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THE CEREBELLUM: COMPARATIVE AND ANIMAL STUDIES
Journal: The Cerebellum
Manuscript ID: MCER-2007-0004.R1
Manuscript Type: Invited Review
Date Submitted by the
Author:
n/a
Complete List of Authors: Sultan, Fahad; HIH for Clinical Brain Research, Cognitive Neurology
Glickstein, Mitchel; University College London, Department of
Anatomy
Keywords: anatomy, cerebellar cortex
URL: http://mc.manuscriptcentral.com/mcer Email: mmanto@uld.ac.be
The Cerebellum
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THE CEREBELLUM: COMPARATIVE AND ANIMAL
STUDIES
FAHAD SULTAN
1
AND MITCHEL GLICKSTEIN
2
1) Dept. of Cognitive Neurology, HIH for Clinical Brain Research, Tuebingen,
Germany; 2) Dept. of Anatomy, University College London, London, UK
Running title: Comparative cerebellar anatomy
11 text pages, 8 figures, including one colour figure
Keywords :motor behaviour, rodents, primates, birds, cortiocpontine projection
Address correspondence to:
Dr. Fahad Sultan
Dept. of Cognitive Neurology, HIH for Clinical Brain Research
University Tuebingen
Otfried-Müllerstr. 21, 72076 Tuebingen
Germany
Tel.: 49-7071-2980464; Fax: 49-7071-295724
E-mail: fahad.sultan@uni-tuebingen.de
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Abstract
The cerebellum has a uniform cellular structure and microcircuitry, but the size of its
subdivisions varies greatly among vertebrates. This variability is a challenge to
anatomists to attempt to relate size differences to differences in characteristic
behaviour. Here we review the early work of Lodewijk Bolk on the mammalian
cerebellum and relate his observations to unfolded maps of the rodent cerebella. We
further take insights from the comparative anatomy of the bird cerebella and find that
cerebellar enlargement in large brains is not a passive consequence of overall brain
enlargement, but is related to specific behaviour. We speculate that for some rodents
(e.g., squirrels), primates and some large-brained birds (crows, parrots and
woodpeckers), specifically enlarged cerebella are associated with either the
elaboration of forelimb control (squirrels and primates) or in the case of the birds with
beak control. The elaboration of such motor behaviour combined with increased
visual control could have helped to furnish manipulative skills in these animals.
Finally, we review the connections of the mammalian cerebellum and show that
several pieces of experimental evidence point to an important function of the
cerebellum in sensory control of movement reflex adjustment, and motor learning.
Introduction
The cerebellum is a distinct and recognizable component of the brain in all true
vertebrates. It is only in the more primitive chordates such as Amphioxus and the
lampreys that there is no cerebellum. The histological structure of the cerebellum is
virtually identical in all mammals and birds. In reptiles, amphibians and fish the
organization differs somewhat from that of mammals and birds, but in those species
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as well, the cerebellum consists of a characteristically large group of cells that receive
sensory input and connect to a group of target cells that provide the output from the
cerebellum. The structure of these connections is so invariant that Ramon y Cajal (1)
proposed it to be a "law of biology". We will first describe the gross appearance and
cellular organization of the human cerebellum and go on to consider some of the ways
in which the cerebellum varies among mammals and birds.
Figure 1 place around here
General morphology
The cerebellum consists of a cortical sheet which covers a massive white matter core.
Buried within the white matter of the cerebellum are the cerebellar nuclei which
receive their major input from the cerebellar cortex. Cells in the cerebellar nuclei, in
turn, constitute the output from the cerebellum, and connect to structures in the
thalamus and brainstem. If you look at the surface of the cerebral cortex in the human
brain, you see about one third of it; the remaining two thirds is buried within the
fissures. If you look at the surface of the human cerebellum, you see only about one
tenth.
Figure 2 place around here
The mammalian cerebellum consists of three lobes; an anterior lobe, a posterior lobe,
and flocculo-nodular lobe. The cortex within each lobe is made up of small
subdivisons called folia.
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Microcircuitry
The cerebellar cortex has five major types of cells. One of these, the Purkinje cell is
named for the 19
th
century Czech physiologist and anatomist who first described
them. Purkinje cells provides the only output from the cerebellar cortex. Purkinje cells
have a massively branched dendritic tree which extends to the surface of the
cerebellar cortex in a single plane transverse to the orientation of the cerebellar folia.
