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D. L. Gruol

Vainchtein ID, Molofsky AV (2020) Astrocytes and microglia: in sick-

ness and in health. Trends Neurosci 43:144–154 van Gassen KL, Netzeband JG, de Graan PN, Gruol DL (2005) The

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The SDF-1/CXCR4 pathway and the development of the cerebellar

system. Eur J Neurosci 22:1831–1839

Wicher G, Husic E, Nilsson G, Forsberg-Nilsson K (2013)

Developmental expression of IL-33in the mouse brain. Neurosci Lett 555:171–176

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mRNA in rat brain. Neuroimmunomodulation 1:110–115

Wright-Jin EC, Gutmann DH (2019) Microglia as dynamic cellular

mediators of brain function. Trends Mol Med 25:967–979

Yu T, Huang H, Li HF (2010) Stromal cell-derived factor-1 promotes

migration of cells from the upper rhombic lip in cerebellar development. J Neurosci Res 88:2775–2786

Zhuang JL, Wang CY, Zhou MH, Duan KZ, Mei YA (2012) TGF-β1

enhances Kv2.1 potassium channel protein expression and promotes maturation of cerebellar granule neurons. J Cell Physiol 227:297–307

Restoring aLoss ofMossy Fiber

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Plasticity inaModel ofFragile X Syndrome

XiaoqinZhan andRayW.Turner

Abstract

Fragile X Syndrome is a monogenic disorder that reects a

loss of Fragile X Mental Retardation Protein (FMRP) that

is needed to regulate translation of proteins important to

circuit development and plasticity. A complete loss of

FMRP is the leading monogenic cause of Autism Spectrum

Disorders (ASD). Mossy ber inputs to cerebellar granule

cells exhibit long-term potentiation (LTP) to process sen-

sory information to the cerebellum. Here we nd that LTP

of mossy ber input is lost in FMRP KO mice. To counter

this loss, we reintroduced an FMRP N-terminal fragment

conjugated to a tat peptide (FMRP- N- tat) by tail vein injec-

tion. This action promoted transport of FMRP(1–297)

across the blood–brain barrier to distribute widely across

the brain within 30min and rescued LTP at the mossy ber-

granule cell synapse. These ndings are important in

revealing that tat-conjugated FMRP fragments can be used

as a therapeutic tool to restore synaptic plasticity and

reduce symptoms of Fragile X Syndrome.

Keywords

Fragile X syndrome · FMRP · Mossy ber · LTP · tat

peptide · Cerebellum

48.1 Introduction

Fragile X Syndrome (FXS) results from a CGG repeat expansion in the 5′-untranslated region (UTR) of the Fmr1 gene that disrupts transcription of Fragile X Mental Retardation Protein (FMRP). This has widespread consequences given that FMRP is involved in circuit development and functions that span from protein translation to synaptic

output (Bear etal. 2004; Darnell etal. 2011; Contractor etal.

2015). FMRP is almost ubiquitously expressed in cells of the

brain, such that disorders in FXS arise from across the cortico- cerebellar axis (Zangenehpour et al. 2009; Wang etal. 2014; Gholizadeh etal. 2015; Hampson and Blatt 2015; Stoodley etal. 2017), leading to its recognition as the leading monogenic cause of Autism Spectrum Disorders (ASD).

Circuit dysfunction in ASD can reect an aberrant processing of sensory information and synaptic plasticity. The cerebellum receives mossy ber projections that convey sensory information to a granule cell layer across 10 lobules to form one of the largest arrays of sensory input in the CNS. The mossy ber-granule cell synapse normally exhibits long-term potentiation (LTP), an activity-dependent enhancement in synaptic transmission (D’Angelo et al. 2005; Rizwan et al.

2016; Sgritta etal. 2017) that we found is lost in FMRP knock-

out (KO) mice (Zhan etal. 2020). This is important in that a loss of FMRP could disrupt sensory processing at the rst stage of information transfer to the cerebellar cortex.

