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60 Cerebellum andDecision-Making
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389
Reward processing includes predicting the current
reward as well as evaluation of the trial after the outcome is
known, thereby updating an internal model in order to
improve future decisions. The cerebellum is involved in
reward processing: cerebellar granule cells encode the
expectation of reward (Wagner etal. 2017), and cerebellar
climbing bers, leading to Purkinje cell complex spikes,
can signal reward prediction errors (Kostadinov et al.
2019). In addition, there are direct projections from the cer-
ebellar nuclei to the VTA (Carta etal. 2019), a brain region
involved in reward processing, although the extent of these
direct projections is debated (Pisano etal. 2021). Further
projections from the cerebellum to reward structures
include a trisynaptic pathway to striatum and hypothalamus
(Pisano etal. 2021), indicating further involvement of the
cerebellum in reward processing. In humans, fMRI data
show that the cerebellum is involved in the evaluation of
the past trial by processing the previous outcome (Shao
etal. 2016). Previous outcome processing includes updating the probabilistic internal model to reect changes in the
external world, allowing for decision-making in uncertain
situations. Indeed, the cerebellum, together with the premotor cortex, inferior parietal lobule, and medial occipital
cortex, mediates the probabilistic inferences that guide
decision-making under uncertainty (Blackwood et al.
2004).
Decision-making can be an emotional process: emotions
can contribute to the processing of previous trials and thereby
affect upcoming decisions. Positive emotions related to
obtaining the reward, as well as negative emotions related to
missing the reward after an incorrect outcome, such as feelings of regret, are important factors inuencing the decisionmaking process. Patients with cerebellar lesions are
signicantly impaired in evaluating the feeling of regret after
an incorrect decision (Clausi etal. 2015). This involvement
of the cerebellum in the feeling of self-responsibility for
making a correct or incorrect decision could be related to the
general contribution of the cerebellum to the sense of self.
60.5 Discussion
It is still debated whether the cerebellum is a critical component of the decision-making process, or whether its role is
restricted to supporting other brain regions involved in the
process. Evidence for the latter comes from veterans with
lesions to both the cerebellum and cerebral cortex, who are
impaired on working memory tasks, in contrast with veterans with lesions limited to the cerebellar cortex who have no
working memory impairments (Beuriat et al. 2020).
Furthermore, the lobule simplex of the cerebellum is involved
in spatial working memory decision-making by modulating
mPFC-hippocampal gamma coherence, showing a support-
ing role to other brain regions (Liu etal. 2021). The magnitude of coherence increase reects decision outcome, with
higher coherence between the mPFC and the hippocampus
in correct trials (Liu etal. 2021). However, in studies in nonhuman animals, disruption to the cerebellum alone is enough
to impair performance (Deverett etal. 2018), and population
activity from the cerebellum alone can be used to accurately
predict decision outcome (Deverett et al. 2018; Lin et al.
2020; Sendhilnathan etal. 2020), suggesting a critical role
for the cerebellum in decision-making.
As the supporting and coordinating role of the cerebellum
is varied across a wide range of behaviors, it is important to
dissociate specic cognitive effects from motor coordination. Support for the idea that the cerebellum plays a role in
the cognitive aspects of decision-making separate from pure
motor aspects, is that generally movements do not differ
across trial types of a decision-making task, and are unable
to predict decision outcome (Deverett et al. 2018;
Sendhilnathan etal. 2020). In contrast to movements, cerebellar population activity is able to predict decision outcome
(Deverett etal. 2018; Sendhilnathan et al. 2020). Together,
this suggests a specic role for the cerebellum in evidence
accumulation or decision-making which is distinct from its
role in movement coordination.
60.6 Conclusion
In conclusion, the cerebellum is an integral part of a wholebrain network involved in the many aspects of decisionmaking. This makes the complex process of decision-making
a tting example to highlight the variety of motor and nonmotor aspects, including higher cognitive functions, in which a
balanced output of the cerebellum can guide forebrain areas.
References
Akrami A, Kopec CD, Diamond ME, Brody CD (2018) Posterior pari-
etal cortex represents sensory history and mediates its effects on
behaviour. Nature 554(7692):368–372
Allen WE, Kauvar IV, Chen MZ, Richman EB, Yang SJ, Chan K etal
(2017) Global representations of goal-directed behavior in distinct
cell types of mouse neocortex. Neuron 94(4):891–907.e6
Balsdon T, Wyart V, Mamassian P (2020) Condence controls percep-
tual evidence accumulation. Nat Commun 11(1):1753
Beuriat P-A, Cohen-Zimerman S, Smith GNL, Krueger F, Gordon B,
Grafman J (2020) A new insight on the role of the cerebellum for
executive functions and emotion processing in adults. Front Neurol
11:1668
Blackwood N, ffytche D, Simmons A, Bentall R, Murray R, Howard
R (2004) The cerebellum and decision making under uncertainty.
Cogn Brain Res 20(1):46–53
Cardoso CDO, Branco LD, Cotrena C, Kristensen CH, DDG SB,
Fonseca RP (2014) The impact of frontal and cerebellar lesions
on decision making: evidence from the Iowa gambling task. Front
Neurosci 8:61
390
https://t.me/medicina_free
B. Deverett and M. Oostland
Carta I, Chen CH, Schott AL, Dorizan S, Khodakhah K (2019)
Cerebellar modulation of the reward circuitry and social behavior.
Science 363(6424):eaav0581
Clausi S, Coricelli G, Pisotta I, Pavone EF, Lauriola M, Molinari M
etal (2015) Cerebellar damage impairs the self-rating of regret feeling in a gambling task. Front Behav Neurosci 9:113
Deverett B, Koay SA, Oostland M, Wang SS-H (2018) Cerebellar
involvement in an evidence-accumulation decision-making task.