Beneath the row of Purkinje cells are the cerebellar granule cells which comprise the
great majority of cell types in the cerebellum. Granule cells receive the vast majority
of the inputs to the cerebellum , and they send their axons towards the cerebellar
surface where they branch in a characteristic T-fashion and extend parallel to the
cerebellar folia to contact the dendrites of the Purkinje cells. Because the Purkinje cell
dendrites are oriented perpendicular to the course of the folia, the granule cell axons
contact Purkinje cell dendrites at right angles. The other cell types, the Golgi cells,
basket and outer stellate cells also extend their dendrites into the outer, molecular
layer of the cerebellar cortex. These three cell types form part of an inhibitory system
that regulate the firing of the Purkinje cells. Golgi cells control the granular cell
activity. Quantitative analysis of basket and stellate cell morphology has revealed
much similarities, suggesting that these two types may be two extremes of one
continuously varying population (2). In addition to these major cell classes two
further cell types have been described in detail, the Lugaro and more recently, the
unipolar brush cell (3,4).
Figure 3 place around here
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At first glance the histological structure of the cerebellar cortex appears to be uniform
throughout. However anatomical and neurochemical studies demonstrate that the
Purkinje cells of the mammalian and bird cerebellum are arranged in a series of
longtitudinal stripes that differ in their anatomical connections and biochemical
properties (5). The pattern can best be seen using a cell specific antibody, Zebrin II
(6). The zebrin positive and zebrin negative stripes receive their climbing fiber
projections from different regions of the inferior olivary nucleus, and they project to
distinct targets within the cerebellar nuclei. Zebrin stripes have so far been described
in most vertebrates, including birds and mammals (7,8).
Cerebellar folial chains
Although the basic histological structure is similar, there are intriguing differences
among mammals and birds in the relative size of one or another region of the
cerebellum. In birds the cerebellar cortex appears to consist almost entirely of vermis
with only the smallest trace of cerebellar hemisphere.
In mammals, the complexity of folding of the mammal cerebellar cortex often makes
it difficult to see the pattern of continuity of the folia. By careful dissection, the
Dutch anatomist Lodewijk Bolk (9) identified a constant plan in the cerebellum of all
mammals (Fig. 4A).
Figure 4 place around here
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Chains of folia extend continuously from the most anterior to the most posterior part
of the cerebellum (Figure 4 A). In the anterior lobe and the adjacent lobulus simplex
the folia are continuous from side-to-side across the midline of the cerebellum.
Just behind lobulus simplex there is a division into three independent folial chains. In
the midline the chain continues caudally as part of the cerebellar vermis (Latin; a
worm). The lateral chains diverge from the midline and extend in two successive
loops that make up the cerebellar hemispheres. The first of these two loops Bolk
called the ansiform (loop-shaped) lobe. In the ansiform lobe, the folial chain extends
outward away from the midline, and then bends back to run parallel to the vermis for
a short distance. This middle segment of the folial chain is called the paramedian
lobule. At the caudal end of the paramedian lobule the chain again diverges away
from the midline forming a second loop. The outward component of this second loop
is the dorsal paraflocculus, the second component is the ventral paraflocculus,. The
folial chain ends in a small group of folia, the flocculus. In humans and the higher
primates the cerebellar hemispheres are very large extending upward and medially so
that the vermis is almost completely covered.
Comparative anatomy of the unfolded mammal
cerebella
In mammals the unrolled cerebellum has a trident-like appearance (Figure 4B and
Figure 5). The folia are narrow anteriorly and become wider as we proceed posteriorly
(Braitenberg's region A (10), equivalent to the Lobus anterior). The cerebella of the
two closely related rodent and lagomorph orders also show these patterns (Fig. 5). In
these cerebella (as in primates) the widest folia are found in the middle cerebellar part
(Region B). In this region the hemispheral folial chains are longer than the vermal
chains, which leads to the formation of loops. In the transitional region BC the folial
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chains of both hemispheres and vermis come back into alignment. Finally, the rodent
and lagomorph cerebella also exhibit the typical mammal three-tailed ending with two
hemisphereal folial chains (region C) and a single vermal chain (region D, posterior
vermis).
In the chinchilla and squirrel , the rodent cerebella shows some noteworthy
modifications of the basic scheme (11). The tree squirrel cerebellum shows a marked
mediolateral expansion of region B (ansiform lobe: Crus I and II) with more complex
foliation patterns, while in the chinchilla the vermal and hemispheral chains of the B
region expand jointly in the antero-posterior direction and more so in the anterior
parts of the cerebellum. Both animals are excellent climbers: chinchillas lived in the
Andes at high altitudes in holes among rocks and are agile rock climbers, while
squirrels are excellent tree climbers. Nevertheless their cerebella differ markedly. This
is likely due to different motor strategies used in climbing. Chinchillas are nocturnal,
with little stereovision and better developed hindlimbs than forelimbs (12).
