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Transverse section through the anterior cerebellum of the starnosed mole, double immunostained for zebrin II (green, a) and PLCß4 (red, b; merged, c). Lobules in the vermis are indicated by Roman numerals. Scale bars=1 mm (color figure online)
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The adult mammalian cerebellum is histologically uniform. However, concealed beneath the simple laminar architecture, it is organized rostrocaudally and mediolaterally into complex arrays of transverse zones and parasagittal stripes that is both highly reproducible between individuals and generally conserved across mammals and birds. Beyond this co...
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... expression patterns of zebrin II and PLCß4 in the starnosed mole cerebellum reveal a complex, reproducible cytoarchitecture in the form of transverse zones and parasagittal stripes (Fig. ...
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... length of the vermis is ∼30 mm. crl crus I, crII crus II, ls lobulus simplex, pm paramedian lobule, psf posterior superior fissure. Scale bars=1 mm (color figure online) midline, and a fourth pair (P4+) is in the paravermis (Fig. 4a, c, e). Both the P1+ and P2+ stripes extend continuously throughout the anterior lobe from lobule I to lobule V (Figs. 3 and 4a, c, e). The P+ stripes are separated by broad stripes of zebrin II−/PLCß4+ Purkinje cells (P1−, P2−; Fig. 4b, d). Three substripes are apparent within P1− (e.g., lobule III; Fig. 5a-c). A substripe architecture is also being present in P2− (likely comprising a strongly immunoreactive PLCß4+ substripe medially and a weakly immunoreactive ...
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... striped architecture of the vermis extends into the hemispheres, and the typical mammalian distribution is generally present, although again with exceptions. The striped array seen in the vermis of lobules VI-VII extends laterally into the putative simplex and ansiform lobules (Fig. 3a-c). First, in most mammals, lobulus simplex a is striped whereas lobulus simplex b is uniformly zebrin II+. In the star-nosed mole, the patterns of zebrin II (Fig. 8a) and PLCß4 (Fig. 8b) expression in the lobulus simplex are striped and complementary (Fig. 8c). However, no uniformly zebrin II+/PLCß4− lobulus simplex b is apparent. ...
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Citations
... Thus, for example, in most mammals the central zone (~ lobules VI-VII) is a strong recipient of visual inputs. Notably, in species in which vision has been lost, e.g., in moles, this central zone is atypically small [21,22]. Conversely, in microchiropteran bats, in which the central zone is the recipient of massive echolocation sensory input, the central zone is unusually large [23]. ...
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.
... In all zones, the zone-and-stripe patterns are highly reproducible between individuals and conserved across species (e.g., Sillitoe et al., 2005), but interspecific size differences are typical, reflecting a species' particular lifestyle. For example, mosaic evolution results in the CZ being especially large in bats (Kim et al., 2009), where it subserves echolocation and vision, whereas it is especially small in blind species such as the naked mole rat (Marzban et al., 2011) or star-nosed mole (Marzban et al., 2015; see also Legué et al., 2015). In parallel to the patterning of the PCs, the granular layer is similarly patterned into transverse domains that align with the PC transverse zones (e.g., Sillitoe et al., 2003). ...
The cerebellar cortex is highly compartmentalized and serves as a remarkable model for pattern formation throughout the brain. In brief, the adult cerebellar cortex is subdivided into five anteroposterior units—transverse zones—and subsequently, each zone is divided into ∼20 parasagittal stripes. Zone-and-stripe pattern formation involves the interplay of two parallel developmental pathways—one for inhibitory neurons, the second for excitatory. In the inhibitory pathway, progenitor cells of the 4th ventricle generate the Purkinje cells and inhibitory interneurons. In the excitatory pathway, progenitor cells in the upper rhombic lip give rise to the external granular layer, and subsequently to the granular layer of the adult. Both the excitatory and inhibitory developmental pathways are spatially patterned and the interactions of the two generate the complex topography of the adult. This review briefly describes the cellular and molecular mechanisms that underly zone-and-stripe development with a particular focus on mutations known to interfere with normal cerebellar development and the light they cast on the mechanisms of pattern formation.