Carey MR, Ivry RB, editors. eLife 7:e36781
Deverett B, Kislin M, Tank DW, Wang SS-H (2019) Cerebellar disrup-
tion impairs working memory during evidence accumulation. Nat
Commun 10(1):3128
Engelhard B, Finkelstein J, Cox J, Fleming W, Jang HJ, Ornelas S etal
(2019) Specialized coding of sensory, motor and cognitive variables
in VTA dopamine neurons. Nature 570(7762):509–513
Ernst M, Bolla K, Mouratidis M, Contoreggi C, Matochik JA, Kurian
V etal (2002) Decision-making in a risk-taking task: A PET study.
Neuropsychopharmacology 26(5):682–691
Gao Z, Davis C, Thomas AM, Economo MN, Abrego AM, Svoboda K
et al (2018) A cortico-cerebellar loop for motor planning. Nature
563(7729):113–116
Giovannucci A, Badura A, Deverett B, Naja F, Pereira TD, Gao Z
et al (2017) Cerebellar granule cells acquire a widespread predictive feedback signal during motor learning. Nat Neurosci
20(5):727–734
Gold JI, Shadlen MN (2007) The neural basis of decision making. Annu
Rev Neurosci 30(1):535–574
Ivry RB, Spencer RM (2004) The neural representation of time. Curr
Opin Neurobiol 14(2):225–232
Keren‐Happuch E, Chen SH, Ho MH, Desmond JE (2014) A meta-
analysis of cerebellar contributions to higher cognition from PET
and fMRI studies. Hum Brain Mapp 35(2):593–615
Kloeters S, Bertoux M, O’Callaghan C, Hodges JR, Hornberger M
(2013) Money for nothing— atrophy correlates of gambling decision making in behavioural variant frontotemporal dementia and
Alzheimer’s disease. NeuroImage Clin 2:263–272
Kostadinov D, Beau M, Blanco-Pozo M, Häusser M (2019) Predictive
and reactive reward signals conveyed by climbing ber inputs to
cerebellar Purkinje cells. Nat Neurosci 22(6):950–962
Lin Q, Manley J, Helmreich M, Schlumm F, Li JM, Robson DN etal
(2020) Cerebellar neurodynamics predict decision timing and outcome on the single-trial level. Cell 180(3):536–551.e17
Liu Y, McAfee SS, Heijden MEVD, Dhamala M, Sillitoe RV, Heck DH
(2021) Causal evidence for a cerebellar role in prefrontal- hippocampal
interaction in spatial working memory decision- making. Biorxiv.
https://doi.org/10.1101/2020.03.16.994541
Musall S, Kaufman MT, Juavinett AL, Gluf S, Churchland AK (2019)
Single-trial neural dynamics are dominated by richly varied move-
ments. Nat Neurosci 22(10):1677–1686
Ohmae S, Kunimatsu J, Tanaka M (2017) Cerebellar roles in
self-timing for sub- and supra-second intervals. J Neurosci
37(13):3511–3522
Oostland M, Kislin M, Chen Y, Chen T, Venditto SJ, Deverett B et al
(2021) Cerebellar acceleration of learning in an evidenceaccumula-
tion task. Biorxiv. https://doi.org/10.1101/2021.12.23.474034
Orsolic I, Rio M, Mrsic-Flogel TD, Znamenskiy P (2021) Mesoscale
cortical dynamics reect the interaction of sensory evidence and
temporal expectation during perceptual decision-making. Neuron
109(11):1861–1875.e10
Pinto L, Rajan K, DePasquale B, Thiberge SY, Tank DW, Brody CD
(2019) Task-dependent changes in the large-scale dynamics and
necessity of cortical regions. Neuron 104(4):810–824.e9
Pisano TJ, Dhanerawala ZM, Kislin M, Bakshinskaya D, Engel EA, Hansen
EJ etal (2021) Homologous organization of cerebellar pathways to sen-
sory, motor, and associative forebrain. Cell Rep 36(12):109721
Rosenbloom MH, Schmahmann JD, Price BH (2012) The func-
tional neuroanatomy of decision-making. J Neuropsychiatry Clin
Neurosci 24(3):266–277
Sendhilnathan N, Semework M, Goldberg ME, Ipata AE (2020) Neural
correlates of reinforcement learning in mid-lateral cerebellum.
Neuron 106(1):188–198.e5
Shao R, Sun D, Lee TMC (2016) The interaction of perceived con-
trol and gambler’s fallacy in risky decision making: an fMRI study.
Hum Brain Mapp 37(3):1218–1234
Stoodley CJ, Schmahmann JD (2009) Functional topography in the
human cerebellum: a meta-analysis of neuroimaging studies.
NeuroImage 44(2):489–501
Wagner MJ, Kim TH, Savall J, Schnitzer MJ, Luo L (2017)
Cerebellar granule cells encode the expectation of reward. Nature
544(7648):96–100
Yartsev MM, Hanks TD, Yoon AM, Brody CD (2018) Causal contribu-
tion and dynamical encoding in the striatum during evidence accu-
mulation. Gold JI, Behrens TE, Gold JI, Humphries MD, editors.
eLife 7:e34929
Part VIII
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Cellular and Animal Models of Cerebellar Disorders
The Zebrafish Cerebellum
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JanKaslin andMichaelBrand
61
Abstract
The general architecture and cellular composition of the
cerebellum is highly conserved within the vertebrate lineage enabling relevant comparative studies at gene and
cell level. The zebrash model is ideally suited for studies
on cerebellar development and function as it’s rapid external development enable direct visualisation of cells and
events at single cell resolution. Furthermore, the versatile
toolbox for genetic manipulation to generate mutants and
genetically encoded uorescent reporters or sensors
enables functional studies at cell, circuit and physiological level invivo.
