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Y. Luo and I. Sugihara
VIa
V
IV
III
II
MN
Xb
Xa
VIb
VIc
IXc
VII
VIII
IXb
IXa
5 mm
1 mm
c
R
Rt
Lt
C
V
VId
VIa
VIb
D
CR
V
1 mm
Fig. 6.1 Axonal path of a single olivocerebellar axon. (a) Lateral view
of a trajectory of a reconstructed single olivocerebellar axon labeled by
localized injection of biotinylated dextran amine in the rat. This axon
originated from the medial and caudal part of the medial accessory
olive, a subnucleus of the inferior olive, and terminated in lobules VI
and VII in the vermis. Arrowhead indicates the most rostral part of the
Upon entering the cerebellum, each axon gives rise to collaterals to the deep cerebellar nuclei and branches into multiple (seven on average in rat) axons, each of which terminates
on a single adult Purkinje cell as a climbing ber. Thus, a
“climbing ber” discovered by Ramón y Cajal (1911) is the
inferior cerebellar peduncle. (b) Distribution of climbing bers originating of this axon (red) and other axons labeled (black) mapped in the
unfolded scheme of the rat cerebellar cortex. (c) Magnied drawing of
the area surrounded by the square in (b). II–Xb lobule II—lobule Xb, C
caudal, IO inferior olive, Lt left, MN medial nucleus, R rostral, Rt right
nal band-shaped area (Fig. 6.1b, c, Sugihara et al. 2001)
inside one zebrin stripe (later section). The olivocerebellar
axon’s longitudinal projection pattern contrasts with the
transversely wide projection pattern of mossy ber axons
(Biswas etal. 2019).
1 mm
VIc
VII
VIII
terminal arbor of one of a number of branches of the olivocerebellar axon. Besides giving rise to nuclear collaterals
and cortical branches that terminate as climbing bers, olivocerebellar axons also give rise to several thin collaterals,
6.3 Topography intheOlivocerebellar
Tract
mainly terminating in the granular layer with a small number
of swellings. Synaptic contact and functional signicance of
these collaterals are not well claried (Sugihara etal. 1999).
The multiple climbing bers originating from a single axon
are usually, but not always, distributed in a narrow longitudi-
The olivocerebellar projection has a topographic arrangement.
Thus, the inferior olive subdivides into many subareas, usually a portion of a single lamella (Fig.6.2a). Neurons in each
subarea of the inferior olive project topographically to a par-
6 The Olivocerebellar Tract
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a
b
Fig. 6.2 Aldolase C stripe-linked topography of the olivocerebellar
projection. (a) Subareas of the inferior olive. Two coronal sections of
the inferior olive of the mouse, labeled with immunostaining of FoxP2,
a marker molecule of the nucleus of inferior olive neurons (Fujita and
Sugihara 2012) at the caudal and rostral levels (reversed epiuorescence image). The percentile indicates the relative caudorostral levels
within the whole inferior olive. The superimposition of colors on the
right side shows the subareas of the inferior olive. (b) Dorsal view of
the whole-mount preparation of the Aldoc-Venus mouse (Fujita et al.
2014), in which aldolase C (zebrin) stripes are visible with uorescence
(reversed epiuorescence image). On the left side, the cerebellar cortex
is divided into multiple zonal areas (colored) that receive the topographic olivocerebellar projection from subareas of the inferior olive.
The boundaries of colored stripes mostly match with the boundaries of
aldolase C stripes. The color-coding indicates the topographic relationship between A and B.The dark gray area in A and the gray area in B
do not have corresponding parts appearing in the other panel. Based on
Sugihara and Shinoda (2004), Sugihara and Quy (2007) and Fujita etal.
(2020). V–IX lobule V–lobule IX, a, b, c, d subnucleus a, b, c, d of the
caudal part of the medial accessory olive, beta subnucleus beta, DM
dorsomedial subnucleus, DC/VLO dorsal cap, and ventrolateral outgrowth subnucleus, dDAO dorsal fold of the dorsal accessory olive,
dPO dorsal lamella of the principal olive, rMAO rostral part of the
medial accessory olive, vPO ventral lamella of the principal olive, Sim
simple lobule, Cr I crus I, Cr II crus II, Par paramedian lobule, Cop
copula pyramidis, PFl paraocculus
ticular subarea in the cerebellar nuclei and a specic striped
subarea in the cerebellar cortex (Sugihara and Shinoda 2004,
2007). These subareas in the cortex and nuclei are topographi-
cally connected to each other by the corticonuclear Purkinje
cell projection (Sugihara etal. 2009). The specic subarea in
the cerebellar nuclei also topographically projects to the par-
ticular subarea in the inferior olive (Ruigrok and Voogd 1990).
As a whole, a triangular topographic loop of neuronal connections forms among subareas in the inferior olive, cerebellar
cortex, and cerebellar nuclei. Each set of topographically connected subareas in the cerebellar cortex, cerebellar nuclei, and
inferior olive is designated as a cerebellar module (Ruigrok
2011). A standing question of how many modules constitute
the entire cerebellum remains. Conventionally, the basic six
modules (A, B, C1, C2, C3, and D) have been recognized
(Voogd and Bigaré 1980). However, most of these modules
have been further subdivided into smaller modules (Ruigrok
2011; Sugihara et al. 2009). In addition, the occulus and
nodulus have distinct modules (Sugihara etal. 2004). Most
cerebellar modules are consistent with the cortical compartments dened by the molecular expression prole in Purkinje
cells (Sugihara and Shinoda 2004, Sugihara et al. 2009).