Consequently, they have to rely more on non-visual information such as vestibular
and proprioceptive inputs from their limbs and trunks to guide their climbing.
Squirrels on the other hand are diurnal with well developed stereovision (13) and
forelimbs (14-17) allowing for visual control of locomotion and grasping. The
squirrels climbing strategies are more similar to those seen in primates which also
have an enlarged ansiform lobe. Hence, it may well be that a specific enlargement of
the cerebellum helps to elaborate climbing skills and the manipulative use of the
forelimbs.
Figure 5 place around here
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Besides these smaller differences within a mammal order, we can also observe major
changes between orders. Two of the most pronounced specializations that have been
described so far are between primates on the one hand and marine mammals on the
other. In humans and other primates the entire cerebellum is dominated by the upper
loop; the ansiform lobe (B region). In cetaceans (whales and dolphins) and pinnipeds
(seals), the second loop containing the dorsal and ventral paraflocculus is much larger
(9,18). The enlargement of the cerebellum in these two highly encephalized
mammalian orders has long fuelled the notion that the cerebellum may be involved in
higher cognitive non-motor functions (19-21). Is this a general attribute of all large
brained vertebrates, i.e., to have a large cerebellum? To address this we took a closer
look at another vertebrate class, the birds. We will observe that cerebellar enlargement
is not a simple attribute of large brains and that cerebellar enlargement itself is not
uniform but behaviour characteristic.
Comparison of avian brain size and correlations of
cerebellar size to behaviour
The presence of a single vermal folial chain in birds offers an excellent opportunity to
study sufficient cerebella in several bird families allowing for a more systematic
correlation of cerebella size and animal behaviour. Cerebellar surface can be
adequately captured by studying the mid-sagittal anterior-posterior extension of the
folia chain, since there is little increase in the latero-lateral extension of the birds
cerebella (22).
Figure 6 place around here
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The length of the midsagittal cerebellar folia of 44 cerebella from 24 bird families
were obtained from scaled drawings of (23,24) and (25). Correlation of cerebellar
length to the birds body weight reveals an allometric relationship with a regression
line: y= 0.25 x + 1.3, r^2= 0.78. Bird families that are significantly above the 95%
confidence band include parrots, crows and woodpeckers. This is not too surprising,
since all these birds have large total brain sizes (Fig 6B). What is surprising is that
two large brained bird families (owls and barn owls) have a smaller cerebellar length
than expected for their brain size (Fig6C). A detailed analysis of the contribution of
different lobuli to the overall cerebellar size reveals that in parrots, crows and
woodpeckers the size increase is due to an increase in lobuli VI-IX (Fig. 7). Owls
show a different pattern of cerebellar enlargement with enlargement of lobuli I, II, and
X. Hence large brains are associated with different enlarged folia, indicating
specialized cerebellar involvement in large brains. We have proposed (22) that
nocturnal owls rely on an elaborated vestibulocerebellum while diurnal "beak
specialists" such as the parrots, crows and woodpeckers rely on vision to control the
manipulation skills of their beaks.
Figure 7 place around here
Inputs to the Cerebellum
The cerebellum receives inputs from many sources. In all mammals the flocculus
receives its major input from those senses that signal body’s position in space,
including the vestibular system and the lateral line organs of fish. In the weakly
electric fish the cerebellum dominates all of the rest of the brain and is the principal
receiver of the input from the electric receptors. In all vertebrates there is a set of
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spino-cerebellar tracts that bring information on body position and movement to the
cerebellum. The spinal tracts terminate preferentially in the vermis and its
immediately adjacent cortex.
In humans and many other mammals the great majority of the input to the cerebellum
comes not from the vestibular system or spinal cord but from the cerebral cortex by
way of a relay in the pontine nuclei. One way to determine the relative contribution
from different areas of the cerebral cortex to the cerebellum is to fill the pontine
nuclei with a retrograde tracer and map the distribution of retroactively labelled cells.
In rats the entire cerebral cortex projects to the pontine nuclei, hence by way of a
single synapse to the cerebellum (26). In monkeys, only about half of the cerebral
cortex projects to the pons (27). The contribution to the cerebellum from different
areas of the cerebral cortex of monkeys is not uniform; some areas send a massive
projection, some none at all. The pattern of cortical input to the pons, hence to the
cerebellum can provide insight into the functions of the cerebellum.