Keywords
Zebrash · Teleost · Fish · Adult neurogenesis · Mutant
Screening · Eurydendroid cell · Genetic model · Cerebellar
development · Morphogenesis · Mid- hindbrain boundary
Isthmic organizer · In vivo imaging
61.1 Introduction
The rapid transparent ex utero development in zebrash
allows direct access and precise visualization of all the major
events in cerebellar development. The supercial position of
the cerebellar primordium and cerebellum further facilitates
in vivo imaging of cerebellar structures and developmental
events at single-cell resolution. Furthermore, zebrash is
amenable to high-throughput screening techniques and forward genetics because of their fecundity and easy keeping.
Forward genetics screens in zebrash have resulted in several isolated cerebellar mutants and substantially contributed
to the understanding of the genetic networks involved in
hindbrain development (Bae etal. 2009). Developments in
genetic tools, including the use of site-specic recombinases,
efcient transgenesis, inducible gene expression systems,
and the targeted genome lesioning technologies TALEN and
Cas9/CRISPR have opened up new avenues to manipulate
and edit the genome of zebrash (Hans etal. 2009; Hwang
etal. 2013; Sander etal. 2011). These tools enable the use of
genome-wide genetic approaches, such as enhancer/exon
traps and cell-specic temporal control of gene expression in
zebrash. Several seminal papers have used these technologies to successfully elucidate mechanisms involved in the
morphogenesis, neurogenesis, and cell migration in the cerebellum (Bae etal. 2009; Takeuchi etal. 2015, 2017; Kaslin
etal. 2009, 2017; Kani etal. 2010; Chaplin etal. 2010). In
addition, the use of genetically encoded sensors and probes
that allow detection and manipulation of neuronal activity
using optical methods have opened up new means to study
the physiology and function of the cerebellum (Matsui etal.
2014; Matsuda etal. 2017; Scalise etal. 2016; Koyama etal.
2021; Chang etal. 2021). Taken together, these features have
allowed zebrash to emerge as a complete model for studies
of molecular, cellular, and physiological mechanisms
involved in cerebellar development and function at both cell
and circuit levels.
61.2 The Cerebellar Anatomy
andArchitecture
J. Kaslin (*)
Australian Regenerative Medicine Institute, Monash University,
Clayton, VIC, Australia
e-mail: jan.kaslin@monash.edu
M. Brand (*)
Biotechnology Center and Center for Regenerative Therapies
Dresden, Dresden University of Technology, Tatzberg, Germany
e-mail: michael.brand@biotec.tu-dresden.de
© 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_61
The general organization and cellular architecture of the cerebellum are highly conserved in vertebrates. The cerebellum
of all jawed vertebrates consists of a major lobe, the corpus
cerebelli (cerebellar corpus), and two bilateral lobes, the
auricle (also known as the vestibulocerebellum) (Fig.61.1a).
The architecture of cerebellum is highly similar to other ver-
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394
de
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J. Kaslin and M. Brand
tebrates but there are some notable differences. The most
striking differences are the lack of deep cerebellar nuclei and
a well-dened white matter but may have equivalent circuitry (see below). Furthermore, the zebrash sh have additional precerebellar and cerebelloid structures.
The zebrash cerebellum can be divided into three major
parts, the valvula cerebelli, the corpus cerebelli, and the vestibulolateral lobe (Fig. 61.1b–c) (Meek 1998; Wullimann
1997). The cerebellar corpus in zebrash consists of a single
a
bc
folia and it has an anterior extension, the valvula cerebelli,
which extends into the tectal ventricle below the optic tectum. The cerebellar corpus is laterally anked by the eminentia granularis and posteriorly by the caudal lobe. The
eminentia granularis and the caudal lobe together form the
vestibulolateral lobe that has been suggested to be homologous to the auricle of other vertebrates (Wullimann 1997). In
addition, teleost sh and zebrash have extra structures associated to the cerebellum, such as the cerebelloid structures
Fig. 61.1 (a) The vertebrate cerebellum consists of a major lobe, the
corpus cerebelli (cerebellar corpus) and two bilateral lobes, the auricle
(occulus in tetrapods). In addition, mammals display a large lateral
expansion of the corpus cerebelli, the neocerebellum. (b) Schematic
drawing of the zebrash brain seen from the side and top. Light green
illustrates the cerebellar corpus and the darker green the auricle. (c)
Schematic parasagittal overview of the zebrash brain showing the
major cerebellar parts and associated cerebellar structures. ACN accessory cerebellar nuclei; CCe cerebellar corpus; CPN central pretectal
nucleus; EG eminentia granularis; LCa caudal lobe of cerebellum; NLV
nucleus lateralis valvulae; PCN paracommissural nucleus; TL torus longitudinalis; Va valvula cerebelli. (d) The zebrash cerebellum has a
three layered architecture consisting of a molecular layer (ML),
Purkinje cell layer (PL), and a granule cell layer (GL). The granule
layer is consisting of small densely packed excitatory granule cells and
inhibitory Golgi neurons (G). The Purkinje cell layer is inhabited with
Purkinje neurons (PN), a specialized macroglia type, Bergmann glia
(BG), and excitatory eurydendroid cells (E). The ML is mainly consisting of nerve bers and scattered inhibitory stellate cells (S). Mossy and
climbing bers excite Purkinje and granule cells. Granule cell axons
provide excitatory input to Purkinje cells and their dendrites as well as
the Golgi and stellate cells. Purkinje cells inhibit eurydendroid cells.
