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Cerebellar Development in Health and Disease
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Cerebellar Development in Health and Disease

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cells of the Nervous System".

Deadline for manuscript submissions: closed (30 November 2022) | Viewed by 16381

Special Issue Editors

Prof. Dr. Freek E. Hoebeek

E-Mail Website
Guest Editor
Department for Developmental Origins of Disease, Wilhelmina Children’s Hospital, University Medical Center Utrecht, Utrecht, The Netherlands
Interests: cerebellum; thalamus; circuit maturation; epilepsy; early life brain damage
Special Issues, Collections and Topics in MDPI journals
Dr. Laurens Witter

E-Mail Website
Guest Editor
Department for Developmental Origins of Disease, Wilhelmina Children’s Hospital, Brain Center, University Medical Center Utrecht, 3584 EA Utrecht, The Netherlands
Interests: cerebellum; development; electrophysiololgy; circuit maturation

Special Issue Information

Dear Colleagues,

The role of the cerebellum in motor coordination and cognition has become clearer over the past few years. In adulthood, the circuitry of the cerebellum shows topographical specializations that support cerebellar function. Additionally, the connections of the cerebellum to and from spinal and cerebral structures adhere to general topographical organization. The design of these brain-wide networks allows for the parallel processing of vast quantities of information from various motor and non-motor domains. However, how these functions, circuit specializations, and connections develop remains largely unknown.

Impaired development of the cerebellum or its connected structures results in specific molecular and cellular compositions, which have been studied with increasing detail. Recent insights into the causes of various neurological disorders, like ataxia, autism spectrum disorder and epilepsy, have highlighted role of the cerebellum. To guide and fuel the search for diagnostic tools and treatments for the debilitating consequences, this Special Issue provides a platform for original research manuscripts and prospective reviews on anatomical, electrophysiological and functional data from the developing cerebellum and its impact on afferent and efferent connections. 

Prof. Dr. Freek E. Hoebeek
Dr. Laurens Witter
Guest Editors

Manuscript Submission Information

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • development
  • cerebellum
  • physiology
  • neonatal damage
  • brain injury

Published Papers (6 papers)