... Scale bars, 1 mm (a, i), 500 µm (e), 150 µm (h), 200 µm (k), 100 µm (m). sisting of alternating ZII+ and ZII-stripes; a central region covering lobules VI and VII where all Purkinje cells are ZII+; a posterior region that includes lobule VIII and part of IX and consisting of ZII stripes; and a nodular region covering lobule X and the posterior part of lobule IX where all Purkinje cells are ZII+ [Leclerc et al., 1992;Ozol et al., 1999;Armstrong, and Hawkes, 2000;Sanchez et al., 2002;Larouche et al., 2003;Marzban et al., 2003;Sillitoe et al., 2003a, b;Marzban and Hawkes, 2011;Marzban et al., 2015]. A strikingly similar pattern occurs in birds, with 4 similar transverse zones Iwaniuk et al., 2009;Marzban et al., 2010;Corfield et al., 2015Corfield et al., , 2016Vibulyaseck et al., 2015]. ...
While in birds and mammals the cerebellum is a highly convoluted structure that consists of numerous transverse lobules, in most amphibians and reptiles it consists of only a single unfolded sheet. Orthogonal to the lobules, the cerebellum is comprised of sagittal zones that are revealed in the pattern of afferent inputs, the projection patterns of Purkinje cells, and Purkinje cell response properties, among other features. The expression of several molecular markers, such as aldolase C, is also parasagittally organized. Aldolase C, also known as zebrin II (ZII), is a glycolytic enzyme expressed in the cerebellar Purkinje cells of the vertebrate cerebellum. In birds, mammals, and some lizards (Ctenophoresspp.), ZII is expressed in a heterogenous fashion of alternating sagittal bands of high (ZII+) and low (ZII-) expression Purkinje cells. In contrast, turtles and snakes express ZII homogenously (ZII+) in their cerebella, but the pattern in crocodilians is unknown. Here, we examined the expression of ZII in two crocodilian species (Crocodylus niloticus and Alligator mississippiensis) to help determine the evolutionary origin of striped ZII expression in vertebrates. We expected crocodilians to express ZII in a striped (ZII+/ZII-) manner because of their close phylogenetic relationship to birds and their larger and more folded cerebellum compared to that of snakes and turtles. Contrary to our prediction, all Purkinje cells in the crocodilian cerebellum had a generally homogenous expression of ZII (ZII+) rather than clear ZII+/- stripes. Our results suggest that either ZII stripes were lost in three groups (snakes, turtles, and crocodilians) or ZII stripes evolved independently three times (lizards, birds, and mammals).
... Purkinje cell layout in the cerebellar cortex. Histological and morphological evidence suggest that species-specific characteristics of the cerebellar architecture could also be linked to behaviour and/or sensory ecology in vertebrates 3,10,11,30,31,68 , although this relationship is yet not well understood. To investigate this aspect in the squamate cerebellum, we first compared the complexity and general organisation of the principal layers and cell types of the cerebellar cortex, using histology and immunohistochemistry (IHC) methods. ...
Ecomorphological studies evaluating the impact of environmental and biological factors on the brain have so far focused on morphology or size measurements, and the ecological relevance of potential multi-level variations in brain architecture remains unclear in vertebrates. Here, we exploit the extraordinary ecomorphological diversity of squamates to assess brain phenotypic diversification with respect to locomotor specialization, by integrating single-cell distribution and transcriptomic data along with geometric morphometric, phylo-genetic, and volumetric analysis of high-definition 3D models. We reveal significant changes in cerebellar shape and size as well as alternative spatial layouts of cortical neurons and dynamic gene expression that all correlate with locomotor behaviours. These findings show that locomotor mode is a strong predictor of cerebellar structure and pattern, suggesting that major behavioural transitions in squamates are evolutionarily correlated with mosaic brain changes. Furthermore, our study amplifies the concept of 'cerebrotype', initially proposed for vertebrate brain proportions, towards additional shape characters.
... One of the more in depth studies on cerebellar specializations in mammals, murine and primate species excluded, comes from the thorough molecular patterning analysis of the star nosed mole by Marzban et al. (2015). The authors undertook this analysis to test the hypothesis that the cerebellar machinery adapts to accommodate specializations that define an animal's way of life. ...
... Similar domain specific hemispheric expansion is seen in the mammals that have been characterized as having vocal production learning (VPL) ( Figure 4B): primates, pinnipeds (fin footed mammals e.g., seals), toothed whales, and elephants (Smaers et al., 2018), although in the latter three more detailed analysis is needed. A final evolutionary observation of the mammalian cerebellum in regards to behavioral specialization that ought to be noted is the presence of a lingular-like zone in lobule I of bats, or microchiroptera (Kim J.Y. et al., 2009;Marzban et al., 2015), which was previously noted not in mammalian but avian cerebellum. It is interesting to speculate on whether this is indicative of another example of convergent evolution, in this case regarding flight, for which the cerebellum is part of the neural substrate. ...