The current study explored the potential to reverse the loss of mossy ber LTP in FMRP KO mice by reintroducing an N-terminal fragment of FMRP as a conjugate of the HIV-1 trans-activator of transcription (tat) (FMRP-N-tat) to facilitate its transfer across the blood–brain barrier. These studies were critical in revealing that FMRP-N-tat introduced by tail vein injection rapidly distributed throughout the brain and rescued mossy ber LTP within 2h of injection. This result suggests that FMRP-N-tat could be a novel potential therapeutic approach to treating cerebellar and other disorders inherent to FXS.

48.2 Results

48.2.1 FMRP Expression inWild-Type Mice

andaFragile X Model

X. Zhan · R. W. Turner (*) Alberta Children’s Hospital Research Institute and Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada e-mail: xiaoqin.zhan1@ucalgary.ca; rwturner@ucalgary.ca

© 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_48

We rst compared the expression of FMRP in adult wild type (WT) mice and an FMRP KO mouse model. Immunocytochemistry on WT sections conrmed FMRP

313

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FMRP FMRP-MAP2

Wild type

X. Zhan and R. W. Turner

500 mm

Granule cells

Purkinje cells

FMRP KO

Fig. 48.1 FMRP is widely expressed in the cerebellum but lost in FMRP KO mice. (a, b) Low power montage images of sagittal cerebellar sections from WT mice labeled with an FMRP C terminal antibody (a) and dual labeled with MAP-2 as a structural marker (b). (c, d) Expanded views of the granule and Purkinje cell layers from Lobule 9

indicates strong FMRP labeling of granule cells as well as Purkinje cells. (e, f) Montage images of FMRP and MAP-2 labeling of sagittal cerebellar sections from FMRP KO mice indicates a lack of FMRP labeling. Dashed lines in (c, d) demark cell layer boundaries

20 mm

500 mm

labeling throughout the cerebellum and the granule cell body layer (Fig.48.1a–d). By comparison, an FMRP antibody detected no label in the FMRP KO mouse (Fig.48.1e,

f). Since FXS reects a loss of FMRP expression, we

attempted to reintroduce a part of the molecule as a tat-

conjugated peptide in the FMRP KO mouse. We used an 11 aa segment of the HIV-1 trans-activator of transcription protein (tat) that facilitates protein transfer across cell membranes (Leibrand et al. 2017) fused to an N-terminal fragment (1–297 aa) of FMRP (Fig. 48.2a).

Neocortex (

)

YPYDVPDYA

YGRKKRRQRRR

48 Restoring aLoss ofMossy Fiber Plasticity inaModel ofFragile X Syndrome

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315

FMRP(1-297)

HA-FMRP-N-

Vehicle injected (Control)

Cerebellum (2 hr)

Purkinje cells

Granule

cells

tat

FMRP-N-tat injected

Purkinje

cells

Granule

cells

50 mm

MAP2 MAP2 & FMRP

30 min

FMRP-tat

FMRP-N-tat injected

Hippocampus (12 hr)

MAP2 MAP2 & FMRP

FMRP-tat

FMRP-N-tat injected

20 mm 20 mm

20 mm

Fig. 48.2 FMRP-N-tat rapidly crosses the BBB to enter CNS neurons. (a) Schematic of the FMRP-N-tat construct with an HA tag delivered by tail vein injection. (b) Nissl stained sagittal section of a mouse brain highlighting regions of interest expanded in (c–e). (c–e magnication images from tissue sections from FMRP KO mice after tail vein injection of vehicle alone or FMRP-N-tat. Sections reect labeling with an N-terminal FMRP antibody (c) or an HA antibody (d, e). Cerebellar neurons exhibit no signicant background immunolabel in vehicle-injected mice (c) but somatic uptake in Purkinje and granule

) High-

We introduced FMRP-N-tat by tail vein injection and processed brains for immunocytochemistry up to 48h after injection. No immunolabel was detected in the cerebellum of FMRP KO mice injected with vehicle, but an extensive distribution of immunolabel was detected 2h after injecting FMRP-N-tat (Fig.48.2c). Neocortical cells positioned in Layer 5 exhibited at least somatic labeling 30min post FMRP-N-tat injection (Fig.48.2d), and immunolabel was retained in hippocampal CA3 pyramidal cells 12h later (Fig.48.2e).