Figure 8 place around here
Figure 8 shows the .distribution of labelled cells in the cerebral cortex of a macaque
monkey after the pontine nuclei had been filled with the retrograde tracer horseradish
peroxidase. All labelled cells in the cerebral cortex are layer V pyramids.. The motor
cortex, both areas 4 and area 6 sends a particularly heavy input to the pons. The visual
areas reflect the nature of the information that is sent to the cerebellum. Almost all of
the cortical visual input arises from the dorsal stream, those visual regions in which
the cells are particularly sensitive to moving stimuli. The cortex in the inferior
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temporal lobe is also dominated by vision, but its cells are relatively insensitive to
motion, and sends no fibers to the pons.
From the nature of the inputs and from studies of impairments in people and animals
that sustained lesions of the cerebellum we can infer something of the functions of the
cerebellum. The vestibular and spinal inputs signal the position of the body in space,
and the movement of the body. The cortical input is heaviest from motor areas of the
cortex, providing corollary discharge during all movements. The cortical visual input
signals motion in the visual field.
The major output from the cerebellum is to structures that control movement of the
eyes, the limbs and the body as a whole. The medial nuclei project heavily to
brainstem structures controlling eye movements. The interposed and lateral nuclei
project heavily to the red nucleus and the ventral thalamus. The red nucleus gives rise
to the rubro-spinal tract which connects to distal musculature. Ventral thalamus
projects primarily to motor areas of the cerebral cortex.
Lesions of the cerebellum produce deficits in gait, articulation and sensory control of
the limbs. Smooth pursuit eye movements are lost. Saccadic eye movements are still
present, but they are typically dysmetric.
In addition to its role in the direct control of movement, the cerebellum is involved in
several forms of reflex modulation and motor learning. Reflexes can be broadly
grouped into closed and open loop types. In a closed loop, such as stretch or flexion,
the reflex acts directly on the sensory stimulus that elicits it. In an open loop reflex it
does not. Turning the head to the left causes a reflex tendency for the eyes to turn in
an equal and opposite direction, thus stabilizing the gaze, but the output does not feed
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back on the vestibular input. Open loop reflexes must be continuously re-calibrated to
maintain their effectiveness. The cerebellum is the major brain structure responsible
for such calibration. Experiments on animals and people have demonstrated that this
vestibulo-ocular reflexes are highly modifiable. If a person or monkey wears a set of
lenses that increase the size of the visual image, there is a corresponding
augmentation of the vestibulo-ocular reflex (28,29). Animals in which a lesion has
been made in the flocculus and ventral paraflocculus are unable to compensate for an
altered visual input.
The saccadic system is typically accurate. People and animals can direct their eyes
accurately to a novel stimulus within the visual field. The evidence suggests that
scccadic accuracy is also maintained by cerebellar circuits. Animals and people with
lesions of a region of the vermis that controls oculomotor function lose the ability to
re-calibrate saccadic eye movements when challenged (30).
In addition to reflex modification and calibration of eye movements, certain forms of
classical conditioning are also mediated by the cerebellum. If a tone is followed by a
puff of air to the cornea, animals and people will acquire a classically conditioned
blink to the tone alone. Such conditioned reflexes are abolished by cerebellar lesions
(31). The cerebellum is a structure which receives input about body position,
movement in the surround, and intended movement. And uses those inputs to plan and
execute the next set of movements and to link new sensory stimuli to such
movements.
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Figure legends
Figure 1 Human cerebellum ventral view
The human cerebellum seen from ventral. Only a fraction of its folded cortical sheet
can be observed on the outer surface.
Figure 2 Human cerebellum transverse section
Cross section through the human cerebellum which shows the massively folded nature
of the cerebellar cortex, and the location of the cerebellar nuclei deep within the white
matter.
Figure 3 Histo From Cajal
Sagittal section through mammalian cerebellar cortex. Shown is a cross-section of one
cerebellar folia with the different cerebellar cell types stained with the Golgi-
technique. Parallel fibers are cross-sectioned and appear as dots in the molecular
layer. Elements oriented parasagittaly are seen in full fron, such as the Purkinje cells
(a), stellate and basket cells (e and b). g: granule cells; h: mossy fibres; n: climbing
fibres; f: Golgi cell. Figure from (1).
