An autoradiographic study of cortical projections from motor thalamic nuclei in the macaque monkey

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Neuroscience Research, 13 (1992) 119-137 © 1992 Elsevier Scientific Publishers Ireland, Ltd. 0168-0102/92/$05.00 NEURES 00523

Research Reports

An autoradiographic study of cortical projections from motor thalamic nuclei in the macaque monkey Katsuma Nakano t, Akinori Tokushige

2 Masako

Kohno z, Yasuo Hasegawa Tetsuro Kayahara i and Kazuo Sasaki 3

l

l Department of.4natomy, School of Medicine, Mie University, Tsu, Mie, 2 Department of Anatomy, Faculty of Medicine, Kagoshima Unicersity, Kagoshima and 3 Department of Integrative Brain Science, Faculty of Medicine, Kyoto UniL,ersity, Kyoto (Japan) (Received 26 July 1991; Revised version received 22 October 1991; Accepted 23 October 1991)

Key words." Motor cortex; Premotor cortex; Thalamic nuclei; Cerebellar nuclei; Basal ganglia; Monkey

SUMMARY The special areal and laminar distributions of cortical afferent connections from various thalamic nuclei in the monkey (Macaca fuscata) were studied by using the anterograde axonal transport technique of autoradiography. The following findings were obtained. The superficial thalamocortical (T-C) projections, terminating in the (superficial half of) cortical layer I, arise mainly from the nucleus ventralis anterior, pars principalis (VApc) and nucleus ventralis lateralis, pars oralis (VLo), and possibly from the nucleus ventralis lateralis, pars medialis (VLm) and nucleus ventralis anterior, pars magnocellularis (VAmc). The VApc gives rise to the superficial T-C and deep T-C projections onto the postarcuate premotor area around the arcuate genu and spur, and onto the dorsomedial part of the caudal premotor area as well as the supplementary motor area (SMA). The VApc also gives rise to only deep T-C projections onto the remaining premotor area and onto the rostral bank of the arcuate sulcus as well as the ventral bank of the cingulate sulcus at the level of the premotor area. The VLo gives rise to the superficial T-C projections onto the ventrolateral part of the motor area (mainly to the forelimb motor area) and onto the dorsomedial part to the mesial cortex at the rostral level of the motor area. The VAmc gives rise to the superficial T-C projections onto the banks of the arcuate genu and adjacent region of area 8. Area X, the nucleus ventralis posterolateralis, pars oralis (VPLo), nucleus ventralis posterolateralis, pars caudalis (VPLc), nucleus ventralis posteromedialis (VPM) and possibly the nucleus ventralis lateralis, pars caudalis (VLc) send only deep T-C projections. The dorsal and medial parts of the VLc project onto the premotor area, the rostral part of the motor area and the SMA, and also the ventral bank of the cingulate sulcus. Area X projects onto the premotor area, the SMA, and the caudal part of area 8. The thalamic relay nuclei projecting onto the frontal association cortex were found to be the VAmc, medial VLc and area X.

INTRODUCTION

Knowledge of thalamic projection onto the cerebral cortex is important in understanding the functional properties of cortical neurons. Various thalamic nuclei project onto the cytoarchitectural boundaries of the cerebral cortex with a variety of laminar patterns 18. Recent studies of the thalamocortical connections have emphasized lamina I Correspondence: Prof. Katsuma Nakano, M.D., Department of Anatomy, School of Medicine, Mie University, Tsu, Mie 514, Japan.

