Functional Outcomes of Cerebellar Malformations

Abstract

The cerebellum is well-established as a primary center for controlling sensorimotor functions. However, recent experiments have demonstrated additional roles for the cerebellum in higher-order cognitive functions such as language, emotion, reward, social behavior, and working memory. Based on the diversity of behaviors that it can influence, it is therefore not surprising that cerebellar dysfunction is linked to motor diseases such as ataxia, dystonia, tremor, and Parkinson's disease as well to non-motor disorders including autism spectrum disorders (ASD), schizophrenia, depression, and anxiety. Regardless of the condition, there is a growing consensus that developmental disturbances of the cerebellum may be a central culprit in triggering a number of distinct pathophysiological processes. Here, we consider how cerebellar malformations and neuronal circuit wiring impact brain function and behavior during development. We use the cerebellum as a model to discuss the expanding view that local integrated brain circuits function within the context of distributed global networks to communicate the computations that drive complex behavior. We highlight growing concerns that neurological and neuropsychiatric diseases with severe behavioral outcomes originate from developmental insults to the cerebellum.

Keywords: Purkinje cell; cerebellar nuclei; cerebellum; circuitry; cognitive; development; motor.

FIGURE 1

Neuronal microarchitecture of the cerebellar cortex. Representative schema of the layers of the cerebellar cortex. Afferent projections are presented in yellow. Climbing fibers (CF; yellow) project to the molecular layer and target the dendritic tree of a single Purkinje cell (PC; black). Mossy fibers (MF; yellow) terminate in the granule cell layer, forming synaptic connections with granule cells (GrC; gray). The granule cell layer also contains golgi cell (GoC; green), Lugaro cell (LuC; pink), and unipolar brush cell (UBC; purple) interneurons. The cell bodies of granule cells are located in the granule cell layer and project axons to the molecular layer where they branch to form parallel fibers, which run orthogonal to the parasagittal plane. The molecular layer contains the cell bodies of inhibitory interneurons (IIN; red), which include both basket and stellate cells as well as neurites from a variety of neurons, as pictured. Finally, the Purkinje cell layer is occupied by the large cell bodies of the Purkinje cell (PC; black) and the smaller cell bodies of the Candelabrum cells (CaC; Cyan). In 3-dimensional space, the transverse projections of the parallel fibers can integrate and process the afferent information supplied by the climbing and mossy fibers. Basket cell axons, which wrap the Purkinje cell soma and initial segment of the axon, and Bergmann glia palisades that extend into the molecular layer were intentionally excluded to focus on the Purkinje cell anatomy.

FIGURE 2

Macroarchitecture of the cerebellum. Rodent cerebellum (A) depicted from the dorsal view (left panel). Rostral is superior and caudal is inferior. Vermis is midline. The cerebellar nuclei (CN) are represented in color. In pink is the lateral nucleus, in green is the medial nucleus, and in blue is the intermediate nucleus (A; inset). Pictured are the primate cerebellar nuclei: lateral is the dentate (Pink) where the convoluted shape in comparison to the rodent lateral nucleus can be appreciated, medial is the fastigial (green), and the globose and emboliform nuclei (blue; together forming the interposed nuclei) are pictured and are analogous to the murine intermediate nucleus. The right panel presents a parasagittal view of the cerebellum at midline. The cerebellar nuclei are indicated as in the left panel (adapted in part from Sugihara et al., 1999 permission was obtained from Wiley Online Library). Light gray arrows represent schematized Purkinje cell output to the CN, while the heavy black arrow represents CN efferent projections to the cerebral cortex and brainstem. Mouse cerebellum (B) depicted from the dorsal view (left panel). Gray indicates representative Zebrin banding pattern. Orientation is as described in (A). The Right panel indicates the mouse cerebellum at midline in the parasagittal plane with zonal nomenclature. Mouse cerebellum adapted from Cerminara et al. (2015). Permission was obtained from Nature research journals.

FIGURE 3

Purkinje cell differentiation, cerebellar expansion, and sensitive periods for developmental disorders. Pictured are various correlations along the time line of gestation through early childhood. Pictured in the upper portion of the figure is a scaled representation of cerebellar size and foliation during gestation. Adapted from Rakic and Sidman (1970) with permission obtained from Wiley Online Library. The superimposed gray triangle represents the incidence of developmental comorbidities associated with premature birth at the corresponding gestational ages. Below the time line in blue are the gestational ages of Purkinje cell birth and differentiation. (Bottom) A gradient showing the time period during which all etiologies of autism are thought to occur. Figure adapted in part from Sathyanesan et al. (2019) with permission obtained from Nature research journals.

FIGURE 4

Comparative evolution of the cerebellum. (A) Sagittal view of cerebellum and cerebellum-like structures across vertebrates, including a sagittal view of the octavolateralis of the lamprey. Adapted from Butts et al. (2011) with permission obtained from SpringerLink. (B) Examples of the posterior cerebella of three species (Bottlenose Dolphin, Sea Lion, Chimpanzee) that display vocal production learning and a single mammal (White Tailed Deer) that does not. Figure inspired by Smaers et al. (2018) but independently processed directly from Brainmuseum.org (Welker et al., 2019) use was as per open source published guidelines for both eLife and Brainmuseum.org, respectively.