48.2.2 An FMRP-Ta t Conjugate Peptide Delivered InVivo Restores LTP ofMossy Fiber Inputs

FMRP has been shown to inuence long-term plasticity at several synaptic inputs (Telias 2019) and can regulate the expression of Kv4 channels that are involved in LTP at the mossy ber synapse (Rizwan etal. 2016). To determine the potential for FMRP to affect mossy ber LTP, we compared

cells within 2 h of injecting 0.2 mg/kg FMRP-N-tat (c). Neocortical neurons in Layer 5 exhibit immunolabel within 30min, with cell structures identied using a MAP-2 counter label (d). Hippocampal CA3 pyramidal cells retain immunolabel 12h post injection, with cytoplasmic uptake evident in the magnied right panel. Dashed lines in (c) delineate major cell layer boundaries and arrowheads in (e) the boundary of pyramidal cell membranes. Image credit for (b): Allen Institute. All other frames are modied from Zhan etal. (2020)

this form of plasticity between WT and FMRP KO mice in physiological studies of synaptic function in vitro using a cerebellar slice preparation. High-frequency stimulation using a theta burst (TBS) pattern delivered to mossy bers in lobule 9 of cerebellum evoked LTP of the excitatory postsynaptic potential (EPSP) amplitude and an increase in spike ring probability in granule cells (Fig.48.3b). However, FMRP KO mice completely lacked the ability to demonstrate LTP of the EPSP or spike output (Fig.48.3b) (Zhan etal. 2020). We therefore tail vein injected 1.0mg/kg FMRP- N- tat and 2 h later prepared cerebellar tissue slices to con- duct whole-cell recordings in vitro. This step proved to rescue mossy ber LTP that persisted for at least 20min after the TBS stimulus (Fig. 48.3b). These effects were dosedependent in that injecting 0.2mg/kg FMRP-N-tat did not rescue mossy ber LTP, even though FMRP immunolabel was detectable in cerebellum 2 h after tail vein injection. Finally, tail vein injection of the tat epitope alone did not rescue LTP tested in vitro, indicating that the effects of FMRP-N-tat on synaptic plasticity did not result from the tat moiety.

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X. Zhan and R. W. Turner

EPSP

TBS

Spike

250

200

150

100

n = 6

0241012141618 02410121416182022240

1.0

0.8

0.6

0.4

0.2

0.0

Probability of spike EPSP Amplitude (%)

0241012141618

WT FMRP KO

n = 7

TBS TBS TBS TBS

TBS TBS TBS

Time (min)

0241012141618

Time (min)

Fig. 48.3 A loss of mossy ber-granule LTP in FMRP KO mice is restored upon tail vein injection of FMRP-N-tat. (a) Representative recordings from a granule cell in the invitro slice preparation showing the subthreshold mossy ber-evoked EPSP (top) and evoked spike (bottom) following delivery of TBS (arrow). (b) Mean values of mossy ber EPSP amplitude (top row) and probability of spike discharge (bot-