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projection from various thalamic nuclei (see Jones 2o for a review). This projection m the frontal cortex has also been reported in the monkey ~2,~.25.5~,,5,~.~,~ Following a thalamic lesion, terminal degeneration in lamina I was demonstrated by an electron-microscopic study 59.~0. Slight lamina 1 projection from the nucleus ventralis lateralis (VI.) was observed in the motor cortex J~, and substantial lamina I projection from the nucleus ventralis anterior (VA) was indicated in the premotor cortex 25 Distinct laminar differentiation was proposed as the superficial and deep thalamocortical (T-C) projections after electrophysiological studies in cats 52. Further experiments ~ in monkeys revealed laminar differentiation as follows: the fastigial cerebellar nucleus projects mainly onto the medial part of the motor cortex and the parietal association cortex via deep T-C projection neurons terminating in the deep layers of the cortex; the interpositus nucleus projects to the intermediate part of the motor cortex and the premotor cortex via superficial T-C projection neurons terminating in the superficial layer of the cortex; and the dentate nucleus projects onto the lateral part of the motor cortex and the premotor cortex via superficial T-C projection neurons, and also onto area 9 via deep T-C projection neurons 51 Sasaki et al. 55 suggested that the caudomedial part of the nucleus ventralis anterior and nucleus ventralis lateralis complex (VA-VL complex) is the relay part of the deep T-C projection conveying the fastigial input, and the rostrolateral part of the nuclear complex is the relay part of the superficial T-C projection conveying input from the dentate and interpositus cerebellar nuclei. Some electrophysiological studies combined with the horseradish peroxidase (HRP) method also suggest these thalamic relay nuclei 45,49,70. However, the locations of these relay nuclei are still not well defined. In the macaque monkey, the VA-VL complex was divided into subnuclei z0.4~ and the segregated projections of the cerebello-thalamo-cortical and pallido-thalamo-cortical connections were reported on the basis of findings from modern tracing techniques 2,20,57,66.However, these cerebral connections of motor thalamic nuclei have not been in full agreement with the findings of other researchers 25.30.36.37,~,4. Systematic studies concerning the areal and laminar projections from individual subnuclei of the motor thalamic nuclei in monkeys are required. No experimental studies, however, have been conducted on these projections using anterograde axonal tracing methods. In the present study, the thalamocortical projections from distinct subnuclei of the motor thalamic nuclei were studied by the autoradiographic technique. A preliminary report of this work has appeared in part elsewhere 43 MATERIALS AND METHODS

Experiments were performed on 26 Japanese monkeys (Macaca fuscata) ranging in weight from 2.8 to 12 kg. Tritiated amino acid was evaporated under nitrogen gas supply and then reconstituted in the following concentrations with sterile saline or deionized, distilled water: 20-100 p~Ci//xl of 3H-leucine (L-4,5-3H-leucine, specific activity 57 Ci/mmol; Radiochemical Centre, Amersham, U.K.), or an equal mixture of 3H-leucine and 3H-proline (L-5-3H-proline, specific activity 22 Ci/mmol; Radiochemical Centre, Amersham, U.K.). The animals were held in a stereotaxic apparatus (David KopD and craniotomies were performed in aseptic conditions to expose the appropriate cortices. They were anesthetized by an intramuscular injection of 7-8 mg/kg of ketamine hydrochloride (Ketalar, 50 mg/ml) followed by intraperitoneal injection of 15-30 mg/kg of sodium pentobarbital. A single stereotaxic injection of the concentrated isotope was made in

121 different parts of the ventral thalamic nuclei of both cerebral hemispheres in each animal. The injection was achieved through a 31-gauge steel needle attached to a 1-~1 Hamilton syringe with the total injected volume varying in different experiments from 0.3 to 0.5/.d. These injections were made over a period of 10 min and the needle was left in place for 10 min after the injection. These animals were deeply re-anesthetized 5-9 days after the injection of the tracer, and perfused through the left ventricle by 2000 ml of 10% buffered neutral formalin. The brains were blocked, then removed immediately and kept in the same fixative with 10% sucrose for more than 1 week. Coronal sections 7 p~m thick were cut on a paraffin microtome. For autoradiography, selected series of sections mounted on slides were processed according to the procedure described by Cowan et al. 8. Alternate series were dipped in Sakura NR-M2 emulsion and exposed for 4 or 8-28 weeks. After developing in Rendol for 8 min, the sections were counterstained with cresyl violet. These sections were examined under dark- and bright-field microscopy using a Nikon phase-contrast condenser, which is able to switch dark and bright fields; silver grains indicative of terminal labeling and labeled fibers were charted on the representative projection drawings. Serial sections through the whole brain of monkey were made 40 tzm in thickness after embedding in celloidin, and stained with toluidine blue for observation of the normal cytoarchitecture of the thalamus and some cortical areas. The terminology used for the diencephalon essentially follows that of Olszewski 46 and for the cerebral cortical areas follows that of Barbas and Pandya 3 and Brodmann 5. RESULTS Animals were divided into 7 groups based on the injection sites. Only one representative case of each group will be described in detail.