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Research

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24 pages, 13083 KiB  
Article
Lobule-Related Action Potential Shape- and History-Dependent Current Integration in Purkinje Cells of Adult and Developing Mice
by Gerrit C. Beekhof and Martijn Schonewille
Cells 2023, 12(4), 623; https://doi.org/10.3390/cells12040623 - 15 Feb 2023
Cited by 1 | Viewed by 1764
Abstract
Purkinje cells (PCs) are the principal cells of the cerebellar cortex and form a central element in the modular organization of the cerebellum. Differentiation of PCs based on gene expression profiles revealed two subpopulations with distinct connectivity, action potential firing and learning-induced activity [...] Read more.
Purkinje cells (PCs) are the principal cells of the cerebellar cortex and form a central element in the modular organization of the cerebellum. Differentiation of PCs based on gene expression profiles revealed two subpopulations with distinct connectivity, action potential firing and learning-induced activity changes. However, which basal cell physiological features underlie the differences between these subpopulations and to what extent they integrate input differentially remains largely unclear. Here, we investigate the cellular electrophysiological properties of PC subpopulation in adult and juvenile mice. We found that multiple fundamental cell physiological properties, including membrane resistance and various aspects of the action potential shape, differ between PCs from anterior and nodular lobules. Moreover, the two PC subpopulations also differed in the integration of negative and positive current steps as well as in size of the hyperpolarization-activated current. A comparative analysis in juvenile mice confirmed that most of these lobule-specific differences are already present at pre-weaning ages. Finally, we found that current integration in PCs is input history-dependent for both positive and negative currents, but this is not a distinctive feature between anterior and nodular PCs. Our results support the concept of a fundamental differentiation of PCs subpopulations in terms of cell physiological properties and current integration, yet reveals that history-dependent input processing is consistent across PC subtypes. Full article
(This article belongs to the Special Issue Cerebellar Development in Health and Disease)
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28 pages, 3062 KiB  
Article
Propranolol Modulates Cerebellar Circuit Activity and Reduces Tremor
by Joy Zhou, Meike E. Van der Heijden, Luis E. Salazar Leon, Tao Lin, Lauren N. Miterko, Dominic J. Kizek, Ross M. Perez, Matea Pavešković, Amanda M. Brown and Roy V. Sillitoe
Cells 2022, 11(23), 3889; https://doi.org/10.3390/cells11233889 - 01 Dec 2022
Cited by 1 | Viewed by 2468
Abstract
Tremor is the most common movement disorder. Several drugs reduce tremor severity, but no cures are available. Propranolol, a β-adrenergic receptor blocker, is the leading treatment for tremor. However, the in vivo circuit mechanisms by which propranolol decreases tremor remain unclear. Here, we [...] Read more.
Tremor is the most common movement disorder. Several drugs reduce tremor severity, but no cures are available. Propranolol, a β-adrenergic receptor blocker, is the leading treatment for tremor. However, the in vivo circuit mechanisms by which propranolol decreases tremor remain unclear. Here, we test whether propranolol modulates activity in the cerebellum, a key node in the tremor network. We investigated the effects of propranolol in healthy control mice and Car8wdl/wdl mice, which exhibit pathophysiological tremor and ataxia due to cerebellar dysfunction. Propranolol reduced physiological tremor in control mice and reduced pathophysiological tremor in Car8wdl/wdl mice to control levels. Open field and footprinting assays showed that propranolol did not correct ataxia in Car8wdl/wdl mice. In vivo recordings in awake mice revealed that propranolol modulates the spiking activity of control and Car8wdl/wdl Purkinje cells. Recordings in cerebellar nuclei neurons, the targets of Purkinje cells, also revealed altered activity in propranolol-treated control and Car8wdl/wdl mice. Next, we tested whether propranolol reduces tremor through β1 and β2 adrenergic receptors. Propranolol did not change tremor amplitude or cerebellar nuclei activity in β1 and β2 null mice or Car8wdl/wdl mice lacking β1 and β2 receptor function. These data show that propranolol can modulate cerebellar circuit activity through β-adrenergic receptors and may contribute to tremor therapeutics. Full article
(This article belongs to the Special Issue Cerebellar Development in Health and Disease)
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23 pages, 11452 KiB  
Article
Anatomical Development of the Cerebellothalamic Tract in Embryonic Mice
by Daniël B. Dumas, Simona V. Gornati, Youri Adolfs, Tomomi Shimogori, R. Jeroen Pasterkamp and Freek E. Hoebeek
Cells 2022, 11(23), 3800; https://doi.org/10.3390/cells11233800 - 27 Nov 2022
Cited by 3 | Viewed by 2449
Abstract
The main connection from cerebellum to cerebrum is formed by cerebellar nuclei axons that synapse in the thalamus. Apart from its role in coordinating sensorimotor integration in the adult brain, the cerebello-thalamic tract (CbT) has also been implicated in developmental disorders, such as [...] Read more.
The main connection from cerebellum to cerebrum is formed by cerebellar nuclei axons that synapse in the thalamus. Apart from its role in coordinating sensorimotor integration in the adult brain, the cerebello-thalamic tract (CbT) has also been implicated in developmental disorders, such as autism spectrum disorders. Although the development of the cerebellum, thalamus and cerebral cortex have been studied, there is no detailed description of the ontogeny of the mammalian CbT. Here we investigated the development of the CbT at embryonic stages using transgenic Ntsr1-Cre/Ai14 mice and in utero electroporation of wild type mice. Wide-field, confocal and 3D light-sheet microscopy of immunohistochemical stainings showed that CbT fibers arrive in the prethalamus between E14.5 and E15.5, but only invade the thalamus after E16.5. We quantified the spread of CbT fibers throughout the various thalamic nuclei and found that at E17.5 and E18.5 the ventrolateral, ventromedial and parafascicular nuclei, but also the mediodorsal and posterior complex, become increasingly innervated. Several CbT fiber varicosities express vesicular glutamate transporter type 2 at E18.5, indicating cerebello-thalamic synapses. Our results provide the first quantitative data on the developing murine CbT, which provides guidance for future investigations of the impact that cerebellum has on thalamo-cortical networks during development. Full article
(This article belongs to the Special Issue Cerebellar Development in Health and Disease)
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20 pages, 3861 KiB  
Article
cATR Tracing Approach to Identify Individual Intermediary Neurons Based on Their Input and Output: A Proof-of-Concept Study Connecting Cerebellum and Central Hubs Implicated in Developmental Disorders
by Willem S. van Hoogstraten, Marit C. C. Lute, Hugo Nusselder, Lieke Kros, Arn M. J. M. van den Maagdenberg and Chris I. De Zeeuw
Cells 2022, 11(19), 2978; https://doi.org/10.3390/cells11192978 - 24 Sep 2022
Cited by 1 | Viewed by 2312
Abstract
Over the past decades, it has become increasingly clear that many neurodevelopmental disorders can be characterized by aberrations in the neuro-anatomical connectome of intermediary hubs. Yet, despite the advent in unidirectional transsynaptic tracing technologies, we are still lacking an efficient approach to identify [...] Read more.
Over the past decades, it has become increasingly clear that many neurodevelopmental disorders can be characterized by aberrations in the neuro-anatomical connectome of intermediary hubs. Yet, despite the advent in unidirectional transsynaptic tracing technologies, we are still lacking an efficient approach to identify individual neurons based on both their precise input and output relations, hampering our ability to elucidate the precise connectome in both the healthy and diseased condition. Here, we bridge this gap by combining anterograde transsynaptic- and retrograde (cATR) tracing in Ai14 reporter mice, using adeno-associated virus serotype 1 expressing Cre and cholera toxin subunit B as the anterograde and retrograde tracer, respectively. We have applied this innovative approach to selectively identify individual neurons in the brainstem that do not only receive input from one or more of the cerebellar nuclei (CN), but also project to the primary motor cortex (M1), the amygdala or the ventral tegmental area (VTA). Cells directly connecting CN to M1 were found mainly in the thalamus, while a large diversity of midbrain and brainstem areas connected the CN to the amygdala or VTA. Our data highlight that cATR allows for specific, yet brain-wide, identification of individual neurons that mediate information from a cerebellar nucleus to the cerebral cortex, amygdala or VTA via a disynaptic pathway. Given that the identified neurons in healthy subjects can be readily quantified, our data also form a solid foundation to make numerical comparisons with mouse mutants suffering from aberrations in their connectome due to a neurodevelopmental disorder. Full article
(This article belongs to the Special Issue Cerebellar Development in Health and Disease)
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Review

