Insights into cerebellar development and connectivity

Abstract

The cerebellum has a well-established role in controlling motor functions such coordination, balance, posture, and skilled learning. There is mounting evidence that it might also play a critical role in non-motor functions such as cognition and emotion. It is therefore not surprising that cerebellar defects are associated with a wide array of diseases including ataxia, dystonia, tremor, schizophrenia, dyslexia, and autism spectrum disorder. What is intriguing is that a seemingly uniform circuit that is often described as being "simple" should carry out all of these behaviors. Analyses of how cerebellar circuits develop have revealed that such descriptions massively underestimate the complexity of the cerebellum. The cerebellum is in fact highly patterned and organized around a series of parasagittal stripes and transverse zones. This topographic architecture partitions all cerebellar circuits into functional modules that are thought to enhance processing power during cerebellar dependent behaviors. What are arguably the most remarkable features of cerebellar topography are the developmental processes that produce them. This review is concerned with the genetic and cellular mechanisms that orchestrate cerebellar patterning. We place a major focus on how Purkinje cells control multiple aspects of cerebellar circuit assembly. Using this model, we discuss evidence for how "zebra-like" patterns in Purkinje cells sculpt the cerebellum, how specific genetic cues mediate the process, and how activity refines the patterns into an adult map that is capable of executing various functions. We also discuss how defective Purkinje cell patterning might impact the pathogenesis of neurological conditions.

Animal Models of Tremor: Relevance to Human Tremor Disorders

“…The microzones of the cerebellum could be traced by a set of PC markers, such as zebrin II or excitatory amino acid transporter type 4 (EAAT4). 55 , 56 The disturbance of microzonal organization within the cerebellum may cause improper neuronal signaling, leading to tremor. It remains to be studied in detail how this altered PC firing in the context of microzonal organization can lead to tremor in wdl mice.…”

Neuronal Migration During Development of the Cerebellum

“…The cerebellar cortex, which is the location of the most of cerebellar neurons, is compartmentalized and the cytoarichtecture is the most elaborately patterned circuit of all the CNS structures (White and Sillitoe, 2013; Beckinghausen and Sillitoe, 2019). The molecular expression patterns, afferent/efferent fibers, and birthdates divide the cerebellar cortex into an array of parasagittal stripes (e.g., Voogd, 1967; Hashimoto and Mikoshiba, 2003; Sugihara and Shinoda, 2004; Pijpers et al, 2006; Apps and Hawkes, 2009; Marzban and Hawkes, 2011; Bailey et al, 2013; Rahimi-Balaei et al, 2016) and is further subdivided into four transverse zones (Sillitoe et al, 2005; Marzban et al, 2008; Marzban and Hawkes, 2011; Bailey et al, 2013, 2014; Rahimi-Balaei et al, 2016).…”

Evidence for Brainstem Contributions to Autism Spectrum Disorders

“…Indeed, embryonic brain development resembles a hierarchical three-dimensional scaffold: the deep ancestral brain structures (like the brainstem) guide the formation of the evolutionarily more recent regions (like the neocortex) ( Stiles and Jernigan, 2010 ). Additionally, cerebellar development is supported by neural signaling that originates in the brainstem’s inferior olive and pontine nuclei and innervates maturing cerebellum via mossy and climbing fibers (reviewed in Beckinghausen and Sillitoe, 2018 ). These processes lead to an integrative brain where both structure and function of the more complex cortical circuitry rely on the fidelity of the ancestral brain wiring and the efficacy of “lower level” processing.…”