Nucleus ventralis anterior, pars principalis (VApc) injection The injection site was confined to the ventral part of the VApc in M 1R, the dorsal part in M 23R, and the central part of VApc in M 28R (Fig. 1A). In M 28R, a reasonably well-confined deposit of isotope was placed in the central part of the VApc with little involvement of the lateral part of the nucleus ventralis anterior pars magnocellularis (VAmc), and only gliosis was observed in its needle tip and track (Fig. 1A, level 3). This injection site was extended caudally to the rostrodorsal part of area X, which was faintly labeled (Fig. 1A, level 1). In this case (Fig. 1B), the labeled fibers emerged from the injection site and ran dorsolaterally through the dorsomedial part of the anterior limb of the internal capsule to reach the subcortical white matter of the frontal cortex. Terminal labelings in the superficial cortical layer (superficial half of lamina I) and the deep cortical layer (laminae III-VI) were observed in the postarcuate premotor area (Figs. 1B and 2A-C) including the rostral bank of the arcuate genu, and in dorsal caudal area 6 (6 DC as defined by Barbas and Pandya 3) as well as the mesial cortex, facing the falx cerebri, rostral to the motor area (supplementary motor area, SMA). Only deep cortical terminations were found in both banks of the rostral part of the inferior limb of the arcuate sulcus (inferior arcuate sulcus, Ai), and in the lower part of ventral area 6 (6 Vb as defined by Barbas and Pandya 3). The terminal labeling in the superficial cortical layer was heaviest in the spur and genu of the arcuate sulcus (Figs. 1B, levels 3-6, and 2A-C). Some of the labeled fibers were observed running ventrolaterally or ventrally through the external capsule and lateral medullary

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Fig. 1. Diagram showing the site and extent of isotope injection (dotted areas) in the central part of VApc and the small dorsolateral part of VAmc in M 28R (A) and its anterograde autoradiographic labeling in representative coronal sections (B). Labeling fibers and terminals are shown by dashes and dots, respectively. Figure on the left middle shows reconstruction drawing of the mesial (mirror image) and lateral surfaces of its brain with the terminal labeling of superficial T-C projection (large dots) and of the deep T-C projection (smaller dots). Some sulci are unfolded. Numbers indicate caudorostral sequence. l a m i n a . A m o d e r a t e a m o u n t of t e r m i n a l l a b e l i n g was s e e n also in the m i d d l e lateral part of the n u c l e u s c a u d a t u s (CN) a d j a c e n t to the i n t e r n a l capsule, a n d in the medial p a r t of the p u t a m e n (Fig. 1B, levels 2 - 4 ) .

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____ i .... ( ~. . . . . . =" :, Fig. 2. (A) Dark-field photomicrograph showing the terminal labeling of superficial and deep thalamocortical (T-C) projections in the postarcuate premotor area after 3H-amino acid injection into VApc (M 28R). Note the terminal labeling of superficial T-C projection in the banks of superior (As) and inferior arcuate sulci (Ai). Coronal section at the adjacent level 6 depicted in Fig. lB. Scale bar = 2 mm. (B) Enlarged photomicrograph of the periarcuate area in panel A. Note the superficial terminal labeling in the banks of inferior arcuate sulcus and its location in the superficial part of lamina I. Scale bar = 2 mm. (C) Higher-power micrographs showing the terminal labeling of the superficial (superficial part of lamina I) and deep T-C projection in the postarcuate premotor area in M 28R in the dark field (left side) and the right side is the bright-field photomicrograph of the same area. I, 1I, - . . . . . V = L a m i n a e I, II, - . . . . . V. Scale bar = 500/xm.

Nucleus ventralis anterior, pars magnocellularis (VAmc) injection The VAmc injection was made in its dorsal part in M 3L, the intermediate to ventromedial part in M 28L and the ventrolateral part in M 15R (Fig. 3). In M 15R, an isotope deposit involved equally the ventrolateral part of the VAmc and the ventromedial part of the VApc (Fig. 3, level 2). The rostral part of the deposit was lightly confined within the ventrolateral part of the VAmc (Fig. 3, level 3), and the caudal part was located in the small ventromedial part of area X (Fig. 3, level 1). The superficial (superficial half of lamina I) and deep (laminae I I I - V I ) cortical terminations were observed in both banks of the arcuate genu. Only deep cortical terminations were seen in dorsal rostral area 6 (6 D R as defined by Barbas and Pandya 3), and in area 8 in the concavity of the arcuate sulcus, as well as in the caudal part of area 9 (rostrodorsal to the superior arcuate sulcus, As) (Fig. 3). A moderate amount of terminal labeling was present in the anterior amygdaloid area and in the central amygdaloid nucleus on the

124

Fig. 3. Diagram showing the site and extent of isotope injection (dotted areas) in VAmc (M 15R). The size of the injection site was determined from its appearance in the dark field. Numbers indicate caudorostrat sequence. Right figure shows the reconstruction drawing of the mesial (mirror image) and lateral surfaces of its brain with the terminal labeling of superficial T-C projection (large dots) and deep T-C projection (smaller dots). ipsilateral side to the injection. These amygdaloid afferent fibers appear to pass through the lateral medullary lamina and external capsule. In M 28L, in which the injection site involved the intermediate to ventromedial part of the VAmc, terminal labeling shifted more rostrally than those in M 15R, and a few labeled terminals were seen additionally in the orbital and medial prefrontal cortices. In M 3L with dorsal V A m c injection, terminal labeling was extended more dorsomedially than those in M 15R, and the dorsolateral part of the prefrontal cortex and banks of the rostral cingulate sulcus contained more labeled terminals.

