New roles for the cerebellum in health and disease

Abstract

The cerebellum has a well-established role in maintaining motor coordination and studies of cerebellar learning suggest that it does this by recognizing neural patterns, which it uses to predict optimal movements. Serious damage to the cerebellum impairs this learning and results in a set of motor disturbances called ataxia. However, recent work implicates the cerebellum in cognition and emotion, and it has been argued that cerebellar dysfunction contributes to non-motor conditions such as autism spectrum disorders (ASD). Based on human and animal model studies, two major questions arise. Does the cerebellum contribute to non-motor as well as motor diseases, and if so, how does altering its function contribute to such diverse symptoms? The architecture and connectivity of cerebellar circuits may hold the answers to these questions. An emerging view is that cerebellar defects can trigger motor and non-motor neurological conditions by globally influencing brain function. Furthermore, during development cerebellar circuits may play a role in wiring events necessary for higher cognitive functions such as social behavior and language. We discuss genetic, electrophysiological, and behavioral evidence that implicates Purkinje cell dysfunction as a major culprit in several diseases and offer a hypothesis as to how canonical cerebellar functions might be at fault in non-motor as well as motor diseases.

Keywords: brain behavior; circuitry; genetics; neural activity; neurological disorders.

Figure 1

Cytoarchitecture and connectivity in the cerebellum. (A) Mouse brain shown from a lateral view with the cerebellum highlighted in color. (B) The basic cerebellar circuit is comprised of granule cells, Purkinje cells, stellate and basket cell interneurons, and deep nuclei. Afferent information is delivered to the cerebellum as climbing fibers or mossy fibers. The plus and minus signs indicate whether each synapse is excitatory or inhibitory. Note that inhibitory connections between the cerebellar nuclei and inferior olive complete the olivo-cortico-nuclear loop and excitatory projections from the cerebellar nuclei loop back to the cerebellar cortex. Panel (B) was modified from (Reeber et al., 2012). For simplicity we have not shown Golgi cells, unipolar brush cells, Lugaro cells, and candelabrum cells.

Figure 2

Purkinje cells have a distinct morphology and electrophysiological profile. (A) Purkinje cell labeled using the classic Golgi-Cox staining method, demonstrating the exquisite morphology and extensive dendritic branching of the Purkinje cell. (B) Purkinje cells can be identified by their unique activity: each one fires complex spikes that are triggered by climbing fibers (asterisks) and simples spikes that are driven either by intrinsic activity or by mossy fiber-granule cell inputs. (C) Higher power image of the Purkinje cell recording shown in panel (B). Defects in Purkinje cell morphology and/or firing are thought to instigate motor and non-motor neurological conditions.

Figure 3

The cerebellum is extensively connected to the brain and spinal cord. (A) Schematic representation of brain regions that send input to the cerebellum. (B) Schematic representation of the regions that receive information from the cerebellum. Note that the TH is a major relay station for cerebellar input to the cortex while the PN is the primary gateway for cerebral cortical input to the cerebellum. Abbreviations: AMG, amygdala; BG, basal ganglia; ECN, external cuneate nucleus; HIP, hippocampus; HYP; hypothalamus; IO, inferior olive; LC, locus coeruleus; PAG, periaqueductal gray; PN, pontine nuclei; RET, reticular nucleus; RN, red nucleus; SC, spinal cord; SUP, superior colliculi; TH, thalamus; VN, vestibular nuclei.

Figure 4

The cerebellum is highly compartmentalized into functional regions. (A) Schematic illustrating the division of the cerebellum into behaviorally relevant domains. The cartoon is a simplified model of the functional cerebellum and is based on functional imaging, human and animal lesions, afferent connectivity, electrophysiology, and animal behavior studies. (B,C) Wholemount immunohistochemical staining of the mouse cerebellum—zebrin II expression reveals the intricate patterning of the cerebellum into zones. The scale bar in (C) = 2 mm (also applies to (B).