Eurydendroid cell axons project to various targets outside the cerebellum. Stellate cells provide inhibitory input to the dendrites of Purkinje
cells and Golgi cells inhibit granule cells. Dendrites from granule cells
together with Golgi cell axons and mossy ber terminals form a specialized synaptic structure known as the glomerulus. (e) Cerebellar
afferents and efferents in teleost sh. CM mammillary body; CPN central pretectal nucleus; DAO dorsal accessory optic nucleus; Hd dorsal
zone of periventricular hypothalamus; DTN dorsal tegmental nucleus;
IL inferior lobe of the hypothalamus; IO inferior olive; LC locus coeruleus; LX vagal lobe; NI isthmic nucleus; NLV nucleus lateralis valvulae;
NMLF nucleus of the medial longitudinal fascicle; OR octavolateral
region; PCN paracommissural nucleus; PPd dorsal periventricular pretectal nucleus; PPp posterior parvocellular preoptic nucleus; RF reticular formation; PL perilemniscal nucleus; TL torus longitudinalis; TS
semicircular torus; TeO optic tectum; TPp periventricular nucleus of the
posterior tuberculum; VL ventrolateral thalamic nucleus; VM ventromedial thalamic nucleus
61 The Zebrash Cerebellum
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(cerebellar-like) and the additional pre-cerebellar nuclei.
These structures are not found in other vertebrates. Zebrash
has two precerebellar nuclei, the nucleus valvula lateralis
and the nucleus paracommissuralis that send the majority of
their projections to the cerebellum (Fig.61.1c). Cerebelloid
structures are architecturally thought to be similar to the cerebellum, although they are spatially well separated.
Cerebelloid structures are found in all vertebrate lineages
except reptiles and birds (Bell etal. 2008). Two cerebelloid
structures are found in zebrash. The medial octavolateral
nucleus, eminentia granularis, and the cerebellar crest (crista
cerebellaris) form one cerebelloid structure the hindbrain,
and the torus longitudinalis together with the optic tectum
form another in the midbrain.
The general vertebrate cerebellum consists of a threelayered cortex and an underlying white matter (Altman and
Bayer 1997). This three layered arrangement is well recognizable in zebrash (Fig.61.1d). In teleost, sh three distinct
subtypes of inhibitory neurons have been found in the cerebellar cortex: stellate, Golgi, and Purkinje cells. Stellate and
Golgi cells are interneurons and only project within the cerebellum. The stellate cells are scattered in the molecular cell
layer of teleost sh, while Golgi cells primarily are found in
the granule cell layer (Fig. 61.1d) (Delgado and
Schmachtenberg 2008; Kaslin et al. 2009). In most vertebrates, the Purkinje cell is the sole cell type that projects outside the cerebellum to the deep cerebellar nuclei. The deep
cerebellar nuclei are located in the white matter beneath the
cerebellum. In zebrash and other teleosts, this is different.
Firstly, teleost sh have an additional efferent cell type in the
cerebellar cortex, the eurydendroid cell, and the teleost
Purkinje cell projects to the eurydendroid cells (Fig.61.1d)
(Bae et al. 2009; Meek 1992). Secondly, teleost sh lack
deep cerebellar nuclei. However, the eurydendroid cells
directly innervate similar targets in the brain stem and spinal
cord as the deep cerebellar nuclei of other vertebrates and
may thus have an equivalent function (Butler and Hodos
2005). Similar to other vertebrates abundant glutamatergic
granule cells are found in the granule cell layer of zebrash
(Bae etal. 2009; Kaslin etal. 2009). Other less abundant cerebellar interneuron types such as unipolar brush, Lugaro, and
basket cells have not yet been identied in zebrash.
The vertebrate cerebellum receives afferent input from
two principal sources, mossy and climbing bers (Fig.61.1e).
In zebrash, the climbing bers originate in the inferior olive
in the caudal hindbrain and predominately terminate on the
soma and the proximal dendrites of Purkinje neurons
(Fig.61.1e) (Bae etal. 2009; Xue etal. 2008; Dohaku etal.
2019). Similar to other vertebrates, the mossy ber-like path-
way in teleost sh originates from multiple sources such as
the spinal cord, reticular formation, and tegmentum
(Fig.61.1e) (Finger 1978; Folgueira etal. 2006; Kani etal.
2010). Systematic retrograde tracing experiments have not
yet been undertaken in zebrash but in agreement abovementioned studies, mossy ber-like input from several precerebellar nuclei has been reported in juvenile zebrash (Bae
etal. 2009; Kani etal. 2010; Volkmann etal. 2008). The cerebellar eurydendroid cells innervate targets such as the thalamus, pretectal nuclei, tegmental nuclei, and motor and
premotor centers (Matsui etal. 2014).
