Connectivity of the Inferior Olivary Complex in Normal and Neonatally Hemicerebellectomized Rats

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1980

Rand S. Swenson Loyola University Chicago

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NORMAL AND NEONATALLY HEMICEREBELLECTOMIZED RATS

Rand S. Swenson

A Dissertation Submitted to the Faculty of the Graduate School

Of Loyola University of Chicago in Partial Fulfillment

of the Requirements for the Degree of

Doctor of Philosophy

February

1981 DEDICATION

To my family, especially my wife, Mardrey Fish, my children,

Krister and Ingrid, and my parents for their encouragement and patient understanding, this dissertation is lovingly dedicated.

ii ACKNOWLEDGEMENTS

The author takes this opportunity to thank Dr. Anthony J.

Castro without whose patience, advice and guidance this dissertation would not have been completed .

. . . the members of his dissertation committee, Dr. John

Disterhoft, Dr. James Hazlett, Dr. Robert Wurster and Dr. E. J.

Neafsey for their helpful suggestions and criticisms.

Miss Rebecca Auten for typing this manuscript.

the anatomy department of Loyola University Stritch

School of Medicine for affording me the opportunity of graduate study in anatomy.

and the National College of Chiropractic for support of my graduate training.

iii VITA

The author, Rand S. Swenson, was born on November 14, 1953 in Mineola, New York.

In 1971 he graduated from Stamford Central School in Stamford,

New York. In September 1971 he entered the State University of

New York College at Oneonta, from which he transfered to the

National College of Chiropractic in September 1973. He received the degree of Bachelor of Science in human biology from the

National College of Chiropractic in 1974 while pursuing his chiropractic studies, which he completed in December 1976 receiving the degree of Doctor of Chiropractic, summa cum laude.

In January 1977 he joined the anatomy faculty of the National

College of chiropractic, where he has taught neuroanatomy and gross anatomy.

In March 1977 he began his graduate studies in the Department of Anatomy at Loyola Univeristy of Chicago's Stritch School of

Medicine.

In ·october 1979 he was awarded a post-doctoral fellowship starting in December 1980 at Loyola University Stritch School of

Medicine, where he will work in the Departments of Anatomy and

Physiology under Drs. Castro and Wurster.

The author is married to Dr. Mardrey Fish and has two children, Krister and Ingrid.

iv TABLE OF CONTENTS

Dedication ...... ii

Acknowledgements ...... ••.....•...... •...... iii

Vita ...... •...... •....•...... iv

List of Figures ...... •...... ••...... ••..•.•.•...... vii

Introduction ...... •...... 1

Background ...... •...... •...... 4

General Morphology ....•...... •...... •.•...•...... 4 Inferior Olivary Af ferents ...... •..•...... •...... 9 Retrograde Experimentation ...... 9 Orthograde Experimentation •...... •...... •...... 13 Olivocerebellar Connections ...... •...... 24 Anterograde Studies .....•...... •...... •..•.•...... 24 Retrograde Studies ....•.•...... •...•....•....•...... 25 Physiology of Olivary Afferents ..•...... •. 29 Plasticity ...... ••.•...... •.•..••..•...... 3 7

Materials and Methods .....•...... 43

Surgical Procedure ...... •...... •. 43 Horseradish Peroxidase Technique ....•...... 44 Fink-Heimer Technique ...... •...... •... 45 Autoradiographic Technique ...... •...... 45

Results ...... •..•..••...... •...... •..•..• 4 7

Retrograde Analysis of Inferior Olivary Afferents ...... 47 Anterograde Analysis of Inferior Olivary Afferents ...... 55 Inferior Olivary Efferents ...... •.••...... 61 Inferior Olivary Afferents in Hemicerebellectomized Rats ...... 63 Inferior Olivary Efferents in Hemicerebellectomized Rats ...... 66 Effects of Vestibular Nerve Lesion in Hemicerebellectomized Rats .. 67

Disc us s ion ...... 6 8

Inferior Olivary Afferents ...... •...... 68 Spinal Cord ...... •...... •...... 6 8 Caudal Brains tern ...... 70 Cerebellum ...... •...... 76 Rostral Brains tern ...... •...... •...... 79 Cortex ...... •...... 89

v Inferior Olivary Efferents ...... 92 Inferior Olivary Afferents in Hemicerebellectomized Rats ...... 93 Effects of Vestibular Nerve Lesion in Neonatally Hemicerebellectomized Rats ...... 99

Summary ...... 101

Figures ...... 104

List of Abbreviations ...... 20Lt

Table ...... 205

References ...... 206.. .

vi TABLE OF FIGURES

Figure Page

1. Inferior olivary subdivisions ...... 105 2. Olivocerebellar topography ...... 107 3. Location of spinal neurons projecting to the IOC, case 877 ...... 109 4. Location of spinal neurons projecting to the IOC, case 923 ...... 111 5. Brain stem neurons projecting to the IOC, case 923 ...... 113 6. Photomicrographs of labeled neurons, case 923 ...... 115 7. Brain stem neurons projecting to the IOC, case 921 ...... 117 8. Photomicrographs of labeled neurons, case 923 ...... 119 9. Brain stem neurons projecting to the IOC, case 924 ...... 121 10. Photomicrographs of labeled neurons, case 924 ...... 123 11. Brain stem neurons projecting to the IOC, cases 922 and 877 ...... 125 12. Photomicrographs of labeled neurons, cases 922 and 877 ...... 127 13. Inferior olivary injection sites ...... 129 14. Spina-olivary projections ...... 131 15. Dorsal Column nuclear projections to the IOC ...... 133 16. Reticula-olivary projections ...... 135 17. Lateral reticular nuclear projections to the IOC ...... 137 18. Spinal trigemino-olivary projections ...... 139 19. Vestibula-olivary projections ...... 141 20. Vestibula-olivary projections ...... 143 21. Nucleus prepositus hypoglossi projections to the IOC ...... 145 22. Rostral dentate projections to the IOC ...... 147 23. Caudal dent a to-olivary projections ...... 149 24. Ventral dentato-olivary projections ...... 151 25. Rostral interposi to-olivary projections ...... 153 2 6. Caudal interposito-olivary projections ...... 155 27. Fastigio-olivary projections ...... 157 28. Caudal pretecto-olivary projections ...... 159 29. Projections from the nucleus of the optic tract to the IOC ...... 161 30. Tecto-olivary projections •...... 163 31. Tecto-olivary project ions ...... 165 32. Rubral and prerubro-olivary projections ...... 167 33. Lateral deep mesencephalic nuclear projection to the IOC ...... 169 34. Medial deep mesencephalic nuclear projections to the IOC ...... 171 35. Medial terminal nuclear projections to the IOC ...... 173 36. Prerubral projections to the IOC ...... 175 3 7. Periaqueducto-olivary projections ...... 177 38. Subparafascicular nucleo-olivary projections ...... 179 39. Nucleus of Darkschewitsch projections to the IOC ...... 181 40. Cortico-olivary projections ...... 183 41. Summary of vestibula-ocular inputs to the IOC ...... 185 42. Somatosensory inputs to the IOC ...... 187 43. Summary of Cerebella-olivary connections ...... 189 44. Summary of reticular inputs to the IOC ...... 191 45. Summary of meso-diencephalic inputs to the IOC ...... 193 46. Summary of inputs to the IOC ...... 195 47. Photomicrographs of inferior olivary efferents ...... 197 48. Inferior olivary efferents ...... 199 49. Brainstem neurons projecting to the IOC after hemicerebellectomy ...... 201 50. Photomicrographs of meso-diencephalic inputs to IOC after neonatal hemicerebellectomy ...... -: ...... 203 " ... the organization of the inferior olive is very precise and almost incredibly complex."

Alf Brodal, 1981

INTRODUCTION

The neurons of the inferior olivary complex (IOC) exert the mast powerful excitatory influence upon the r.ich dendritic arbors of the cerebellar Purkinje cells. By this direct well-developed association, the IOC can strongly affect the many and varied functions related to the cerebellum which in spite of virtually countless studies are not satisfactorily understood. Accordingly, the major premise for undertaking a thorough analysis of olivary afferents is to further the understanding of cerebellar function.

As stated by Professor Brodal, who has devoted forty years to the study of cerebellar anatomy, "The input to the cerebellum from the olive must, therefore, be assumed to play a particular and important role in the general mode of operation of all parts of the cerebellar cortex, regardless of which spheres of activity

(vision, hearing, voluntary or reflex motor functions, etc.) a region is primarily concerned with" (Brodal, 1981).

As the functional implications of the cerebellum are very complex, not surprisingly so are the connections of the IOC. The numerous pathways to this nuclear complex, implicating several functional systems, have for the most part only recently been determined from studies on several species. Considerable effort has been invested toward determining the origin of olivary

1 2 afferents as well as toward describing their overlapping distribution patterns within.the olive. This work has been stimulated by the development of new techniques involving the orthograde or retrograde transport of tracer molecules. Parallelling the increasing knowledge of olivary afferent systems, is an increased understanding of olivocerebellar climbing fiber projections. The high degree of organization within this projection demands analysis in light of the highly ordered olivary afferent projections, with the goal of understanding the various pathways of climbing fiber activation of the cerebellum. Physiological experiments have basically considered the nature of the olivocerebellar input, the type of input transmitted along these pathways and the specific influences of olivocerebellar climbing fibers on Purkinje cells and cerebellar output.

The specific goals of this dissertation include the determination of the origins of olivary afferents, as determined by retrograde tracing techniques using HRP, and the subsequent analysis of the distribution patterns of these afferents within the olive using autoradiographic or axonal degeneration techniques. Additionally, the distribution of olivocerebellar fibers was examined by autoradiography.

Although numerous reports have examined many olivary connections in various animals, this study constitutes the only attempt to undertake a comprehensive analysis of those pathways in a single species. As the IOC has been implicated in the recovery of 3 functions seen after cerebellar lesions, which has been documented in numerous studies, an analysis of neuroanatomical remodelling of olivary afferents after neonatal hemicerebellectomy was also undertaken. This study is derived from several reports suggesting that anomalous pathways, which often develop after neonatal lesions, may provide the anatomical substrate for functional compensation. BACKGROUND

General Morphology

The inferior olivary complex (IOC) is comprised of small, generally spherical neurons situated immediately dorsal to the pyramids in the caudal brainstem. This complex has been shown to be present in all vertebrates investigated with the possible exception of cyclostomes (Kooy, 1916) and assumes a characteristic and rather uniform appearance in mammals.

Three major subnuclei have been identified in the roc (figure

1), the principal olive (Po), the medial accessory olive (Mao), and the dorsal acessory olive (Dao). Both the Po and Mao in turn have subdivisions. In coronal sections, the Po is generally "C" shaped although it is somewhat flattened dorsoventrally resulting in a dorsal lamella (Pod) and a ventral lamella (Pov). The open side of the "C" faces medially, and the closed side is identified as the lateral bend. In comparison to the Po which is only present in the rostral half to two-thirds of the IOC, the Mao is present at almost all levels. It is most extensive in the caudal third of the roc where it is elongated transversely into three small aggregations identified laterally to medially as subdivisions a, b and c. Subnucleus c is surmounted dorsally by a group of cells known as the beta subnucleus. A small group of cells identified as the dorsal cap lie dorsal to the beta subnucleus and at more rostral levels becomes continuous with a small projection of cells known as the ventrolateral outgrowth. Over the rostral

4 5

two-thirds of the IOC, the Mao is smaller and is located adjacent

to the midline, directly medial to the Po. The Dao is a mediolaterally

elongated nucleus which is present for the rostral two thirds of

the IOC, forming a dorsal layer over the Po and separating it

from the overlying reticular formation. Lastly, a relatively

small subdivision, the dorsomedial cell column (DMCC), is present

over much of the rostral half of the IOC. It is situated immediately

dorsal to the Mao and some consider it to be a subdivision of

that nucleus (Bowman and Sladek, 1973). This general pattern has

been confirmed in several mammals including the opossum (Martin

et al., 1975, Watson and Herron, 1977), vampire bat (Escobar,

Sampedro and Dow, 1968), rat Gwyn, Nicholson and Flumerfelt,

1977), rabbit (Jansen and Brodal, 1954), cat (Jansen and Brodal,

1954; Scheibel and Scheibel, 1955; Escobar et al., 1968), pig

(Breazile, 1967), elephant (Kooy, 1916), whale (Korneliussen and

Jansen, 1964), squirrel monkey (Rutherford and Gwyn, 1980) and

rhesus monkey (Bowman and Sladek, 1973).

The proportion of the IOC which is devoted to each of the

subnuclei varies from species to species. In general, the

phylogenetically more advanced the animal, the proportionally

larger is the Po. For example, in the rat the Po comprises approximately 25% of the IOC neurons (Schild, 1968) while in man

it contains 85% of the cells (Moatamed, 1966). The size of the

roc apparently relates to the size of its target, the cerebellum

(Marsden and Rowland, 1965) and more specifically, the size of 6

an individual subnucleus of the roc correlates with that portion

of the cerebellum to which it projects. This relationship is most effectively demonstrated in man, with the larger Po related

to large lateral cerebellar hemispheres, and in cetaceans which

posess an enlarged rostral Mao corresponding to a well developed

cerebellar anterior lobe (Korneliussen and Jansen, 1964).

Inferior olivary neurons, while appearing to be of rather

uniform size and generally spherical shape, do show an increase

in size according to phylogeny and size of the animal. For example,

roc neurons have been estimated to be 13.2u in diameter in the

rat, 14.6u in the vampire bat, 24u in the cat and 25u in humans (Schild, 1968; Escobar et al., 1968; Moatamed, 1966).

Furthermore, the phylogenetically newer portion of the IOC (i.e.,

the Po) has been shown in man to contain generally larger neurons

then do the accessory olives (Moatamed, 1966).

The dendritic trees of roc neurons have been described as

being among the more complex in the nervous system (Cajal, 1909).

The dendrites arborize in restricted areas around the cell body,

but due to close packing of cells within the IOC, there is a

considerable amount of overlap between the dendritic arbors of adjacent neurons (Scheibel and Scheibel, 1955). As opposed to

the trend for olivary cells to be of larger diameter with ascent of the phylogenetic scale, the diameter of the dendritic tree appears to decrease, for example from 200u in the cat to 150u

in the monkey and 115u in man (Scheibel and Scheibel, 1955). 7

This reduction in diameter occurs concurrently with an increased complexity of the arborization (Scheibel and Scheibel, 1955) and a decrease in the packing density of neurons in the roc from

65,406 cells/mm3 in the vampire bat, to 43,900/rnm3 in the rat,

8,400/mm3 in the cat and 5000/rnm3 in man (Schild, 1968; Escobar et al., 1968). The smaller, albeit more complex, dendritic arbor, coupled with fewer cells/mm3 in higher forms probably assures a greater degree of independence in the activation of olivary neurons, even though electrotonic coupling appears between small groups of olivary neurons even in man (Scheibel and Scheibel,

1955).

Axons of olivary neurons give off short collaterals within the IOC before decussating in many small bundles (Cajal, 1909).

They pass through the contralateral IOC, apparently without synapsing, and enter the medial portion of the inferior cerebellar peduncle. These fibers branch, some perhaps terminating, within the lateral vestibular nucleus (Lorente de No', 1924) and deep cerebellar nuclei (Matsushita and Ikeda, 1970; Groenwegen and

Voogd, 1977; Groenewegen, Voogd and Freedman, 1979), before continuing on to the cerebellar cortex as the classically described climbing fibers. Prior to entering the cerebellar cortex, the climbing fibers generally bifurcate (Fox, Andrade and Schwyn,

1969; Faber and Murphy, 1969; Armstrong, Harvey and Schild, 1971,

1973a,b), and project a single branch to each Purkinje cell arbor

(Cajal, 1909). 8

On an ultrastructural level, the site of interaction between

afferent axons and olivary dendrites has been decribed as a

glomerular structure (Bowman and King, 1973; Gwyn, Nicholson and

Flumerfeld, 1977; Rutherford and Gwyn, 1980) consisting of a

central dendrite or dendrites surrounded by axon terminals containing

spherical, flattened or, rarely, dense core vesicles. Occasionally,

gap junctions can be observed between the dendrites, ostensibly

providing a substrate for the mass discharge which may be observed within IOC neurons from individual regions. 9

Inferior olivary afferents

Retrograde experimentation

Methods employing the retrograde transport of horseradish peroxidase (HRP) have been used to define the various sites of origin of afferents to the IOC. The reports by Brown, Chan-Palay and Palay (1977) and by Buisseret-Delmas and Batini (1978) were intended to provide a comprehensive picture of the origins of olivary afferents in rats and cats respectively, while numerous other reports on various species were limted to examination of one specific site or region.

Comprehensive Studies

Brown et al. (1977) injected the inferior olivary complex of rats with HRP via a ventral approach to the brainstem. The injection spread was largely confined to the IOC, thereby decreasing complications associated with spread to the reticular formation.

Numerous sites of labeled neurons were observed extending from the cervical spinal cord to the cerebral cortex. In general, labeled neurons situated caudal to the IOC were found contralateral to the injection site in the nucleus proprius of the cervical spinal cord, and the dorsal column and lateral reticular nuclei of the medullary brainstem. Rostral to the level of the IOC, labeled somata were almost entirely ipsilateral to the roc and were distributed in the subparafascicular nucleus, central gray, nucleus of Forel's field, nucleus of Darkschewitsch, nucleus of

Cajal, Edinger-Westphal nucleus, red nucleus, pretectal complex 10 and tegmentum. At the level of the IOC, the laterality was shown to be less precise. A contralateral predominance was shown for labeled neurons in the dentate and interposed cerebellar auclei and the spinal nucleus of the trigeminal nerve, while the nucleus preposius hypoglossi and the medial and descending vestibular nuclei were primarily ipsilateral. The gigantocellular reticular nucleus was labeled bilaterally and the nucleus raphe obscuris was labeled along the midline of the brainstem. The cerebral cortex contained reactive neurons primarily ipsilaterally, although this may not reflect the true distribution of cortico-olivary fibers considering that the ventral approach to the IOC as used in this experiment necessarily damages fibers of the pyramidal tract. Transected axons are known to incorporate and transport

HRP, in this case back to the ipsilateral cerebral cortex. Brown et al. (1977) specifically noted the absence of labeled cells in the fastigial nucleus, the globus pallidus, the caudato-putamen and the locus coeruleus.