Aldolase C (zebrin II, or just “zebrin,” Brochu et al. 1990),
which is the representative of such molecules, is highly
expressed in Purkinje cells arranged in tens of alternate longitudinal stripes in the cerebellar cortex (Fig.6.2b, right). The
topographic relationship between the subarea of the inferior
olive and aldolase C stripes has been well identied (colorcoded in Fig.6.2), although details may still be revised in the
future. In the cerebellar nuclei, to which the collaterals of
olivocerebellar axons project topographically, the arrangement of subareas (or modules) is different from that in the
cerebellar cortex. Subareas linked with aldolase C-positive
and -negative compartments are all located in the caudoventral and rostrodorsal parts of the cerebellar nuclei, respectively
(Sugihara and Shinoda 2007). Output neurons in different
subareas of the cerebellar nuclei linked with aldolase C stripes
generally project to distinct targets and are involved in different cerebellar functions (Fujita etal. 2020).
6.4 Physiological Properties
The inferior olive neurons show the oscillatory uctuation of
membrane potential at about 10Hz (Llinás and Yarom 1986).
This activity synchronizes among nearby neurons through
dendro-dendritic gap junctions (Llinás and Yarom 1986;
Long et al. 2002). Excitatory input to the inferior olive,
which mainly originates from the somatosensory and vestibular systems in the medulla and spinal cord and visual,
corticofugal, and other systems in the midbrain and mesodiencephalic junction (see Sugihara and Shinoda 2004), may
reset the oscillatory rhythm to evoke ring (Leznik and
Llinás 2005). Olivary cells may re at the peak of the oscillation of one action potential or a few action potentials in a
burst. The ring of an action potential (or a brief burst of
action potentials) occurs as a solitary event or in sequence
with about 100-ms intervals (Marthy etal. 2009). On average, the ring frequency of the olivary neuron is about 1Hz
(Eccles etal. 1966).
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Y. Luo and I. Sugihara
The ring of olivary neurons is conveyed to the axon terminals, i.e., climbing ber terminals, with a conduction time
of approximately 4 ms (in rat, Sugihara et al. 1993). An
action potential (or a brief burst of action potentials) in the
climbing ber produces a complex spike response in target
Purkinje cells (Eccles etal. 1966). In addition, olivocerebellar axon collaterals elicit an excitatory effect in the cerebellar
nuclei (Blenkinsop and Lang 2011). However, its effect on
the granular layer is yet unclear.
Since adjacent inferior olive neurons generally project to a
narrow longitudinal striped area in the cerebellar cortex, it
often matches with a single aldolase C stripe (Sugihara etal.
2007). Because of this property in the olivocerebellar projec-
tion, Purkinje cells arranged in the longitudinal band
(width=~0.25mm) tend to re complex spikes synchronously
in awake and anesthetized states (Sasaki et al. 1989; Lang
etal. 1999). The band of complex spike synchrony generally
matches with a single aldolase C stripe (Sugihara etal. 2007).
Functionally, climbing ber inputs in each aldolase C stripe
are activated in particular timing/aspects during the sensorimotor behavior of animals (Horn et al. 2010; Tsutsumi et al.
2019). This synchronous complex spike ring of Purkinje
cells may be functionally important to form cerebellar output
in the cerebellar nuclei (Blenkinsop and Lang 2011).
6.5 Development oftheOlivocerebellar
Projection
The immature olivocerebellar axonal projection is formed in
the late embryonic stage when Purkinje cells form clusters
before settling into striped compartments in rats and mice
(Fujita etal. 2012). A basic topographic projection pattern
appears in the olivocerebellar bundle at this stage (Chédotal
and Sotelo 1992). Axonal terminals form a delicate plexus
with abundant branching known as the creeper terminal
(Sugihara 2005). In the second postnatal week, many axonal
branches disappear, leaving only those that begin to form a
dense arbor around a single Purkinje cell soma (nest terminal). The nest terminals grow to an entire climbing ber terminal in the following few weeks.
The above process of climbing ber development leads to
the establishment of a one-to-one synaptic connection
between a single climbing ber terminal and a single target
Purkinje cell. A loss of granule cells caused by X-ray irradiation or other procedures and some genetic mutations prevent
the normal development of climbing ber morphology
(Sugihara etal. 2000). In these situations, multiple climbing
bers originating from one olivocerebellar axon (pseudomultiple innervation) of different olivocerebellar axons (true
multiple innervations) may remain to innervate a single
Purkinje cell (impairment of one-to-one innervation,
Sugihara etal. 2000).
6.6 Plasticity ofOlivocerebellar Axons
Since the average olivocerebellar projection is nearly exclusively contralateral, an increase of ipsilateral projection indicates a plastic change in the projection. Such plastic change is
seen after a unilateral cut of the cerebellar peduncle in the neonatal stage in rats (Sugihara etal. 2003). A similar transcommissural olivocerebellar projection to the ipsilateral cerebellum
is seen even in adults after administering substances that can
facilitate axonal plasticity (Dixon and Sherrard 2006).