61.3 Cerebellar Development
andNeurogenesis
The initial phase of midbrain and cerebellar development in
vertebrates depends on the formation and function of the
isthmic organizer which lies at the midbrain-hindbrain
boundary (MHB, Fig.61.2). The MHB organizer formation
and maintenance are dened by an intricate cascade of
genetic interactions that are marked by complex temporal
and spatial patterns of gene expression (Fig.61.2). Initially,
the MHB is positioned along the anterior–posterior axis
early within the neural plate by the opposing boundary created by mutual repression between the transcription factors
otx2 and gbx2 (Millet etal. 1999; Rhinn and Brand 2001). In
contrast to other vertebrates, gbx1 and not gbx2 positions the
MHB in zebrash (Rhinn etal. 2005, 2009). At the end of
gastrulation, a complex genetic network with several regionspecic transcription factors such as Pax2/5 and En1/2, and
the secreted molecules Wnt1 and Fgf8 are expressed at the
Otx/Gbx interface (Rhinn and Brand 2001). The secreted sig-
nals from the isthmic organizer in turn determine and pattern
the development of the surrounding mid and hindbrain tissue
(Fig.61.2c) (Lun and Brand 1998; Raible and Brand 2004;
Reifers etal. 1998). During later somitogenesis stages, the
expression of the region-specic transcription factors is
under the control of Fgf8, 17, 18 and Wnt1, 8b 10, secreted
by the isthmic organizer itself (Raible and Brand 2004;
Foucher etal. 2006; Buckles etal. 2004; Lekven etal. 2003).
These factors are involved in regulating cell proliferation and
patterning of the cerebellum as well as cell differentiation
and maintenance.
The cerebellar neurons and glia originate from two principal germinal zones in the hindbrain, the rhombic lip (RL), and
the ventricular zone (VZ) (Wingate 2001). Excitatory neurons
are generated by the RL and the inhibitory neurons are generated from the VZ (Hoshino etal. 2005). The transcription factor Ptf1a marks progenitors of inhibitory neurons in the VZ,
while the transcription factor Ato1 labels progenitors for excitatory cells in the RL and subsequent EGL (Ben-Arie et al.
1997). In zebrash, the cerebellar primordium becomes mor-
phologically distinguishable during mid-segmentation stages
(Fig.61.2b). The upper and lower rhombic lip parts are well
recognizable 1day after fertilization and atoh1a-b expression
is detected in the whole RL (Adolf et al. 2004; Kani et al.
396
a
bc
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J. Kaslin and M. Brand
d
f
e
Fig. 61.2 (a) Positioning of the midbrain–hindbrain boundary orga-
nizer in the neural plate of zebrash. The interface between cells
expressing otx and gbx transcription factors marks the location in the
neural plate where the midbrain–hindbrain boundary organizer forms.
During gastrulation, Wnt8 is secreted by the blastoderm margin (red
arrows), and is required for the initial subdivision of the neuroectoderm,
including onset of gbx1 (yellow) and otx2 (blue) expression. Towards
the end of gastrulation, the otx2 and gbx1 expression form sharp and
complementary patterns. Grey area = developing axial mesoderm.
Light grey = yolk. Black arrows indicate the repressive interactions.
(b–c) Morphogenetic events of the cerebellar primordium. At 24 hpf the
midbrain-hindbrain boundary, midbrain structures and the cerebellar
primordium are distinguishable in the zebrash embryo. (c) At the end
of gastrulation, a complex genetic network with several region-specic
transcription factors and the secreted molecules Wnt1 and Fgf8 are
expressed at the otx/gbx interface. The secreted signals from the isthmic
organizer in turn determine the development of the surrounding mid
and hindbrain tissue. (d) Summary of the early morphogenetic events
and the establishment of the progenitor domains. There is a morphogenetic rotation of the cerebellar primordium (blue arrow). From 36 hpf
onwards, the dorsomedial part of the IVth ventricle is shifted anteriorly
creating a dorsomedial extension of the IVth ventricle (red arrow).
Ventricularly located progenitors (orange line) are found in the LRL of
the hindbrain and in the VZ of the cerebellum. Cerebellar progenitors
adjacent to the roof plate are induced to turn in to granule cell progenitors (URL, green line). (e) Schematic summary of tissue growth and
displacement of the progenitor niche. Displacement of the URL progenitor niche through tissue growth begins around 7 dpf. During juvenile stages there is vast generation of granule cells and massive
expansion of the granule cell layer. URL progenitors (green) are maintained dorsal to the recessus of the IVth ventricle, while ventricular zone
derived progenitors and glia (orange) are found ventral. (f) Schematic
summary of the zebrash cerebellar progenitor niche. The adult cerebellar stem cell niche consists of polarized neuroepithelial-like cells
that inhabit the dorsal part of the IVth ventricle. Produced cells rapidly
migrate in a distinct outside-in fashion into the granule cell layer where
they differentiate into granule cells (1). A few glia with a radial morphology (light blue) are found close to the midline and they are used as
scaffolds during the initial dorsal migration of granule precursors (2).
Although several subtypes of inhibitory and excitatory cells are found
in the zebrash cerebellum, mainly granule cells are produced in the
adult. A low amount of Bergmann glia-like cells (dark blue) and inhibitory neurons (yellow) are generated from VZ progenitors (3) that are
found lateral and ventral to the progenitor niche. CB cerebellar primordium; HB hindbrain; GL granule cell layer; IVth V IVth ventricle; LRL
lower rhombic lip; MHB midbrain–hindbrain boundary; ML molecular
layer; PL Purkinje cell layer; URL upper rhombic lip; VZ ventricular
zone
61 The Zebrash Cerebellum
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2010; Koster and Fraser 2001; Kidwell et al. 2018), while
ptf1a expression is conned to the lower part of the RL (Elsen
etal. 2008; Kani etal. 2010; Volkmann etal. 2008). The generation of cerebellar neurons starts around 2days after fertilization in zebrash and all the three cortical layers can be
distinguished 5days after fertilization. Initiation of layer formation starts at 3days after fertilization when the rst differentiated Purkinje cells are detected (Bae etal. 2009; Volkmann
etal. 2008). Granule cell production starts at 2days after fertilization when granule cell precursors leave the URL (Adolf
etal. 2004; Bae etal. 2009; Koster and Fraser 2001; Volkmann
etal. 2008). In contrast, to amniotes zebrash and other sh
and amphibian’s lack a transient secondary zone for amplication of granule progenitors (external granule layer in amniotes) (Chaplin etal. 2010; Butts etal. 2014). This suggests that
neurogenesis and production of granule cells in zebrash are
more likely to be controlled on the level of the primary progenitors (Kaslin et al. 2009). Cerebellar progenitor activity
and neurogenesis continue into adulthood in zebrash
(Fig.61.2e). In the zebrash cerebellum, the stem cell niche
and its composition play a critical role in regulating homeostatic growth and neural regeneration after injury (Kaslin etal.