48.3 Discussion

48.3.1 Restoring FMRP inFragile X Syndrome

A great deal of work has been conducted to understand how translation of FMRP is disrupted and the myriad of cellular and behavioral disorders it gives rise to in FXS. Several attempts have been made to restore FMRP translation or mitigate the loss of circuit function through pharmacological approaches (Gholizadeh et al. 2014; Park et al. 2015; Liu etal. 2018; Protic etal. 2019; Telias 2019; Graef etal. 2019). A previous attempt at using a tat-conjugate approach used the full-length FMRP.Unfortunately, a protein of this length led to problems in preparation, blood–brain barrier access, and toxicity in cultured broblasts (Reis et al. 2004). We used a 1–297 aa N-terminal fragment of FMRP, which proved to cross the blood–brain barrier and distribute across the cortico-cerebellar axis within 30min. The effects of this compound on cell function were very fast, with rescue of mossy ber LTP when tested at 2h post injection. The shorttime course was even more dramatic invitro, where internal infusion of FMRP(1–297) through an electrode rescued LTP in the FMRP KO mouse within 10 min. Remarkably, direct application of FMRP-N-tat onto dissociated cerebellar granule cells at levels far higher than we expect it to reach following transport across the blood–brain barrier showed no toxicity tested with a live-dead cell kit up to 5days later. The levels of three different proteins known to be disrupted in FXS were also stabilized by FMRP-N-tat injection for at

FMRP KO + 1 mg/kg FMRP-N-tat

n = = 5

1.0

0.4

0.2

0.0

024 10 12 14 16 18 20 22 24

Time (min)

FMRP KO

+ 1 mg/kg tat epitope

10 12 14 16 18 20024

024101214161820

TBS

Time (min)

tom row) in WT mice, FMRP KO mice, and FMRP KO mice 2h after tail vein injection of FMRP-N-tat or the tat epitope alone. An initial control period of 5min is followed by delivery of TBS (arrows) and 5min later recorded at 0.1 Hz. Average values are mean±SEM with sample values shown at the base of EPSP plots. Modied from Zhan etal. (2020)

least 24 h after tail vein injection (Zhan et al. 2020). All together these ndings emphasize the potential value of FMRP-tat conjugate peptides as a therapeutic strategy that could be developed to reduce the symptoms of FXS.

48.3.2 Role ofFMRP inSynaptic Plasticity

Recent work has shown that the actions of FMRP extend beyond control of protein translation as an RNA-binding molecule to modifying ion channels that control membrane excitability (Contractor etal. 2015; Ferron 2016; Yang etal.

2018; Ferron etal. 2020; Zhan etal. 2020). Indeed, FMRP

proves to be an integral component of a Cav3-Kv4 channel complex that can modify biophysical properties of Kv4 current inherent to invoking LTP at the mossy ber-granule cell synapse (Zhan etal. 2020). The number of other forms of plasticity that rely on FMRP regulation of ion channels that could benet from FMRP-N-tat is not yet known. For instance, we have not determined the inuence of FMRP-Ntat on long-term depression at the mossy ber synapse (Sgritta etal. 2017), or other forms of plasticity inherent to parallel bers in the cerebellar cortex, the output axons of granule cells (Koekkoek et al. 2005; Jorntell and Hansel

2006; Piochon etal. 2014). However, a loss of FMRP has

been shown to invoke excess GABA release from cerebellar basket cells when a downregulation of Kv1.2 channels increases presynaptic terminal excitability (Yang etal. 2018). By infusing FMRP(1–297) through a patch recording elec-

48 Restoring aLoss ofMossy Fiber Plasticity inaModel ofFragile X Syndrome

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317

trode, these authors were able to rebalance excitability and GABA release from these interneurons, identifying a second potential target for FMRP-N-tat injections.

Given the growing list of functions for FMRP in regulating synaptic function, plasticity, and now ion channel activities, we expect delivery of FMRP-N-tat to have widespread effects on circuit function and signal processing. Yet much work remains to evaluate this novel potential therapeutic approach to treating cerebellar and other disorders expressed in patients with FXS.

References

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mental retardation. Trends Neurosci 27:370–377 Contractor A, Klyachko VA, Portera-Cailliau C (2015) Altered neuronal

and circuit excitability in Fragile X syndrome. Neuron 87:699–715 D’Angelo E, Rossi P, Gall D et al (2005) Long-term potentiation of

synaptic transmission at the mossy ber-granule cell relay of cer-

ebellum. Prog Brain Res 148:69–80 Darnell JC, Van Driesche SJ, Zhang C etal (2011) FMRP stalls ribo-

somal translocation on mRNAs linked to synaptic function and

autism. Cell 146:247–261 Ferron L (2016) Fragile X mental retardation protein controls ion chan-

nel expression and activity. J Physiol 594:5861–5867 Ferron L, Novazzi CG, Pilch KS et al (2020) FMRP regulates pre-

synaptic localization of neuronal voltage gated calcium channels.