Nucleus ventralis lateralis, pars oralis (VLo) injection The injection site was centered in the ventrolateral part of the caudal VApc and the ventromedial part of the VLo in M 22R (Figs. 4A and 5A, level 3), the dorsolateral part of the VLo with involvement of the dorsal part of the nucleus reticularis thalami in M 23L, the dorsal part of the VLo with partial involvement of the laterodorsal part of the V A p c in M 25L (Fig. 4B), and in the caudal part of the VLo in M 34R. In M 22R, an isotope deposit was placed in the ventromedial part of the VLo as well as the ventrolateral part of the VApc at the level of the rostral end of the subthalamic nucleus (Figs. 4A and 5A). The rostral and caudal parts of this injection site were confined ventrolaterally in the VApc and ventromedially in the VLo, respectively (Fig. 5A, levels 5 and 1). No involvement of other nuclei was noted at the injection site. Only gliosis was observed in the needle tip and track. The labeled fibers from the injection site ran dorsolaterally through the dorsal parts of posterior and anterior limbs of the internal capsule to reach the subcortical white matter of motor and premotor cortices. The terminal labeling was seen clearly in the superficial cortical layer (superficial half of lamina I) of the m o t o r and postarcuate premotor areas (Fig. 5B, levels 1-5). This terminal labeling was observed most strongly in the forelimb motor area defined by Woolsey 6~, and the adjacent postarcuate premotor area, with the maximum labeling in the region surrounding the arcuate spur (Fig. 6). Less intense superficial terminal labeling was present also in the regions from the mesial to dorsomedial parts of the

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Fig. 4. Bright-field photomicrographs showing -~H-aminoacid injections located in the ventrolateral part of caudal VApc and ventromedial VLo in M 22R (A) and in the dorsal part of VLo with partial involvementof the laterodorsal part of VApc in M 25L (B). Scale bar = 1 mm. rostral motor area (Fig. 5B, levels 1, 2). Terminal labeling in the deep cortical layers (deep lamina III to superficial lamina VI) was detected only rarely in the dorsomedial edge and ventrolateral parts of the motor and premotor areas (Fig. 5B, levels 1-6). There was also a moderate amount of terminal labeling in the superficial and deep cortical layers in the dorsal bank and deep corner of the cingulate sulcus adjoining the motor and premotor areas. Some of the labeled fibers passed through the lateral medullary lamina and the external capsule to terminate in the dorsomedial part of the putamen. In M 34R with injection centered in the caudal VLo, terminal labeling in the superficial cortical layer was intense in the rostral bank of the ventrolateral part of the central sulcus. In M 25L with the injection site centered in the dorsal part of VLo (Fig. 4B), terminal labeling in the superficial and deep layers was most intense in the dorsomedial and mesial surface of the rostral motor area, and adjacent SMA. In M 23L with the injection site in the dorsolateral part of the VLo, terminal labeling was observed only in the deep layers of the dorsomedial and mesial surface of the rostral motor area.

Nucleus L,entralis lateralis, pars caudalis (VLc) injection The injection site was localized in the ventromedial part of the VLc in M 91L and M 92R, the medial part in M 112R and in the dorsal part of the VLc in M 145R (Fig. 7B). In M 145R, a relatively large deposit of isotope was centered in the dorsal half of the VLc (Fig. 7B, level 2), and isotope lightly affected a small dorsal part of the nucleus reticularis thalami rostrally and caudally (Fig. 7B, levels 3 and 1). The needle track was partially labeled in the subcortical white matter due to backflowing of isotope, but was minimal. In this case (Fig. 7A), the labeled fibers arising from the injection site passed through the dorsal parts of the posterior and anterior limbs of the internal capsule and reached the subcortical white matter of the frontal lobe. Most of these fibers traveled

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Fig. 5. Diagram showing the site and extent of isotope injection (dotted areas) in the ventral to ventromedial parts of VLo and ventrolateral part of VApc in M 22R (A) and its anterograde autoradiographic labeling in representative coronal sections (B). Figure on the left middle shows reconstruction drawing of the mesial (mirror image) and lateral surfaces of its brain with the terminal labeling of the superficial T-C projection (large dots) and of deep T-C projection (smaller dots). Some sulci are unfolded. Numbers indicate caudorostral sequence. Details as in Fig. I.