Semitotal lesion of the inferior olive by neurotoxin
3- aminopyridine (3-AP) induces axonal sprouting of remaining olivary neurons to compensate for the loss of many olivocerebellar axonal terminals (Rossi et al. 1991). Axonal
sprouting occurs only in their terminal portions, mainly in
the terminal arbor of climbing bers and possibly also at the
terminal of thin collaterals in the granular layer and cerebellar nuclei. However, no axonal sprouting from the stem axon
in the cerebellar white matter was evident, at least in adults
(Aoki and Sugihara 2012).
6.7 Conclusion
Our current knowledge of the olivocerebellar projection’s
morphological, physiological, and developmental aspects
are summarized above. The olivocerebellar projection is an
essential component of the cerebellar system. The projection
is well organized at the level of single axons and at the level
of topographic compartmentalization of the whole cerebellar
cortex. The input from the olivocerebellar system produces
signicant effects on the activity of Purkinje cells and the
output of neurons of the cerebellar nucleus. To consider the
signicance of such effect in various cerebellar functions,
the general morphological property of the olivocerebellar
system as summarized here would be necessary.
References
Aoki H, Sugihara I (2012) Morphology of single olivocerebellar axons
in the denervation–reinnervation model produced by subtotal lesion
of the rat inferior olive. Brain Res 1449:24–37
Biswas MS, Luo Y, Sarpong GA, Sugihara I (2019) Divergent projec-
tions of single pontocerebellar axons to multiple cerebellar lobules
in the mouse. J Comp Neurol 527:1966–1985
Blenkinsop TA, Lang EJ (2011) Synaptic action of the olivocer-
ebellar system on cerebellar nuclear spike activity. J Neurosci
31:14708–14720
Brochu G, Maler L, Hawkes R (1990) Zebrin II: a polypeptide antigen
expressed selectively by Purkinje cells reveals compartments in rat
and sh cerebellum. J Comp Neurol 291:538–552
Chédotal A, Sotelo C (1992) Early development of olivocerebellar pro-
jections in the fetal rat using CGRP immunocytochemistry. Eur J
Neurosci 4:1159–1179
Dixon KJ, Sherrard RM (2006) Brain-derived neurotrophic factor
induces post-lesion transcommissural growth of olivary axons
6 The Olivocerebellar Tract
https://t.me/medicina_free
45
that develop normal climbing bers on mature Purkinje cells. Exp
Neurol 202:44–56
Eccles JC, Llinás R, Sasaki K (1966) The excitatory synaptic action of
climbing bres on the Purkinje cells of the cerebellum. J Physiol
182:268–296
Fujita H, Sugihara I (2012) FoxP2 expression in the cerebellum
and inferior olive: development of the transverse stripe-shaped
expression pattern in the mouse cerebellar cortex. J Comp Neurol
520:656–677
Fujita H, Morita N, Furuichi T, Sugihara I (2012) Clustered ne com-
partmentalization of the mouse embryonic cerebellar cortex and its
rearrangement into the postnatal striped conguration. J Neurosci
32:15688–15703
Fujita H, Aoki H, Ajioka I, Yamazaki M, Abe M, Oh-Nishi A, Sakimura
K, Sugihara I (2014) Detailed expression pattern of aldolase C
(Aldoc) in the cerebellum, retina and other areas of the CNS studied
in Aldoc-Venus knock-in mice. PLoS One 9:e86679
Fujita H, Kodama T, du Lac S (2020) Modular output circuits of the
fastigial nucleus for diverse motor and nonmotor functions of the
cerebellar vermis. Elife 9:e58613
Horn KM, Pong M, Gibson AR (2010) Functional relations of cerebel-
lar modules of the cat. J Neurosci 30:9411–9423
Lang EJ, Sugihara I, Welsh JP, Llinás R (1999) Patterns of spontaneous
complex spike activity in the awake rat. J Neurosci 19:2728–2739
Leznik E, Llinás R (2005) Role of gap junctions in synchronized neu-
ronal oscillations in the inferior olive. J Neurophys 94:2447–2456
Llinás R, Yarom Y (1986) Oscillatory properties of guinea-pig inferior
olivary neurones and their pharmacological modulation: an invitro
study. J Physiol 376:163–182
Long MA, Deans MR, Paul DL, Connors BW (2002) Rhythmicity
without synchrony in the electrically uncoupled inferior olive. J
Neurosci 22:10898–10905
Marthy A, Ho SSN, Davie JT, Duguid IC, Clark BA, Häusser M (2009)
Encoding of oscillations by axonal bursts in inferior olive neurons.
