Ins and outs of cerebellar modules - PubMed (original) (raw)

Ins and outs of cerebellar modules

Tom J H Ruigrok. Cerebellum. 2011 Sep.

Abstract

The modular concept of cerebellar connections has been advocated in the lifetime work of Jan Voogd. In this concept, a cerebellar module is defined as the conglomerate of one or multiple and non-adjacent, parasagittally arranged zones of Purkinje cells, their specific projection to a well-defined region of the cerebellar nuclei, and the climbing fiber input to these zones by a well-defined region of the inferior olivary complex. The modular organization of these olivo-cortico-nuclear connections is further exemplified by matching reciprocal connections between inferior olive and cerebellar nuclei. Because the different regions of the cerebellar nuclei show highly specific output patterns, cerebellar modules have been suggested to constitute functional entities. This idea is strengthened by the observation that anatomically defined modules adhere to the distribution of chemical markers in the cerebellar cortex suggesting that modules not only differ in their input and output relations but also may differ in operational capabilities. Here, I will briefly review some recent data on the establishment of cerebellar modules in rats. Furthermore, some evidence will be shown suggesting that the other main afferent system (i.e., mossy fibers), at least to some extent, also adheres to the modular organization. Finally, using retrograde transneuronal tracing with rabies virus, some evidence will be provided that several cerebellar modules may be involved in the control of individual muscles.

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Figures

Fig. 1.

Fig. 1.

Schematic diagrams of cerebellar modules. a Basic diagram of a generalized cerebellar module and its connections. A strip of Purkinje cells receives input from a selected area of the inferior olive and projects to a specific region of the cerebellar nuclei. Reciprocal connections between olive and nuclei complete the module. The output of a module is directed to premotor areas in the brainstem as well as to the thalamus. In addition, feedback is provided to precerebellar mossy fiber systems such as the pontine nuclei, as well as to midbrain areas known to provide input to the inferior olive. b Diagram illustrating parallel organization of three cerebellar modules, each with their own specific output. Parallel fiber beams are included because they represent an obvious way of connecting modules. Modified from Ruigrok [59]

Fig. 2.

Fig. 2.

a Diagram of the unfolded and flattened cerebellar cortex of the rat on which the zebrin II pattern has been indicated. b Similar diagram together with the longitudinal zonal climbing fiber pattern with colors that reflect the position of the BDA injections in a flattened reconstruction of the inferior olivary complex (c) and the related climbing fiber collateral labeling in a similarly prepared image of the flattened cerebellar nuclei (d). e1 Example of a BDA-labeled climbing fiber (black) terminating on the soma and dendrite of a zebrin II-positive Purkinje cell. e2 Example of a zebrin II-positive Purkinje cell (arrow), retrogradely labeled with gold–lectin after a small gold–lectin injection in the posterior interposed nucleus and innervated by a BDA-labeled climbing fiber resulting from a BDA injection into the rostral part of the medial accessory olive. Modified from Pijpers et al. [7]

Fig. 3.

Fig. 3.