2009, 2013, 2017; Lindsey etal. 2018). The zebrash cerebel-
lum proportionally grows more than other brain structures
during juvenile stages. In particular, the main body of the cerebellum that contains granule cells expands signicantly
throughout life. However, the growth is selective and mainly
granule cells are added, while other core components of the
cerebellar circuitry such as the Purkinje cells cease to be produced during the late phase of juvenile development. The
selective growth is controlled by sub-lineage specic progenitor cells (Kaslin etal. 2013, 2017).
References
Adolf B, Bellipanni G, Huber V, Bally-Cuif L (2004) atoh1.2 and
beta3.1 are two new bHLH-encoding genes expressed in selective precursor cells of the zebrash anterior hindbrain. Gene Expr
Patterns 5(1):35–41. https://doi.org/10.1016/j.modgep.2004.06.009
Altman J, Bayer SA (1997) Development of the cerebellar system: in
relation to its evolution, structure, and functions. CRC Press, Boca
Raton
Bae YK, Kani S, Shimizu T, Tanabe K, Nojima H, Kimura Y, Higashijima
S, Hibi M (2009) Anatomy of zebrash cerebellum and screen for
mutations affecting its development. Dev Biol 330(2):406–426.
https://doi.org/10.1016/j.ydbio.2009.04.013
Bell CC, Han V, Sawtell NB (2008) Cerebellum-like structures and
their implications for cerebellar function. Annu Rev Neurosci 31:1–
24. https://doi.org/10.1146/annurev.neuro.30.051606.094225
Ben-Arie N, Bellen HJ, Armstrong DL, McCall AE, Gordadze PR, Guo
Q, Matzuk MM, Zoghbi HY (1997) Math1 is essential for genesis of
cerebellar granule neurons. Nature 390(6656):169–172
Buckles GR, Thorpe CJ, Ramel MC, Lekven AC (2004) Combinatorial
Wnt control of zebrash midbrain-hindbrain boundary formation. Mech Dev 121(5):437–447. https://doi.org/10.1016/j.
mod.2004.03.026
Butler AB, Hodos W (2005) Comparative vertebrate neuroanatomy,
2nd edn. Wiley, NewYork
Butts T, Hanzel M, Wingate RJ (2014) Transit amplication in the
amniote cerebellum evolved via a heterochronic shift in NeuroD1
expression. Development 141(14):2791–2795. https://doi.
org/10.1242/dev.101758
Chang W, Pedroni A, Koster RW, Giacomello S, Ampatzis K (2021)
Purkinje cells located in the adult zebrash valvula cerebelli exhibit
variable functional responses. Sci Rep 11(1):18408. https://doi.
org/10.1038/s41598- 021- 98035- 3
Chaplin N, Tendeng C, Wingate RJ (2010) Absence of an external
germinal layer in zebrash and shark reveals a distinct, anamniote
ground plan of cerebellum development. J Neurosci 30(8):3048–
3057. https://doi.org/10.1523/JNEUROSCI.6201- 09.2010
Delgado L, Schmachtenberg O (2008) Immunohistochemical localiza-
tion of GABA, GAD65, and the receptor subunits GABAAalpha1
and GABAB1in the zebrash cerebellum. Cerebellum 7(3):444–
450. https://doi.org/10.1007/s12311- 008- 0047- 7
Dohaku R, Yamaguchi M, Yamamoto N, Shimizu T, Osakada F, Hibi M
(2019) Tracing of afferent connections in the zebrash cerebellum
using recombinant rabies virus. Front Neural Circuits 13:30. https://
doi.org/10.3389/fncir.2019.00030
Elsen GE, Choi LY, Millen KJ, Grinblat Y, Prince VE (2008) Zic1
and Zic4 regulate zebrash roof plate specication and hindbrain
ventricle morphogenesis. Dev Biol 314(2):376–392. https://doi.
org/10.1016/j.ydbio.2007.12.006
Finger TE (1978) Efferent neurons of the teleost cerebellum. Brain Res
153(3):608–614. https://doi.org/10.1016/0006- 8993(78)90346- 3
Folgueira M, Anadon R, Yanez J (2006) Afferent and efferent con-
nections of the cerebellum of a salmonid, the rainbow trout
(Oncorhynchus mykiss): a tract-tracing study. J Comp Neurol
497(4):542–565. https://doi.org/10.1002/cne.20979
Foucher I, Mione M, Simeone A, Acampora D, Bally-Cuif L, Houart
C (2006) Differentiation of cerebellar cell identities in absence
of Fgf signalling in zebrash Otx morphants. Development
133(10):1891–1900
Hans S, Kaslin J, Freudenreich D, Brand M (2009) Temporally-
controlled site-specic recombination in zebrash. PLoS One
4(2):e4640. https://doi.org/10.1371/journal.pone.0004640
Hoshino M, Nakamura S, Mori K, Kawauchi T, Terao M, Nishimura
YV, Fukuda A, Fuse T, Matsuo N, Sone M, Watanabe M, Bito H,
Terashima T, Wright CV, Kawaguchi Y, Nakao K, Nabeshima Y
(2005) Ptf1a, a bHLH transcriptional gene, denes GABAergic
neuronal fates in cerebellum. Neuron 47(2):201–213
Hwang WY, Fu Y, Reyon D, Maeder ML, Tsai SQ, Sander JD, Peterson
RT, Yeh JR, Joung JK (2013) Efcient genome editing in zebraf-
ish using a CRISPR-Cas system. Nat Biotechnol 31(3):227–229.