Neuron 62:388–399
Ramón y Cajal S (1911) Histologie du système nerveux de l’homme et
des verébrés, vol 2. Maloine, Paris
Rossi F, Wiklund L, Van der Want JJL, Strata P (1991) Reinnervation
of cerebellar Purkinje cells by climbing bers surviving a subtotal lesion of the inferior olive in the adult rat. I.Development of
new collateral branches and terminal plexuses. J Comp Neurol
308:513–535
Ruigrok TJ (2011) Ins and outs of cerebellar modules. Cerebellum
10:464–474
Ruigrok TJ, Voogd J (1990) Cerebellar nucleo-olivary projections in the
rat: an anterograde tracing study with Phaseolus vulgaris leucoagglutinin (PHA-L). J Comp Neurol 298:315–333
Sasaki K, Bower JM, Llinás R (1989) Multiple Purkinje cell recording
in rodent cerebellar cortex. Eur J Neurosci 1:572–586
Sugihara I (2005) Microzonal projection and climbing ber remodeling
in single olivocerebellar axons of new born rats at postnatal days
4–7. J Comp Neurol 487:93–106
Sugihara I, Quy PN (2007) Identication of aldolase C compartments
in the mouse cerebellar cortex by olivocerebellar labeling. J Comp
Neurol 500:1076–1092
Sugihara I, Shinoda Y (2004) Molecular, topographic and functional
organization of the cerebellar cortex: a study with combined aldol-
ase C and olivocerebellar labelling. J Neurosci 24:8771–8785
Sugihara I, Shinoda Y (2007) Molecular, topographic and functional
organization of the cerebellar nuclei: analysis by three-dimensional
mapping of the olivonuclear projection and aldolase C labeling. J
Neurosci 27:9696–9710
Sugihara I, Lang EJ, Llinás R (1993) Uniform olivocerebellar conduc-
tion time underlies Purkinje cell complex spike synchronicity in the
rat cerebellum. J Physiol Lond 470:243–271
Sugihara I, Wu H-S, Shinoda Y (1999) Morphology of single olivocer-
ebellar axons labeled with biotinylated dextran amine in the rat. J
Comp Neurol 414:131–148
Sugihara I, Bailly Y, Mariani J (2000) Olivocerebellar climbing
bers in the granuloprival cerebellum: morphological study of
individual axonal projections in the X-irradiated rat. J Neurosci
20:3745–3760
Sugihara I, Wu H-S, Shinoda Y (2001) The entire trajectories of single
olivocerebellar axons in the cerebellar cortex and their contribution
to cerebellar compartmentalization. J Neurosci 21:7715–7723
Sugihara I, Lohof AM, Letellier M, Mariani J, Sherrard RM (2003)
Post-lesion transcommissural growth of olivary climbing
bres creates functional synaptic microzones. Eur J Neurosci
18:3027–3036
Sugihara I, Ebata S, Shinoda Y (2004) Functional compartmentaliza-
tion in the occulus and the ventral dentate and dorsal group y
nuclei: an analysis of single olivocerebellar axonal morphology. J
Comp Neurol 470:113–133
Sugihara I, Marshall SP, Lang EJ (2007) Relationship of complex spike
synchrony bands and climbing ber projection determined by refer-
ence to aldolase C compartments in crus IIa of the rat cerebellar
cortex. J Comp Neurol 501:13–29
Sugihara I, Fujita H, Na J, Quy PN, Li BY, Ikeda D (2009) Projection
of reconstructed single Purkinje cell axons in relation to the cortical
and nuclear aldolase C compartments of the rat cerebellum. J Comp
Neurol 512:282–304
Tsutsumi S, Hidaka N, Isomura Y, Matsuzaki M, Sakimura K, Kano
M, Kitamura K (2019) Modular organization of cerebellar climbing
ber inputs during goal-directed behavior. eLife 8:e47021
Voogd J, Bigaré F (1980) Topographical distribution of olivary and cor-
ticonuclear bers in the cerebellum: a review. In: Courville J, de
Montigny C, Lamarre Y (eds) The inferior olivary nucleus anatomy
and physiology. Raven Press, NewYork, pp207–234
Precerebellar Nuclei: Embryological
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Principles
MayumiYamada andMikioHoshino
7
Abstract
The cerebellar cortex receives several inputs from the surrounding nuclei, the precerebellar systems. Two major
types of precerebellar systems are known: mossy ber
(MF) and climbing ber (CF) systems. MF neurons are
found in several nuclei in the brain stem. Four major
nuclei in the hindbrain contain MF neurons; the pontine
gray nucleus (PGN), the reticulotegmental nucleus
(RTN), the lateral reticular nucleus (LRN), and the external cuneate nucleus (ECN). In addition, MF neurons also
reside in the spinal trigeminal nucleus (Sp5) in the hindbrain and Clarke’s column (CC) in the spinal cord. MF
neurons extend their glutamatergic projection to granule
cells conveying peripheral and cortical information to the
cerebellum. In contrast, CF neurons are located exclusively in the inferior olive nucleus (ION), which receive
inputs from the cerebral cortex, the red nucleus, spinal
cord, and other brain stem nuclei, and extend their glutamatergic projection to Purkinje cells. Both types of precerebellar neurons also project to neurons in the cerebellar
nuclei. It is thought that these precerebellar systems transmit the external and internal information to the cerebellar
cortex to modulate cerebellar function, including the regulation of animal movement.