Figure 4 Bolk and Braitenberg diagram
Subdivision of the mammalian cerebellum based on comparative anatomy of the folial
chains. (A) Arabic numerals denote Bolks subdivision of the mammalian cerebellum
into the single anterior chain (1-4) that divides into two hemispheral (4-11) and one
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vermal chain (12). (B) Braitenberg and Attwood subdivision of the cerebellum into
different regions A-D. Regions AB and BC are transitional regions of the folial
patterns observed in the neighbouring regions. (C) Corresponding nomenclature
obtained from comparative mammalian anatomy. Modified from (9,10)
Figure 5 Sultan and Braitenberg
Unfolded cerebella of four rodents and two lagomorphs (11). Delineated are
Braitenberg's folial regions. Region A shows a single chain of folia that gradually
increase in width from anteriorly (upward end) to posteriorly. This pattern can be
observed in all mammal cerebella. This region scales with cerebellar size in the
anterior-posterior as in the medio-lateral direction. In region B the single chain
divides into two hemispheral and one vermal chain. Here the hemispheral chains
show anterior-posterior and medio-lateral extension with cerebellar size increase.
Furthermore the bifurcation patterns of the folia begin to become more complex. In
region BC the three folial chain come back in alignment and we have similar
expansion in the hemispheres and vermis which now occurs mainly in the anterior-
posterior direction. Finally, we have the three-tailed ending with again two
hemispheral chains and one vermal. In this region in rodents and logomorphs the
expansion also occurs mainly in the anterior-posterior direction. Unfolded maps were
drawn as follows: Cerebella were carefully dissected by systematic cleavage of the
folial chain beginning at the anterior/rostral cerebellar end. Drawn are the latero-
lateral extensions folia or ridges that further demark the individual folia. Anterior-
posterior spacing of these lines was based on cerebellar regions were the most of the
foliation occurred. For instance in the rabbit cerebellar region B, most of the foliation
occurred in the hemispheres and hence the vermal folial chain show a paucity of folia
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in this region. The spacing in regions of maximal foliation was determined from
measurements on midsagittal histological sections. Modified from (11)
Figure 6 Sultan/ bird brains
Comparison of bird cerebellar size and brain size. (A) double logarithmic plot of
cerebellar length to body weight (y= 0.25 x + 1.3, r^2= 0.78). Dashed lines demark
the 95% confidence band. In this sample only birds of the parrot, crow and
woodpecker families lie above this confidence band. Birds of the owl and barn owl
family show a mixed pattern, with some lying below the regression line.
(B) shows a double logarithmic plot of total brain size to body size. Data reported in
the literature (32-41) were analyzed, referring to 792 species, 21 orders and 100
families. Nine bird families lie above the 95% confidence bands (rank ordered high to
low) : tytonidae (barn owls), psittacidae (parrots), bucorvidae (ground hornbills),
corvidae (crows), menuridae (lyrebirds), strigidae (owls), picidae (woodpeckers),
bucerotidae (hornbills) and sulidae (gannets). Major axis regression: y= 0.55 x - 0.88
(r^2= 0.92).
(C) Total brain size residuals from (B) versus cerebellar residuals from (A). Residuals
were obtained from regressing total brain size and cerebellar length to body weight.
Total brain residuals and cerebellar residuals showed a positive linear relationship (y=
0.47 x +0.01, r^2=0.7, F-ratio= 41, p= 10^-5). In the large brained birds, owls have
smaller cerebellar residuals than predicted from the regression line.
Figure 7 Sultan/ bird cerebella
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Quantitative comparison of folia size in different birds. (A) Colour coded midsagittal
drawings of bird cerebella obtained from Larsell and Senglaub. Roman numerals
surrounding the cormorant cerebellum indicate Larsell’s ten lobuli. Cerebella of the
same species (here barn owl) showed similar folial pattern. Also within a given bird
family the cerebellum also shows marked consistency (barn owl's and long-eared
owl). (B) Principal component (PC) analysis of the lobuli lengths. Scores of the
individual bird species on the first two PCs are shown. Generally birds of the same
family tended to score similarly. Owls scored high on the second PC, while crows,
parrots and woodpeckers scored high on the first PC. (C) Two exemplary bird
cerebella of roughly equal body size (long-eared owl: 276g; green woodpecker: 195g)
are shown for each group of birds scoring high on the first and second PC. The
contributions of the lobuli to the two first PCs are colour coded: red codes first PC,
blue second PC. Owls had enlarged lobuli I, II and X, while parrots, cros and
woodpeckers had enlarged lobuli IV, VI-IX. Reprinted from (22).
Figure 8 from Glickstein et. al.
The figure shows the locus and extent of an injection of wheat germ agglutinin horse
radish peroxidase into the pontine nuclei of a monkey. All of the retrogradely labeled
cortical cells were layer V pyramids. The dots reflect the relative density of retrograde
filling in vrious cortical areas. Note the density of filling in motor and pre-motor areas
of the cerebral cortex. The dorsal stream of extrastriate visual areas project heavily to
the pons. There is little or no projection from the ventral stream.
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