic tracts and centers of the opossum, Didelphis virginiana. J. Camp. Neurol. 99: 173-216. WHITTIER, J. R., and F. i\. METTLER. 1949. Studies on the subthalamus of the rhesus monkey. I. Anatomy and fiber connections of the subthalamic nucleus of Luys. J. Comp. Neurol. 99: 281-317.

TREMBLY,