Modular organization of mossy fiber projections. a Example of BDA injection in center of the left basal pontine nuclei of the mouse (B036). b Resulting labeling of mossy fiber rosettes in crus 2. Arrows point to two separate clusters of terminals. c 3D reconstruction based on plots of one out of every two sections showing the brainstem and transparent cerebellum (case B036). Labeled mossy fiber rosettes are indicated with yellow dots. In this view, approximately four longitudinal patterns of mossy fiber terminals can be appreciated at the right hand side of the posterior cerebellum. d Location of four CTb injections in the paravermis of lobules VII and VIII indicated in a standardized zebrin II representation of the caudal cerebellum. e Example of the resulting labeling in case AP09 in the anterior cerebellum. Red coloring indicates the position of terminal climbing fiber collaterals within the molecular layer, whereas green dots represent mossy fiber rosettes. Note that climbing fiber labeling is accompanied by dense labeling of mossy fiber rosettes. f Relation of resulting climbing fiber collateral labeling with that of mossy fiber collateral labeling in case AP03 with an injection into the C1 zone of lobule VII (paramedian lobule; PMD). Left hand panel shows position of labeled climbing fibers in a representation of the unfolded and flattened cerebellar cortex. Injection site is marked with an arrow. Right hand panel shows the distribution and density of mossy fiber terminals. Again, note that regions with climbing fiber labeling relate to high densities of labeled rosettes. g Similar to f for case GR03 with an injection in C1 of lobule VIII (COP copula). Note the difference in general lobular distribution of the labeling. h 3D reconstruction of resulting terminal climbing and mossy fiber labeling in case 979 where the injection was centered on C1 of PMD. Left hand panel shows the subpial surface of lobules V, simple lobule, and crus 1 (yellow). Middle panel shows the Purkinje cell layer (light blue) with labeled climbing fiber terminals (red). Left hand panel shows white matter contours with climbing fiber (red) and mossy fiber terminals (green). Note two strips of mossy fiber labeling, the middle of which accompanies the climbing fiber strip. Modified from Pijpers et al. [25]

Fig. 4.

Fig. 4.

Demonstration of modular organization of mossy fiber projection with nuclear injection of CTb. a Injection of CTb in the anterior interposed nucleus (AIN). b Distribution of retrogradely labeled olivary neurons (arrow) was confined to the dorsal accessory olive (DAO). c Overview of cortical labeling in lobules IV and V indicating strip-like pattern of labeling (arrows). d Detail of labeling in lobule V where retrogradely labeled Purkinje cells are noted with overlying labeled climbing fibers (arrows) and underlying labeling of mossy fiber rosettes (arrowheads). e 3D representations of anterior lobe and simple lobule (SL) with fourth ventricle (green). Left hand upper panel shows Purkinje cell layer (light blue) with location of labeled climbing fibers (red). Middle panel shows transparent Purkinje cell layer with labeled Purkinje cells (yellow) together with climbing fiber labeling (red). Bottom panel shows white matter contour (dark blue) together with mossy fiber terminal labeling (green), Purkinje cell labeling (yellow), and climbing fiber labeling (red). Labeling is seen without cerebellar contours in right hand panels (upper panel climbing and mossy fiber terminals and Purkinje cells; middle panel mossy fiber terminal labeling together with Purkinje cell labeling; bottom panel mossy fiber terminal labeling only). Note that all types of labeling clearly overlap in a parasagittally arranged strip in lobules IV/V of the cerebellar cortex

Fig. 5.

Fig. 5.

Demonstration of involvement of multiple cerebellar modules in the control of single muscles using transneuronal retrograde transport of rabies virus in rat. a1 Pattern of Purkinje cell labeling in the lateral vermis 5 days after rabies injection in the ipsilateral gastrocnemius. a2 3D reconstruction of the anterior lobe of this case indicating rabies-labeled Purkinje cells (red) together with zebrin II-labeled Purkinje cells (yellow). Note that the zebrin II-labeled bands identified as p1–p6 can all be recognized. The position of the rabies-labeled Purkinje cells between p2 and p3 (left hand white arrowhead) is identical to that of the B zone [11]. In addition, a contralateral strip of labeled Purkinje cells is noted just medial to the p2 zebrin II band (right hand white arrowhead), which corresponds to the location of the lateral A1 zone. b1, 2 Similar to a1, 2 after injection of rabies virus in the ipsilateral tibialis anterior muscle. This time both the B and lateral A1 zone (arrowhead) are noted ipsilateral to the injection. c Pattern of infection 6 days after injection of the gastrocnemius muscle. Note that the original zones can still be recognized but also have a mirror representation in the other cerebellar half. However, several additional zones are also recognized (arrowhead) in paravermis and hemisphere (not shown). d Similar to c for injection of the tibialis anterior. Modified from Ruigrok et al. [28]

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