M. Yamada
Graduate School of Biostudies, Kyoto University, Kyoto, Japan
M. Hoshino (*)
Department of Biochemistry and Cellular Biology, National
Institute of Neuroscience, National Center of Neurology and
Psychiatry, Kodaira, Tokyo, Japan
e-mail: hoshino@ncnp.go.jp
Keywords
Precerebellar system · Mossy ber neuron · Climbing
ber neuron · PGN · RTN · LRN · ECN · ION
Cerebellum · Transcription factor · Rhombomere
Neuroepithelial domain
7.1 Anatomy andHistology
ofthePrecerebellar Nuclei
The cerebellar cortex receives several inputs from the surrounding nuclei, the precerebellar systems. Two major types
of precerebellar systems are known: mossy ber (MF) and
climbing ber (CF) systems. MF neurons are found in several nuclei in the brain stem. Four major nuclei in the hindbrain contain MF neurons; the pontine gray nucleus (PGN),
the reticulotegmental nucleus (RTN), the lateral reticular
nucleus (LRN), and the external cuneate nucleus (ECN)
(Altman and Bayer 1987) (Fig.7.1a–c). In addition, MF neurons also reside in the spinal trigeminal nucleus (Sp5) in the
hindbrain and Clarke’s column (CC) in the spinal cord
(Fig.7.1a–d). MF neurons extend their glutamatergic projection to granule cells conveying peripheral and cortical information to the cerebellum. In contrast, CF neurons are located
exclusively in the inferior olive nucleus (ION) (Fig.7.1a, c),
which receive inputs from the cerebral cortex, the red
nucleus, spinal cord, and other brain stem nuclei, and extend
their glutamatergic projection to Purkinje cells (Ruigrok
etal. 1995). Both types of precerebellar neurons also project
to neurons in the cerebellar nuclei. It is thought that these
precerebellar systems transmit external and internal information to the cerebellar cortex to modulate cerebellar function,
including the regulation of animal movement.
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023
D. L. Gruol et al. (eds.), Essentials of Cerebellum and Cerebellar Disorders, https://doi.org/10.1007/978-3-031-15070-8_7
47
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M. Yamada and M. Hoshino
a
b
e
Fig. 7.1 Precerebellar systems in the brain stem. (a–d) Two types of
precerebellar afferent systems; MF (red) and CF (blue) systems. Cb
cerebellum, CN cerebellar nucleus. (e) In the caudal hindbrain (rhombomere 6–8), the dorsal neuroepithelium can be divided into six
domains (dP1–dP6) according to the expression pattern of transcription
factors during embryonic development. While MF neurons (red) are
derived from the dP1 domain, CF neurons (blue) are generated from the
dP4 domain
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49
7.2 Specication ofPrecerebellar Nuclei
Neurons
Birthdating studies using 3H-thymidine and BrdU in mice
showed that CF neurons are produced at relatively early
neurogenesis stages [embryonic day (E) 9.5–11.5] and MF
neurons are generated at slightly later stages (E10.5–16.5)
(Pierce 1973). Avian grafting studies as well as mammalian
fate map analyses have revealed that in the hindbrain, both
MF and CF neurons are generated from the caudal part,
around rhombomeres 6–8 (Fig. 7.1e) (Ambrosiani et al.
1996; Cambronero and Puelles 2000; Farago et al. 2006;
Kawauchi etal. 2006). In contrast, MF neurons in Clarke’s
nucleus are produced in the spinal cord (Bermingham etal.
2001). Classic anatomical and immunohistochemical stud-
ies have suggested that these precerebellar nuclei neurons in
the hindbrain are generated from the dorsal part of the
rhombomere and migrate circumferentially to their nal loci
(Bloch- Gallego etal. 1999; Yee etal. 1999; Kyriakopoulou
etal. 2002). However, they take slightly different pathways;
MF and CF neurons migrate extramurally and intramurally,
respectively (Fig.7.1e). Introduction of a GFP-expressing
vector into the embryonic dorsal hindbrain enabled the dramatic visualization of migrating precerebellar nuclei neurons during development (Kawauchi et al. 2006; Okada
et al. 2007; Shinohara et al. 2013). Recent studies have
revealed that precerebellar neuron migration is regulated by
various molecules or signaling cascades, such as netrin,
SLIT/ROBO proteins, bone morphogenetic protein (BMP)
signaling, sonic hedgehog signaling (SHH), and Calmodulin
(Dominici etal. 2018; Martinez-Chavez etal. 2018; MorenoBravo et al. 2018; Yung et al. 2018; Qin et al. 2019;
Kobayashi etal. 2015).
Several transcription factors are reportedly expressed
within the dorsal neuroepithelium of the caudal rhombomeres 6–8 during embryonic development and have been
used to try to dene domains along the dorsoventral axis.
Lmx1a is expressed in the roof plate, the dorsal-most part of
rhombomere, which gives rise to the choroid plexus
(Chizhikov et al. 2006). Other transcription factors are
expressed in the dorsal neuroepithelium, which can be
divided into six domains (dP1–dP6) according to the pattern
of transcription factors, such as Atoh1, Ngn1, Ascl1, Ptf1a,
Pax6, and Olig3 (Fig.7.1e). Using genetic lineage tracing
methods, a series of studies have tried to clarify the precise
origins of MF and CF neurons.
Analyses of genetically engineered mice that express lacZ
or Cre recombinase under the control of the endogenous or
exogenous Atoh1 promoter revealed that MF neurons of
PGN, RTN, LRN, and ECN were generated from the Atoh1expressing neuroepithelial domain (dP1, Ben-Arie et al.
2000; Rodriguez and Dymecki 2000; Landsberg etal. 2005;
Wang etal. 2005). Loss of the Atoh1 gene resulted in a defect
in the production of these MF neurons, suggesting the
involvement of Atoh1 in MF neuron development.