https://doi.org/10.1038/nbt.2501
Kani S, Bae YK, Shimizu T, Tanabe K, Satou C, Parsons MJ, Scott
E, Higashijima S, Hibi M (2010) Proneural gene-linked neurogen-
esis in zebrash cerebellum. Dev Biol 343(1–2):1–17. https://doi.
org/10.1016/j.ydbio.2010.03.024
Kaslin J, Ganz J, Geffarth M, Grandel H, Hans S, Brand M (2009) Stem
cells in the adult zebrash cerebellum: initiation and maintenance of
a novel stem cell niche. J Neurosci 29(19):6142–6153. https://doi.
org/10.1523/JNEUROSCI.0072- 09.2009
Kaslin J, Kroehne V, Benato F, Argenton F, Brand M (2013)
Development and specication of cerebellar stem and progenitor
cells in zebrash: from embryo to adult. Neural Dev 8:9. https://doi.
org/10.1186/1749- 8104- 8- 9
Kaslin J, Kroehne V, Ganz J, Hans S, Brand M (2017) Distinct roles
of neuroepithelial-like and radial glia-like progenitor cells in cer-
ebellar regeneration. Development 144(8):1462–1471. https://doi.
org/10.1242/dev.144907
Kidwell CU, Su CY, Hibi M, Moens CB (2018) Multiple zebrash
atoh1 genes specify a diversity of neuronal types in the zebraf-
398
https://t.me/medicina_free
J. Kaslin and M. Brand
ish cerebellum. Dev Biol 438(1):44–56. https://doi.org/10.1016/j.
ydbio.2018.03.004
Koster RW, Fraser SE (2001) Direct imaging of invivo neuronal migra-
tion in the developing cerebellum. Curr Biol 11(23):1858–1863
Koyama W, Hosomi R, Matsuda K, Kawakami K, Hibi M, Shimizu T
(2021) Involvement of cerebellar neural circuits in active avoidance
conditioning in zebrash. eNeuro 8(3). https://doi.org/10.1523/
ENEURO.0507- 20.2021
Lekven AC, Buckles GR, Kostakis N, Moon RT (2003) Wnt1 and
wnt10b function redundantly at the zebrash midbrain-hindbrain
boundary. Dev Biol 254(2):172–187. https://doi.org/10.1016/
s0012- 1606(02)00044- 1
Lindsey BW, Hall ZJ, Heuze A, Joly JS, Tropepe V, Kaslin J (2018) The
role of neuro-epithelial-like and radial-glial stem and progenitor
cells in development, plasticity, and repair. Prog Neurobiol 170:99–
114. https://doi.org/10.1016/j.pneurobio.2018.06.004
Lun K, Brand M (1998) A series of no isthmus (noi) alleles of the
zebrash pax2.1 gene reveals multiple signaling events in development of the midbrain-hindbrain boundary. Development
125(16):3049–3062
Matsuda K, Yoshida M, Kawakami K, Hibi M, Shimizu T (2017)
Granule cells control recovery from classical conditioned fear
responses in the zebrash cerebellum. Sci Rep 7(1):11865. https://
doi.org/10.1038/s41598- 017- 10794- 0
Matsui H, Namikawa K, Babaryka A, Koster RW (2014) Functional
regionalization of the teleost cerebellum analyzed invivo. Proc Natl
Acad Sci U S A 111(32):11846–11851. https://doi.org/10.1073/
pnas.1403105111
Meek J (1992) Comparative aspects of cerebellar organization. From
mormyrids to mammals. Eur J Morphol 30(1):37–51
Meek J (1998) Holosteans and teleosts. In: Nieuwenhuys R, Ten
Donkelaar HJ, Nicholson C (eds) The central nervous system of
vertebrates. Springer, Berlin
Millet S, Campbell K, Epstein DJ, Losos K, Harris E, Joyner AL
(1999) A role for Gbx2in repression of Otx2 and positioning the
mid/hindbrain organizer. Nature 401(6749):161–164. https://doi.
org/10.1038/43664
Raible F, Brand M (2004) Divide et Impera—the midbrain-hindbrain
boundary and its organizer. Trends Neurosci 27(12):727–734.
https://doi.org/10.1016/j.tins.2004.10.003
Reifers F, Bohli H, Walsh EC, Crossley PH, Stainier DY, Brand M
(1998) Fgf8 is mutated in zebrash acerebellar (ace) mutants and is
required for maintenance of midbrain-hindbrain boundary develop-
ment and somitogenesis. Development 125(13):2381–2395
Rhinn M, Brand M (2001) The midbrain—hindbrain boundary orga-
nizer. Curr Opin Neurobiol 11(1):34–42
Rhinn M, Lun K, Ahrendt R, Geffarth M, Brand M (2009) Zebrash
gbx1 renes the midbrain-hindbrain boundary border and medi-
ates the Wnt8 posteriorization signal. Neural Dev 4:12. https://doi.
org/10.1186/1749- 8104- 4- 12
Rhinn M, Lun K, Luz M, Werner M, Brand M (2005) Positioning of
the midbrain-hindbrain boundary organizer through global pos-
teriorization of the neuroectoderm mediated by Wnt8 signaling.