dorsomedially or dorsally and terminated in the deep cortical layers of the dorsomedial part of the rostral m o t o r area (around the superior precentral sulcus), and of dorsal caudal area 6 (6 DC), as well as in the S M A and the mesial cortex of the rostral motor area (Fig. 7A, levels 3-6). The terminal labeling was much denser in dorsal caudal area 6 (6 DC). No terminal labeling was observed in dorsal rostral area 6 (6 DR). In M l 1 2 R with a large deposit of isotope in the medial half of the VLc, the deep cortical termination was observed in the forelimb motor area as defined by Woolsey 69, and adjacent postarcuate p r e m o t o r area as well as in the u p p e r part of ventral area 6 (6 Va as defined by Barbas and Pandya 3). T h e other findings were similar to those of M 145R.

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Fig. 6. Dark-field photomicrograph showing the terminal labeling of the superficial T-C projection in the ventrolateral part of motor area and around the arcuate spur after 3H-amino acid injection into the ventromedial part of rostral VLo with involvement of the ventral part of posterior VApc (M 22R). Coronal section at the adjacent level 1 depicted in Fig. 5B. Scale bar = 1 mm.

Nucleus t.~entralis lateralis, pars medialis (VLm) injection The VLm injection was successful only in one case (M 54R, not illustrated). In this case, a deposit of isotope was involved in a large triangular area which affected a small ventral part of the VPLo, the rostral part of the nucleus ventralis posterior inferior (VPI), and the nucleus ventralis posteromedialis, pars parvicellularis (VPMpc), but the bulk of the labeled area was found in the VLm. The rostral part of the deposition site was mainly localized in the lateral part of the VLm and in the caudal part located largely in the VPMpc with minimum involvement of the lateral part of the nucleus centrum medianum (CM). The needle track was faintly labeled in area X and the medial part of the VPLo. In this case, the superficial and deep cortical terminations were observed in the frontal operculum and the rostrodorsal part of the insula. Only superficial cortical terminations were seen in the ventrolateral part of the motor area and in the postarcuate premotor area adjoining the arcuate genu and spur. Area X injection The injection site was centered in the central part of area X in M 69R (Fig. 8A) and M 101R, in the dorsomedial corner in M 97R, and in the ventral part in M 147R. In M 69R, the central portion of an isotope deposit covered the middle third of the dorsoventral extent and full mediolateral extent (Fig. 8A, level 2). The rostral portion of the deposit was restricted to the lateral part of middle area X (Fig. 8A, level 3), and the caudal portion to the small medial portion of the middle third of the dorsoventral extent of the VPLo and the adjacent paracentral nucleus (Fig. 8A, level 1). In this case, the terminal labeling was intense and regularly seen in the postarcuate premotor area, and moderate in the SMA as well as in both banks of the arcuate sulcus. There was also terminal labeling in dorsal rostral area 6 (6 DR) (Fig. 8B). In M 97R with an injection centered in the dorsomedial end of area X, terminal labeling occurred in the dorsomedial part of the caudal levels of the prefrontal cortex (area 9) in addition to the regions mentioned above. These terminal labelings were observed exclusively in the deep layers. Terminal labelings in the ventrolateral part of area 4 were present only in M 69R.

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Nucleus ventralis posterolateralis (VPL) injection Injections were made into the various parts of the posterior ventral thalamic nucleus in 7 cases (not illustrated). In M 34L, with an injection site centered in the ventromedial part of the nucleus ventralis posterolateralis, pars oralis (VPLo), the terminal labeling was observed only in the deep cortical layers of the intermediate to ventrolateral parts o f the motor area and area 3a. This terminal labeling was maximal in lamina III (Fig. 9A, B). In M 169R, with an injection centered in the transitional level of the nucleus ventralis posterolateralis, pars caudalis (VPLc) and VPLo, terminal labeling was seen in the deep

130

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Fig. 9. Dark (A)- and bright (B)-field photomicrographs showing the deep T-C projection in the forelimb motor area and area 3a after 3H-amino acid injection into the ventromedial part of VPLo (M 34L). Coronal section. Scale bar = 1 rnm. layers of both banks of the ventrolateral half of the central sulcus (areas ventrolateral part of the postcentral gyrus (roughly corresponding to area dorsal bank of the cingulate sulcus adjacent to the caudal motor area. labeling was profuse in areas in the fundus and caudal bank of the central 3b).