It is noteworthy, when comparing the above findings by Brown and colleagues with those of the current study, that they used 24 to 36 hour post injection survival times and that they utilized diamino-benzidine as the chromogen for the HRP reaction whereas our results were derived from animals with 48 to 72 hour post injection survival times and utilized the more sensitive 0- dianisidine chromogen (de Olmos, 1977). 11

Generally corroborative data were reported after small injections of HRP into the ICC of cats (Buisseret-Delmas and

Batini, 1978). In this study labeled cells were found in the contralateral lamina VI of the cervical spinal cord, the contralateral deep cerebellar nuclei and the ipsilateral interstitial nucleus of Cajal. They also found a topologic distribution pattern in the dorsal column nuclear and vestibular complex input to the roc:

Restricted studies

A more restricted region, i.e. the mesencephalon and diencephalon, was examined following large HRP placements within the IOC and reticular formation of opossum (Henkel, Linauts and Martin,

1975). Regions found to project to the ipsilateral IOC included the subparafascicular nucleus, nucleus of Forel's field, the nucleus of Cajal, the nucleus of Darkschewitsch, the pretectum and the red nucleus, and bilateral projections arose from the tegmentum, periaqueductal gray and nucleus of the posterior commissure.

In addition to above mentioned reports (Brown et al., 1977;

Henkel et al., 1975), a number of studies have examined the origin of pretecto-olivary fibers. For example, labeled neurons within the nucleus of the optic tract, dorsal and lateral terminal nuclei of the accessory optic tract, and, to a lesser extent, in the anterior pretectal nucleus following injections centered in 12 the dorsal cap of the IOC in rabbits (Takeda and Maekawa, 1976).

This report is generally supported by studies of the tree shrew where reactive cells were reported to be largely confined to the nucleus of the optic tract (Weber and Harting, 1980). These findings are at some variance with other reports (Brown et al.,

1977; Henkel et al., 1975; Abols and Basbaum, 1979) which identified labeled cells primarily within the anterior and posterior pretectal nuclei.

Olivary afferents from small cells of the stratum profundum of the superior colliculus have been identified using HRP in the cat (Weber, Partlow and Harting, 1978). This pathway was found to be predominantly crossed, as distinct from other mesencephalo olivary connections which are mainly ipsilateral.

The vestibula-olivary projections described in rats (Brown et al., 1977) have been confirmed and extended in cats (Saint-Cyr and Courville, 1979). In addition to input from the medial and descending vestibular nuclei, olivary inputs were described in cats from the vestibular subnuclei g, s.v., x and z and from the prepositus hypoglossi.

A bilateral distribution from the primary and secondary motor cortex (layer V) to the IOC, as well as a small projection from the sensory cortex, has been reported in cats (Bishop,

McCrea and Kitai, 1976). This is markedly different from the predominantly ipsilateral connection reported for rats (Brown et al. , 1977). 13

Orthograde experimentation

In ·comparision to retrograde analysis, more numerous studies

of olivary afferents have been performed using orthograde techniques

owing to longer availability of these methods. Before the 1970's

these studies were accomplished by tracing degenerating fibers

produced by lesions placed within the central nervous system. various tracing techniques which are primarily based on silver degeneration methods (Nauta and Gygax, 1951; Fink and Heimer,

1967) have been developed for this purpose. The principal drawbacks

to these procedures include the questionable resolution, especially of fine fibers, and the damage inevitably done to fibers passing

through an ablated area, thereby often producing degeneration in undesired fiber systems and thus complicating the analysis. The more recent development of orthograde tracing techniques dependent upon the neuronal uptake and subsequent transport of radio- labeled amino acids has circumvented the later complication since

these radioactive amino acids are thought to be taken up only by neuronal perikarya and not by fibers of passage (Cowan and Cuneod,

1975). This, of course, allows a more accurate determination of the exact fiber system being followed in any given experiment.

Spinal cord. Numerous studies have investigated the anatomy of spinal projections to the IOC (Cajal, 1909; Wilson and Magoun, 1945; Brodal, Walberg and• Blackstad, 1950; Blackstad, Brodal and Wallberg, 1951; Ogawa and Kusama, 1954; Stotler, 1954; Nauta and 14

Kuypers, 1958; Kusama, 1961; Mizuno, 1966; Boesten and Voogd,

1975; Berkley and Worden, 1978). Uniformly, the more recent of these studies have reported spinal projections to be confined to the caudal and lateral parts of the medial and dorsal accessory olives (Mao and Dao). Studies in the cat revealed that lower spinal cord projections terminated more caudally and laterally then did the cervical cord projections (Boesten and Voogd, 1975).

Dorsal Column Nuclei. The spino-olivary terminal distribution was found to overlap extensively with the distribution of fibers from the contralateral dorsal column nuclei, a point strongly made in the work of Boesten and Voogd (1975) and Berkley and

Worden (1978). Furthermore, a similarity in the somatotopy of spinal cord and dorsal column nuclear projections, i.e., lower cord and nucleus gracilis to one area (lateral and caudal Mao and

Dao) and cervical cord and cuneatus to another area (slightly more medial and rostral) has been demonstrated (Boesten and

Voogd, 1975). Similar descriptions of dorsal column nuclear olivary connections appear in numerous other studies (Hand and

Liu, 1966; Ebbesson, 1968; Martin, Dom, King, Robards and Watson,

1975; Berkley, 1975; Hand and Van Winkle, 1977).

Spinal trigeminal nucleus. The somatotopy of olivary afferents was further examined by comparing dorsal column nuclear input with that from the spinal trigeminal nucleus (Berkley and Hand,

1978). Fibers from the nucleus gracilis were found to terminate primarily in the caudolateral part of the Dao while fibers from 15

the nucleus cuneatus and spinal trigeminal nucleus were found to

terminate successively more rostromedially within that same nuclear subdivision of the IOC. This progression represents a somatotopic progression from the lower part of the body, to the upper body and, finally, head.

Vestibular nuclei. Using autoradiographic methods in cats, vestibula-olivary fibers were observed to project ipsilaterally

to the subnucleus B and bilaterally to the dorsomedial cell column (Saint-Cyr and Courville, 1979). These connections were considered a possible pathway for climbing fiber activation in

the cerebellar uvula and fastigial nucleus by vestibular stimulation

(see the section on olivocerebellar projections).

Cerebellum. A number of studies have described cerebella olivary connections since they were first demonstrated unequivocally by Graybiel Nauta, Lasek and Nauta (1973). In more recent studies a rather well defined somatotopy has been established for dentato olivary connections in the rat (Haroian, Massopust, Young and

Murphy, 1978; Swenson and Castro, 1979), cat (Tolbert, Massopust,

Murphy and Young, 1976; Beitz, 1976) and monkey (Chan-Palay,

1977). However, this somatotopy has proven to be different for each species. In the monkey, the caudal part of the Po receives input from the rostral part of the dentate nucleus while the rostral Po receives from the caudal part. This projection was shmm to be very precise by the use of small injections into what is a relatively large nucleus in this species (Chan-Palay, 1977). 16

In the cat, the Pov and lateral bend receives projections from the ventral dentat~ while the Pod receives from the dorsal dentate

(Tolbert et al., 1976; Beitz, 1976). The rat, on the other hand, showed the Pov and Pod to receive projections from the caudal and rostral dentate, respectively (Haroian et al., 1978; Swenson and castro, 1979). It is probable that these minor differences do indeed reflect species variations due to the consistency between studies within species.

Interposito-olivary projections also present a somatotopic organization in cats in which the rostral interpositus nucleus projects to the rostral Mao and Dao while the caudal interpositus projects to the caudal Mao and Dao (Tolbert et al., 1976). A somewhat different pattern has been found in rats wherein the rostral interpositus projects to the Dao while the caudal interpositus to the Mao and Pov (Swenson and Castro, 1979). The pattern in the rodent is similar to that reported in the opossum (Martin,

Henkel and King, 1976) although projections to the Pov were not reported in the opossum.

Fastigio-olivary projections have been examined with divergent results in a variety of species. In the cat, no fastigio-olivary projections were discerned in studies where other cerebella olivary projections were quite evident (Graybiel et al., 1973;

Tolbert et al., 1976). In the rat (Achenbach and Goodman, 1968) and the opossum (Martinet al., 1976), however, the fastigial nucleus projects to the caudal part of the contralateral Mao. 17

Central tegmental bundle. Considerable interest has been evidenced concerning mesodiencephalic projections to the roc.

Most early experimentation was focused around the central tegmental bundle which has been long conjectured to arise in proximity to

the oculomotor nuclei (Tilney, 1928), and the periaqueductal gray

(Alexander, 1931; Mettler, 1944). In the cat, this bundle may be represented by a fine fibered tract ventral to the medial longitudinal

fasciculus, which Ogawa (1939) called the medial tegmental tract.

He believed these fibers to arise primarily from the nucleus of

Darkschewitsch and Cajal and the nucleus of Forel's field. With the classical Marchi staining method these fibers were shown to terminate in the rostral part of the Mao and the Po.

Periaqueductal gray. Recent evidence has corroborated many of the early observations concerning mesodiencephalic projections to the IOC. The periaqueductal gray has been confirmed as the site of origin for a substantial projeciton to the IOC in the cat

(Walberg, 1956; Hamilton and Skultety, 1970; Mabuchi and Kusama,

1970), opossum (Linauts and Martin, 1978a) and rat (Swenson and

Castro, 1979). These studies all demonstrate a projection to the ipsilateral Po while most report additional projections to the rostral part of the Mao (Walberg, 1956; Hamilton and Skultety,

1970; Mabuchi and Kusama, 1970; Swenson and Castro, 1979) and others describe additional projections to the dorsal cap of Kooy, the ventrolateral outgrowth, the dorsomedial cell column and the subnucleus B (Mabuchi and Kusama, 1970; Swenson and Castro, 18

1979). The caudal Mao and the Dao are uniformly considered to have few, if any, terminals of periqueductal fibers. These inputs to the IOC are described to originate primarily from the ventral part of the periaqueductal gray in cats (Walberg, 1956;

Hamilton and Skultety, 1970).

Superior colliculus. An early study suggesting olivary afferents from the superior colliculus was not supported by a series of experiments done with the Marchi, Glees, and Fink

Heimer techniques (Rasmussen, 1936; Walberg, 1956; Martin et al.,

1975). However, more recent autoradiographic and degeneration experiments have clearly demonstrated this pathway in the tree shrew (Harting, Hall, Diamond and Martin, 1973) cat (Graham,

1977; Weber et al., 1978), and primate (Frankfurter, Weber,

Royce, Strominger and Harting, 1976). Unlike most other olivary projections from midbrain regions which are ipsilateral, this particular pathway displayed a contralateral distribution to the subnucleus b of the Mao in the primate (Frankfurter et al., 1976) and to the subnucleus b (Graham, 1977) or c (Weber et al., 1978) in cats.

Red nucleus. Rubral efferents to the ipsilateral Po, especially the Pod, have been reported in cats (Verhaart, 1949;

Walberg, 1956). More recent work has generally confirmed this observation in the opossum (Martinet al., 1975; Linauts and

Martin, 1978a), cats (Hinman and Carpenter, 1959; Edwards, 1972; 19

Courville and Otabe, 1974) and monkey (Pourier and Bouvier,

1966). Other work in monkeys (Miller and Strominger, 1973;

Strominger, Truscott, Miller and Royce, 1979) has shown a somatotopy within the rostral red nucleus where the lateral part projects to the Pod while the medial part projects to the Pov. Transection of the central tegmental bundle in monkeys resulted in degeneration in the roc and considerable cell loss in the parvocellular red nucleus which suggested that rubro-olivary projections arise from this part of the nucleus (Pourier and Bouvier, 1966).

Pretectum. The pretectal complex has been shown to project to the roc in rabbits (Mizuno, Mochizuki, Akimoto and Matsushima,

1973) and tree shrew (Weber and Harting, 1980). Both species evidenced a primary projection to the ipsilateral dorsal cap of

Kooy, although the rabbit also had a small projection to the B subnucleus. Both of these experiments were primarily concerned with the projections to the rostral part of the pretectal complex and the nucleus of the optic tract in particular. This projection pattern was inadvertently demonstrated in the primate (Frankfurter et al., 1976) with injections at the rostral pole of the superior colliculus. Although ablation studies in the opossum showed bilateral pretecto-olivary projections (Martin et al., 1975) subsequent autoradiographic studies in the same species, found projections from the pretectum to the Dao and caudal Mao to be exclusively ipsilateral (Linauts and Martin, 1978a). 20

Nucleus of Darkschewitsch and Cajal. Although the intial description of olivary afferents from the nuclei of Darkschewitsch and Cajal has been questioned (Walberg, 1956) the presence of these connections has been reaffirmed by autoradiographic means in the opossum (Linauts and Martin, 1978a) and by degeneration techniques in the cat (Mabuchi and Kusama, 1970; Walberg, 1974).

The reports are unified in stating that the principal target of these fibers is the Po although a more extensive distribution including the rostral Mao and dorsal cap (Mabuchi and Kusama,

1970) or the DMCC (Walberg, 1974) has been described in cats.

The use of more precise autoradiographic methods in the opossum has shown that while both the nucleus of Darkschewitsch and Cajal project to the Po, the nucleus of Darkschewitsch additionally projects to the Mao (Linauts and Martin, 1978a).

Subparafascicular nucleus. Only since the advent of recent retrograde tracing techniques has the large olivary input from the subparafascicular nucleus been realized (Henkel and Martin,

1975; Brown et al., 1977). Autoradiographic studies in the opossum demonstrated subparafascicular projections to all olivary subdivisions with most fibers terminating in the lateral part of the Mao at mid-olivary levels and few terminating in the Dao

(Linauts and Martin, 1978a). A similar projection pattern was observed with degeneration methods after large lesions which included the subparafascicular nucleus in cats (Walberg, 1974).

This subparafasciculo-olivary distribution is similar to olivary 21 afferents from Forels' field as found in the opossum (Linauts and

Martin, 1978a).

Mesencephalic reticular formation. Early reports indicated

that the mesencephalic reticular formation does not project to the IOC in cats (Mettler, 1944; Walberg, 1956), although subsequent studies reported the possibillty of these projections (Walberg,

1974; Martinet al., 1975). Recent autoradiographic experiments have clearly demonstrated this connection to the Dao and the B subnucleus in the opossum (Linauts and Martin, 1978a) while in the rat these fibers were found to terminate in the Po as well as extensive regions of the Mao and ventrolateral outgrowth of the dorsal cap (Swenson and Castro, 1979).

Thalamus, basal ganglia and hippocampus. Early descriptions of a thalamo-olivary connnection were based on observation of normal and pathological tissue (Bechterew, 1899; Riese, 1924;

Schenk, 1937). This projection has been denied by numerous reports using experimental techniques (Weisschedel, 1938; Mettler,

1944; Verhaart, 1949; Stotler, 1954; Walberg, 1956) and has not been observed with modern techniques.

A pathway reported to exist between the basal ganglia (the caudate nucleus and the globus palladus) and the IOC in cats

(Walberg, 1956), has been convincingly denied by studies on several species (Stettler, 1954; Nauta and Mehler, 1966; Martin et al., 1975; Kim, Nakano, Jayaraman and Carpenter, 1976; Brown et al., 1977; McBride and Larsen, 1980). 22

The description of degenerating fibers descending to the IOC in the lateral lemniscus following lesions of the hippocampal fornix (Powell, 1966) has not been carefully examined with modern techniques.

Cerebral cortex. Cerebral cortical projections to the IOC have been investigated primarily by use of degeneration techniques.

The principal drawback of these techniques as applied to cortico olivary fibers is the large number of cortical fibers which traverse the IOC on their way to extra-olivary targets, presenting the problem of distinguishing degenerating fibers of passage from terminal degeneration. Walberg (1956) using the Glees method in cats determined the motor cortex to project bilaterally to the

Pov, the rostral Dao, the caudal, medial Mao and, to a lesser extend the subnucleus B, DMCC, the dorsal cap and ventrolateral outgrowth. This pattern was basically supported by later work

(Sousa-Pinto, 1969; Sousa-Pinto and Brodal, 1969) with the exception that the rostral part of the Mao also received cortical input, that the supplementary motor area gives rise to a small number of cortico-olivary fibers, that this projeciton is primarily contralateral, and that there is some somatotopy within this projection.

A similar projection pattern was found in the opossum, with the exception that the majority of degeneration was ipsilateral to the cortical lesion (Martinet al., 1975).

Summary of orthograde studies. Orthograde experimentation has demonstrated multiple projection patterns to the IOC. While 23 these patterns are specific for each region having an olivary projection, the patterns frequently overlap with the projections from other parts of the central nervous system, implying that the roc is not simply a relay for information but that some complex integration occurs within the olive.

In general however, afferent input from levels at or below the IOC is topographically segregated from that of more rostrally situated regions. Caudally arising input tends to terminate within the caudal Mao and Dao, while more rostral areas project to the rostral Mao and Dao as well as the Po. Areas related to vestibular and ocular function project primarily upon the subnucleus B and the dorsal cap or ventrolateral outgrowth. 24 olivocerebellar connections.

While there has been a considerable amount of controversy

(see Armstrong, 1974) concerning the origin of cerebellar climbing fibers, recent studies have largely settled this question by showing that the vast majority, if not all, of these fibers arise from the IOC (Murphy, O'Leary and Cornblath, 1973; Desciin, 1974;

Courville, Faraco-Cantin and Diakiw, 1974; Courville, 1975;

Groenewegen and Voogd, 1977; Montarlo, Raschi and Strata, 1980).

The somatotopic termination of these fibers was first described in a systematic fashion by Brodal (1940) by examining retrograde cell loss following cerebellar lesion and has been extensively re-examined since the advent of anterograde and retrograde tracing techniques.

Anterograde studies. As applied to olivocerebellar climbing fibers, anterograde studies (Murphy et al., 1973; Courville,

1975; Groenewegen and Voogd, 1976, 1977; Chan-Palay, Palay, Brown and Van Itallie, 1977; Courville and Faraco-Cantin, 1978; Groenewegen,

Voogd and Freedman, 1979; Kawamura and Hashikawa, 1979) have been instrumental in the further delineation of the cerebellar parasagittal zonation system as first described anatomically by Voogd (1969).

According to this system four longitudinal zones (AD from medial to lateral) have been identified in the cerebellar cortex of the cat; zone C contains three subzones (c ) and zone D contains two 13 subzones (u ). 12 25

In reference to olivocerebellar projections each zone has

been shown to receive projections from specific regions of the

~ rOC. Accordingly, zone A recieves inputs from the caudal Mao,

zone B from the caudolateral Dao, subzones c and c from the 1 3 rostromedial Dao, subzone from the rostral Mao and subzones c2 n1 and n from the Po. The dorsal cap and ventrolateral outgrowth 2 project to the flocculonodular lobe (Groenewegen and Voogd, 1977;

Groenewegen et al., 1979; Kawamura and Hashikawa, 1979) (fig. 2).

The portions of the IOC giving rise to projections to particular cerebellar cotical zones have also been shown to project to particular subcortical nuclei i.e., caudal Mao to zone A and fastigial and lateral vestibular nuclei, caudolateral Dao to zone

B and interpositus and lateral vestibular nuclei, rostral Mao and

Dao to zone C and interpositus nucleus and Po to zone D and the denate nucleus (Groenwegen and Voogd, 1977; Groenewegen et al.,

1979).

Retrograde studies. A delineation of the precise somatotopy of olivary projection to given cerebellar lobules has been the primary goal of retrograde studies, although it has also provided

some support for the concept of parasagittal zonation.