Neurobiol Dis 138:104779 Gholizadeh S, Arsenault J, Xuan IC et al (2014) Reduced pheno-

typic severity following adeno-associated virus-mediated Fmr1

gene delivery in fragile X mice. Neuropsychopharmacology

39:3100–3111 Gholizadeh S, Halder SK, Hampson DR (2015) Expression of fragile X

mental retardation protein in neurons and glia of the developing and

adult mouse brain. Brain Res 1596:22–30 Graef JD, Wu H, Ng C etal (2019) Partial FMRP expression is suf-

cient to normalize neuronal hyperactivity in Fragile X neurons. Eur

J Neurosci. https://doi.org/10.1111/ejn.14660 Hampson DR, Blatt GJ (2015) Autism spectrum disorders and neuropa-

thology of the cerebellum. Front Neurosci 9:420 Jorntell H, Hansel C (2006) Synaptic memories upside down: bidirec-

tional plasticity at cerebellar parallel ber-Purkinje cell synapses.

Neuron 52:227–238

Koekkoek SK, Yamaguchi K, Milojkovic BA et al (2005) Deletion

of FMR1 in Purkinje cells enhances parallel ber LTD, enlarges spines, and attenuates cerebellar eyelid conditioning in Fragile X syndrome. Neuron 47:339–352

Leibrand CR, Paris JJ, Ghandour MS etal (2017) HIV-1 Tat disrupts

blood-brain barrier integrity and increases phagocytic perivascular macrophages and microglia in the dorsal striatum of transgenic mice. Neurosci Lett 640:136–143

Liu XS, Wu H, Krzisch M etal (2018) Rescue of Fragile X syndrome

neurons by DNA methylation editing of the FMR1 gene. Cell 172:979–992.e6

Park CY, Halevy T, Lee DR etal (2015) Reversion of FMR1 methyla-

tion and silencing by editing the triplet repeats in fragile X iPSCderived neurons. Cell Rep 13:234–241

Piochon C, Kloth AD, Grasselli G etal (2014) Cerebellar plasticity and

motor learning decits in a copy-number variation mouse model of autism. Nat Commun 5:5586

Protic D, Salcedo-Arellano MJ, Dy JB etal (2019) New targeted treat-

ments for fragile X syndrome. Curr Pediatr Rev 15:251–258

Reis SA, Willemsen R, van Unen L et al (2004) Prospects of TAT-

mediated protein therapy for fragile X syndrome. J Mol Histol 35:389–395

Rizwan AP, Zhan X, Zamponi GW, Turner RW (2016) Long-term

potentiation at the mossy ber-granule cell relay invokes postsynaptic second-messenger regulation of Kv4 channels. J Neurosci 36:11196–11207

Sgritta M, Locatelli F, Soda T etal (2017) Hebbian spike-timing depen-

dent plasticity at the cerebellar input stage. J Neurosci 37:2809–2823

Stoodley CJ, D’Mello AM, Ellegood J etal (2017) Altered cerebellar

connectivity in autism and cerebellar-mediated rescue of autismrelated behaviors in mice. Nat Neurosci 20:1744–1751

Telias M (2019) Molecular mechanisms of synaptic dysregulation in

fragile X syndrome and autism Spectrum disorders. Front Mol Neurosci 12:51

Wang SS, Kloth AD, Badura A (2014) The cerebellum, sensitive peri-

ods, and autism. Neuron 83:518–532

Yang Y-M, Arsenault J, Bah A etal (2018) Identication of a molecular

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Part VI

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Neuroimaging of the Cerebellum

Cerebellar Closed Loops

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ChristopheHabas

Abstract

Data from histological tracing studies in non-human pri-

mate strongly support the view that the cerebellar system

is organized into distinct, motor and non-motor, and par-

allel closed-loop circuits interconnecting the cerebellum

and the cerebral cortex. Functional imaging data in human

seem to conrm this specic network organization in

human, and to extend the role of the cerebellum from

motor control to regulation of cognition and emotion.