4, 3a and 3b), 1), and of the This terminal sulcus (3a and

DISCUSSION The identification of injection sites is one of the most important procedures in the present experiments and further clarification is required regarding the extent of injection sites where the uptake and transport of isotope are considered. The possibility of spurious labeling due to the passage of the injection needle may be negligible, because

131 TABLE I MAJOR FINDINGS OF THE THALAMOCORTICAL (T-C) PROJECTIONS FROM MOTOR THALAMIC NUCLEI Superficial and deep T-C projections VApc VAmc VLo

Superficial T-C projection

Area 6 (postarcuate premotor area, 6 DC), SMA Area 6 (banks of arcuate genu) Dorsomedial to mesial parts of rostral area 4, dorsal bank and fundus of cingulate sulcus

Area 4 (ventrolateral part) Rostral area 4 (around the superior precentral sulcus), mesial part of rostral area 4, 6 DC, SMA

VLc

VLm

Deep T-C projection 6 DR, 6 Vb, rostral part of inferior arcuate sulcus 6 DR, area 8, caudal part of area 9

Frontal operculum, rostrodorsal part of insula

Ventrolateral part of area 4, postarcuate premotor area adjoining to the arcuate genu and spur

Area X VPLo

Area 6, SMA, banks of arcuate sulcus Area 4, area 3a

6 DC = dorsocaudal part of area 6 as defined by Barbas and Pandya 3; 6 DR = dorsorostral part area 6; 6 Vb = lower part of ventral area 6 as defined by Barbas and Pandya 3. t h e l a b e l i n g a l o n g t h e n e e d l e t r a c k was least, e x c e p t for 2 cases (M 2 3 R a n d M 54R) in w h i c h a r e a X o r t h e v e n t r a l p a r t of t h e b o d y of t h e c a u d a t e nucleus was faintly l a b e l e d .

Thalamic projection onto the cortical lamina I L a m i n a I p r o j e c t i o n s in t h e f r o n t a l c o r t e x w e r e r e p o r t e d to arise f r o m t h e V A - V L n u c l e u s v e n t r a l i s m e d i a l i s (VM) 9,13,14,35 t h e n u c l e u s m e d i a l i s dorsalis (MD)33,49,62, and f r o m the i n t r a l a m i n a r nuclei 11.19,28,50. L a m i n a I p r o j e c t i o n s also in t h e p a r i e t a l c o r t e x w e r e r e p o r t e d from the V A - V L comp l e x 11,24,27,31,53,54.J i n n a i et al. 17 s h o w e d t h a t t h e t h a l a m i c n e u r o n s receiving i n h i b i t o r y i n p u t from the e n t o p e d u n c u l a r n u c l e u s p r o j e c t to l a m i n a I o f the a n t e r i o r s i g m o i d gyrus, w h i l e the t h a l a m i c n e u r o n s excited by t h e c e r e b e l l a r nuclei project m a i n l y to d e e p e r l a y e r s in t h e cat. I n the p r e s e n t e x p e r i m e n t , the s u p e r f i c i a l T - C p r o j e c t i o n was o b s e r v e d in t h e s u p e r f i c i a l half of l a m i n a I a f t e r 3 H - a m i n o acid i n j e c t i o n s in the VLo, V L m , V A p c a n d V A m c (Fig. 2C, a n d T a b l e I). In all c a s e s o f t h e V L o injections e x c e p t for M 23L, t h e s u p e r f i c i a l cortical t e r m i n a t i o n was s e e n in t h e f o r e l i m b m o t o r a r e a d e f i n e d by Woolsey 69. This s u p e r f i c i a l t e r m i n a t i o n was o b s e r v e d also in the r e g i o n s f r o m t h e m e s i a l c o r t e x to t h e d o r s o m e d i a l p a r t o f t h e r o s t r a l m o t o r area, a n d in t h e p o s t a r c u a t e p r e m o t o r a r e a a r o u n d t h e a r c u a t e g e n u a n d s p u r in M 22R a n d M 25L, in which t h e V L o injection site e n c r o a c h e d p a r t i a l l y u p o n the V A p c , b u t no t e r m i n a t i o n s o r only a few, if any, w e r e s e e n in t h e p o s t a r c u a t e p r e m o t o r a r e a in 2 o t h e r cases with n o l e a k a g e o f t h e injection into V A p c . T h e t e r m i n a t i o n in t h e p o s t a r c u a t e p r e m o t o r a r e a a p p e a r s to b e d u e to t h e V A p c p r o j e c t i o n . T h e s e f i n d i n g s i n d i c a t e V L o p r o j e c t i o n to t h e s u p e r f i c i a l c o r t i c a l layer in t h e f o r e l i m b m o t o r a r e a a n d p o s s i b l y in t h e regions f r o m t h e d o r s o m e dial p a r t to t h e m e s i a l c o r t e x o f the r o s t r a l m o t o r a r e a .