In a study on the anterior lobe of the cat cerebellum Brodal and Walberg (1977a) demonstrated that mid vermal HRP injections

(presumably zones A and B) of all lobules of this lobe produced labeling in the caudal Mao and caudolateral Dao, while injections of intermediate regions (presumably zone C) labeled the rostral, 26 medial Dao and rostral Mao. HRP injections of the lateral part of the anterior lobe (zone D) demonstrated projections from Pod.

While there were some minor differences in the distribution of labeled olivary cells dependent upon which particular lobule was injected, medial to lateral zonation was found to be a much more significant determinant for the position of labeled cells, and was therefore generally supportive of the concept of zonation.

When the paramedian lobule was studied by HRP methods

(Brodal, Walberg and Hoddevik, 1975; Brodal and Walberg, 1977b), some minor differences were found in zonation patterns. Midvermal injections produced labeling within the rostral Mao instead of the caudal Mao as would be expected from the aforementioned anterograde experiments, although the intermediate and lateral cortex received projections from the rostral Dao and Pod as would be expected.

A parasagittal zonation of olivocerebellar fibers has also been demonstrated within the lobulus simplex, crus I and crus II

(Kotchabhakdi, Walberg and Brodal, 1978). The lateralmost parts of these lobules were found to receive projections from the Po

(both lamella) and slightly more medial regions contained two zones of light rostromedial Dao labeling on either side of a zone of rostral Mao labeling. This was a rather precise demonstration of the presence of zones D and C within these lobules of the cerebellar hemisphere. Additionally, the vermis between these 27 portions of the hemisphere (presumably zone A) were found to receive a somatotopic projection from the caudal Mao, and the vermis of lobule VII received a projection from the subnucleus B

(Hoddevik, Brodal and Walberg, 1976).

Retrograde studies of the flocculonodular lobe revealed projections from the dorsal cap of Kooy and the rostralmost part of the Mao and the nodulus received olivocerebellar fibers from the rostral part of the DMCC (Hoddevik and Brodal, 1977). In the same study the dorsal paraflocculus was shown to receive fibers from the Po, expecially the lateral part of the Pov. Analysis of the roc projections to the uvula demonstrated strong projections from the B subnucleus and DMCC and that the lateralmost part of the lobe also receives a small projection from the Hao (Brodal,

1976).

The findings described above for retrograde experiments in the cat have been shown to correspond to studies in the rat

(Brown, 1980) and opossum (Linauts and Martin, 1978b) although these species have not been examined in the same detail. Armstrong et al. (1974) have demonstrated a strikingly similar, albeit slightly more complex pattern using electrophysiological techniques in the cat.

In attempting to correlate the studies of olivary afferent systems with those of olivocerebellar systems certain points become clear. The regions of the IOC which receive input from caudal levels of the brainstem and the spinal cord (the caudolateral 28

Mao and Dao) project primarily to the vermis in zones A and B.

Descending input to the IOC terminates for the most part in the more rostral levels of the Mao and Dao, which in turn project to the subzones of zone C, and in the Po, which mainly distributes to the lateral regions (zone D) of the cerebellar cortex. vestibular input, which primarily terminates in B and the DMCC, is relayed most prominently to the uvula, with smaller projections to the vermis of lobule VII and the nodulus. Visual input can relay from the pretectum, through the dorsal cap, to the flocculus and nodulus of the cerebellum or it can pass from the superior colliculus, through the caudal medial Mao, to the cerebellar vermis. The physiology of some of these pathways will be discussed in the next section. 29

Physiology of olivary afferents

Much of the understanding of the physiology of IOC afferents is derived from electrophysiological recordings of the cerebellar cortex. As described in the previous section, the neurons of the roc are probably the sole origin of climbing fibers to the cerebellum. Climbing fibers have been shown to evoke a well defined response in Purkinje cells which is characterized by a unitary excitatory postsynaptic potential (EPSP) (Eccles, Llinas and Sasaki, 1966) which is large enough to be recorded extracellularly

(Faber and Murphy, 1969; Fujita, 1968; Murphy and Sabah, 1971;

Eccles, Provini, Strata and Taborikova, 1968) and which behaves in an all or none fashion. A single action potential, or a short series of spikes at approximately 500/second, are superimposed on this EPSP (Eccles et al., 1966). This has been termed a "climbing fiber response" (Granit and Phillips, 1956). The climbing fiber response is followed by a climbing fiber pause. This pause, which blocks simple spikes in the Purkinje cell which are generated by mossy fibers, may be attributed to climbing fiber collaterals to inhibitory interneurons (Eccles, Llinas and Sasaki, 1966) although this has recently been questioned (Desclin, 1976).

Alternatively, it has been attributed to collaterals from Purkinje cells (Armstrong, 1974). The latter possibility is also questionable in that Purkinje cell collaterals contact and presumably inhibit some inhibitory interneurons of the cerebellar cortex (Hamori and

Szentagothai, 1968; Laramendi and Lemkey-Johnston, 1970) which 30 suggests that their effect would be disinhibitory rather then inhibitory. Current studies (Colin, Manil and Desclin, 1980) have proposed that the observed inhibition may be a direct result of the interaction between the climbing fiber and the Purkinje cell and may be independent of other cortical neurons.

Both the climbing fiber response (Eccles, Ito and Szentagothai,

1967) and the climbing fiber pause (Latham and Paul, 1971; Bloedel and Roberts, 1971) have been proposed as a mechanism whereby the olivocerebellar climbing fiber "reads-out" the excitability of

Purkinje neurons, in that the more excitable the Purkinje cell at the time of arrival of climbing fiber input, the more spikes would be generated in the climbing fiber response and the shorter would be the climbing fiber pause. Climbing fiber input has been shown to exert a strong and long lasting inhibitory effect on the pattern of simple spike generation by the mossy fiber in the

Purkinje cell (Colin et al., 1980).

Since olivocerebellar climbing fibers are arranged in a topographic fashion (see the preceeding section), recordings of climbing fiber activation within the cerebellar cortex provides a good indication of the particular regions of the roc which are activated by the stimulation of any given olivary afferent.

Somatosensory input. Spina-olivary fibers have been the most extensively investigated of olivary afferent systems. The numerous studies on the physiology of this system have been reviewed by Oscarsson (1973). In a series of papers, Oscarsson 31 and his co-workers demonstrated five spinal pathways which project to the cerebellum via the roc. These pathways were first catagorized according to their position in the spinal cord and then described in terms of the number of synapses enroute to the cerebellum, the regions of termination within the cerebellum and the types of information conveyed. One pathway, the ventral spino-olivocerebellar pathway, is a direct pathway from the spinal cord to the roc and thence to the anterior lobe. The other four spino-olivocerebellar pathways relay in the brainstem before reaching the roc. While the precise sites of relay for most of these indirect pathways are not known, the dorsal spina- olivocerebellar pathway has been shown to relay in the dorsal column nuclei.

The majority of the spino-olivocerebellar pathways have large receptive fields which Oscarsson classifies as providing flexor reflexes afferent information (i.e., the type of afferent information which triggers flexor reflexes). However, the dorsolateral spino-olivocerebellar pathway conveys more precise information from the foot pads, possibly concerning footstrike in locomotion (Armstrong, 1974). The lateral spino-olivocerebellar pathway and the ventral funiculus climbing fiber spinocerebellar pathway, project information from receptive fields covering all four limbs. Visceral sensory input has also been demonstrated to project via climbing fibers to the anterior lobe (~euman and

Paul, 1969) and the paramedian lobe Laur and Ogura, 1952), 32

probably by way of the lateral or ventral spino-olivocerebellar

pathway (Lam and Ogura, 1952; Widen, 1955).

Numerous studies have reported that stimulation of branches

of the trigeminal nerve will produce climbing fiber responses in

the cerebellar cortex (Calne, 1959; Azzena, Desole and Palmieri,

1970; Baker, Precht and Llinas, 1972; Bowman and Combs 1969).

The pattern of this projection is rather precise, with no discontinuous areas of skin projecting to single recording points (Miles and

Weisendanger, 1975). Two principal sites of termination were

identified for the olivocerebellar fibers conveying trigeminal

information, one in the ipsilateral lobule VI and the adjacent part of lobule V, and the other in lobule VII (Miles and Weisendanger,

1975). These same areas of the cerebellar cortex were reported

to contain climbing fiber responses following stimulation of the

face area of the primary sensory cortex. Extracellular recordings of olivary neurons have since shown this pathway to relay in the

IOC (Cook and Wiesendanger, 1976).

Vestibular input. Although primary vestibular fibers have been shown to project directly to the climbing fibers in the frog

(Hillman, 1969; Llinas, Precht and Kitai, 1967; Precht and Llinas,

1969), it is generally agreed that vestibular evoked climbing fiber responses in the cerebellar cortex are primarily, if not completely, relayed in the IOC in mammals (Ferin, Grigorian and

Strata, 1970, 1971; Ito, Nisimaru and Yamamoto, 1973; Precht,

Volking and Blanks, 1977). While these responses were recorded 33 mainly in the vestibula-cerebellum, they were occasionally recorded elsewhere (Ferin et al., 1970). As opposed to this vestibular input, cochlear stimulation has been ineffective in evoking climbing fiber responses, in spite of substantial mossy fiber responses in portions of the vermis (Shafer and Nahvi, 1969).

Mesencephalon and Dienc~phalon. Considering the substantial input from the mesencephalon and diencephalon to the roc, relatively little work has been done on the physiologic categorization of these fibers. However, some work has been done in attempting to determine what effect descending pathways from this region have on transmission of spino-olivocerebellar pathways (Miller,

Nezlina and Oscarsson, 1969; Appelberg and Jeneskog, 1973; Appelberg,

1967; Appelberg and Molander, 1967). These studies are inherently limited because of the restricted region of overlap between descending projections to the roc and the ascending projections

(see the section on olivary afferents).

Pretectum. The pretectal complex is the only portion of the mesencephalon whoes projection to the roc has been physiologically examined in any detail. This work has been prompted by the observation that flashes of light evoked potentials in the cerebellar folium and tuber vermis (Snider and Stowell, 1942). These responses have been subsequently described as climbing fiber responses

(Buchtel, rosif, Marchesi, Provini and Strata, 1972; Roper and

Bourassa, 1972). The pathway for this activation was mapped and demonstrated to relay principally via the dorsal cap of the roc 34 to the cerebellar flocculus (Maekawa and Simpson, 1973; Alley,

Baker and Simpson, 197 5). Later work has confirmed that· the nucleus of the optic tract (Hoffman, Behrend and Schoppmann,

1976) and the region of the medial terminal nucleus of the accessory optic tract (Maekawa and Takeda, 1979) project to the dorsal cap and ventrolateral outgr-owth, respectively. A recent series of papers has characterized the nature of the retinal input to the dorsal cap and has examined eye movements evoked by stimulation of the dorsal cap and the effects of lesions of this area (Barmack and Hess, 1980a,b; Barmack and Simpson, 1980). They report alterations in both vestibulo-occular and optokinetic reflexes after dorsal cap lesions. Other work (Haddad, Derner and Robinson,

1980) also found disruption of vestibulo-occular reflexes but denies that ablation of the dorsal cap of the roc has an effect on optokinetic reflexes.

Basal ganglion input. A caudato-olivary pathway has been described physiologically by single unit recordings in the roc

(Sedgewick and Williams, 1967) and by recordings of climbing fiber potentials in the cerebellar cortex (Fox and Williams,

1968). The precise pathway for this activation remains a mystery since the early report of a caudate-olivary projection (Walberg,

1956) has not received anatomical support (Stotler, 1954; Nauta and Mehler, 1966; Martinet al., 1975).

Cerebral cortical input. Stimulation of the cerebral cortex has long been known to evoke responses in the cerebellar cortex 35

(Jansen, 1957; Deura, 1961), and the longer latency of these responses have since been identified as climbing fiber responses

(Jansen anu Fangel, 1961; Armstrong and Harvey, 1968; Miller et al., 1969; Provini, Redman and Strata, 1968). Physiologic experiments have unanamously determined this pathway to be uncrossed to the roc (crossed to the cerebellar cortex). The laterality of these reports confict with anatomical evidence in the cat (Sousa-Pinto and Brodal, 1969; Sousa-Pinto, 1969; Walberg,

1956) but is supported by observations in the opossum (Martin et al., 197 5).

Vestibular compensation. Numerous studies have demonstrated considerable functional recovery from deficits caused by cerebellar or vestibular system lesions (see Dow and Moruzzi, 1958). Although the precise functions of the roc have not been clearly defined, studies involving the chemical destruction of the roc have particularly implicated it in the recovery mechanism following vestibular nerve lesion (Llinas, Walton, Hillman and Sotelo, 1975). Specifically, these studies demonstrated that lesion of the roc prevents compensation for vestibular lesions and will abolish the compensation which has been established to a previously existing vestibular nerve lesion. Cerebellar cortical ablation was not found to have any substantial effect on vestibular compensation, suggesting that climbing fiber collaterals to deep cerebellar and/or vestibular nuclei probably mediate this compensation. Since this initial observation, Walton and Llinas (1978) have applied the 2-deoxyglucose 36 technique, which provides a metabolic map based on the differential uptake of glucose in order to determine which sites demonstrated altered metabolic activity in response to vestibular nerve lesion.

In addition to the contralateral IOC (expecially the Mao), they found increased activity in the granular cell layer of the uvula and nodulus, the deep cerebellar nuclei and the lateral reticular nucleus, all ipsilaterally. 37 plastid ty

Recovery of function following nervous system lesions has been particularly well documented for the cerebellar motor systems

(Dow and Moruzzi, 1958; Smith, Mosco and Lynch, 1974; Smith, parks and Lynch, 1974). While various theories have been advanced to explain recovery of function after nervous system lesions (see

Finger, 1978), among the more prominent of these theories is the phenomenon of neuroanatomical remodelling or plasticity, i.e., the reorganization of neural connections in response to nervous system lesion.

An early study by Liu and Chambers (1958) demonstrated that dorsal root fibers of adult cats will "sprout", that is increase their terminal density, in response to removal of other dorsal roots, or in response to removal of descending input from the cerebral cortex to the spinal cord. Subsequent studies demonstrated that optic tract axons of adult rats will sprout into portions of the lateral geniculate nucleus and pretectum in response to lesions which remove the descending input to these regions of the brainstem from the occipital cortex (Goodman and Horel, 1966).

Since the observation of pronounced plasticity in corticospinal fibers (Hicks and D'Amato, 1970) and in the visual system (Lund and Lund, 1973; Schneider, 1973) following neonatal brain damage, further experiments demonstrated that this plasticity declines precipitously at certain postnatal ages (Leong and Lund, 1973;

Mustari and Lund, 1976; So and Schneider, 1978). Many experiments 38 since that time have shown the remarkable plasticity of the neonatal brain and hava lead to the principle that many neural systems remodel more readily in the newborn.

Voluminous literature (see table 1) has reported sprouting in virtually all systems including the somatosensory system, the visual system, the auditory system, the limbic system, the noradrenergic system and the motor system (see Stein, Rosen and

Butters, 1974; Cotman, 1978; Lund, 1978).

Many of the experiments demonstrating plasticity have used similar paradigms in order to induce sprouting and therefore have led to certain hypotheses concerning the conditions which cause sprouting. These conditions include the concept of available postsynaptic space, which states that aberrant projections may develop to reinnervate areas deafferented by particular lesions.

While exceptions have been found, the available postsynaptic space most probably must be a specific type with characteristics compatable with the sprouted axons (Goodman and Horel, 1966;

Castro, 1979).

A further explanation for axonal sprouting hypothesizes that neurons attempt to maintain a certain volume of axonal arborization

(Schneider, 1973). Refered to as the "pruning" theory, this concept states that the removal or limitation of one part of a neurons axonal arbor causes it to sprout new collaterals elsewhere.

Numerous experiments have shown that both available postsynaptic space and pruning are capable of producing anomalous connections 39 by themselves. However, these two mechanisms may also be operative in the same experiment, and in fact may be additive, implying some independence of these processes (Castro and Mihailoff, in preparation).

Plasticity has been recognized in the motor systems since the observations of Hicks and D'Amato (1970) on the sprouting of one corticospinal tract into the area denervated by the neonatal destruction of its contralateral mate. Subsequently, many papers have reported altered cortical projections to several regions, including the spinal cord, dorsal column nuclei, pontine gray, superior colliculus, pretectal complex, red nucleus, ventral basal complex of the thalamus and basal ganglia, following neonatal destruction of the sensorimotor cortex of one hemisphere

(Leong and Lund, 1973; Leong 1976; Nah and Leong, 1976; Castro,

1975, 1979; Goldman, 1978). These aberrant pathways are presumed to contribute to cortical recovery mechanisms as supported by ultrastructureal observations of anatomically functional synapses in association with anomalous connections to the spinal cord, superior colliculus and pontine gray (McClung and Castro, 1975;

Leong, 1976; 1980). However, the functional implications of neuroplasticity are unresolved, and indeed behavioral studies concerning the functional efficacy of the aberrant corticospinal projections have led to conflicting results (Castro, 1977;

Kartje-Tillotson and Castro, 1980). 40

The above cited work on cortical efferents have basically reflected plasticity in response to synaptic site availability, i.e., lesion of one cerebral hemisphere opening up sites for the sprouting of fibers from the other hemisphere. According to this same paradigm, altered cerebellar efferents have also been described. With neonatal removal of one half of the cerebellum, the outputs of the remaining half of the cerebellum have been shown to deviate from the normal, overwhelmingly crossed, pattern and to distribute an increased number of fibers to the ipsilateral red nucleus and ventrolateral nucleus of the thalamus (Lim and

Leong, 1975; Leong, 1977; Castro, 1975). This results in a substantially more bilateral projection system, similar to the bilaterality of cortical outputs from the remaining hemisphere following hemidecortication. Aberrent cerebellar efferents have also been verified electrophysiologically (Kawguchi, Yamamoto and

Semejima, 1979).

Neuroanatomical remodelling has also been observed in other cerebellar an~ related pathways such as the spinocerebellar, spinovestibular and corticopontine systems. In normal animals, the spinocerebellar tracts enter the cerebellum ipsilateral to their spinal cord position and decussate within the cerebellum to distribute bilaterally within the cerebellar cortex. With hemicerebellectomy in newborn rats, the more distal crossed axonal branches are destroyed (pruned) apparently causing the more proximal uncrossed axon branches within the spared side of 41 the cerebellum to sprout and thereby increase their ipsilateral distribution (Castro and Hazlett, 1979). Additionally, this process may be potentiated by the deafferentation aspects of the lesion which interrupted fibers passing within the destroyed side enroute to the spared hemisphere.

In further studies on rats, neonatal hemicerebellectomy resulted in an increase of spinal projections to the ipsilateral lateral vestibular nucleus, a nucleus which is functionally related to the cerebellum (Castro and Smith, 1979). Considering that the vestibular nuclei have been implicated in recovery from cerebellar lesion, this sprouting may be significant in this recovery (Smith et al., 1974).