Keywords

Cerebellum · Closed-loops · Tracing · Fmri

Resting-state

49.1 Histological Tracing inAnimal Models

In the cerebellar system, cerebral cortex projects via pontine nuclei within the basis pontis to contralateral cerebellum (deep nuclei and cortex), which, in turn, sends it back projections via the thalamus. The closed-loop architecture of the cerebellar system relies on three main results. First, separate and non-overlapping territories of the dentate nuclei (DN), the main output source of the primate cerebellum, specically target distinct thalamic and associated motor, premotor and associative cortical areas (Strick etal. 2009). In particular, cerebellar projections to prefrontal and pre- supplementary motor cortices originate in the ventral part of DN, whereas cerebellar projections to (pre-)motor cortex arise from the dorsal part of DN (Middleton and Strick 2001). Second, viral transneuronal tracing investigations in the macaque have demonstrated two closed-loops interconnecting via the den-

C. Habas (*) Service de NeuroImagerie, Centre Hospitalier National d’Ophtalmologie des Quinze-Vingts, Paris, France

Université Versailles-Saint-Quentin, Versailles, France e-mail: chabas@15-20.fr

tate nucleus, motor cortex and lobules III–VI/VIII, and prefrontal cortex (BA 46) and lobule VII (crus II) (Kelly and Strick 2003). Third, except primary visual cortex and some ventrolateral prefrontal and orbitofrontal cortices, the rest of the cerebral cortex innervates the cerebellum via pontine nuclei (Schmahmann and Pandya 1997). Therefore, the cerebellum would take part in several closed-loops whose cortico- ponto-cerebellar afferents remain to be rmly established, for major part of them, but whose efferents are successively (Clower etal. 2001; Middleton and Strick 2001; Dum and Strick 2003):

1. Dorsal DN, caudal ventrolateral thalamus, motor cortex (BA 4).

2. Lateral DN, X thalamus, lateral, and medial premotor cortex (BA 6, supplementary motor area).

3. Caudal DN, X thalamus, prefrontal eye eld cortex (BA

8).

4. Ventromedial DN, caudal ventrolateral and mediodorsal thalamus, dorsolateral prefrontal cortex (BA 9 medial and lateral).

5. Ventrolateral DN, caudal ventrolateral and mediodorsal thalamus, dorsolateral prefrontal cortex (BA 46 dorsal).

6. Lateral DN, caudal ventrolateral thalamus, inferior parietal cortex (BA 7b).

In addition to cerebello-cortical loops, cerebellosubcortical loops may exist as well, especially through reticular, red, and bulbar olivary nuclei. Recently, potential motor and associative striato-cerebellar loops have been also traced: DN projects to the external pallidum via intralaminar and anterior/lateral ventral thalamus in rat (Hoshi etal. 2005) and striatum in monkey, while subthalamic nucleus projects topographically back to cerebellar cortex (crus II and lobule VIIb) via pontine nuclei in monkey (Bostan etal. 2010).

321

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C. Habas

49.2 Functional Neuroimaging Data

Has this closed-loop organization of the cerebellar system been observed in human? Up to now, only partial arguments can be put forth in favor of such network architecture since no histological tracing data are available. Resting state functional connectivity and diffusion tensor imaging have provided some in vivo results in support of cerebellar closed-loops.

49.2.1 Cerebellar Subregional Connectivity

Cerebellar cortex can be parcellated into separate and nonor very narrow overlapping regions encompassing mainly sensorimotor (anterior lobe and lobule VIII), executive (lobules VI caudal, VII with crus I and II and IX), and limbic (lobule VI/VII especially the vermis) (Habas et al.