complex 11,17,18,25,45.49.58,59,62,63,71,the

132 In M 15R (Fig. 3), the injection site in the VAmc was extended partially to a ventromedial portion of the VApc, and the labeled terminals in the postarcuatc premotor area and the dorsomedial part of the premotor area might be considered as from the VApc, since labeled terminals were not observed in these areas in M 281. or M 3L in which the injection site was shifted m o r e medially. The VAmc projection to the banks of the principal sulcus, frontal eye field, and to the orbitofrontal cortex were indicated by the H R P method i~,. Our data support these findings. The ventrolateral part of the V A m c projects to the frontal eye field but not to the orbital cortex, in agreement with the findings of Ilinsky et al. 16. Our most important finding of the VAmc projection are the lamina I terminations around the arcuate genu and arcuate spur (Fig. 3, right side). Segregated projection of nigro-VAmc-prefrontal connections was suggested 16 Only the deep T-C projection was observed in all other cases with -~H-amino acid injections into the VLc, area X, VPLo, VPLc, VPM, M D and intralaminar nuclei (iLa). but we have no cases of injections limited within the iLa (Table I). Some authors reported fiber projections onto lamina I from the thalamic sensory nuclei 18,22,63. Lamina 1 projection from the MD was denied in the rhesus monkey ~2. The parietal projection from the motor thalamic nuclei was not detected in the present experiments. As the present observation focused on the frontal projections, further detailed studies are needed in this field. On the basis of electron-microscopic findings {,0x,7, the terminations of deep T-C projections appear to make excitatory synaptic connections, mainly axo-spinosus synapses, with apical dendrites of pyramidal cells or stellate cells, and to exert a powerful effect on the discharges of the pyramidal cells. The terminations of superficial T-C projections were considered to synapse with the distal part of apical dendrites of pyramidal cells and dendrites of inhibitory interneurons of superficial layers (small basket cells and axonal tuft cells), and to exert a focusing effect on the pyramidal ceil discharge via these interneurons.

Cerebello-thalamo-cortical projections In spite of many studies on the cerebello-thalamic projections, the thalamic targets of each cerebellar nucleus still remain to be debated. The cerebellar projection onto the VLo, VLc, area X, VPLo, nucleus centralis lateralis (CL) and lateral part of the MD are reported 1,2,7,15,26,29,34,38,39,48,61,65 but some investigators 1,2,J5,48 did not describe the termination in the VLo. There are also some disagreements about the projection onto the VA 7,26,29,34,38,39,61. Others 1,2,15,48 indicated no projection to the VA. The rostral part of the lateral cerebellar nucleus projects onto the lateral parts of the ventral thalamic nuclei 1,7,26.61,65. Sasaki et al. 55 suggested that the superficial T-C responses in the precentral gyrus set up by stimulation of the lateral and intermediate cerebellar nuclei are relayed by the rostrolateral part of the V L and the caudal part of the VA. Our data substantially indicated the superficial thalamocortical projection to the ventrolateral part of the motor area and adjacent arcuate premotor area from the VLo and VApc, respectively. The VApc and V i m may be considered as relay nuclei in the superficial T-C projection from the rostral part of the cerebellar nuclei. However, the cerebellar projections to the VApc and V L o have been denied 1,2,20 Investigators are still not in agreement regarding the cortical targets of VLo projections. Since the reports of Schell and Strick 57 and Jones 20, the VLo projection to the SMA 57,68, or p r e m o t o r area 23,66 have been accepted by many researchers, although the VLo projection to the motor area 10,25,30,36,37,40,64 and VA projection to the p r e m o t o r