The normal corticopontine projection, which is largely ipsilateral, also undergoes alteration following hemicerebellectomy.

Since neonatal hemicerebellectomy causes a marked reduction in the number of neurons in the contralateral pontine gray, many of the corticopontine fibers which would normally terminate in this nucleus sprout into the intact pons, thus increasing the normally small crossed corticopontine projection (Leong, 1976; Castro,

1979; Mihailoff and Castro, in press). Once again this sprouting may be interpreted as an attempt by these fibers to maintain the same volume of terminal distribution in the face of removal of their target.

Search for a unifying theme to the remodeling observed after neonatal hemicerebellectomy reveals that the spared half of the 42 cerebellum is characterized by a bilaterality of both efferent and afferent connections. Specifically, principal cerebellar efferents which normally are predominately contralateral show a pronounced bilaterality to the red nucleus and ventrolateral thalamus. A similar shift toward bilateral afferents is found in the sprouting of crossed corticopontine fibers, which results in an increased bilateral cortical influence upon the spared hemicerebellum as relayed via pontocerebellar mossy fibers. Collectively, this remodeling supports previous speculation (Castro, 1978) that the hemicerebellum may functionally compensate for the missing half of the cerebellum.

Further support for this theory necessitates analysis of the roc climbing fiber system. Since both the contralateral pontine nuclei and roc degenerate after hemicerebellectomy, afferents normally destined to the missing roc might instead project to the opposite spared olive in a fashion similar to the corticopontine plasticity described above. Such remodeling would in effect imply a bilateral effect of olivary afferents on the spared hemicerebellum as relayed via the olivocerebellar climbing fibers. MATERIALS AND METHODS

Surgical Procedure. Long-Evans black hooded rats were used

in all experiments. Animals were anesthetized with sodium pentobarbital

(42 mg./kg), supplemented by inhalation of penthrane as needed, and were secured in a stereotaxic headframe during surgery. In approaching'the spinal cord, incisions were made longitudinally, muscles were dissected away from the spinous processes, and the vertebral laminae were removed with rongeurs. The dorsal surgical approach to the brain followed a longitudinal skin incision over

the calvarium which was opened with a trephine and expanded with rongeurs to produce adequate exposure. The alternative ventral approach to the brainstem consisted of a midline skin incision from the symphysis menti to the sternum, reflection of the infrahy.oid muscles, retraction of the great vessels laterally and the trachea medially, removal of the longus capitus muscle from the base of the occiput and removal of the basilar portion of the occiput rostrally from the foramen magnum.

Following exposure of the brain and spinal cord, lesions or injections of various regions were made depending upon the particular pathways being examined and the tracing techniques employed. Lesions of the frontal cortex were made by aspiration through a drawn glass pipette; lesions of the dorsal column nuclei were accomplished by use of a hot probe, and lesions of the spinal cord were performed with a #11 scalpel blade. Injections

43 44 were made by use of a one microliter Hamilton syringe with a glass micropipette cemented to its tip and filled with sesame oil. Tip diameters for the micropipette ranged between 20 and 40u.

Neonatal hemicerebellectomies were performed within three days of birth using hypothermic anesthesia. After midline skin incision and removal of the bone overlying the cerebellum with a dissecting hook and forceps, half the cerebellum was aspirated through a drawn glass pipette. The incision was closed with 000 silk, and the animal was warmed by use of an incandescent lamp until recovered from hypothermia and returned to its mother until weaning at about three weeks of age.

Horseradish Peroxidase Technique. HRP (Worthington or Sigma) was dissolved in physiologic saline to a 30% concentration, and

0.02 ul of it was injected over a 20 minute period, allowing ten minutes after the completion of injection before removing the needle. After a two day postoperative survival, animals were overdosed with sodium pentobarbital and sacrificed by transcardiac perfusion of saline followed by a 1% paraformaldehyde, 1.25% gluteraldehyde solution. The brains and spinal cord were removed, notched on the side opposite the injection, postfixed for approximately six hours and stored in cold, buffered sucrose prior to cutting.

Alternate 40u forzen sections were reacted according to a modification of the De Olmos (1977) protocol for the demonstration of HRP using

0-dianisidine as the chromogen. The sections were then mounted and coverslipped wthout counterstaining in order to avoid obscuring the 45

reactive neurons. The remaining sections were mount~ed and stained

with cresyl violet.

HRP is incorporated into axon terminals and severed

axons and transported retrogradedly toward the cell body where it

can be visualized within vesicles in the cytoplasm (Kristensson and

Olsson, 1971; La Vail and La Vail, 1972; Cowan and Cuneod, 1975).

This technique can therefore be used to define the multiple inputs

to a particular HRP injection site, in this study of the IOC.

Fink-Heimer Technique. Degenerating axonal debris was traced

by the use of the Fink-Heimer technique (1967) following lesions of

the spinal cord, dorsal column nuclei and cerebral cortex. Animals having sustained these lesions were sacrificed from four to seven days postoperatively by overdose of Aentobarbital followed by

transcardiac perfusion with saline and 10% buffered formalin.

Brains were removed, cut at 33u on a freezing microtome, processed according to the Fink-Heimer protocol (1967) and mounted out of a gelatin-alcohol mixture onto chrome alum-gelatin subbed slides.

Autoradiographic Technique. Tritiated leucine (l mCi, llOCi/mmol,

New England Nuclear) was evaporated to dryness in a freeze dryer and then reconstituted in 20 ul of physiologic saline to a final concentration of 50 uCi/ul. Stereotaxic injections of 0.02 to 0.04 ul quanties were made using the injection system described above.

When injected into the vicinity of a neuron, amino acid is taken up into the cell, incorporated into proteins and transported anterogradedly 46 down the axon toward the axon terminal where the labeled compounds, and therefore the labeled axons, can be identified by standard autoradiographic procedures (Lasek, Joseph and Whitlock, 1968; cowan and Cuneod, 1975). This technique is employed for tracing the efferent connections from particular sites, which in these studies included the sites of origin of most olivary afferent pathways. According to routine animals were sacrificed seven to ten days postinjection by overdose of pentobarbital followed by transcardiac perfusion of saline and 10% buffered formalin.

Brains were removed, cut at 50 u on a freezing mictorome and mounted on slides. Slides were then processed for autoradiography according to the protocol of Chan-Palay (1977). In a humidified darkroom, slides were dipped in a 1:1 mixture of Kodak NTB2 emulsion and distilled water at 42°C. They were stored vertically in a rack to dry and were then placed in light-tight dehumidified boxes for five to ten week exposures. The slides were then developed for four minutes in Dl9 developer at 18-20°C, rinsed in distilled water for one minute and fixed in Kodak rapid fixer for five minutes. Slides were subsequently passed through distilled water, hypo clear, and distilled water prior to staining with cresyl violet and coverslipping. Autoradiographs were examined using clarkfield microscopy. RESULTS

Retrograde analysis of inferior olivary afferent~

Injections of HRP were made into the IOC of 52 animals in order to identify the sites of origin of olivary afferents.

Spinal Cord

Two animals sustained HRP injections which occupied substantial portions of the spinal receiving areas of the roc, i.e. the lateral half of the caudal medial accessory olive (Mao) and the lateral extent of the dorsal accessory olive (Dao), following a ventral approach to the brainstem. Camera lucida drawings of these injection sites and the corresponding labeled neurons within the spinal cord are presented in figures 3 and 4. Labeled cells were most numerous at cervical and upper lumbar levels while fewer were found in the thoracic cord and none were found below 16. They were located predominantly on the side of the cord contralateral to the injection site and were generally found in lamina VII and lamina V.

The rostral-caudal distribution of reactive neurons showed some differences dependent upon the location of the primary injection site. In the case of the injection centered in the lateral part of the Dao (fig. 3), more labeled cells were found at lumbar levels, while the injection which included the caudal portion of the Mao (fig. 4) showed more cervical then lumbar labeling.

47 48

Regional differences in the distribution of cells in lamina

VII and V were evident. In upper cervical cord, labeled neurons in lamina VII were clustered lateral to the central canal. Some of these cells appeared to overlap the region of the central cervical nucleus. In the lower cervical segments, reactive neurons were clustered in two groups ventrolateral and dorsolateral to the central canal at the medial aspect of the base of the ventral and dorsal horns, respectively. In the thoracic region more labeled cells were distributed laterally within lamina VII then was the case in the cervical cord, although a number of them remained at the base of the dorsal horn and extended into the region of the nucleus dorsalis. These cells were of small size and were lightly labeled. At upper lumbar levels a pattern, similar to that of the lower cervical cord was resumed and most of the reactive neurons were again located medially at the base of the dorsal and ventral horns.

While most labelled cells in lamina V proved to be in the medial subdivision and in the medial part of the lateral or reticular subdivision, following injections into the lateral portion of the Dao, a group of labeled cells were found in the lateral part of the lateral subdivision of lamina V in the lumbar region (fig. 3). 49

Caudal Brainstem

The dorsal column nuclei were consistently bilaterally labeled following injections within the roc (fig. 5B, 7B, 9B).

This labeling may be partially attributed to the uptake of HRP by internal arcuate fibers passing from the ipsilateral dorsal column nuclei through the injected roc on the way to the contralateral

IOC and medial lemniscus (Matzke, 1951). However, in one animal

(fig. llA,B) in which the injection was centered in the lateral part of the Dao, thereby missing the internal arcuate fibers, labeled dorsal column nuclear cells were identified, but only contralateral to the injection site.

The spinal trigeminal nucleus also contained labeled neurons bilaterally with a contralateral predominance (fig. 5,7,11).

Most of these neurons were located within the interpolar subdivision.

Since fibers from the spinal trigeminal nucleus project through as well as to the roc (Carpenter and Hanna, 1961), it was impossible to determine the relative quantity of cells labeled due to the uptake of HRP by axon terminals as opposed to the uptake by axons severed by the injection needle.

The lateral reticular nucleus contained reactive neurons primarily contralateral to the injection site (fig. llA,B). Most of the labeled cells were contained within the external subdivision with less in the internal subdivision and only a few cells within the trigeminal subdivision. Bilateral labeling of neurons was also found in the magnocellular, gigantocellular, paramedian and 50 ventral reticular nuclei. Occasionally the contralateral nucleus reticularis dorsalis contained a cluster of reactive neurons.

The vestibular complex contained labeled neurons in a number of animals, especially those having injections encompassing the caudal part of the Hao and dorsal cap of Kooy (fig. 5,7,9). Most of the reactive cells were within the descending and medial vestibular nuclei and had an ipsilateral predominance. Generally, injections which produced vestibular labeling also produced labeling of the nucleus prepositus hypoglossi. Labeled cells were also found in a group of cells similar in position to the nucleus y of the vestibular complex of the cat (Brodal and

Pompeiano, 1957) (fig. lOg).

Cerebellum

Depending upon the locus of the olivary injection, labeled neurons were consistently found within the dentate and interposed nuclei, especially on the contralateral side (fig. lOd,e). The soma were generally of small diameter and were lightly labeled.

Occasional larger and more darkly reacting neurons were identified particularly in the dorsal part of the dentate nucleus and the ventral part of the nucleus interpositus posterior. The fastigial nuclei were notably devoid of labeled neurons except when olivary injections included the caudal part of the medial accessory olive. The labeled neurons were bilaterally distributed in the ventral part of the fastigial nuclei, and were large relative to 51 the size of other cerebella-olivary neurons (fig. lOf).

Midbrain

Labeled neurons within the midbrain were distributed in various nuclear clusters as well as diffusely throughout the mesencephalic reticular formation and prerubral field especially on the side ipsilateral to IOC injection. The nuclear areas which showed labeled cells included the pretectal complex, the interstitial nucleus of Cajal, the periaqueductal gray, the red nucleus, the superior colliculus, and the ventral tegmental area.

Additionally, a previously undescribed cluster of reactive neurons directly medial to the magnocellular medial geniculate was observed within the deep mesencephalic nucleus following olivary injections of HRP.

The pretectum contained reactive neurons in most of the injected animals. These cells were more numerous after injections which included the caudal part of the Mao and dorsal cap of Kooy

(fig. 5,7,9). Labeled neurons within the caudal aspects of the anterior and posterior pretectal nuclei were predominantly contralateral in location. The nucleus of the optic tract, however, contained labeled cells primarily ipsilateral to the injected IOC. Labeling in the latter cell group occured only in four animals with caudal and medial olivary injections (fig. 7,8d,e).

Labeled neurons of small diameter were observed within the stratum profundum of the superior colliculus. While these neurons 52 were predominantly contralateral to the injection site, some ipsilateral labeling was observed as well.

The interstitial nucleus of Cajal was labeled ipsilaterally by all olivary injections (fig. 5,11C,l2b) and most animals showed a small but definite contralateral projection as well. At the ventral side of the medial longitudinal fasciculus reactive neurons of the nucleus of Cajal were continuous with a group of neurons positioned near the third nerve fibers (fig. 5,6e).

These cells were situated about the rostromedial border of the red nucleus and extended into the ventral tegmental areas. Only a few labeled neurons were found in other portions of the red nucleus.

With injections centered within the caudal part of the Mao and the dorsal cap, a considerable number of labeled cells could be observed interposed between the medial lemniscus and the pars compacta at the medial aspect of the substantia nigra. Many of these cells were situated within the medial terminal nucleus of the accesso~y optic tract (fig. 5,6d,7,8f).

The periaqueductal gray appeared to contain two populations of labeled neurons, one dorsal and the other lateral to the cerebral aquaduct (fig. 5,7,11C). The majority of the labeled periaqueductal cells were ipsilateral to the injection site although some contralateral labeling was observed.

A well-defined and densely packed group of labeled neurons was identified in the lateral part of the deep mesencephalic 53

nucleus. They were directly medial to the ipsilateral magnocellular

medial geniculate nucleus, ventral to the pretectum, and rostral

to the parabigeminal nucleus (fig. lld). This cluster of neurons was approximately 600u long and 300u in diameter and had dendrites which ramified within the region of labeled cells (fig. 10h,l2d).

These cells did not appear to conform to the boundries of previously

named nuclei in spite of their well circumscribed appearance.

Scattered labeling was identified within the ipsilateral nucleus of the lateral lemniscus and in the nucleus of the posterior

commissure. However, this labeling appeared to be much less

consistent than that of other mesencephalic regions.

Diencephalon

Labeled diencephalic neurons were predominantly ipsilateral

to the side of olivary injection. The majority of the reactive

cells were located in the subparafascicular nucleus and in the nucleus of Darkschewitsch (fig. 5,6f,llC,l2c). In addition to the

ipsilateral labeling, each of these locations had a small, but

consistent group of contralaterally labeled cells. Scattered

labeled neurons were found within the ipsilateral zona incerta

(fig. 5,6h); the amount of this labeling increasing as caudal

levels of the IOC were included in the injection site. Occasional neurons were found within the ipsilateral parafascicular nucleus. 54 cortex

Pyramidal shaped cortical neurons were found to label bilaterally within layer V of the frontal and parietal cortex. No labeled neurons were identified within the occipital or temporal cortices.

With ventral injections into the IOC, more cells labeled ipsilateral to injection while dorsal injections produced a more balanced bilaterality. 55

Anterograde analysis of inferior olivary afferents

Spinal cord

Projections from the spinal cord to the IOC were examined in

12 animals, using the Fink-Heimer stain for degenerating axons following unilateral spinal cord lesions at mid thoracic or upper cervical levels. In all cases, degeneration was observed in the subnucleus a and b of the caudal Mao and in the caudolateral part of the Dao (fig. 14). However, upper cervical cord lesions produced degenerating axonal debris which extended slightly more rostrally and medially then did mid thoracic lesions even though, in both cases, degeneration was confined to the same general regions.

Caudal Brainstem

Dorsal column nuclei. Projections from the dorsal column nuclei to the IOC were investigated with the Fink-Heimer stain following lesion of the dorsal column nuclei in five animals and with autoradiography after dorsal column nuclear injections of tritiated leucine in four animals. Results obtained with the two techniques were relatively consistent, although the autoradiographic labeling of these projections was more striking. Although the analysis of dorsal column nuclear-olivary projections is somewhat complicated by the large number of internal arcuate and medial lemniscal fibers which pass through the IOC, apparent terminal 56 labeling was observed to be mainly within the caudola teral portions of the contralateral Mao and Dao (fig. 15).

Reticular formation. Injections centered in the nucleus reticularis gigantocellularis produced labeling primarily ipsilaterally in the caudal Mao (subnuclei b, c and B) and contralaterally in the rostral Dao (fig. 16).

Lateral reticular nucleus. Injection of the lateral part of the lateral reticular nucleus in four animals produced labeling bilaterally within the subnuclei a and b of the caudolateral Mao

(fig. 17).

Spinal trigeminal nucleus. In four animals with injections into the interpolar subdivision of the spinal trigeminal nucleus, a substantial number of axons were observed autoradiographically to decussate and subsequently ascend the brainstem in close proximity to the IOC. Coursing from these projections terminations were observed within the roc primarily contralateral to the injection site within the medial Dao at rostral olivary levels

(fig. 18).

Vestibular nuclei. With seven injections of the descending and medial vestibular nuclei labeling appeared in two circumscribed regions of the IOC, one in the ipsilateral subnuclei b, c and B of the caudal Mao and the other in the contralateral DMCC (fig.

19). The labeling in the DMCC was observed to increase when injections were centered in more ventrolateral portions of the descending vestibular nucleus (fig. 20). 57

Nucleus prepositus hypoglossi. In two cases, -following midline injections of tritiated leucine into the nucleus prepositus hypoglossi and the surrounding reticular formation, fibers could be observed coursing ventralward, some to terminate in the roc, but many to sweep lateralward along the ventral surface of the brainstem to enter the inferior cerebellar peduncle. Regions of olivary termination included the caudal Mao, especially c and B, the dorsal cap and the DMCC. Since the injections were bilateral, the precise laterality of these projections could not be discerned, although most fibers appeared to course ipsilaterally (fig. 21).

Cerebellum

Dentate nucleus. In 17 cases, injection of the dentate nucleus produced prominent labeling in the superior cerebellar peduncle and its crossed descending limb, which could be traced caudally to the Po of the inferior olive. A well defined topography was evident in this projection with the rostral and caudal dentate projecting to the Pod (fig. 22) and Pov (fig. 23), respectively.

While not as clearly defined as the rostral-caudal topography, injections into the more ventral portions of the dentate appeared to produce labeling within more lateral portions of the Po (fig.

24). All dentate injections produced some labeling of the ventrolateral outgrowth. 58

Interposed nucleus. Fibers from the nucleus interpositus of ten animals followed·a similar course to that described for the dentate nucleus, however, within the superior cerebellar peduncle, interpositus fibers were situated more medially then those from the dentate. The rostral portion of the interpositus was found to project to the Dao (fig. 25) while more caudal levels projected to the rostral half of the Mao and the Pov (fig. 26).

