Establishment of topographic circuit zones in the cerebellum of scrambler mutant mice

Abstract

The cerebellum is organized into zonal circuits that are thought to regulate ongoing motor behavior. Recent studies suggest that neuronal birthdates, gene expression patterning, and apoptosis control zone formation. Importantly, developing Purkinje cell zones are thought to provide the framework upon which afferent circuitry is organized. Yet, it is not clear whether altering the final placement of Purkinje cells affects the assembly of circuits into topographic zones. To gain insight into this problem, we examined zonal connectivity in scrambler mice; spontaneous mutants that have severe Purkinje cell ectopia due to the loss of reelin-disabled1 signaling. We used immunohistochemistry and neural tracing to determine whether displacement of Purkinje cell zones into ectopic positions triggers defects in zonal connectivity within sensory-motor circuits. Despite the abnormal placement of more than 95% of Purkinje cells in scrambler mice, the complementary relationship between molecularly distinct Purkinje cell zones is maintained, and consequently, afferents are targeted into topographic circuits. These data suggest that although loss of disabled1 distorts the Purkinje cell map, its absence does not obstruct the formation of zonal circuits. These findings support the hypothesis that Purkinje cell zones play an essential role in establishing afferent topography.

Cerebellar physiology: links between microcircuitry properties and sensorimotor functions

“…Regional localization then becomes important as it can be expected that the details of the connectivity within the cortex are locally adapted to the specific control function of the motor output system to which the zone is connected. Whereas the macro-organization described above mostly originates from work made decades ago, the discovery that the expression of different molecular markers such as aldolase C and excitatory amino acid transporter 4 (EAAT 4 ) are topographically congruent with the sagittal zonal structure (Sugihara & Shinoda, 2004;Apps & Hawkes, 2009;Ruigrok, 2011;Reeber et al 2013) suggest that a very fine molecular map parallels the zonal functional structure. Under different names, such as zebrins, these molecular markers are currently emerging as a widely used tool for reference to localization.…”

“…; Ruigrok, ; Reeber et al . ), and experimental scrambling of the topographical climbing fibre organization in the cortex is paralleled by a scrambling in the topography of the ingrowing mossy fibres (Reeber et al . ).…”

“…But from a physiological point of view it is interesting to note that the olivocerebellar and the corticonuclear connections may be examples of genetically pre-programmed connectivity (Altman & Bayer, 1997;Leto et al 2015), which draws up the main line of circuitry organization before other connections grow in and distribute themselves according to the framework established. For example, the distribution pattern of mossy fibres is closely related to that of the climbing fibres (Pijpers et al 2006;Ruigrok, 2011;Reeber et al 2013), and experimental scrambling of the topographical climbing fibre organization in the cortex is paralleled by a scrambling in the topography of the ingrowing mossy fibres (Reeber et al 2013). The zonal organization is likely to be a universal anatomical-organizational feature of the cerebellum across many species (Voogd & Glickstein, 1998).…”

Cerebellar sub-divisions differ in exercise-induced plasticity of noradrenergic axons and in their association with resilience to activity-based anorexia

“…Specifically, the longitudinal zones of the cerebellar hemisphere receive little to no input from the spinal cord and are, instead, heavily interconnected to non-motor areas, including the prefrontal cortex that mediates behavioral flexibility (Strick et al 2009; Stoodley 2015; Balsters et al 2010). In contrast, the vermal region modules are densely connected with the motor cortex and receive heavy direct innervations from the spinal cord (Coffman et al 2011; Provini et al 1968; Strata et al 2012; Sengul et al 2014; Reeber et al 2013). While much is known about the neuronal wiring, less is known about the modules’ contrasting roles in behavior.…”

Rearing conditions differently affect the motor performance and cerebellar morphology of prenatally stressed juvenile rats

“…Although cerebellar circuits are structurally quite simple, anatomical studies in both humans and experimental animals show that they contain millions of connections to the cerebral cortex, hippocampus, amygdala, hypothalamus, periaqueductal gray, basal ganglia, thalamus, brain stem and spinal cord [5]. A quantitative study of the human cerebellum with unbiased stereological techniques showed that approximately 25 million mossy fibers enter the cerebellum and synapse on 50 billion granule cells [6].…”