Landsberg etal. also performed lineage tracing using two
variants of FLP (Flippase recombinase) with different
recombinase activities that were expressed under the control
of the Wnt1 promoter whose strength is the highest at the
dorsal-most part and decreases ventrally. They observed that
CF neurons are generated from the neuroepithelial region
where Wnt1 is very weakly expressed, whereas MF neurons
are derived from the strong Wnt1-expressing region
(Landsberg et al. 2005). In addition, Nichols and Bruce
showed that in mice carrying a Wnt1-enhancer/lacZ transgene, MF neurons but not CF neurons were labeled by β-gal
(Nichols and Bruce 2006). These ndings suggested that CF
neurons are derived from the neuroepithelial region ventral
to the Atoh1-expressing domain.
Yamada et al. performed Cre-loxP-based lineage trace
analysis and showed that all CF neurons in the ION are generated from the Ptf1a-expressing neuroepithelial domain
(Yamada etal. 2007). Targeted disruption of the Ptf1a gene
caused defects in the production of these CF neurons and in
fate change of some CF neurons to MF neurons, suggesting
that Ptf1a plays a critical role in fate determination of CF
neurons. They also showed that Ptf1a is important for migration, differentiation, and survival of CF neurons. Storm etal.
used Cre-loxP-based linage tracing to show that not only MF
neurons but also CF neurons are generated from the Olig3expressing neuroepithelial region that broadly expands
within the dorsal hindbrain (Storm etal. 2009). Loss of the
Olig3 gene resulted in the disorganized development of MF
neurons and complete loss of CF neurons (Liu etal. 2008;
Storm etal. 2009). Moreover, ectopic co-expression of Olig3
and Ptf1a induced the expression of a CF neuron marker in
chick embryos (Storm etal. 2009). These ndings suggest
that CF neurons are derived from the Ptf1a/Olig3-expressing
neuroepithelial domain (dP4) and that Ptf1a and Olig3 cooperatively regulate the development of CF neurons. The
domain structure of the dorsal neuroepithelium in the caudal
hindbrain is shown in Fig.7.1e.
References
Altman J, Bayer SA (1987) Development of the precerebellar nuclei in
the rat. I–IV.J Comp Neurol 257:477–552
Ambrosiani J, Armengol JA, Martinez S, Puelles L (1996) The avian
inferior olive derives from the alar neuroepithelium of the rhombo-
meres 7 and 8: an analysis by using chick-quail chimeric embryos.
Neuroreport 7:1285–1288
Ben-Arie N, Hassan BA, Bermingham NA, Malicki DM, Armstrong
D, Matzuk M, Bellen HJ, Zoghbi HY (2000) Functional conser-
vation of atonal and Math1 in the CNS and PNS. Development
127:1039–1048
50
https://t.me/medicina_free
M. Yamada and M. Hoshino
Bermingham NA, Hassan BA, Wang VY, Fernandez M, Ban S, Bellen
HJ, Fritzsch B, Zoghbi HY (2001) Proprioceptor pathway development is dependent on Math1. Neuron 30:411–422
Bloch-Gallego E, Ezan F, Tessier-Lavigne M, Sotelo C (1999) Floor
plate and netrin-1 are involved in the migration and survival of inferior olivary neurons. J Neurosci 19:4407–4420
Cambronero F, Puelles L (2000) Rostrocaudal nuclear relationships in
the avian medulla oblongata: a fate map with quail chick chimeras.
J Comp Neurol 427:522–545
Chizhikov VV, Lindgren AG, Currle DS, Rose MF, Monuki ES, Millen
KJ (2006) The roof plate regulates cerebellar cell-type specication
and proliferation. Development 133:2793–2804
Dominici C, Rappeneau Q, Zelina P, Fouquet S, Chédotal A (2018)
Non-cell autonomous control of precerebellar neuron migration by
Slit and Robo proteins. Development 145(2):150375. https://doi.
org/10.1242/dev.150375
Farago AF, Awatramani RB, Dymecki SM (2006) Assembly of the
brainstem cochlear nuclear complex is revealed by intersectional
and subtractive genetic fate maps. Neuron 50:205–218
Kawauchi D, Taniguchi H, Watanabe H, Saito T, Murakami F (2006)
Direct visualization of nucleogenesis by precerebellar neurons:
involvement of ventricle-directed, radial bre-associated migration.
Development 133:1113–1123
Kobayashi H, Saragai S, Naito A, Ichio K, Kawauchi D, Murakami
F (2015) Calm1 signaling pathway is essential for the migration
of mouse precerebellar neurons. Development 142(2):375–384.
https://doi.org/10.1242/dev.112680
Kyriakopoulou K, de Diego I, Wassef M, Karagogeos D (2002) A com-
bination of chain and neurophilic migration involving the adhesion
molecule TAG-1in the caudal medulla. Development 129:287–296
Landsberg RL, Awatramani RB, Hunter NL, Farago AF, DiPietrantonio
HJ, Rodriguez CI, Dymecki SM (2005) Hindbrain rhombic lip is
comprised of discrete progenitor cell populations allocated by Pax6.
Neuron 48:933–947
Liu Z, Li H, Hu X, Yu L, Liu H, Han R, Colella R, Mower GD, Chen
Y, Qiu M (2008) Control of precerebellar neuron development by
Olig3 bHLH transcription factor. J Neurosci 28:10124–10133
Martinez-Chavez E, Scheerer C, Wizenmann A, Blaess S (2018) The
zinc-nger transcription factor GLI3 is a regulator of precerebellar neuronal migration. Development 145(24):166033. https://doi.
org/10.1242/dev.166033
Moreno-Bravo JA, Roig Puiggros S, Blockus H, Dominici C, Zelina P,
Mehlen P etal (2018) Commissural neurons transgress the CNS/
PNS boundary in absence of ventricular zone-derived netrin 1.