Fastigial nucleus. Following injections of the fastigial nucleus of five rats, labeled fibers were observed to the caudomedial

Mao, primarily in the ventrolateral outgrowth and subnuclei c and

B (fig. 27).

Mesencephalon and Diencephalon

Mesencephalic and diencephalic projections to the IOC uniformly course within the medial longitudinal fasciculus. At olivary levels, fibers pass ventrally toward their olivary targets.

Pretectal complex. Two regions of the roc were labeled following six injections which involved most of the caudal pretectal complex as well as the lateral part of the stratum profundum of the superior colliculus. Dense labeling occured over the subnucleus c of the caudal Mao primarily contralaterally, while somewhat lighter labeling was found over the medial part of the ipsilateral

Pod (fig. 28). With more rostral pretectal injections, which included most of the rostral part of the nucleus of the optic tract, heavy labeling was observed in the ipsilateral dorsal cap

(fig. 29) . 59

Superior colliculus. Six injections of the stratum profundum of the superior colliculus displayed a labeling pattern similar to that observed after caudal pretectal injections, i.e., contralateral subnucleus c of the Mao and the medial part of the ipsilateral Pod (fig. 30).

Red nucleus. Placements of tritiated leucine proved to be difficult to confine to the red nucleus in seven attempts, as some spread was commonly observed into the prerubral field or the overlying tegmentum. The heaviest concentration of silver deposition was commonly observed over the ipsilateral Pod although lesser amounts were observed over the Pov, DMCC, ventrolateral outgrowth and caudolateral Mao. With injections more confined to the limits of the red nucleus, smaller amounts of labeling were observed in the accessory olives with a greater relative concentration over the Pod (fig. 31).

Deep mesencephalic nucleus, pars lateralis. A predominantly ipsilateral projection was observed from the lateral deep mesencephalic nucleus to the IOC in six animals. Terminations of this pathway appeared heaviest within the subnucleus B and the Dao. A lighter projection was also present to the DMCC, subnucleus c and ventrolateral outgrowth (fig. 33).

Deep mesencephalic nucleus, pars medialis. With the inje~tions of the reticular formation directly dorsal to the red nucleus in four rats, the strongest projection appeared to be into the Pod, with a lesser projection into the Mao, DMCC, Pov and ventrolateral 60 outgrowth (fig. 34). This pattern was similar to that observed after injections which included the rostral red nucleus (fig.

32).

Medial terminal nucleus of the accessory optic tract.

Injections of the medial part of the pars compacta of the substantia nigra and the adjacent medial terminal nucleus of the accessory optic tract in five rats produced striking labeling of the ipsilateral ventrolateral outgrowth (fig. 35).

Nucleus of Forels' field, subparafascicular nucleus, nucleus of Darkschewitsch. Essentially the same labeling pattern within the roc was found after injections centered in the nucleus of

Forels' field (four cases) (fig. 36), the periaqueductal gray

(ten cases) (fig. 37), the subparafascicular nucleus (15 cases)

(fig. 38) or the nucleus of Darkschewitsch (12 cases) (fig. 39).

In the caudal Mao, the subnuclei a and b were lightly labeled along with the medialmost portions of the subnucleus c and B.

The ventrolateral outgrowth is relatively heavily labeled along with the rostral Mao, DMCC and Po (both lamella). The regions consistently not labeled by these injections include the dorsal cap, the Dao and most of subnucleus b.

Cerebral cortex. Ablation of the frontal cortex of six animals produced heavy degeneration in fibers of the pyramidal tract and fibers coursing through the roc, and light degeneration in diverse portions of the roc, bilaterally. This preterminal degeneration was heaviest within the Dao, the DMCC and the caudomedial Mao (fig. 40). 61

Inferior Olivary Efferents

Tritiated leucine injections into the IOC of six rats produced labeling of fibers which decussated and passed through and around the contralateral IOC to enter the inferior cerebellar peduncle

(fig. 47A). These olivary efferent fibers were found to occupy the medialmost part of the peduncle (fig. 47B) and, as they passed into the cerebellum, some were observed to terminate in the lateral vestibular nucleus (fig. 47C). Within the cerebellum, labeling was present within the deep cerebellar nuclei (fig.

47D), and within the cerebellar white matter (fig. 47C,F). From the cerebellar medullary regions labeled fibers could be traced through the granular layer of the cerebellar cortex and into the molecular layer. Labeling in the cerebellar cortex was entirely contralateral to the IOC injection site and appeared as bands of labeled fibers within the molecular layer (fig. 47E,F). Analysis of sequential sections revealed these bands of labeling as continuous strips in the form of parasagital rows through the rostral-caudal extent of the cerebellum (fig. 48). Since it was necessary to inject substantial amounts of isotope in order to satisfactorily label the distal ends of the olivocerebellar climbing fibers, it was not possible to confine the injections to individual subdivisions of the IOC. However, caudally placed IOC injections centered in the Dao and Mao were found to label more medially situated cerebellar rows and the more medially situated deep nuclei (i.e. fastigial and interposed) while more rostral injections centered 62 in the Po labeled more lateral rows and nuclei (i.e. interposed and dentate). Additionally, injections which included the caudomedial Mao also produced substantial labeling in the flocculus of the cerebellum (fig. 47G). 63

Inferior Olivary Afferents in Hemicerebellectomized Rats

Retrograde Studies

In search of anomalous connections HRP was injected into the spared roc of 17adult rats that sustained neonatal hemicerebellectomy.

Although the HRP method is not considered a precise quantitative technique, careful inspection revealed no change in the distribution of labeled cells as compared to normal animals (fig. 49). For example, predominantly ipsilaterally labeled nuclei (such as the subparafascicular nucleus, the zona incerta, the nucleus of

Darkschewitsch, the nucleus of Forels' field, the nucleus of

Cajal, the lateral deep tegmental nucleus, the rostromedial red nucleus or the nucleus of the otpic tract) showed no obvious tendency toward a greater proportion of labeled cells contralateral to the injection site. Similarly, predominantly contralaterally labeled cell groups (such as the superior colliculus, the caudal pretectum or the dorsal column nuclei) showed no apparent shift toward ipsilaterality.

Orthograde Studies

In further search of remodeling, the projection from the cerebral cortex, subparafascicular nucleus, nucleus of Darkschewitsch, nucleus of Forels' field, lateral deep mesencephalic nucleus, superior colliculus, caudal pretectum, and the dorsal column nuclei were investigated by either autoradiographic or degeneration 64 staining methods in neonatally hemicerebellectomized rats.

Similar to the HRP study (described in the preceeding section), the objective of this experiment was to determine whether regions which normally project primarily to the missing IOC of a hemicerebellectomized animal will redirect their projections into the spared roc.

Projections from the subparafascicular nucleus, the nucleus of Darkschewitsch and the nucleus of Forels' field in normal rats are predominantly ipsilateral to the DMCC, the entire Po, the rostral Mao and portions of the caudal Mao, notably portions of subnuclei a, b and c, the subnucleus B and the ventrolateral outgrowth and posesses a small crossed projection to similar portions of the contralateral IOC. Striking alteration in the laterality was observed after neonatal hemicerebellectomy.

Injections of tritiated leucine into these areas (the subparafascicular nucleus, the nucleus of Darkschewitsch or the nucleus of Forels' field) on the side ipsilateral to the missing roc (i.e., contralateral to the hemicerebellectomy) in 12 rats, produced an abnormally large decussation of labeled axons 100 to 300u from the rostral pole of the roc (fig. SOC-H). These fibers were observed to terminate in the same portions of the contralateral roc which normally receive projections from these mesencephalic and diencephalic nuclei. While this abnormally large crossed projection, which is most noticeable within the DMCC, is markedly greater than the normally small crossed projection (compare fig. 50A,B with fig. 65

SOC-H), it nonetheless is considerably less than the density of normal terminations within the ipsilateral IOC (figs. 38-39).

Results derived from injections within the lateral deep mesencephalic nucleus, also contralateral to the side of he hemicerebellectomy, were suggestive of an abnormally large contralateral projection, especially into the subnucleus c of the caudal Mao and into the DMCC and medial Dao. This apparent remodeling was less certain due to difficulties in obtaining suitably consistent injections in this region, which was complicated by the brainstem distortion which occurs after neonatal hemicerebellectomy, and also due to the normally lighter nature of this projection.

Remodeling of olivary afferents in response to neonatal hemicerebellectomy was not observed from the dorsal column nuclei and the superior colliculus, both contralateral to the missing

IOC, and the medial terminal nucleus of the accessory optic tract and the cerebral cortex ipsilateral to the missing IOC. 66

Inferior Olivary Efferents in Hemicerebellectomized Rats

Tritiated leucine injections of the spared IOC in four neonatally hemicerebellectomized rats revealed a normal distribution of olivocerebellar fibers. Olivary efferents were entirely crossed, passed through the region of the missing IOC, coursed through the medial part of the contralateral inferior cerebellar peduncle and distributed to the lateral vestibular nucleus, the deep cerebellar nuclei and the molecular layer of the cerebellar cortex. No aberrent pathways were observed within the cerebellum nor were anomalous projections traced to the ipsilateral lateral vestibular nucleus.

Injections into the region of the missing IOC and the surrounding medullary reticular formation in three rats, produced mossy fiber labeling within the ipsilateral inferior cerebellar peduncle. Mossy fiber labeling, which represents non olivary afferents, does not course along the medial edge of the inferior cerebellar peduncle and therefore can be readily distinguished from olivary climbing fibers. This labeling is attributed to fibers from the reticular formation and is therefore not considered to represent anomalous projections.

Additionally, no projection could be observed from the region of the missing roc to the contralateral lateral vestibular nucleus, as would be expected were there olivary neurons remaining in this region. 67

Effects of Vestibular Nerve Lesion in Hemicerebellectomized Rats

Lesions of the vestibular nerve ipsilateral to tt~e side of neonatal hemicerebellectomy in four rats, produced the typical signs of vestibular dysfunction, i.e., severe nystagmus and rolling towards the side of lesion. These signs persisted with no noticeable recovery throughout the week long course of observation. DISCUSSION

The discussion section will be divided so that roc afferents

as discerned by retrograde and orthograde means will be discussed

together followed by a discussion of roc efferents, afferents in

hemicerebellectomized rats and, finally, the effects of vestibular

nerve lesion after hemicerebellectomy.

Inferior Olivary Afferents

Spinal Cord

Spina-olivary fibers have been previously reported to arise

from cell bodies within the nucleus proprius of the cervical

spinal cord in rats (Brown et al., 1977) and from cells localized within lamina VI of the cervical cord in cats (Buisseret-Delmas and Batini, 1978). Both groups of investigators used HRP and

found only crossed projections and furthermore reported no

labeled cells below cervical levels. The present study shows a much more extensive origin for spina-olivary projections, predominantly

from the contralateral laminae V and VII which were identified

throughout the cervical, thoracic and lumbar cord down to approximately

the 16 level. The lamina V neurons were distributed within both

the medial and lateral subdivisions and were observed at cervical,

thoracic and lumbar levels. Within lamina VII, two collections of neurons were generally observed, one situated medially at the base of the ventral horn and the other at the medial aspect of

the base of the dorsal horn (fig. 3,4). The cells at the base of the ventral horn appeared to be most numerous at cervical and

68 69 lumbar levels, while those at the base of the dorsal horn appeared most prominently in the lower cervical and thoracic regions. some of these latter neurons were located within the nucleus dorsalis of Clarke and were of small diameter. These findings correlate with recent cytoarchitectural studies of Clarke's column following neonatal hemicerebellectomy which revealed a loss of large neurons but with a persistence of smaller cells

(Smith and Castro, 1979). The persisting cells appear to correspond to the labeled cells projecting to the IOC.

Our finding of a considerably more extensive origin of spina-olivary fibers in comparison to previous reports (Brown et al., 1977; Buisseret-Delmas and Batini, 1978) may reflect technical differences such as survival time, differing sensitivity of various HRP reactions and the use of counterstaining which can obscure reactive cells. Indeed, in previous work we have found that even light counterstaining may obscure neurons that are lightly, but definitely labeled with HRP from Sigma.

The pattern of spinal projections into the IOC as defined in the present study by the use of the Fink-Heimer stain following unilateral spinal cord lesions (fig. 14) closely matches that described in previous work (Brodal, Walberg and Blackstad, 1950;

Blackstad, Brodal and Walberg, 1951; Ogawa and Kusama, 1954;

Stotler, 1954; Nauta and Kuypers, 1958; Kusama, 1961; Mizuno,

1966; Boesten and Voogd, 1975; Berkley and Worden, 1978). The principal sites of termination for these spinal projections are 70 in the caudolateral portions of the Mao (i.e., subnucleus a and b) and in the caudolateral part of the Dao. In accord with findings in the cat (Boesten and Voogd, 1975), cervical cord lesions produced degeneration which extended somewhat more rostral and medial within the caudal Mao and Dao then did mid thoracic lesions.

The pattern of spinal distribution within the caudolateral Mao and Dao and the projections of these portions of the IOC upon vermal and paravermal zones of the cerebellum (Groenewegen and

Voogd, 1977; Groenwegen et al., 1979) is in good agreement with electrophysiological studies of the cerebellar distribution of climbing fibers conveying spinal information (Oscarsson, 1973).

Caudal Brainstem

Dorsal column nuclei. The presence of labeled cell bodies in the dorsal column nuclei after olivary injections of HRP corroborates anterograde (Morest, 1967; Ebbeson, 1968, Hazlett et al., 1972;

Boesten and Voogd, 1975; Groenewegen, Boesten and Voogd, 1975;

Berkley and Worden, 1978; Berkley and Hand, 1978) and retrograde

(Brown et al., 1977; Buisseret-Delmas and Batini, 1978) evidence for these projections. However, the retrograde labeling within these nuclei is in most cases partially attributed to the uptake of HRP by damaged internal arcuate or medial lemniscal fibers which travel through and in close proximity to the IOC. This interpretation is particularly evident in several animals demonstrating bilateral dorsal column nuclear labeling, a feature which is contrary to 71 studies with anterograde techniques which show the great majority of these projections to be contralateral (Berkley and Hand, 1978). In one animal in which the injection avoided the area of passage of internal arcuate and medial lemniscal fibers (fig. 9A,B), the labeling of neurons in the dorsal column nuclei was entirely contralateral to the injection. This injection, even though it did evidence some spread to the reticular formation, was centered in the lateral part of the Dao, an area which has been shown to receive dorsal column nuclear input especially from the nucleus gracilis

(Berkley and Hand, 1978).

The termination of dorsal column nuclear axons within the caudolateral Mao and Dao (fig. 15), as shown in the experiment is supported by a recent study also done in the rat (Feldman and

Druger, 1980) and is consistent with findings in the cat (Ebbeson,

1968; Boesten and Voogd, 1975; Hand and Van Winkel, 1977; Berkley and Worden, 1978; Berkley and Hand, 1978). The degree of bilaterality herein demonstrated by the use of autoradiography (fig. 15) is somewhat suprising in light of the prior studies which report only a small ipsilateral connection. This discrepancy is possibly due to a lesser sensitivity of the degeneration techniques employed in most of the earlier work.

Olivary afferents from the dorsal column nuclei provide the anatomical basis for the physiologically identified dorsal funiculus spino-olivo-cerebellar fiber system (see Oscarson, 1973 for review) conveying somatic information to the cerebellum via the roc. 72

Spinal trigeminal nucleus. The interpolar subdivision of the spinal trigeminal nucleus consistently contained HRP labeled neurons.

These neurons were primarily contralateral to the injection site although many injections did demonstrate considerable bilaterality.

These findings are at some variance with the orthograde data presented in this study as well as with orthograde studies in the cat (Berkley and Hand, 1978) which showed a predominantly crossed projection from the spinal trigeminal nucleus to the IOC. A partial explanation for the bilaterality observed in retrograde experiments considers the possibility that HRP may have been incorporated into the severed ends of axons coming from the spinal nucleus of the trigeminal through the inferior olive (Carpenter and Hanna, 1961).

The termination of axons from the spinal trigeminal nucleus within the rostromedial Dao (fig. 18), as here reported in the rat, corresponds to results reported in the cat (Berkley and Hand, 1978).

Since as previously discussed, the terminations of spinal and dorsal column nuclear inputs to the IOC are also similar between rats and cats, the somatopy which has been described within the feline Dao

(Berkley and Hand, 1978) probably also holds true for the rat. This somatotopy describes more rostromedial levels of the Dao as receiving somatosensory inputs from more rostral portions of the animal.

The function of connections from the spinal trigeminal nucleus to the IOC is not clear although cutaneous afferents from the face have been shown to be capable of evoking responses in olivary neurons in a rather precise manner (Miles and Wiesendanger, 1975;

Cook and Wiesendanger, 1976). Trigemino-olivary projections have 73 also been considered a possible route for extraoccular muscle stretch information to effect climbing fibers and, thereby, the cerebellum (Brown et al., 1977).

Reticular formation. The present study demonstrates bilateral projections from the lateral reticular nucleus to the roc. Numerous labeled neurons were found within the external subdivision with fewer in the principal and only occasional labeled neurons within the trigeminal subdivisions of this nucleus. As has been previously suggested (Oscarson, 1973; Brown et al., 1977), these projections may represent yet another relay for spinal information projecting to the roc.

Bilateral reticular formation labeling, as found in this study within the nucleus reticularis gigantocellularis and to a lesser extent within the paramedian reticular nucleus, agrees with earlier studies (Brown et al., 1977). The present study also found the nucleus reticularis dorsalis to contain labeled neurons, generallly contralaterally, following certain olivary HRP injections.

The autoradiographic corroboration of the pathways from the reticular formation and the lateral reticular nucleus is difficult due to the proximity of these nuclei to the IOC, and the consequent tendency of injection sites within these regions to spread into the

IOC. However, one injection which labeled the extreme lateral aspect of the lateral reticular nucleus did demonstrate some labeling of the caudal Mao (subnuclei a and b) without noticeable direct spread. Likewise, injections primarily within the dorsal part of 74 the nucleus reticularis gigantocellularis and the nucleus reticularis dorsalis produce labeling within the Dao primarily contralaterally and in the subnuclei a, b and B mainly ipsilaterally. It is possible that a portion of the projection to the Dao may be due to spread of injection to the spinal trigeminal nucleus and that some of the labeling identified in the caudal Mao may be due to inclusion of the vestibular complex within a portion of the injection site.