2009; Krienen and Buckner 2009; O’Reilly et al. 2009;

Buckner etal. 2011). It is noteworthy however that the oculomotor cerebellum must overlap part of the executive/limbic cerebellum (Voogd etal. 2012). These regions are in functional coherence with specic zones of the cerebral cortex which may represent cortico-ponto-cerebellar connections. For instance, motor and premotor cortex are linked to the sensorimotor cerebellum, and prefrontal, cingulate, temporal, and parietal cortices to the executive cerebellum. Moreover, functional connectivity of DN that may reect

cerebellar outputs, implicates prefrontal, temporal, cingulate and parietal cortices and thalamus and striatum (Allen etal. 2005; Bernard etal. 2014), in accordance with tractographic data (Habas and Cabanis 2007; Jissendi etal. 2008; Salmi etal. 2010; Pelzer etal. 2013; Palesi etal. 2015) and partly reciprocating cortical inputs. It is also noteworthy that DN also sends direct efferents to the ventral tegmental area in mouse (Carta etal. 2019) and that reward-related activity has been detected in granule cells and climbing bers within the cerebellum (Wagner and Luo 2020). Functional coherence has also been demonstrated between cerebellum and: accumbens nucleus, substantia nigra, and amygdala. Therefore, there also exists direct subcortical cerebello-striatal loops allowing combination of rewardbased (ventral striatum) and error-based (cerebellum) learning process.

49.2.2 Cerebellar Circuits

Independent component analysis-based functional connectivity has delineated specic parallel cerebro-cerebellocortical networks including Habas etal. (2009) (Fig.49.1):

1. The sensorimotor network (motor and premotor cortex,

cerebellar lobules V–VI and VIII).

2. The right and left executive networks (dorsolateral pre-

frontal and parietal prefrontal cortices, crus I and II).

Fig. 49.1 The main cerebro-cerebellar networks determined by independent component analysis (ICA) applied to brain resting-state data. Abbreviations: DLPFC dorsolateral prefrontal cortex, DMPFC dorsomedian prefrontal cortex, FEF frontal eye eld, INS insula, IPC inferior

parietal cortex, IPS intraparietal sulcus, MPFC medial prefrontal cortex, RSC/PCC retrosplenial cortex/posterior cingulate cortex, SMA supplementary motor area, SPC superior parietal cortex, THAL thalamus

49 Cerebellar Closed Loops

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3. The limbic “salience” network (frontal and insular cortices, lobules VI/VII) involved in interoception, emotional, and autonomic regulation.

4. The “default-mode network” (dorsomedian prefrontal, posterior cingulate, retrosplenial and parahippocampal cortices, precuneus, lobules IX and VII) devoted to consciousness, self-agency, memory, and mental imagery.

5. The dorsal attentional network (precentral sulcus, intraparietal sulcus, MT+, lobules VIIb/VIIIa) implicated in top-down attention and visual working memory (Brissenden etal. 2016).

These cognitive and emotional circuits are represented thrice at the cerebello-cortical surface according to a spatially oriented, gradient-based organization (Guell and Schmahmann 2020).

We can also add a language-dedicated network including Broca and Wernicke areas and right crus 1–2 (Tomasi and Volkow 2012).

It is noteworthy that the dentate nucleus, which constitutes the main target of the overlying Purkinje cells and the main output channel of the cerebellar cortex, encompasses during the brain resting-state of three functional territories in relation with the default-mode, the salience-motor and visual cortical networks (Guell etal. 2020).

All these genetically prewired and epigenetically modulated circuits correspond to cerebellar closed-loops rst identied in animals.

49.3 Conclusion

Altogether, available data from animal and human studies agree with the existence of anatomical and functional well- segregated parallel cerebro-ponto-cerebello-thalamo-cortical circuits which may function as distinct modules applying a common type of computation (putatively internal models or timing function) to different mental activities from motor coordination and automation to cognition and emotion (Schmahmann 1991,

1996; Ramnani 2006; Schmahmann et al. 2019). Subcortical

loops also enable direct coordination between the cerebellum and the striatum, including the ventral (limbic) basal ganglia.

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