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.
... Brain size and structure evolve to generate adaptive behavior [Pravosudov and Clayton, 2002;Catania, 2012;Marzban et al., 2015;Carlson, 2016;Stöckl et al., 2016;Hoops et al., 2017], reflecting demands for cognitive ca-pability with respect to ecology as well as challenges associated with living in groups [Gronenberg and Liebig, 1999;Farris and Roberts, 2005;Dunbar and Shultz, 2007;O'Donnell et al., 2011;Herculano-Houzel, 2012;Muscedere and Traniello, 2012;Sheehan et al., 2019]. Although the association of brain structure and social evolution is unclear and controversial [Wehner et al., 2007;Riveros et al., 2012;Farris, 2015;Lihoreau et al., 2015;DeCasien et al., 2017], sociality has been considered a driver of brain size and organization in vertebrates and invertebrates. ...
The behavioral demands of living in social groups have been linked to the evolution of brain size and structure, but how social organization shapes investment and connectivity within and among functionally specialized brain regions remains unclear. To understand the influence of sociality on brain evolution in ants, a premier clade of eusocial insects, we statistically analyzed patterns of brain region size covariation as a proxy for brain region connectivity. We investigated brain structure covariance in young and old workers of two formicine ants, the Australasian weaver ant Oecophylla smaragdina, a pinnacle of social complexity in insects, and its socially basic sister clade Formica subsericea. As previously identified in other ant species, we predicted that our analysis would recognize in both species an olfaction-related brain module underpinning social information processing in the brain, and a second neuroanatomical cluster involved in nonolfactory sensorimotor processes, thus reflecting conservation of compartmental connectivity. Furthermore, we hypothesized that covariance patterns would reflect divergence in social organization and life histories either within this species pair or compared to other ant species. Contrary to our predictions, our covariance analyses revealed a weakly defined visual, rather than olfactory, sensory processing cluster in both species. This pattern may be linked to the reliance on vision for worker behavioral performance outside of the nest and the correlated expansion of the optic lobes to meet navigational demands in both species. Additionally, we found that colony size and social organization, key measures of social complexity, were only weakly correlated with brain modularity in these formicine ants. Worker age also contributed to variance in brain organization, though in different ways in each species. These findings suggest that brain organization may be shaped by the divergent life histories of the two study species. We compare our findings with patterns of brain organization of other eusocial insects.
... However, the presence of evolutionarily conserved zones-and-stripes raises the possibility that patterning is important for functional compartmentalization, information processing, and the execution of behaviors (Attwell et al. 1999;Horn et al. 2010;Mostofi et al. 2010;Graham and Wylie 2012). This hypothesis is especially intriguing since stripe and zone representations can vary with ecological niche (Corfield et al. 2016), which is perhaps a reflection of species-related functional specializations (tenrec, Sillitoe et al. 2003; star-nosed mole, Marzban et al. 2015). Moreover, severe motor deficits develop in disease models where zone formation is delayed or stripe boundaries are left unrefined (Sarna and Hawkes 2003;Strømme et al. 2011;White et al. 2014White et al. , 2016. ...
Cerebellar architecture is organized around the Purkinje cell. Purkinje cells in the mouse cerebellum come in many different subtypes, organized first into four transverse zones and then further grouped into hundreds of reproducible topographical units – stripes. Stripes are identified by their functional properties, connectivity, and expression profiles. The molecular pattern of stripes is highly reproducible between individuals and is conserved through evolution. Pattern formation in the cerebellar cortex is a multistage process that begins with the generation of the Purkinje cells in the ventricular zone (VZ) of the fourth ventricle. During this stage, or shortly after, Purkinje cell subtypes are specified toward specific positions. Purkinje cells migrate from the VZ to form an array of clusters that form the framework for cerebellar topography. At around birth, these clusters begin to disperse, triggered by Reelin signaling pathway proteins, to form the adult stripe array.
The chapter will begin with a brief overview of adult cerebellar topography, primarily focusing on the mouse cerebellum, and then discuss the cellular and molecular mechanisms that establish these remarkable patterns. Considering how functionally diverse the cerebellum is despite its conserved organization of patterns, this chapter will end exploring how stripes might contribute to neuronal activity and the execution of cerebellar-dependent behaviors.
