Emerging connections between cerebellar development, behaviour and complex brain disorders

Abstract

The human cerebellum has a protracted developmental timeline compared with the neocortex, expanding the window of vulnerability to neurological disorders. As the cerebellum is critical for motor behaviour, it is not surprising that most neurodevelopmental disorders share motor deficits as a common sequela. However, evidence gathered since the late 1980s suggests that the cerebellum is involved in motor and non-motor function, including cognition and emotion. More recently, evidence indicates that major neurodevelopmental disorders such as intellectual disability, autism spectrum disorder, attention-deficit hyperactivity disorder and Down syndrome have potential links to abnormal cerebellar development. Out of recent findings from clinical and preclinical studies, the concept of the ‘cerebellar connectome’ has emerged that can be used as a framework to link the role of cerebellar development to human behaviour, disease states and the design of better therapeutic strategies.

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Fig. 1: Essential features of cerebellar connections, circuitry and development.
Fig. 2: Features of the cerebellar connectome and dependent factors.
Fig. 3: Regions of cerebellar developmental vulnerability and multisensory integration.
Fig. 4: Deep brain stimulation of the cerebellum in mouse.

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Acknowledgements

J.S. was supported by the US National Institute of Neurological Disorders and Stroke (NINDS) grant 5R01NS099461. R.V.S. received support from the Hamill Foundation, the Baylor College of Medicine Intellectual and Developmental Disabilities Research Center grant U54HD083092 and NINDS grants R01NS089664 and R01NS100874. D.H.H. received support from the University of Tennessee Health Science Center (UTHSC) Neuroscience Institute and the UTHSC Cornet Award. R.V.S. and D.H.H. were also supported by the US National Institute of Mental Health grant R01MH112143. V.G. was supported by the District of Columbia Intellectual and Developmental Disabilities Research Center grant U54 HD090257 and NINDS grants R01NS105138 and R37NS109478 (Javits Award).

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Nature Reviews Neuroscience thanks J. Fernandez-Ruiz and A. Watt, and the other anonymous reviewer, for their contribution to the peer review of this work.

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A.S., J.Z., D.H.H. and R.S. researched data for the article and made substantial contributions to the discussion of content, writing, review and editing of the manuscript before submission. V.G. made substantial contributions to the discussion of content, writing, review and editing of the manuscript before submission. J.S. made a substantial contribution to the discussion of content, review and editing of the manuscript before submission.

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Correspondence to Aaron Sathyanesan or Vittorio Gallo.

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Glossary

Complex developmental brain disorders

Neurodevelopmental disorders that affect multiple brain regions, gene loci and behavioural domains. These disorders do not have a clearly defined hereditary basis.

Neurodevelopmental disorders

(NDDs). Disorders that emerge during the course of CNS development, often having long-term effects on behaviour.

Cerebellar connectome

A map of neuronal connections within the cerebellum as well as that between the cerebellum and other CNS regions, including the cerebral cortex and subcortical regions.

Autism spectrum disorder

(ASD). A broad range of neurodevelopmental conditions characterized by social skill deficits, repetitive motor behaviour and communication deficits.

Down syndrome

(DS). A neurodevelopmental disorder wherein persons have abnormalities associated with chromosome 21. Persons with DS have reduced muscle tone (hypotonia) during infancy, characteristic facial features and mild to moderate intellectual disability and experience developmental delay, among other symptoms.

Attention deficit hyperactivity disorder

(ADHD). A complex developmental brain disorder that is characterized by deficits in attentional processes and increased frequency, intensity and variability of motor behaviour.

Intellectual disability

(ID). A neurodevelopmental disorder and/or condition that often co-occurs with other disorders and is characterized by reduced intellectual functioning (such as learning and abstract reasoning) and deficits in flexible or adaptive behaviours (such as social and motor behaviour).

P-Hacking

The selective reporting of statistically significant results on the basis of inappropriate, faulty or loosely defined data analysis schemes.

Finger-sequencing task

A behavioural task to assess motor function wherein subjects are directed to tap their fingers, on either hand, in a particular sequence. This task is commonly used to identify motor-related regional activation during functional brain imaging.

Bootstrapping

A statistical method used to measure how strong a given grouping or cluster is supported by the data.

Vestibulo-ocular reflex

(VOR). A reflex that generates eye movement in the opposite direction to head movement in order to stabilize vision. The cerebellar flocculus is an integral part of VOR circuitry, contributing to adaptive control of the VOR during trial-based learning.

Eyeblink conditioning paradigm

An associative conditioned-learning paradigm wherein an acoustic or light stimulus (conditioning stimulus (CS)) is paired with an air-puff stimulus (unconditioned stimulus (US)) over multiple trials to eventually yield anticipatory eyelid closure (conditioned response (CR)) as soon as the CS is presented, before US onset. Whereas delay eyeblink conditioning involves co-terminous CS and US and is primarily cerebellar-dependent, trace eyeblink conditioning involves non-overlapping CS and US and requires multiple brain regions including the hippocampus.

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Sathyanesan, A., Zhou, J., Scafidi, J. et al. Emerging connections between cerebellar development, behaviour and complex brain disorders. Nat Rev Neurosci 20, 298–313 (2019). https://doi.org/10.1038/s41583-019-0152-2

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