Vestibular nuclei. The vestibular projection to the olive has recently received considerable attention, particularly as a result of climbing fiber responses which have been identified primarily within the flocculus, nodulus and vermis of the cerebellum in response to vestibular stimulation (Ferin, Grigorian and Strata,

1970, 1971; Ghelarducci, Ito and Yagi, 1975; Precht, Volking and

Blanks, 1977). Using retrograde tracing techniques the medial and descending vestibular nuclei have been shown to project to the IOC in the rat (Brown et al., 1977). These pathways were followed in the cat (Saint-Cyr and Courville, 1979) using both retrograde and orthograde means, and subnucleus z is also reported to contribute vestibula-olivary projections in the cat (Saint-Cyr and Courville,

1979; Buisseret-Delmas and Batini, 1978). Similarily, the present study shows bilateral neuronal labeling within the medial and descending vestibular nuclei, which was heaviest when HRP injections included the caudo-medial part of the Mao and the dorsal cap of Kooy

(fig. 3,5,7). Additionally, labeling was demonstrated within cells apparently analogous to the nucleus y of the cat (Brodal and Pompeiano,

1957). 75

After autoradiographic injection of the medial and descending vestibular nuclei, the demonstrated projection pattern (fig. 19,20) was similar to that described in the cat (Saint-Cyr and Courville,

1979). The prinicpal sites of termination of vestibula-olivary projections in both species appear to be in the B subnucleus and the

DMCC. Additionally, the present study demonstrated a light distribution within the subnucleus b and c of the caudal Mao. While both the cat and the rat present a predo~inantly ipsilateral connection to the B subnucleus, the connection to the DMCC has been reported to be bilateral in the cat while being primarily contralateral in the rat.

The finding of labeling within the medial Dao with injections situated more ventrolateral in the descending vestibular nucleus may be partially attributable to spread of label to the dorsal part of the spinal trigeminal nucleus.

Although physiologically-identified activation of climbing fibers within the nodulus and large portions of the vermis (Ferin et. al., 1970; Ghelarducci et al., 1975; Precht et al., 1977) is consistent with the sites of termination of climbing fibers deriving from the DMCC, B subnucleus and caudal Mao (Groenwegen and Voogd,

1977; Groenwegen et al., 1979), the route of vestibular activation of floccular climbing fibers is less clear. A possible explanation for floccular activation considers the nucleus prepositus hypoglossi, which has been strongly associated with vestibulo-occular reflexes

(Baker and Berthoz, 1975) and which has been shown by retrograde techniques to project to the IOC in the cat (Saint-Cyr and Courville, 76

1978) and in the present study on rats. Furthermore, the present study demonstrates that the nucleus prepositus hypoglossi projects

to the dorsal cap of the roc' the primary site of origin of cerebellar climbing fibers to the flocculus (Hoddevik and Brodal, 1977) In spite of the possibility of direct, primary vestibular climbing fiber termination in the cerebellar cortex in the frog (Llinas,

Precht and Kitai, 1967; Hillman, 1969), anatomical findings suggest that vestibula-olivary connections may represent the primary mechanism of vestibular activation of climbing fibers in mammals.

Raphe nuclei. The nucleus raphe obscuris has been reported, both in this study and in the work of Brown et al. (1977), to be a site of origin of olivary afferents and is considered to be the source of serotonin which has been identified within the IOC (Fuxe,

1965; Wicklund, Bjorklund and Sjolund, 1977). While the present study has not considered the distribution of raphe-olivary axons, the overlap between the localization of serotonergic axons and the regions of termination of spina-olivary axons (the caudolateral Mao and Dao) has been discussed elsewhere (Wicklund et al., 1977).

Cerebellum

The projection of deep cerebellar nuclear neurons to the IOC, as suspected by studies using degeneration techniques, has been substantiated by the use of autoradiographic tracing methods

(Graybiel, Nauta, Lasek and Nauta 1973; Martin, Henkel and King

1976; Beitz, 1976; Tolbert, Massopust, Murphy and Young, 1976). 77

This projection has also been shown electrophysiologically to consist partially of descending axon collaterals from ascending cerebellar efferent fibers (Ban and Ohno, 1977).

HRP studies have shown these connections to arise primarily from small neurons of the dentate and interposed nuclei (Tolbert et al., 1976; Martinet al., 1976; Brown et al., 1977;~Buisseret-Delmas and Batini, 1978). In the rat, lightly labeled neurons were located contralaterally in the lateral part of the interpositus nucleus and medial hilar region of the dentate nucleus, predominantly contralateral to the injection site (Brown et al., 1977). Our results generally support these findings.

Rather precise autoradiographic analyses have revealed a topographic distribution of dentate-olivary projections. In the monkey, the caudal dentate projects to the rostral Po and vice versa

(Chan-Palay, 1977), and feline studies (Tolbert et al., 1976; Beitz,

1976) have demonstrated the ventral dentate. to project to the Pov while the dorsal dentate projects to the Pod. The present rodent study corroborates previous work on rats (Haroian et al., 1978) demonstrating that the caudal and rostral dentate project to the Pov and to the Pod, respectively. The close agreement between studies done within species, such as the cat and rat, suggest that the topographic differences between species reflect true species variations.

Our findings suggest an additional organization with the dorsal and ventral dentate, distributing to the medial and lateral Po, respectively.

Apparent across species differences are also described in reference to the topography of interposito-olivary projections. In 78 the cat, the rostral and caudal interpositus pr~ject with a rostral to caudal localization within both the Mao and Dao (Tolbert et al.,

1976), whereas the rostral and caudal interpositus projects to the

Dao and Mao, respectively, in the opossum (Martinet al., 1976). As seen in the present study, the rodent interposito-olivary topography is similar to the opossum with the exception that the rat also demonstrates projections from the caudal interpositus to the Pov.

Some controversy has surrounded the question of fastigial projections to the roc. The fastigial nuclei are reported to distribute bilaterally within the caudal roc (Achenback and Goodman,

1968; Dom, King and Martin, 1973; Martin et al., 1976; King, Andrezek,

Falls and Martin, 1976) while others have denied this projection using both orthograde (Walberg, 1956; Tolbert et al, 1976) and retrograde (Brown et al., 1977; Busseret-Delmas and Batini, 1978) techniques. The presence of substantial numbers of large, heavily labeled neurons in the ventral portion of the fastigial nuclei following HRP injections of the caudal portions of the Mao, as well as autoradiographic labeling of this pathway in our study argues in favor of a fastigioolivary connection in rats. Considering that several studies have examined this question, it seems reasonable to conclude that fastigioolivary connections may not be present in the cat, (Walberg, 1956; Tolbert et al., 1976; Busseret-Delmas and

Batini, 1978), whereas they may be present in other animals such as the rat (Achenbach and Goodman, 1968) and the opossum (Dom et al.,

1973; Martinet al., 1976; King et al., 1976). The discrepancy 79

between our findings and the report by Brown et al. (1977), which was an HRP study also in rats, may be explained by our use of a more

sensitive HRP reaction and by our having obtained a few injections

centered within the caudal part of the medial accessory olive.

The function of cerebellar projections to the olive, and their

possible interaction with olivocerebellar projections remains to be

investigated. The possibility of indirect cerebellar feedback to

the olive by way of preolivary nuclei also remains an interesting, albeit unsubstantiated possibility. The termination of cerebellar efferents in nuclei which feedback to the cerebellum via the IOC is strongly suggestive of some interaction. The several areas in which this interaction might occur include the zona incerta, nucleus of

Darkschewitsch, the interstitial nucleus of Cajal, the periaqueductal gray, the red nucleus, the pretectum, the vestibular complex and portions of the reticular formation.

Cerebellar projections to the IOC are thought particularly interesting in light of the specificity which is demonstrated in the olivo-cerebello- olivary circuit. For example, the dentate nucleus which projects to the Po, receives projections from the Po. Similarly, the interpositus which projects to the rostral portion of the accessory olivary nuclei receives afferents from these same regions, as does the fastigial nucleus which both receives from and projects to the caudal Mao.

Rostral Brainstem

The rostral pons and caudal midbrain are consistently reported 80 to contain relatively few labeled neurons following inferior olivary injection (Brown et al., 1977; Henkel et al., 1975) In the mesencephalon, the number of cells containing reaction product tend to increas~ at more rostral levels becoming numerous in the caudal diencephalon.

Mesencephalon. Many nuclei of the mesencephalon have been reported to be sites of origin for olivary afferents (Brown et al.,

1977; Henkel et al., 1975). Additionally, the mesencephalic tegmentum appears to provide a heavy input to the roc, predominantly from the ipsilateral side.

Mesencephalic tegmento-olivaries have only been definitively shown since the advent of autoradiographic techniques. In the opossum, the tegmentum surrounding the red nucleus was observed to project to the subnucleus c of the Mao and to the Dao (Linauts and

Martin, 1978a), while in the rat relatively equivalent regions of the tegmentum were observed to project to the rostral Mao, the DMCC and extensive regions of the Po. This distribution pattern was similar to that from the fields of Forel. With tegmental injections in the area of the red nucleus, the Pod was more heavily labelled than the Pov, and only limited projections to the caudal Mao and none to the Dao were found. The divergent results from reasonably equivalent injections in the opossum and rat are difficult to reconcile but may reflect species differences as seen particularly with cerebella-olivary projections.

Olivary afferents from the periaqueductal gray have been previously described using HRP in the opossum (Henkel et al., 1975) 81 and in the rat (Brown et al., 1977) and have been been also described in several anterograde studies (Mettler, 1944; Mabuchi and Kusama,

1970; Hamilton and Skultety, 1970; Walberg, 1974; Linauts and

Martin, 1978). The laterality of these fibers is somewhat in question since Henkel et al. (1975) reports them as primarily contralateral while all other studies, including our own data, suggest a primarily ipsilateral pathway. Our HRP findings additionally suggest a certain topography within the periaqueductal gray whereby retrogradedly labeled neurons were generally localized in two populations, one lateral and the other dorsal to the aqueduct (fig.

9C).

Orthograde examination of periaqueducto-olivary connections was unable to confirm olivary projections from the dorsal part of the periaqueductal gray. However, injections of the ventrolateral periaqueductal gray (invariably including portions of the interstitial nucleus of Cajal) produced substantial amounts of labeling, primarily ipsilaterally, within the Po, the rostral Mao, and certain portions of the caudal Mao (i.e. the ventrolateral outgrowth, the B subnucleus and portions of subnuclei a and c). This pattern is generally similar to that reported in the cat (Walberg, 1956; Mabuchi and

Kusama, 1970; Hamilton and Skultety, 1970) and resembles the projection pattern from the nucleus of Darkschewitsch, the subparafascicular nucleus and the nucleus of Forels' Field.

When examined with a retrograde tracer most of the red nucleus was consistently found to contain only few labeled neurons following olivary injections, a finding in agreement with previous studies 82

(Henkel et al., 1975; Brown et al., 1977). However, numerous labeled cells were observed in the rostromedial edge of the red nucleus similar to those described in the opossum (Henkel et al.,

1975). It is possible that these neurons give rise to much of the classically described rubro-olivary tract, at least in the rat and opossum. The existance of this pathway is further supported by autoradiographic data in the opossum which, in agreement with our findings, showed that rubral injections including the rostral or medial aspects of the red nucleus produce the greatest concentration of label over the Pod (Linauts and Martin, 1978a).

Scattered cells containing peroxidase reaction product were found in the region of the ventral nucleus of the lateral lemniscus.

These cells have been reported previously (Brown et al., 1977) and may represent a relay for auditory information through the roc to the cerebellum.

A cluster of neurons not previously reported to project to the

IOC was identified in the lateral part of the deep mesencephalic nucleus, directly medial to the magnocellular medial geniculate nucleus and ipsilateral to the injection site. These neurons were located rostral to the parabigeminal nucleus and ventral to the pretectal complex. In fact, in adjacent cresyl violet stained sections, these cells did not appear to correspond to any particular nuclear subdivision. Projections from this region to the Dao and medial part of the subnucleus c, as seen by autoradiography, are in accord with observations in the opossum (Linauts and Martin, 1978a), 83 but the rat additionally demonstrates a significant projection to the ventrolateral outgrowth and subnucleus B.

This cluster of labelled neurons within the lateral mesencephalic tegmentum appears to represent a substantial olivary afferent system, possibly related to vestibular or ocular function, as suggested by their projection to the subnucleus B and ventrolateral outgrowth. The presence of these cells along with the scattering of other labeled cells in this region is surprising in light of a recent autoradiographic study showing few descending projections from the lateral deep mesencephalic nucleus (Veazey and Severin,

1980). On the other hand, since the authors have proposed a motor function for this region based on their finding of projections to the basal ganglia, a connection with the IOC might seem reasonable.

The projection of pretectal neurons to the IOC has been demonstrated anatomically in numerous accounts and in many species (Mizuno,

Mochizuki, Akimoto and Matsushima, 1973; Graybiel, 1974; Henkel et al., 1975; Takeda & Maekawa, 1976; Brown et al., 1977; Abols and

Basbaum, 1979; Weber and Harting, 1980). In the rat, Brown et al.,

(1977) reported pretecto-olivary projections to arise from the anterior, posterior and olivary pretectal nuclei and the nucleus of the optic tract, but not from the terminal nuclei of the accessory optic tract. Other reports, in cats and opossum, have shown olivary a££erents to arise from the posterior pretectal nucleus (Henkel et al., 1975; Abols and Basbaum, 1979) and in rabbits to arise from the nucleus of the optic tract and dorsal and lateral terminal nuclei of 84 the accessory optic tract (Takeda and Maekawa, 1976). These projections have been consistently reported to be predominantly ipsilateral. our retrograde data demonstrates an ipsilaterality with regards to labeled neurons of the nucleus of the optic tract although projections from the caudal portions of the anterior and posterior pretectal nuclei were found to be predominantly contralateral.

These impressions concerning laterality are generally supported by the orthograde part of this study. Injections of the caudal pretectal complex produced labeling similar to that found following superior collicular injections, i.e., primarily in the contralateral subnucleus c and to a lesser extent in the ipsilateral medial part of the Pod. Injections of the rostral pretectal complex (expecially the nucleus of the optic tract) demonstrated the previously reported projection pattern into the ipsilateral dorsal cap (Mizuno et al.,

1973; Weber and Harting, 1980).

Since the nuclei of the pretectal complex receive inputs primarily from the optic nerve (Singleton and Peele, 1965; Laties and Sprague, 1966; Siminoff, Schwassm~n and Kruger, 1967; Giolli and

Guthrie, 1969; Scalia, 1972), the pretecto-olivary projection is considered to provide a route for the observed visual activation of climbing fibers (Buchtel, Iosif, Marchesi, Provini and Strata, 1972;

Maekawa and Simpson, 1973; Alley, Baker and Simpson, 1975; Hoffmann,

Behrend and Schoppmann, 1976;Barmack and Hess, 1980a). This pathway has also been implicated in the feedback control of vestibulo occular reflexes (Ito, Nisimaru and Yamamoto, 1973). Recent 85 experimentation tends to support the involvement of the IOC in vestibulo-occular reflexes (Barmack and Hess, 1980b; Barmack and

Simpson, 1980; Haddad, Derner and Robinson, 1980), although there is still some question as to the involvement of the roc in optokinetic phenomena.

Olivary afferents from the superior colliculus have been previously reported (Harting, Hall, Diamond and Martin, 1973;

Frankfurter, Weber, Royce, Strominger and Harting, 1976; Graham,

1977; Weber, Partlow and Harting, 1978). As corroborated by our studies, these afferents were shown to arise from the small neurons of the stratum profundum and course to the caudomedial aspect of the contralateral Mao.

Anterograde studies also show a predominantly contralateral tecto-olivary projection to the subnucleus b of the primate (Frankfurter et al., 1976) and the subnucleus b (Graham, 1977) or c (Weber et al., 1978) in the cat. The findings of the present study support connections between the superior colliculus and the contralateral subnucleus c of the rat, while also demonstrating a small termination within the ipsilateral medial aspect of the Pod (figs. 30,31) It has been suggested that these fibers may provide a relay pathway for the transmission of eye movement information to the cerebellar cortex (Frankfurther et al., 1976; Weber et al., 1978), and indeed the caudomedial Mao projects to the visual area of the cerebellar vermis (Hoddevik et al., 1976). 86

Maekawa and Takeda (1979) have demonstrated labeled neurons in the ventral tegmentum following HRP injections into the rostral part of the dorsal cap of the IOC. These investigators had previously shown this area to receive input from the ipsilateral eye, while optic inputs to other parts of the IOC arise from the contralateral eye (Maekawa and Takeda, 1977). Three of the HRP injections reported in the present study included the dorsal cap of the IOC (fig. 3,5), and demonstrated a similar labeling pattern.

While some of the labeled cells of the ventral tegmental area were rather diffusely organized, most were packed between the medial lemniscus and the pars compacta of the substantia nigra, extending medially into the medial terminal nucleus of the accessory optic tract. The autoradiographic observation that this region projects to the ventrolateral outgrowth is consistent with a pathway for relay of visual information to the cerebellar flocculus (Hoddevik and Brodal, 1977).

Diencephalon. Degeneration studies of efferents from the midbrain and caudal diencephalon (Ogawa, 1939; Mettler, 1944;

Walberg, 1956, 1960, 1974; Carpenter, Harbison and Peter, 1970,

Mabuchi and Kusama, 1970; Hamilton and Skultety, 1970; Brodal, 1974;

Martin, Dam, King, Robards and Watson, 1975) have suggested connnections from the nucleus of Darkschewitsch and interstitial nucleus of Cajal to the IOC. The more recent use of retrograde techniques has demonstrated the origin for these pathways with greater precision

(Henkel et al., 1975; Brown et al., 1977; Busseret-Delmas and 87

Batini, 1978), and our findings have basically corroborated these retrograde studies. However, in addition to the previously reported ipsilaterality of the labeled neurons within the nucleus of Darkschewitsch and Cajal, we observed a small but definite number of labeled neurons on the side contralateral to the olivary injection.

Injections of tritiated leucine into the nucleus of Cajal

(along with the ventral periaqueductal gray) and into the nucleus of

Darkschewitsch produced a similar labeling pattern in the IOC. Both project primarily ipsilaterally and terminate heavily in the rostral

Mao, the DMCC, the Po and the ventrolateral outgrowth, with lighter terminations in the caudal Mao (subnuclei a and b and the medial part of subnucleus c and B). This distribution pattern is consistent with that reported in studies on the cat (Hamilton and Skultety,

1970; Mabuchi and Kusama, 1970; Walberg, 1974) and opossum (Linauts and Martin, 1978a). Since the nuclei of Darkschewitsch and Cajal have been described as centers for vertical and rotatory gaze, Brown et al. (1977) suggested that fibers projecting to the roc may be conveying information regarding reflex eye movement.

The subparafascicular nucleus has been shown to contain many reactive cells following injections of HRP into the inferior olive

(Henkel et al., 1975; Brown et al., 1977). These studies report a strict ipsilaterality in this projection. However, our animals consistently contained a small number of labeled neurons contralateral to the side of olivary HRP placement. It is probable that the use of a more sensitive HRP reaction in the current study accounts for this discrepancy. 88

Autoradiographic studies of subparafascicular-olivary projections, aside from the present one in the rat, have been performed only in the opossum (Linauts and Martin, 1978a). Both the rat and opossum show strong projections to the rostral Mao and Po with lighter projections into the subnuclei a and b of the caudal Mao. The rat also demonstrates projections into the ventrolateral outgrowth, the

DMCC and the medialmost part of the subnucleus c and B, while avoiding termination in the Dao.