Development 145(2):159400. https://doi.org/10.1242/dev.159400
Nichols DH, Bruce LL (2006) Migratory routes and fates of cells
transcribing the Wnt-1 gene in the murine hindbrain. Dev Dyn
235:285–300
Okada T, Keino-Masu K, Masu M (2007) Migration and nucleogenesis
of mouse precerebellar neurons visualized by in utero electropora-
tion of a green uorescent protein gene. Neurosci Res 57:40–49
Pierce ET (1973) Time of origin of neurons in the brain stem of the
mouse. Prog Brain Res 40:53–65
Qin L, Ahn KJ, Wine Lee L, de Charleroy C Jr, Crenshaw EB 3rd
(2019) Analyses with double knockouts of the Bmpr1a and Bmpr1b
genes demonstrate that BMP signaling is involved in the forma-
tion of precerebellar mossy ber nuclei derived from the rhombic
lip. PLoS One 14(12):e0226602. https://doi.org/10.1371/journal.
pone.0226602
Rodriguez CI, Dymecki SM (2000) Origin of the precerebellar system.
Neuron 27:475–486
Ruigrok TJ, Cella F, Voogd J (1995) Connections of the lateral reticu-
lar nucleus to the lateral vestibular nucleus in the rat. An antero-
grade tracing study with Phaseolus vulgaris leucoagglutinin. Eur J
Neurosci 7:1410–1413
Shinohara M, Zhu Y, Murakami F (2013) Four-dimensional analysis
of nucleogenesis of the pontine nucleus in the hindbrain. J Comp
Neurol 521:3340–3357
Storm R, Cholewa-Waclaw J, Reuter K, Brohl D, Sieber M, Treier M,
Muller T, Birchmeier C (2009) The bHLH transcription factor Olig3
marks the dorsal neuroepithelium of the hindbrain and is essential
for the development of brainstem nuclei. Development 136:295–305
Wang VY, Rose MF, Zoghbi HY (2005) Math1 expression redenes
the rhombic lip derivatives and reveals novel lineages within the
brainstem and cerebellum. Neuron 48:31–43
Yamada M, Terao M, Terashima T, Fujiyama T, Kawaguchi Y,
Nabeshima Y, Hoshino M (2007) Origin of climbing ber neu-
rons and their developmental dependence on Ptf1a. J Neurosci
27:10924–10934
Yee KT, Simon HH, Tessier-Lavigne M, O'Leary DM (1999) Extension
of long leading processes and neuronal migration in the mammalian
brain directed by the chemoattractant netrin-1. Neuron 24:607–622
Yung AR, Druckenbrod NR, Cloutier JF, Wu Z, Tessier-Lavigne M,
Goodrich LV (2018) Netrin-1 connes rhombic lip-derived neurons
to the CNS. Cell Rep 22(7):1666–1680. https://doi.org/10.1016/j.
celrep.2018.01.068
Vestibular Nuclei andTheir Cerebellar
https://t.me/medicina_free
Connections
NealH.Barmack
8
Abstract
The vestibular nuclei and the vestibulocerebellum comprise the anatomical crossroads where primary vestibular
information is collected, stored, and modied by other
sensory inputs (visual, proprioceptive, autonomic) and
central cortical commands. Secondary vestibular neurons
are clustered into ve nuclei in which different subsets of
vestibular primary afferents terminate. This distributed
organization may be based on the targeted outputs of the
clustered secondary neurons rather than on selective
afferent targeting. Vestibular primary and secondary afferent mossy bers activate a large mediolateral extent of
granule cells in multiple folia of vermal lobules
IX–X. However, the vermal and hemispheric lobules
IX–X are organized in three dimensions by vestibular and
visual climbing ber inputs that are arrayed in narrow
sagittal strips. In vermal lobules IX–X, these climbing
ber strips encode linear acceleration imposed by changes
in head movement with respect to gravity using the
utricular otoliths and angular acceleration of the head
about the anatomical axes of the two vertical semicircular
canals. Hemispheric lobule X encodes self-motion using
climbing ber structured optokinetic feedback imposed
by the three axes of the semicircular canals. Vestibular
and visual adaptation of this circuitry is needed to maintain balance during postural perturbations. Secondary
neurons in the vestibular nuclei and cerebellar neurons
may contribute to storage and modication of postural
reexes. Compensation of postural reexes following
unilateral damage to the vestibular nerve provokes
changes in cellular expression of protein kinase C-δ without causing a change in transcription of PKC-δ mRNA.
N. H. Barmack (*)
Department of Physiology and Pharmacology, Oregon Health and
Science University, Portland, OR, USA
e-mail: barmackn@ohsu.edu
Keywords
Flocculus · Nodulus · Uvula · Purkinje cells · PKC
Compensation
8.1 Introduction
The cerebellum and vestibular nuclei are two major components of a larger neural system that controls how vestibular
information is received, how it is stored, and how it is modied. This review describes connections between the cerebellum and vestibular nuclei that are multiple and complex.
8.2 Vestibular Nuclei
Five vestibular nuclei are located just below the dorsal surface
of the medullary brainstem (Fig. 8.1A1). They include
descending, lateral, medial, and superior nuclei (DVN, LVN,
MVN, and SVN) as well as the parasolitary nucleus (Psol).