Development 132(6):1261–1272
Sander JD, Cade L, Khayter C, Reyon D, Peterson RT, Joung JK, Yeh
JR (2011) Targeted gene disruption in somatic zebrash cells using
engineered TALENs. Nat Biotechnol 29(8):697–698. https://doi.
org/10.1038/nbt.1934
Scalise K, Shimizu T, Hibi M, Sawtell NB (2016) Responses of cerebel-
lar Purkinje cells during ctive optomotor behavior in larval zebraf-
ish. J Neurophysiol 116(5):2067–2080. https://doi.org/10.1152/
jn.00042.2016
Takeuchi M, Matsuda K, Yamaguchi S, Asakawa K, Miyasaka N, Lal
P, Yoshihara Y, Koga A, Kawakami K, Shimizu T, Hibi M (2015)
Establishment of Gal4 transgenic zebrash lines for analysis of
development of cerebellar neural circuitry. Dev Biol 397(1):1–17.
https://doi.org/10.1016/j.ydbio.2014.09.030
Takeuchi M, Yamaguchi S, Sakakibara Y, Hayashi T, Matsuda K, Hara
Y, Tanegashima C, Shimizu T, Kuraku S, Hibi M (2017) Gene
expression proling of granule cells and Purkinje cells in the zebraf-
ish cerebellum. J Comp Neurol 525(7):1558–1585. https://doi.
org/10.1002/cne.24114
Volkmann K, Rieger S, Babaryka A, Koster RW (2008) The zebrash
cerebellar rhombic lip is spatially patterned in producing granule
cell populations of different functional compartments. Dev Biol
313(1):167–180
Wingate RJ (2001) The rhombic lip and early cerebellar development.
Curr Opin Neurobiol 11(1):82–88
Wullimann MF (1997) The central nervous system. In: Evans DH (ed)
The physiology of shes, vol II.CRC Press, Boca Raton
Xue HG, Yang CY, Yamamoto N (2008) Afferent sources to the inferior
olive and distribution of the olivocerebellar climbing bers in cyp-
rinids. J Comp Neurol 507(3):1409–1427. https://doi.org/10.1002/
cne.21622
The Teleost Fish
https://t.me/medicina_free
TakanoriIkenaga
62
Abstract
In vertebrates, the basic structure of the central nervous
system, including the cerebellum, is conserved from mammals to teleosts. The cerebellum of teleost sh is subdivided into three parts: the corpus cerebelli, valvula
cerebelli, and vestibulolateral lobe. Although the existence
of basket cells remains unconrmed, the teleost cerebellum possesses intracerebellar neurons that are similar to
those of other vertebrates. Additionally, there are similarities in the pattern of connectivity of these neurons and the
neurotransmitters that are used. In the teleost cerebellum,
the structure corresponding to the deep cerebellar nuclei is
absent. Instead, the teleost cerebellar efferent neurons do
not make clusters and are distributed within the ganglionic
layer, which is equivalent to the Purkinje cell layer of other
vertebrates. Efferent neurons use excitatory neurotransmitters and project their axons outside of the cerebellum.
These efferent neurons are unique to the teleost cerebellum, so a detailed understanding of their structure and
function may yield important clues about the evolution
and function of the teleost cerebellum. Afferent and efferent ber connection patterns suggest that the basic functions of the teleost cerebellum are similar to those of other
vertebrates, but each subdivision of the teleost cerebellum
is functionally separated. The functional role of the teleost
cerebellum is still not fully understood, but research suggests that the teleost cerebellum has an important role in
the execution of swimming gait and emotional learning.
Keywords
Corpus cerebelli · Valvula cerebelli · Caudal lobe ·
Teleost · Evolution · Goldsh · Efferent cell ·
T. Ikenaga (*)
Graduate School of Science and Engineering, Kagoshima
University, Kagoshima, Japan
e-mail: ikenaga@sci.kagoshima-u.ac.jp
Purkinje cell · Deep cerebellar nuclei · Neurotransmitter ·
Fiber connection · Motor control · Fair conditioning ·
Zebrash · Actinopterygian sh
The actinopterygii (ray-nned sh) includes approximately
27,000 species, the majority of which are teleost sh
(approximately 26,800 species) (Nelson 2006). The basic
organization of the central nervous system of teleost sh is
similar to that of other vertebrates including the cerebellum.
In this chapter, I review the morphology, cellular organization, ber connections, and functions of the teleost
cerebellum.
62.1 Morphology, Cellular Organization,
andNeural Circuits oftheTeleost
Cerebellum
The cerebellum of teleosts is subdivided into three major
parts: the corpus cerebelli, valvula cerebelli, and the vestibulolateral lobe (including the eminentia granularis and lobus
caudalis) (Fig.62.1). The corpus cerebelli, considered to be
homologous to the vermis of other vertebrates (Ito 1978),
lies in the central portion of the teleost cerebellum and
extends dorsally and curves either rostrally (e.g., mormyrids,
catsh) or caudally (e.g., cyprinids, salmonids) (Fig.62.1a,
c). The valvula cerebelli is unique to actinopterygian sh and
is not an obvious homolog of any cerebellar components of
other vertebrates. It protrudes rostrally into the mesencephalic ventricle and is covered by the optic tectum (Fig.62.1a,
b). In some species, including goldsh, the valvula is subdi-
vided into medial and lateral lobes (Fig.62.1b). The vestibulolateral lobe consists of the eminentia granularis and lobus
caudalis. In goldsh, the eminentia granularis is located in
the ventrolateral region of the corpus cerebelli as a granular
cell mass (Fig.62.1c). The lobus caudalis is an easily distin-
© 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_62
399
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