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18 pages, 4412 KiB  
Review
Purkinje Cell Patterning—Insights from Single-Cell Sequencing
by Elizabeth J. Apsley and Esther B. E. Becker
Cells 2022, 11(18), 2918; https://doi.org/10.3390/cells11182918 - 18 Sep 2022
Cited by 2 | Viewed by 4979
Abstract
Despite their homogeneous appearance, Purkinje cells are remarkably diverse with respect to their molecular phenotypes, physiological properties, afferent and efferent connectivity, as well as their vulnerability to insults. Heterogeneity in Purkinje cells arises early in development, with molecularly distinct embryonic cell clusters present [...] Read more.
Despite their homogeneous appearance, Purkinje cells are remarkably diverse with respect to their molecular phenotypes, physiological properties, afferent and efferent connectivity, as well as their vulnerability to insults. Heterogeneity in Purkinje cells arises early in development, with molecularly distinct embryonic cell clusters present soon after Purkinje cell specification. Traditional methods have characterized cerebellar development and cell types, including Purkinje cell subtypes, based on knowledge of selected markers. However, recent single-cell RNA sequencing studies provide vastly increased resolution of the whole cerebellar transcriptome. Here we draw together the results of multiple single-cell transcriptomic studies in developing and adult cerebellum in both mouse and human. We describe how this detailed transcriptomic data has increased our understanding of the intricate development and function of Purkinje cells and provides first clues into features specific to human cerebellar development. Full article
(This article belongs to the Special Issue Cerebellar Development in Health and Disease)
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Other

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8 pages, 250 KiB  
Opinion
Development of Cerebellar Reserve
by Hiroshi Mitoma, Shinji Kakei and Mario Manto
Cells 2022, 11(19), 3013; https://doi.org/10.3390/cells11193013 - 27 Sep 2022
Cited by 4 | Viewed by 1484
Abstract
The cerebellar reserve is defined as the capacity of the cerebellum for compensation and restoration following injury. This unique cerebellar ability is attributed to various forms of synaptic plasticity that incorporate multimodal and redundant cerebellar inputs, two major features of the cerebellar circuitry. [...] Read more.
The cerebellar reserve is defined as the capacity of the cerebellum for compensation and restoration following injury. This unique cerebellar ability is attributed to various forms of synaptic plasticity that incorporate multimodal and redundant cerebellar inputs, two major features of the cerebellar circuitry. It is assumed that the cerebellar reserve is acquired from the age of 12 years after the maturation of both the cerebellar adaptative behaviors and cerebellar functional connectivity. However, acquiring the cerebellar reserve is also affected by two other factors: vulnerability and growth potential in the developing cerebellum. First, cerebellar injury during the critical period of neural circuit formation (especially during fetal and neonatal life and infancy) leads to persistent dysfunction of the cerebellum and its targets, resulting in the limitation of the cerebellar reserve. Secondly, growth potential appears to facilitate cerebellar reserve during the stage when the cerebellar reserve is still immature. Based on these findings, the present mini-review proposes a possible developmental trajectory underlying the acquisition of cerebellar reserve. We highlight the importance of studies dedicated to the understanding of the cerebellar resilience to injuries. Full article
(This article belongs to the Special Issue Cerebellar Development in Health and Disease)
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