All ve vestibular nuclei receive a mixture of ipsilateral vestibular primary afferents. Each vestibular nucleus is differentiated by a combination of cytological features, axonal
boundaries, cell sizes, and immunohistological characteristics. The DVN, LVN, MVN, and SVN contain a variety of
cell types. The LVN contains the largest neurons in the brain,
Dieter’s neurons, whose soma are ~50μm in diameter. The
LVN also contains many smaller cell types (Brodal and
Pompeiano 1957; Brodal 1974; Barmack et al. 1998a). This
variability in cell size within a nucleus is regional, suggesting
that these nuclei may have multiple circuits and functions. At
the other extreme, neurons in the Psol are uniformly small,
5–7μm in diameter, and are immunolabeled by an antiserum
to glutamic decarboxylase, the synthetic enzyme for the neurotransmitter gamma amino butyric acid (GABA) (Barmack
etal. 1998b). The distributed organization of the vestibular
nuclei may be based on common targeted outputs rather than
on selected afferent targeting of homogeneous circuitry.
© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023
D. L. Gruol et al. (eds.), Essentials of Cerebellum and Cerebellar Disorders, https://doi.org/10.1007/978-3-031-15070-8_8
51
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N. H. Barmack
Vestibular nuclei
1
SVN
VIII n
2
1.0 mm
3
Vestibular climbing fibers
Xb
0.5 mm
LVN
DVN
0.5 mm
Mossy fiber terminals
Xa
IXc
Psol
IXa
MVN
IXb
Vestibular primary afferent MFTs
1
X
2
Vestibular secondary afferent MFTs
IX
X
3
X
IXd
0.5 mm
IXd
midline
IXc
IXb
VIII n
Cerebellar vestibular circuitry
mf
LCN
Pc
MCN
Y
SVN
MVN
Psol
DMCC
DC
Psol
β
DVN
MVN
Gc
IntP
cf
X
DVN
Fig. 8.1 Projections of vestibular primary and secondary mossy and
climbing ber afferents to the vestibular nuclei and lobules IX–X and
how these projections are embedded in cerebellar circuitry. (A1) Viewed
dorsally, ve horizontal semicircular canal afferents, intra-axonally
labeled with HRP project to all vestibular nuclei except the LVN.
Modied from (Sato and Sasaki 1993). (A2) Mossy ber terminals from
a BDA-labeled lateral reticular nucleus neuron project bilaterally as
they reach the anterior cerebellar vermis. (A3) Sagittal view of several
BDA-labeled climbing bers that project in narrow sagittal bands to the
contralateral lobules IX–X. Modied from (Wu et al. 1999). (B1)
Vestibular primary afferents are labeled with the C fragment of tetanus
toxin (TTC) injected into the left labyrinth of rabbit. TTC is transported
orthogradely and trans-synaptically and labels MFTs and granule cells
in lobules IX–X.Arrows bracket the regions of profuse labeling. Note
absence of labeling in other folia. (B2) A horizontal section through
lobules IX–X shows that the projection of TTC-labeled vestibular pri-
Vestibular secondary afferents, labeled with an injection of WGA–HRP
into the caudal medial and descending vestibular nuclei, reveals labeling of mossy ber terminals in lobules IX–X. (c) Schematic illustrates
the vestibular mossy (green) and climbing ber (blue) projections to the
brainstem and posterior cerebellar cortex. Vestibular primary afferent
mossy bers (mf) (green) project to the ipsilateral parasolitary, medial,
descending, superior vestibular nuclei (Psol, MVN, DVN and SVN).
GABAergic Psol neurons (dashed red lines) project to the ipsilateral
β-nucleus (β) and dorsomedial cell column (DMCC) in the inferior
olive (yellow). Y-group neurons (Y) (purple) project to contralateral
DC, β and DMCC (purple lines). Neurons in β and DMCC project as
climbing bers (blue) (cf) to contralateral lobules VIII–X.Modied
from (Barmack and Yakhnitsa 2000). cf climbing ber, DC dorsal cap,
LVN lateral vestibular nuclei, Gc granule cell, LCN, IntP and MCN lat-
eral, interpositus and medial cerebellar nuclei, Pc Purkinje cell, mf
mossy ber, Nsol nucleus solitarius
mary afferents is unilateral. Modied from (Barmack etal. 1993b). (B3)
8.3 Cerebellum
vestibular primary afferent. (2) A vestibular mossy ber
projection to granule cells in both vermal and hemispheric
Lobules IX (uvula) and X (nodulus), including the hemispheric X (occulus), are the principal, but not exclusive
cerebellar focus for interactions with vestibular nuclei. The
circuitry embedded within these lobules is engaged by
three distinct vestibular inputs. (1) Granule cells within
vermal lobules IX and X receive a vestibular primary afferent collateral mossy ber projection from every ipsilateral
lobules IX–X is bilateral and originates from vestibular
secondary mossy ber afferents from the vestibular nuclei.
(3) A third pathway to vermal lobule X is conveyed by vestibular climbing bers (Fig. 8.1A3). Vestibular climbing
bers originate from two subnuclei of the contralateral
inferior olive, β-nucleus, and dorsomedial cell column. The
dendritic tree of each Purkinje cell receives ~500 synaptic
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