133 a r e a 10,25,30,40 have been described. According to Shell and Strick 57, the p r e m o t o r area receives afferents from area X. On the basis of our previous H R P studies 44 in the Japanese monkey, the p r e m o t o r area receives afferents from both the VApc and a r e a X, but more strongly from the VApc. In the present experiment, the superficial T-C projection of the VApc was seen in the postarcuate premotor area, and dorsal caudal area 6 (6 D C ) as well as the SMA. A r e a X indicated by Shell and Strick 57 seems to be extended m o r e rostrally, and the VApc was defined only dorsally. The discrepancy of the p r e m o t o r projection from the V A or area X among authors appears to be due to the difference in thalamic nuclear bordering. Neurons projecting to the premotor cortex were indicated continuously caudomedially in the VA through VLc, area X and also VLm, but not in the lateral VLo 10, in agreement with our findings 44 The medial cerebellar nucleus projects onto the VPLo, VLc, and the ventrolateral part of the V L o 4,26,29, but A s a n u m a et al. l have reported this nucleus projection into the entire extent of the thalamic cell sparse region. Y a m a m o t o et al. 70 have suggested that the medial cerebellar nucleus sends the deep T-C projection onto the medial part of the precentral area via the lateral part of the VPLo. The present observations in M 84L provide additional evidence in support of this thalamocortical connection. It was indicated that the rostromedial part of the ventral thalamic nuclei (VAmc, medial VLc, area X), the iLa and the lateral part of the MD send deep T-C projections to the frontal association cortex and the dorsomedial part of the rostral premotor cortex, on the basis of our findings in which injections involved various parts of the medial thalamic area (M 15R, Fig. 3; M 69R, Fig. 8; M 91L, M 97R, M 101R, M 112R and M 147R). The d e e p T-C responses were found in the frontal association cortex after lateral cerebellar nucleus stimulation 56. As the caudal part of the lateral cerebellar nucleus projects onto the medial thalamic area 1,7,26,61,65, the caudal part of the lateral cerebellar nucleus appears to send deep T-C projections onto the frontal association cortex via the thalamic relay nuclei mentioned above.

Pallido-thalamo-cortical projections Recent studies using axonal transport techniques support the segregated thalamic projections from the pallidum, substantia nigra and the cerebellar nuclei 21. The medial pallidal segment projects onto the VLo and V A p c 32, and the substantia nigra onto the VLm, V A m c and the paralamellar part of the M D 6,16 The VLo was considered as the relay nucleus of the pallidal projection to the p r e m o t o r cortex 2.20 or the SMA 57,68. It was postulated that the cerebellar efferents project exclusively to area 4 via the VPLo 20,23,66 Recently, Orioli and Strick 47 indicated the cerebellar projections to the arm areas of premotor and m o t o r cortices via area X and VPLo, respectively. On the other hand, motor area projections were indicated from the ventrolateral or lateral VLo 10,30,40, the caudal VLo 16, or the VLo and rostral V P L o 25. Recently, Mattelli et al. 37 have indicated that the cortical area ventrocaudal to the arcuate genu and arcuate spur (area F4), and rostral m o t o r cortex receive afferent fibers from the VLo. Also in our cases, the superficial cortical terminations were observed in these regions following the V L o and VApc injections. Using the electrical stimulation method, N a m b u et al. 41,42 reported that the pallidal input is relayed to the motor cortex via the VLo in the monkey. The present finding supports the motor cortical projections from the VLo, V P L o and VLc, in a g r e e m e n t with some other authors 111,30,36,40,64. Our data confirmed the VLc projection to the anterior part of the motor area 23. Our data also indicated the VLo projection to the motor cortex, at least to its rostral portion. The superficial T-C

134 projection to the premotor and motor cortices from the pallidum via the VApc and VLo might be considered. No physiological study, however, has been done on this projection except by Jinnai et al. ~7 and Nambu et al. 4J.42. Further studies are required concerning the functional significance of interaction between the pallidal projection and the cerebellar nucleus projection. The thalamic nuclei relaying cerebellar affercnts to the superficial cortical layer were not clarified in the present experiment. ACKNOWLEDGEMENTS This study was partly supported by grants for scientific research (Nos. 557017. 56570022 and 57570023) from the Japanese Ministry of Education. The authors wish to express their appreciation to Kazuo Yamaguchi, Satoru Imamura and Chiharu Moriya for their technical assistance and to Sachiko Ogata for her help in preparing the manuscript. ABBREVIATIONS Ai As Asp Ce Ci CL CM CN GPm GP1

sulcus arcuatus, ramus inferior sulcus arcuatus, ramus superior arcuate spur sulcus centralis sulcus cinguli nucleus centralis lateralis nucleus eentrum medianum nucleus caudatus globus pallidus, medial segment globus pallidus, lateral segment

La MD P

sulcus lateralis nucleus medialis dorsalis sulcus principalis

Pc Prs Put SMA SN STN VAmc

nucleus paracentralis sulcus precentralis superior putamen supplementary motor area substantia nigra nucleus subthalamicus nucleus ventralis anterior,

VApc VI_z VLm VLo VPLo

VPMpc

X 3a 3b 4 6 8

pars magnocellularis nucleus ventralis anterior, pars principalis nucleus ventralis lateralis, pars caudalis nucleus ventralis lateralis, pars medialis nucleus ventralis iateratis, pars oralis nucleus ventralis posterolateralis, pars oralis nucleus ventralis posteromedialis, pars parvocellularis area X area 3a area 3b area 4 area 6 area 8

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