The similarity in olivary projection pattern from the periaqueductal gray, the nuclei of Darkschewitsch and Cajal, the field of Forel, the midbrain tegmentum and the subparafascicular nucleus implies some commonality of function. While functions of most of these regions are not definitively known, the nuclei of Darkschewitsch and

Cajal have been suggested as being optic reflex centers (Cohen,

Goto, Shanzer and Weiss, 1965) implying that their IOC projections might be involved in the control of the eye movements. The projections from the subparafascicular nucleus to the medial vestibular nucleus

(Barmack, Henkel and Pettorossi, 1979), an area known to be involved in vestibular and occular functions (Baker and Berthoz, 1975), suggests that it too may be involved in eye motions. This hypothesis is supported by the relatively strong projection from these regions to the ventrolateral outgrowth, an area which has been shown to be involved in eye motions, in the relay of visual information and in vestibulo-occular reflexes (Barmack and Hess, 1980 a,b; Barmack and Simpson, 1980) 89

The present study showed scattered labeled neurons within the zona incerta on the side ipsilateral to the HRP injection site.

Labeling in this nucleus appeared to be more extensive following injections of the caudal IOC. Brown et al. (197 7) reported only a few cells labeled within this region in one animal.

Other areas~identified as containing occasional reactive cells include the parafascicular nucleus and the nucleus of the posterior commissure. In accordance with previous studies (Brown et al.,

1977) extensive examination revealed no labeled cells within the basal ganglia. Earlier work had suggested a projection from the caudate and globus pallidus to the IOC both by anatomical (Walberg,

1956) and physiological (Sedgwick and Williams, 1967; Fox and

Williams, 1968; Hablitz and Wray, 1977) means. Relatively large autoradiographi~ injections of the caudotoputamen failed to produce any labelling of the IOC, a finding which is consistent with other orthograde anatomical studies (Stotler, 1954; Nauta and Mehler,

1966; Martin et al., 1975; Kim, Nakano, Jayaraman and Carpenter,

1976; HcBride and Larsen, 1980). The exact route for the physiologically observed activation of the IOC and cerebellum by basal ganglia stimulation remains unknown.

Cortex

Difficulties exist in the interpretation of cortical labeling following olivary injections due to the uptake of HRP by terminals as well as disrupted fibers along the needle tract. The present 90 study examin€d cortical labeling following both ventral and dorsal approaches to the brainstem and did demonstrate a bilaterality in this projection, with an ipsilateral predominance. The ventral approach showed a greater ipsilateral dominance then did the dorsal approach. This finding was not surprising in light of the labeling of disrupted "pyramidal fibers upon needle penetration into the roc from the ventral side. In agreement with an earlier report (Brown et al., 1977) the labeled pyramidal-shaped soma were located in layer V of the frontal and parietal cortex. In the cat, Bishop et al. (1976) demonstrated an almost even distribution of cells in the two hemispheres followng HRP injections dorsally into the IOC. In their study the labeled perikarya were found in both the anterior and posterior sigmoid gyri. Electrophysiological studies have shown a predominantly ipsilateral pathway from the cortex to the roc (see

Armstrong, 1974 for review), although it is difficult to determine whether these connections are mono or polysynaptic. Orthograde degeneration studies have equivocated on the subject of laterality of cortico-olivary projections, primarily due to the large number of corticobulbar fibers passing through the roc following cortical lesion (Walberg, 1956; Sousa-Pinto and Brodal, 1969; Sousa-Pinto,

1969). However, there is general agreement among these studies that cortico-olivary fibers arise predominantly from the motor cortex. 91

Figures 41-46 are summary drawings derived from the orthograde data. Vestibula-ocular inputs primarily terminate within the caudomedial Mao, including the B subnucleus, dorsal cap and ventrolateral outgrowth (fig. 41). Somatosensory inputs terminate in the caudolateral

Mao and somatotopically in the Dao (fig. 42) Cerebella-olivary connections from the dentate nucleus and the nucleus interpositus are topographically organized and, generally, terminate within regions of the roc which project back upon the same deep cerebellar nucleus. This is also true of the fastigial nuclear connections with the roc (fig. 43). Reticula-olivary projections overlap with regions of vestibular and somatosensory input to the roc (fig. 44) while olivary afferents from many of the nuclei at the mesencephalo diencephalic junction overlap with vestibula-ocular, and some somatosensory inputs in addition to their distinctively heavy inputs to the Po and rostral Mao (fig. 45). Fig. 46 summarizes the convergence of some of the inputs to the roc. 92

13ferior Olivary Efferents

The distribution of olivocerebellar fibers discerned in the present experiment closely follows that shown in other anterograde studies

(Murphy et al., 1973; Courville, 1975; Groenewegen and Voogd, 1977;

Chan-Palay et al., 1977; Courville and Faraco-Cantin, 1978; Groenewegen et al., 1979; Kawamura and Hashikawa, 1979). The observed decussation of roc efferents as well as their course within the medial aspect of

the inferior cerebellar peduncle has been recognized since observations by Cajal (1909). Termination of olivary axons within the lateral vestibular nucleus, first observed by Lorente de No (1924) has since been confirmed autoradiographically, as have terminations within the deep cerebellar nuclei (Groenewegen and Voogd, 1977; Groenewegen et al., 1979). While some fundamentals of the topography of olivocerebellar connections were discerned in the current study, the small size of the rodent roc precluded the precise anterograde analysis as done in cats (Groenewegen and Voogd, 1977; Groenwegen et al., 1979; Kawamura and Hashikawa, 1979). In general, rostral IOC injections produced labeling primarily over paravermal and lateral portions of the cerebellar cortex while caudal regions of the roc were found to project to vermal and paravermal regions. Additionally, caudomedial placements were found to project to the cerebellar flocculus. As suggested in the cat (Groenewegen and Voogd, 1977; Groenewegen et al., 1979), caudal injections, which project to vermal areas, also project to the fastigial and interposed nuclei. Rostral injections, which project to paravermal and lateral cerebellar regions, also

project to the interposed and dentate nuclei. 93

Inferior Olivary Afferents in Hemicerebellectomized Rats

One of the common paradigms for inducing sprouting of a neural pathway is to remove its normal target. Remodelling by target removal has been shown to occur in retinotectal following surgical destruction of their normal target, i.e. the tectum, either neonatally

(Schneider, 1973; So, 1979) or prenatally (Miller and Lund, 1975;

Baisinger et al., 1977). Similarly, corticopontine fibers have been shown to sprout following indirect removal of part of the pons by neonatal ablation of the contralateral half of the cerebellum (Leong and Lund, 1973; Leong, 1976, 1980; Castro, 1979). In both the retinotectal and corticopontine systems, the fibers whose normal target is missing sprout into remaining portions of the same nucleus.

This has been explained as an attempt by neurons to conserve a critical volume of terminal arborization by sprouting into regions which normally do not receive, or which receive only limited projections from these neurons (Devor and Schneider, 1975).

The sprouting of corticopontine fibers is particularly relevant to the present study. Normal corticopontine fibers are primarily ipsilateral with only a small contralateral distribution. However, after neonatal hemicerebellectomy the majority of the basilar pons contralateral to the cerebellar lesion degenerate. Corticopontine fibers which are normally targeted primarily at the missing pons, increase their distribution to the spared side, presumably maintaining their critical volume of axonal arborization. 94

Since neonatal hemicerebellectomy causes an apparently complete neuronal loss in the contralateral roc' similar to the subtotal cell loss in the contralateral pons, a study was performed to determine whether afferents to the missing olive would form aberrant connections with the spared roc. This experiment is analagous to the above studies indicating changes in the laterality of corticopontine fibers after neonatal hemicerebellectomy.

The olivary afferent systems examined for sprouting in response to neonatal hemicerebellectomy included those from the dorsal column nuclei, the medial terminal nucleus of the accessory optic tract, the lateral deep mesencephalic nucleus, the superior colliculus, the field of Forel, the nucleus of Darkschewitsch, the subparafascicular nucleus and the cerebral cortex. Of these projections, only those from the nucleus of Darkschewitsch, the subparafascicular nucleus and the field of Forel unequivocally demonstrated altered laterality of projection following hemicerebellectomy, showing a shift toward the spared roc. The olivary projection of the lateral deep mesencephalic nucleus also evidenced some equivocal shift in laterality of projection.

The reason for the observed lack of plasticity from the other regions investigated, in addition to the possibility that there may not be any, include: 1) the Fink-Heimer stain used for the studies of cortical and dorsal column nuclear projections to the roc may be unsuitable for these particular projections; 2) the extremely light nature of the normal projection from some of these nuclei, notably the superior colliculus and the lateral deep mesencephalic nucleus, 95 which would presumably afford even lighter sprouted projections; 3) in the case of the strong projections from the medial terminal nucleus of the accessory optic tract to the IOC, their axons were frequently found to terminate extensively on the few cells which often remained in the ventrolateral outgrowth on the lesioned side of the IOC (due to the frequent sparing of portions of the cerebellar flocculus during hemicerebellectomy). This increased density might be in lieu of sprouting into the spared side.

Other portions of the cerebellar motor system demonstrate plasticity. These include cerebellar efferents from (Lim and Leong,

1975; Leong, 1977; Castro, 1978; Kawaguchi et al., 1979), as well as cerebellar afferents to (Leong, 1976; Castro, 1979; Castro and

Smith, 1979; Castro and Hazlett, 1979) the spared side of the cerebellum following neonatal hemicerebellectomy. It has been speculated that the observed functional recovery from cerebellar injury (Dow and Moruzzi, 1958; Smith et al., 1974 a,b) is related to alterations in these cerebellar motor system pathways.

Several anatomical studies have suggested that the remaining half of the cerebellum may function bilaterally after neonatal hemicerebellectomy. For example, hemicerebellar lesions in neonatal rats (Lim and Leong, 1975; Leong, 1977; Castro, 1978) and kittens

(Kawaguchi et al., 1979) resulted in the development of bilateral projections from the unablated cerebellum to the red nucleus and ventrobasal thalamus. These pathways are predominantly contralateral in normal animals. Electrophysiological studies have supported the 96 efficacy of these anomalous connections in kittens (Kawaguchi et al., 1979). Additionally, sprouting of corticopontine fibers into the part of the pontine gray which projects to the spared cerebellar hemisphere after neonatal hemicerebellectomy (Leong and Lund, 1973;

Leong, 1976; Castro, 1979; Mihailoff and Castro, in press) further supports the above hypothesis.

The current study shows alterations of olivary afferents similar to the changes observed in pontine afferents. Since the pathways from certain diencephalic regions which would normally terminate within the ablated roc, sprout into the spared side, they presumably relay along climbing fibers into the spared side of the cerebellum. Additionally, this sprouting is not random, but occurs into the same regions of the spared roc that the fibers would normally terminate in on the ablated side. This specificity of the sprouting phenomenon, which corresponds to the specificity of sprouting of retinotectal (Miller and Lund, 1975) and corticopontine axons (Lund, 1977a, 1978; Castro, 1979), further supports speculation that this sprouting may be of functional significance, and that the remaining part of the cerebellum, to which this information is relaying, may be important to recovery from cerebellar lesion.

While the appropriate behavioral studies have not been performed to confirm that the spared part of the cerebellum is significant to functional recovery following neonatal hemicerebellectomy, experiments have shown this to be the case following hemicerebellectomy in adult animals (Smith et al., 1974a) 97

Of some theoretical significance is the question of the precise origin of these sprouted axons. It is possible that the sprouted fibers derive from axons which normally terminate entirely on the ablated side of the ICC. When prevented from doing so by the neonatal lesion, the fibers may send out collaterals, some of which may cross the midline to terminate abnormally in the spared IOC.

Alternatively, the sprouting may derive from axons which normally have a small distribution to the spared IOC. Since all of the regions from which sprouting has been identified in the present study, do have a normally small contralateral projection in addition to their predominantly ipsilateral distribution, this is a viable possibility.

While not a quantitative technique, the data derived from HRP injections within the spared IOC of hemicerebellectomized animals suggests that the latter possibility is more likely. The presence of a similar proportion of ipsilaterally versus contralaterally labeled cells in the subparafascicular nucleus and nucleus of

Darkschewitsch following HRP placements in the IOC of normal and neonatally hemicerebellectomized rats (compare figs. 5,7,9 and fig.

49) suggests that the abnormally large number of crossed fibers in the neonatally hemicerebellectomized rat probably arise as sprouts of fibers from cells which already had a small number of crossed fibers. Similar conclusions were reached in a study on the sprouting of spinocerebellar fibers in neonatally hemicerebellectomized rats (Castro and Hazlett, 1979). 98

The observed plasticity of anatomical connections following neonatal hemicerebellectomy, demonstrating a greater bilaterality of cerebellar afferent and efferent pathways, suggest a possible mechanism for recovery of function following cerebellar injury.

Indeed, certain behavioral data suggest that circuits through the remaining side of the cerebellum are partially responsible for recovery from adult hemicerebellectomy (Smith et al., 1974a).

Unfortunately for comparison with the observed anatomical plasticity, the behavioral correlations have not been performed in neonatally hemicerebellectomized animals.

Just as the remaining half of the cerebellum may not be the only regions responsible for recovery for hemicerebellectomy, plasticity of cerebellar afferents and efferents may not be the only plasticity significant to this recovery. For example, the lateral vestibular nucleus ipsilateral to the side of cerebellar lesion has been found to be significant to recovery (Smith et al., 1974a), likewise sprouting of certain vestibular afferents (spinovestibulars) have been observed following neonatal hemicerebellectomy, and this sprouting may contribute to recovery mechanisms (Castro and Smith,

1979).

The work on inferior olivary plasticity provides additional evidence of reorganization of cerebellar motor systems following neonatal injury. The long range goal of studies on plasticity is to correlate eventually the observed anatomical changes with behavioral effects of lesions in order to more fully understand the mechanisms of recovery from brain damage. 99

Effects of Vestibular Nerve Lesion in Neonatally Hemicerebellectomized Rats

Lesions of the vestibular nerve produce a characteristic set of symptoms including nystagmus and rolling toward the side of lesion, which disappear by 24 hours post-lesion. This compensation for vestibular nerve lesion does not oecur if the IOC has been chemically destroyed by acetylpyridine, harmaline and niacinamide (Llinas et al., 1975). Additionally, in animals which have compensated for a pre-existing vestibular nerve lesion, chemical destruction of the roc will reinstate the symptoms of vestibular involvement, and these symptoms will not attenuate with time. Since vestibular compensation has been shown to be a function of the roc and since compensation will occur in animals which have sustained lesions of the cerebellar cortex (Linas et al., 1975), the compensation must depend on subcortical connections of the IOC. It was subsequently determined, using the

2-deoxyglucose technique, that the contralateral roc and the ipsilateral lateral reticular nucleus, deep cerebellar nuclei and portions of the cerebellar cortex increase their metabolic activity in response to unilateral vestibular nerve lesion, and presumably are involved in recovery (Llinas and Walton, 1978).

Our finding that rats did not compensate for vestibular nerve lesion ipsilateral to the side of neonatal hemicerebellectomy is explicable on the grounds that all of the regions mentioned as being significant to recovery are either directly or indirectly removed by the hemicerebellectomy (i.e. the contralateral roc and the ipsilateral lateral reticular nucleus, deep cerebellar nuclei and cerebellar 100

cortex. Further, even though the hemicerebellectomy was longstanding,

having been performed neonatally, the current study argues against

reorganization of brainstem systems sufficient to provide an alternate mechanism for recovery from vestibular lesion, for example by

developing anomalous connections between the spared roc and the

ipsilateral lateral vestibular nucleus. In fact, possible connections

between the spared roc and the ipsilateral lateral vestibular nucleus were sought autoradiographically and found to be lacking.

The studies done on vestibular nerve lesions in neonatally hemicerebellectomized rats, then, support the findings of previous

investigators with regards to brain regions significant to recovery

form vestibular nerve lesion as well as the laterality of these structures while arguing against the possibility of reorganization

of brainstem systems to a degree adequate to provide noticeable compensation in neonatally hemicerebellectomized animals. SUMMARY

The origins and distributions of afferents to the inferior olivary complex (IOC) were investigated by the retrograde transport of horseradish peroxidase (HRP) and the orthograde transport of tritiated leucine, respectively.

General categories of afferent input to the roc included somatosensory, vestibula-ocular, cerebellar, reticular and inputs from the rostral mesencephalon and caudal diencephalon.

Olivary afferent pathways related to somatosensory function included: spina-olivary fibers, which were found to arise contralaterally in laminae V and VII of the cervical, thoracic and lumbar cord, to cross in the spinal cord and project to the lateral portions of the dorsal accessory olive (Dao) and the caudal medial accessory olive (Mao); dorsal column nucleo-olivary fibers which distribute contralaterally in the caudal Mao and in the lateral Dao; spinal trigemino-olivary fibers, which decussate and terminate in the rostromedial Dao; and projections from the lateral reticular nucleus, which distribute to the caudolateral Mao, bilaterally.

Olivary afferents with vestibula-ocular functions include: vestibula-olivary fibers from the medial and inferior vestibular neclei to the contralateral dorsomedial cell column (DMCC) and ipsilateral B subnucleus; projections from the nucleus prepositus t;:':'03 1 :)ss: ::o ~he cat;domedial "!ao, ~~'1e 1orsal cap (De) ~nd ':~e B subnucleus; projections from the caudal pretectum and superior colliculus (stratum profundum) to the dorsal lamella of the principle

101 102 olive (Pod) ipsilaterally and the caudomedial Mao contralaterally; projections from the nucleus of the optic tract and the medial terminal nucleus of the acessory optic tract to the De and the ventrolateral outgrowth (Vlo) of the De, respectively.

Differential projections were observed from the deep cerebellar nuclei to the contralateral roc. The dentate and interposed nuclei projected topographically to the principal olive (Po) and accessory olives, respectively. The fastigial nucleus was observed to project to the ventral Mao and the B subnucleus.

Reticula-olivary projections arose from several areas including: the gigantocellular reticular nucleus, which projected to the contralateral medial Dao, the ipsilateral B subnucleus and the caudomedial Mao; the lateral deep mesencephalic nucleus, which projected to the ipsilateral Dao and the B subnucleus; and the medial deep mesencephalic nucleus, which projected to the Pod and the caudointermediate Mao, ipsilaterally.

Several nuclei at the mesencephalo-diencephalic junction showed a similar projection pattern to the roc. These regions included the rostromedial border of the red nucleus, nucleus of Forel's field, periaqueductal gray, nucleus of Cajal and Darkschewitsch, and the subparafascicular nucleus. They project primarily ipsilaterally to the Po, Mao, B subnucleus, De and Vlo.