... Transverse zones evolve independently in response to different lifestyles (mosaic evolution). For example, in bats the echolocation centers in lobules VI/VII are accommodated by an expansion of the CZ- [87], and in the blind star-nosed mole, the CZ and NZ (visual receiving areas) are reduced and the trigeminal (star)receiving areas (NZ and crus I/II) are expanded [88]. In sum, the cerebellar cortex comprises of the order~10 1 transverse zones: in a mouse each of~10 4 Purkinje cells (PCs). ...
In the original version of this paper, the Title should have been written with "A Consensus paper" to read "Cerebellar Modules and Their Role as Operational Cerebellar Processing Units: A Consensus paper".
... Transverse zones evolve independently in response to different lifestyles (mosaic evolution). For example, in bats the echolocation centers in lobules VI/VII are accommodated by an expansion of the CZ- [87], and in the blind star-nosed mole, the CZ and NZ (visual receiving areas) are reduced and the trigeminal (star)receiving areas (NZ and crus I/II) are expanded [88]. In sum, the cerebellar cortex comprises of the order~10 1 transverse zones: in a mouse each of~10 4 Purkinje cells (PCs). ...
The compartmentalization of the cerebellum into modules is often used to discuss its function. What, exactly, can be considered a module, how do they operate, can they be subdivided and do they act individually or in concert are only some of the key questions discussed in this consensus paper. Experts studying cerebellar compartmentalization give their insights on the structure and function of cerebellar modules, with the aim of providing an up-to-date review of the extensive literature on this subject. Starting with an historical perspective indicating that the basis of the modular organization is formed by matching olivocorticonuclear connectivity, this is followed by consideration of anatomical and chemical modular boundaries, revealing a relation between anatomical, chemical, and physiological borders. In addition, the question is asked what the smallest operational unit of the cerebellum might be. Furthermore, it has become clear that chemical diversity of Purkinje cells also results in diversity of information processing between cerebellar modules. An additional important consideration is the relation between modular compartmentalization and the organization of the mossy fiber system, resulting in the concept of modular plasticity. Finally, examination of cerebellar output patterns suggesting cooperation between modules and recent work on modular aspects of emotional behavior are discussed. Despite the general consensus that the cerebellum has a modular organization, many questions remain. The authors hope that this joint review will inspire future cerebellar research so that we are better able to understand how this brain structure makes its vital contribution to behavior in its most general form.
... ZII is expressed heterogeneously such that bands of high ZII expression (ZII+) are interdigitated with bands of little to no ZII expression (ZII−; Figure 1). ZII stripes are seen in several mammalian ( Leclerc et al., 1992;Ozol et al., 1999;Armstrong and Hawkes, 2000;Sanchez et al., 2002;Marzban et al., 2003Marzban et al., , 2015Sillitoe et al., 2003a,b;Marzban and Hawkes, 2011) and avian species Iwaniuk et al., 2009;Marzban et al., 2010;Corfield et al., 2015Corfield et al., , 2016Vibulyaseck et al., 2015), as well as in one genus of lizards ( Wylie et al., 2016). The prevalence of ZII stripes across various species suggests that the role for ZII is highly conserved, and is likely crucial to cerebellar function. ...
This study was aimed at mapping the organization of the projections from the inferior olive (IO) to the ventral uvula in pigeons. The uvula is part of the vestibulocerebellum (VbC), which is involved in the processing of optic flow resulting from self-motion. As in other areas of the cerebellum, the uvula is organized into sagittal zones, which is apparent with respect to afferent inputs, the projection patterns of Purkinje cell (PC) efferents, the response properties of PCs and the expression of molecular markers such as zebrin II (ZII). ZII is heterogeneously expressed such that there are sagittal stripes of PCs with high ZII expression (ZII+), alternating with sagittal stripes of PCs with little to no ZII expression (ZII−). We have previously demonstrated that a ZII+/− stripe pair in the uvula constitutes a functional unit, insofar as the complex spike activity (CSA) of all PCs within a ZII+/− stripe pair respond to the same type of optic flow stimuli. In the present study we sought to map the climbing fiber (CF) inputs from the IO to the ZII+ and ZII− stripes in the uvula. We injected fluorescent Cholera Toxin B (CTB) of different colors (red and green) into ZII+ and ZII− bands of functional stripe pair. Injections in the ZII+ and ZII− bands resulted in retrograde labeling of spatially separate, but adjacent regions in the IO. Thus, although a ZII+/− stripe pair represents a functional unit in the pigeon uvula, CF inputs to the ZII+ and ZII− stripes of a unit arise from separate regions of the IO.
