Cerebellum Lecture: the Cerebellar Nuclei—Core of the Cerebellum

Abstract

The cerebellum is a key player in many brain functions and a major topic of neuroscience research. However, the cerebellar nuclei (CN), the main output structures of the cerebellum, are often overlooked. This neglect is because research on the cerebellum typically focuses on the cortex and tends to treat the CN as relatively simple output nuclei conveying an inverted signal from the cerebellar cortex to the rest of the brain. In this review, by adopting a nucleocentric perspective we aim to rectify this impression. First, we describe CN anatomy and modularity and comprehensively integrate CN architecture with its highly organized but complex afferent and efferent connectivity. This is followed by a novel classification of the specific neuronal classes the CN comprise and speculate on the implications of CN structure and physiology for our understanding of adult cerebellar function. Based on this thorough review of the adult literature we provide a comprehensive overview of CN embryonic development and, by comparing cerebellar structures in various chordate clades, propose an interpretation of CN evolution. Despite their critical importance in cerebellar function, from a clinical perspective intriguingly few, if any, neurological disorders appear to primarily affect the CN. To highlight this curious anomaly, and encourage future nucleocentric interpretations, we build on our review to provide a brief overview of the various syndromes in which the CN are currently implicated. Finally, we summarize the specific perspectives that a nucleocentric view of the cerebellum brings, move major outstanding issues in CN biology to the limelight, and provide a roadmap to the key questions that need to be answered in order to create a comprehensive integrated model of CN structure, function, development, and evolution.

Structured connectivity in the output of the cerebellar cortex

“…Alternatively, the multiple functionality transform hypothesis 34 posits that distinct tasks require distinct algorithms which may be mediated by factors such as Purkinje cell firing rate, molecular profile, or timing rules 34–36 . Since neither theory has incorporated a role for CN neurons in cerebellar processing 37 , our findings suggest that theories of cerebellar function may need to be updated.…”

Protective Effect of Dexmedetomidine against Hyperoxia-Damaged Cerebellar Neurodevelopment in the Juvenile Rat

“…Thus, an existing correlation between the proliferative capacity of the cerebellum and the expression of Syp in the rat was demonstrated in a hypoxia-ischemia model [ 107 ]. The cerebellar nuclei cells (CN) and UBCs migrate tangentially beneath the surface of the cerebellum and possibly express various transcription factors, including Tbr1 and Tbr2, which promote migration from the anterior end of the cerebellum to the interior of the cerebellum [ 108 , 109 , 110 ]. Hyperoxia exposure to the developing cerebellum reduced these two transcription factors close in time to the toxic insult, which was also evident for the pluripotent transcription factor Sox2.…”

A spatial-temporal map of glutamatergic neurogenesis in embryonic cerebellar nuclei uncovers a high degree of cellular heterogeneity

“…The function of the cerebellum requires an interplay between its cortex and output circuitry, represented almost entirely by the CN. A broad range of inputs from the entire central nervous system is elaborated by the cerebellar cortex 1 and forwarded to the CN, which project their output mainly to the brainstem and diencephalon.…”

“…Although there are differences in size and complexity between the mouse and human CN, the general organization and function are well-conserved across mammalian species. The human CN comprise four separate nuclei named fastigial, globose, emboliform and dentate, from medial to lateral 1,2 . Instead, rodent cerebella contain three separate nuclei, since the globose and emboliform nuclei are anatomically fused, giving rise to the so-called interposed nucleus.…”

“…Recently, CN neurons were subdivided in five classes reviewed in 1 . This classification was based on different lines of evidence including neurotransmitter production, morphology, location, and transcriptomic signatures identified in adult mice.…”