Other regions projecting to the roc include the cerebral cortex and the zona incerta. 103

Olivary efferent projections were traced by the use of autoradiography following tritiated leucine injections into the roc. Axons of olivary neurons crossed the midline to course in the medial part of the inferior cerebellar peduncle and terminate in parasagittal rows in the molecular layer of the cerebellar cortex.

En route, collateral branches were observed in the lateral vestibular nucleus and the deep cerebellar nuclei.

Following neonatal hemicerebellectomy, the roc contralateral to the lesion completely degenerates. A study was initiated to determine whether olivary afferents, which would normally terminate in the missing roc, will instead distribute to the spared roc. The use of the HRP technique, which is not quantitative, showed a pattern of labeling which was not appreciably different whether injections were made in normal animals or in the spared olive of neonatally hemicerebellectomized animals. However, autoradiographic studies revealed an increase of crossed projections to the spared roc from the subparafascicular nucleus, the nucleus of Darkschewitsch and the nucleus of Forel's field. 104

Figure 1: A series of camera leucida drawings (rostral at the top,

caudal at the bottom) at 300u intervals through the roc.

This basic format is used to depict the roc in all figures

from anterograde experiments (figures 14-40). 105

Pod - Principal olive, dorsal lamella Dao - Dorsal accessory olive

Pov - Principal olive, ventral lamella Mao - Medial accessory olive

DMCC - Dorsomedlal cell column IJ - IJ subnucleus

Vlo - Ventrolateral outgrowth De - Dorsal cap 106

Figure 2: Summary drawing demonstrating the topography of

olivocerebellar climbing fiber distribution in the

cerebellar cortex of the cat, adapted from Kawamura

and Hashikowa (1979) .

•. 107

Mao Pov Pod Dao

Cauda I 108

Figure 3: Composite camera lucida drawings through the spinal cord

of animal 877, showing the neuronal labeling produced by

the HRP injection illustrated in the upper left corner.

Numbers within the gray matter (T6-l0, Tll-11) indicate the

numbers of labeled cells within the regions circumscribed

by dashed lines. 109 110

Figure 4: Similar format to figure 1, showing labeled spinal cord

neurons from animal 923 .

,. 111 112

Figure 5: Animal 923, large injection. A. Composite camera lucida

drawings at 400u intervals through the injection site.

B. Composite camera lucida drawings at SOOu intervals

depicting labeled cells of the caudal brainstem.

C. Drawings through the rostral brainstem in a similar

format to section B of this figure.

Letters a-h in this figure refer to the regions of the

brainstem shown in photomicrographs a-h of figure 6. 113

Nv•

A 114

Figure 6: Photomicrographs from the regions of the brainstem of animal

923 which are labeled a-h in figure 5. The sections are

unstained. a. injection site. b. dorsal column nuclei.

c. inferior vestibular nucleus. d. ventral tegmental area.

e. rostromedial border of the red nucleus. f. nucleus

subparafascicularis and nucleus of Darkschewitsch (to the

right in the picture) g. nucleus subparafascicularis.

h. zona incerta. 115 .. . . " -. ~ ; . J ... -io.. . a b • - • • • • • .. .. • .. ' ., f ... ,. ' ' ) • • ...... • .... c , - • d \ - • f .!.'• -~ -~ -- ~ .. ~ ~ ~ ~ .!...... ~ ....·-·. . . , I . ll' ...... J . .. . " ...... ,.!. .- .t ' ( . -- ,-' .• · -~A__... · . ;J so .. f ~ ~ - . - - : ~ ,;- so.,. ~ e _ ~ - - '

'·

•

J, .. ..,-... ,., ...... , ., · so~ • 50~ g ... h - 116

Figure 7: Animal 921, medial Mao, dorsal cap, ventrolateral outgrowth

injection. Similar in format to figure 3, depicting the

injection site in section A, the labeling of the caudal

brainstem in B and the labeling of the rostral brainstem

in C. Letters a-f refer to the regions of the brainstem

shown in photomicrographs a-f in figure 8. 117 118

Figure 8: Photomicrographs from the regions of the brainstem of

animal 921 labeled a-f in figure 7. a. injection site.

b. inferior vestibular nucleus. c. posterior pretectal

nucleus. d. nucleus of the optic tract. e. nucleus of

the optic tract. f. ventral tegmental area.

I 119 120

Figure 9: Animal 924, caudal Mao injection. Similar in format

to figures 5 and 7, depicting the injection site in A, the

labeling of the caudal brainstem in B and the labeling

of the rostral brainstem in C. Letters a-c refer to the

regions of the brainstem shown in photomicrographs a-c

of figure 10. 121 122

Figure lO:Photomicrographs a-c are form the regions of the brainstem

of animal 924 labeled a-c in figure 9. a. injection

site. b. inferior vestibular nucleus. c. posterior

pretectal nucleus.

Photomicrographs d-h are from several animals and show regions

not depicted in any of the other illustrations. d. dentate

nucleus (animal 923). e. interpositus nucleus (animal 923)

f. fastigial nucleus (animal 921). g. nucleus y of the

vesitbular complex (animal 921). h. the region directly medial

to the mddial geniculate nucleus (animal 878, see figure 13). 123

•

•• a

.. ~ • . \ • • • .. ~ •• .. • • • • •• •. •• • .... •' ie. c - • - · , , , . ' ., - • • ~~ ~ I • ' • I / J k . •. -. • WI - , • 4 ' .. - , • ~..,. e , .... f - • •

•

• g . .... h - •• ..-. 124

Figure ll:Animal 877, lateral Dao injection and animal 922, Dao and Po

injection. A,B. labeling of the caudal brainstem and injection

site of animal 877. C,D. labeling of the rostral brainstem and

injection site of animal 922. Letters a-i refer to the regions

of the brainstem shown in photomicrographs a-i in figure 12. 125

B 126

Figure 12: Photomicrographs from the regions of the brainstem of

animal 922 labeled a-f, and from animal 877 labeled

g-i in figure ll. a. injection site in animal 922.

b. interstitial nucleus of Cajal. c. deep

mesencephalic nucleus. d. the region directly medial

to the medial geniculate nucleus. e. subparafascicular

nucleus and nucleus of Darkschewitsch. f. nucleus

subparafascicularis g. injection site in animal 877.

h. dorsal column nuclei i. lateral reticular nucleus 127

...... - ...-

. ' \ . ; .. ~ - ~ . -- · lt'1-~j - .~ : ~ -~ - _ •••- •• .· •

. .~ . - ~ · · h -so., -so .. 128

Figure 13: Depicts the injection sites in a number of animals which

were useful in defining certain olivary afferents. 129 130

Figure 14: Camera leucida drawings of ICC (left) from animal having

sustained mid thoracic spinal cord hemisection (right)

Brightfield photomicrographs of Fink-Heimer stained

sections from regions of IOC contained within the boxes.

Calebration bars represent SOu. 131

. . ,~, : ...:. .. -,.~·,~ '/.: .. ' I~·_., ~ .. :. .·•;...... ·. , . • ~ ·- .•... ·. • ~~,*(...... , _ ~~·~.fit: '·· . · · ·.- . '·'• • f.• ;* .~ ~-.Ill' ~ •• •• • ,.. 6 ~~·. • 4 • . , ~. 7~ • >t • .. ~: • ' • ~f1

: J' ~- ~• .-;- ~-~- .,."'f •,. ~ ~ * ""..... •· -:... • .• ... - .- ~ .~-·· · .· . ~~~.r- ., .-~·,_, ... .. ~.. . .1-'"' ...... ;...... (·· . . ·~'"· • · ...• ~ • . • c #. ;-- r ., "''I 132

Figure 15: Represents IOC labeling following the dorsal column

nuclear injection of tritiated leucine shown at the right.

Calebration bars on clarkfield pholomicrographs represent

lOOu in A and 150u in B. 133 134

Figure 16: IOC labeling folloiwng autoradiographic injection

primarily into the gigantocellular reticular nucleus.

Calebration bars represent SOu. 135 136

Figure 17: IOC labeling after an injection which included part

of the lateral reticular nucleus. Calebration bar SOu .

•. 137 138

Figure 18: IOC labeling after an injection of the spinal trigeminal

nucleus (primarily the interpolar subdivision)

Calebration bar lOOu. 139 140

Figure 19: IOC labeling after an injection of the vestibular

complex. Calebration bars SOu. 141 142

Figure 20: IOC labeling after an injection of the ventral vestibular

complex, probably including some of the spinal trigeminal

nucleus and reticular formation. Calebration bars SOu. 143 144

Figure 21: IOC labeling following an injection of the nucleus

prepositus hypoglossi. Calebration bar represents SOu. 145 146

Figure 22: IOC labeling after a rostral dentate injection.

Calebration bar SOu .

,. 147

--___G:? ~ ~ - 148

Figure 23: IOC labeling after a caudal dentate injection.

Calebration bar SOu. 149 150

Figure 24: IOC labeling after a caudoventral dentate injection.

Calebration bar 50 u. 151 152

Figure 25: IOC labeling after a rostral nucleus interpositus

injection. Calebration bar SOu. 153 154

Figure 26: IOC labeling after a caudal nucleus interpositus

injection. Calebration bar SOu. 155 156

Figure 27: IOC labeling after a fastigial nucleus injection

Calebration bars equal SOu. 157 158

Figure 28: IOC labeling after an injection into the caudal part

of the pretectal complex. Calebration bars SOu.

: 159 160

Figure 29: IOC labeling after an injection into the nucleus of

the optic tract. Calebration bar SOu. 161 162

Figure 30: IOC labeling after an injection into the stratum

profundum of the superior colliculus. Calebration bars SOu.

J 163 164

Figure 31: IOC labeling after an injection into the stratum

profundum of the superior colliculus. Calebration bars SOu. 165 166

Figure 32: IOC labeling after an injection into the red nucleus

and prerubral field. Calebration bars SOu. 167 168

Figure 33: IOC labeling after an injection into the lateral deep

mesencephalic nucleus. Calebration bars SOu. 169 170

Figure 34: IOC labeling after an injection into the medial deep

mesencephalic nucleus. Calebration bars SOu. 171 172

Figure 35: IOC labeling after an injection into the medial part of

the substantia nigra and the medial terminal nucleus of

the accessory optic tract. Calebration bar lOOu. 173 174

Figure 36: IOC labeling after an injection into the medial deep

mesencephalic nucleus and prerubral field. Calebration

bar 150u in A and lOOu in B. 175 176

Figure 37: Ioc labeling after an injection into the periaquaductol

gray. Calebration bars lOOu. 177 178

Figure 38: IOC labeling after an injection primarily into the

subparafascicular nucleus. Calebration bars lOOu. 179

fJ; .41:) (JFR 180

Figure 39: IOC labeling after an injection primarily into the

nucleus of Darkschewitsch. Calebration bars lOOu. 181 182

Figure 40: Fink-Heimer degeneration plotted in the IOC after

frontal cortical lesions. 183 184

Figure 41: Summary of the various inputs to the IOC from regions

related to vestibulo-occular function. Depicted are

the inputs from these structures on the left side of the

brainstem. 185

Summary of Vestibulo-occular Inputs to IOC

11111111 Pt - Pretectum ~Mtn - Medial terminal nucleus of AOT

Sc - Superior colllculus ~~~~~~Not - Nucleus of the optic tract

Vc - Vestibular complex ~PPXII - Nucleus prepositus hypoglossi 186

Figure 42: Summary of the inputs to the IOC from regions related to

somatosensory functions, i.e. the left side of the spinal

cord, the left spinal trigeminal nucleus, the left

dorsal column nuclei and the left lateral reticular

nucleus. 187

Somatosensory Inputs to the IOC

lllllllllcaudal spinal cord ~Dorsal column nuclei Rostral spinal cord ~Spinal trigeminal nucleus

~ ~ ~ ~ ~ ~ Lateral reticular nuc. 188

Figure 43: Summary of inputs from the left deep cerebellar nuclei

to the IOC. 189

Summary of Cerebella-olivary Connections

IIIII III Rostral dentate nucleus ~ Caudal nucleua lnterpoaltua Caudal dentate nucleus ~ Roatral nucleua lnterpoaltue

Fastlglal nucleus 190

Figure 44: Summary of inputs from portions of the left reticular

formation to the roc. 191

Summary of Reticular inputs to IOC

~ ~ ~ ~ ~ ~ Glgantocellular reticular nuc.

11111111 Lateral deep mesencephalic nuc.

Medial deep mesencephalic nuc. 192

Figure 45: Summary of inputs from the left mesencephalo-diecephalic

junction to the IOC.

: 193

Summary of Meso-diencephalic Inputs to IOC

Perlaqueductal gray Nucleus of Darkschewltsch

Red nucleus Subparafasclcular nuc.

all project to: :::::: 194

Figure 46: Composit depiction of inputs from those systems (i.e.

vestibula-ocular, somatosensory, reticular and

mesencephalo-diecephalic) represented in figures 41, 42,

44, and 45. 195

Summary of Inputs to IOC

1111111111 Vestlbulo-ocular ~Meso-diencephalic Somatosensory ~Reticular

DMCC 196

Figure 47: Photomicrographs from animals having sustained injections

of tritiated leucine into the IOC. A. Injection site and

decussating fibers. B. Labeled fibers entering the inferior

cerebellar peduncle. C. Labeling in the lateral vestibular

nucleus. D. Labeling of cerebellar white matter and the

nucleus interpositus and fastigii. E. Labeling of

cerebellar white matter and in rows within the molecular

layer. ~. Rows within the cerebellar cortex.

G. Labeling within the flocculus. Calebration bars 150u.

198

Figure 48: Depicts labeing within the cerebellar cortical molecular

layer following an injection of tritiated leucine centered

in the caudal half of the roc. 199 200

Figure 49: Depicts labeling of brainstem neurons after injection

of HRP into the remaining IOC in a neonatally

hemicerebellectomized rat.

: ·.@ 202

Figure 50: Shows labeling approximately 300u caudal to the rostral

pole of the roc in animals having sustained injections of

tritiated leucine into the subparafascicular nucleus,

Forels field and nucleus of Darkschewitsch. All

photomicrographs are centered on the midline, and all

injections were to the left of the photomicrographs.

A,B. Maximum labeling observed decussating at olivary

levels in normal animals. C-H. Decussating fibers after

neonatali hemicerebellectomy. Calebration bars lOOu.

204 List of Abreviations

B, beta subnucleus BCS, brachium of the superior colliculus CC, crus cerebri Dao, dorsal accessory olive De, dorsal cap of Kooy DMCC, dorsomedial cell column Dmnl, lateral deep mesencephalic nucleus FC, Fasciculus cuneatus FR, fasciculus retroflexus Ic, inferior colliculus ICP, inferior cerebellar peduncle Mao, medial accessory olive ~~F, medial longitudinal fasciculus Mtn, medial terminal nucleus of the accessory optic tract Ndk, Nucleus of Darkschewitsch Nfc, nucleus cuneatus Nfg, nucleus gracilis Ngm, medial geniculate nucleus Nip, interpeduncular nucleus Not, nucleus of the optic tract N~C, nucleus of the posterior commissure Nr, red nucleus Nrg, gigantocellular reticular nucleus Nrl, lateral reticular nucleus Nspf, subparafascicular nucleus NspV, nucleus of the spinal tract of the trigeminal Nvi, inferior vestibular nucleus Nvm, medial vestibular nucleus Pag, periaqueductal gray PC, posterior commissure Po, principal olivary nucleus Pr, pretectum Sc, superior colliculus Sn, substantia nigra TrV, spinal tract of the trigeminal Vlo, ventrolateral outgrowth Zi, zona incerta XII, hypoglossal nucleus 205

TABLE ffl

Somatosensory system: Liu and Chambers, 1958; Van der Laos and Woolsey,

1973; Murray and Goldberger, 1974; Goldberger and Murray, 1974;

Bernstein, Geldered and Bernstein, 1974; Kerr, 1975.

Visual system: Goodman and Horel, 1966; Goodman, Bagdasarian and

Borel, 1973; Guillery 1972; Schneider, 1973; Chow, Mathers

and Spear, 1973; Lund and Lund, 1973; Ralston and Chow, 1973;

Hickey, 1975; Stanfield and Cowan, 1973; Casagrande, Guillery and

Harting, 1978; Mosko and Moore, 1979; Finlay and So, 1979; Finlay,

Wilson and Schneider, 1979; Frost and Schneider, 1979; Lund and

Mitchell, 1979; Land and Lund, 1979; Rhoades and Chalupa, 1980.

Auditory system: Sotelo, 1975.

Limbic system: Raisman, 1969; Raisman and Field, 1973; Lynch, Mosko,

Parks and Cotman, 1973; Lynch, Deadwyler and Cotman, 1973; Goldwitz,

1975; Westrum, 1975; Steward, Cotman and Lynch, 1973, 1973; Devor,

1976; Zimmer, 1974; Lenn, 1978; Graziadei, Levine and Graziadei,

1979.

Noradrenergic system: Bjorklund, Katzman, Senevi and West, 1971; Katzman,

Bjorklund and Owman, 1971; Singh and de Champlain, 1972; Pickel,

Krebs and Bloom, 1973; Bjerre, Bjorklund and Stenevi, 1973; Bowman,

Karpick, Deuriryian and Katzman, 1975; Stenevi, Bjorklund and

Svendgaard, 1976; Robinson, Bloom and Batterburg, 1977; Kostrzewa

and Garey, 1977; Bjorklund and Stenevi, 1971, 1977; Kostrzewa,

Klara, Robertson and Walker, 1978; Jonsson, Wiesel and Hallman,

1979; Kasamatsu and Pettigrew, 1979; Kasamatsu, Pettigrew and

Ary, 1979. 206

Abels, I.A. and Basbaum, A.I. (1979) The posterior pretectal nucleus:

evidence for a direct projection to the inferior olive of the cat.

Neurosci. Letters 13, 111-116.

Achenbach, K.E. and Goodman, D.C. (1968) Cerebellar projections to pons,

medulla and spinal cord in the albino rat. Brain Behav. and Evol.

1, 43-57.

Alexander, A. (1931) Untersushungen uber die zentrale Haubenbahn. As

reported by Walberg (1956)

Alley, K., Baker, R. and Simpson, J.I. (1975) Afferents to the vestibule

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with the Timm method. Brain Res. 76, 336-342. APPROVAL SHEET

The dissertation submitted by Rand S. Swenson has been read and a?provec t>y the following committee:

Dr. Anthony J. Castro, Director Associate Professor, Anatomy, Loyola

Dr. James Hazlett Associate Professor, Anatomy, Wayne State University

Dr. Robert D. Wurster Professor, Physiology, Loyola

Dr. John Disterhoft Associate Professor, Anatomy, Northwestern University

Dr. E. J. Neafsey Assistant Professor, Anatomy, Loyola

The final copies have been examined by the director of the dissertation and the signature which appears below verifies the fact that any necessary changes have been incorporated and that the dissertation is now given final approval by the committee with reference to content and form.

The dissertation is therefore accepted in partial fulfillment of the requirements for the degree of Doctor of Philosophy.

Date Director's~~ j~ ature