The Theories of Gerbrandus Jelgersma (1859-1942) on the Function of the Cerebellum.

Gerbrandus Jelgersma published extensively on the (pathological) anatomy of the cerebellum between 1886 and 1934. Based on his observations on the double innervation of the Purkinje cells, he formulated a hypothesis on the function of the cerebellum. Both afferent systems of the cerebellum, the mossy fiber-parallel fiber system and the climbing fibers terminate on the Purkinje cell dendrites. According to Jelgersma, the mossy fiber-parallel fiber system is derived from the pontine nuclei and the inferior olive, and would transmit the movement images derived from the cerebral cortex. Spinocerebellar climbing fibers would transmit information about the execution of the movement. When the Purkinje cell compares these inputs and notices a difference between instruction and execution, it sends a correction through the descending limb of the superior cerebellar peduncle to the anterior horn cells. Jelgersma postulates that this cerebro-cerebellar coordination system shares plasticity with other nervous connections because nerve cell dendritic protrusions possess what he called amoeboid mobility: dendritic protrusions can be extended or retracted and are so able to create new connections or to abolish them. Jelgersma's theories are discussed against the background of more recent theories of cerebellar function that, similarly, are based on the double innervation of the Purkinje cells. The amoeboid hypothesis is traced to its roots in the late nineteenth century.

Cerebellum: What is in a Name? Historical Origins and First Use of This Anatomical Term.

In this paper, we study who first used the Latin anatomical term "cerebellum" for the posterior part of the brain. The suggestion that this term was introduced by Leonardo da Vinci is unlikely. Just before the start of the da Vinci era in the fifteenth century, several authors referred to the cerebellum as "cerebri posteriorus." Instead, in his translation of Galen's anatomical text De utilitare particularum of 1307, Nicolo da Reggio used the Latinized Greek word "parencephalon." More peculiar was the Latin nautical term "puppi," referring to the stern of a ship, that was applied to the cerebellum by Constantine the African in his translation of the Arabic Liber regius in the eleventh century. The first to use the term "cerebellum" appears to be Magnus Hundt in his Anthropologia from 1501. Like many of the anatomists of this period, he was a humanist with an interest in classical literature. They may have encountered the term "cerebellum" in the writings by classical authors such as Celsus, where it was used as the diminutive of "cerebrum" for the small brains of small animals, and, subsequently, applied the term to the posterior part of the brain. In the subsequent decades of the sixteenth century, an increasing number of pre-Vesalian authors of anatomical texts started to use the name "cerebellum," initially often combined with one or more of the earlier terms, but eventually more frequently in isolation. We found that a woodcut in Dryander's Anatomia capitis humani of 1536 is the first realistic picture of the cerebellum.

Correction to: Cerebellar Modules and Their Role as Operational Cerebellar Processing Units: A Consensus paper.

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".

Cerebellar Modules and Their Role as Operational Cerebellar Processing Units: A Consensus paper [corrected].

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.

Deiters' Nucleus. Its Role in Cerebellar Ideogenesis : The Ferdinando Rossi Memorial Lecture.

Otto Deiters (1834-1863) was a promising neuroscientist who, like Ferdinando Rossi, died too young. His notes and drawings were posthumously published by Max Schultze in the book "Untersuchungen über Gehirn und Rückenmark." The book is well-known for his dissections of nerve cells, showing the presence of multiple dendrites and a single axon. Deiters also made beautiful drawings of microscopical sections through the spinal cord and the brain stem, the latter showing the lateral vestibular nucleus which received his name. This nucleus, however, should be considered as a cerebellar nucleus because it receives Purkinje cell axons from the vermal B zone in its dorsal portion. Afferents from the labyrinth occur in its ventral part. The nucleus gives rise to the lateral vestibulospinal tract. The cerebellar B module of which Deiters' nucleus is the target nucleus was used in many innovative studies of the cerebellum on the zonal organization of the olivocerebellar projection, its somatotopical organization, its microzones, and its role in posture and movement that are the subject of this review.

The horseshoe-shaped commissure of Wernekinck or the decussation of the brachium conjunctivum methodological changes in the 1840s.

Up till the 1840s, gross dissection was the only method available to study the tracts and fascicles of the white matter of the human brain. This changed dramatically with the introduction by Stilling (1842, 1843, 1846) of the microscopy of serial sections and his demonstration of the discriminative power of this method. The decussation of the brachium conjunctivum (the superior cerebellar peduncle) (International Anatomical Terminology (1998)) originally was known as the horseshoe-shaped commissure of Wernekinck. The first use of this name and the first illustrations of this commissure date from a book by Wernekinck's successor, Wilbrand (1840).Using gross dissection, he concluded that the commissure connects the dentate nucleus with the contralateral inferior olive. A few years later, Stilling (1846), using microscopy of serial sections through the human brain stem, illustrated the entire course of the brachium conjunctivum, its decussation,and its crossed ascending branch, up to the red nucleus. From his work, it became clear that Wernekinck and Wilbrand had included the central tegmental tract in their commissure, and that they had failed to identify its ascending branch.

Integrated assessment of agricultural practices on large scale losses of ammonia, greenhouse gases, nutrients and heavy metals to air and water.

To gain insight in the environmental impacts of crop, soil and nutrient management, an integrated model framework INITIATOR was developed predicting: (i) emissions of ammonia (NH3) and greenhouse gases (GHG) from agriculture, including animal husbandry and crop production and (ii) accumulation, leaching and runoff of carbon, nutrients (nitrogen, N, phosphorus, P, and base cations) and metals in or from soils to groundwater and surface water in the Netherlands. Key processes in soil are included by linear or non-linear process formulations to maintain transparency and to enable data availability for spatially explicit application from field up to national level. Calculated national trends in nutrient losses over 2000-2020 compared well with independent estimates and showed a reduction in N and P input of 26 to 33 %, whereas the surplus declined by 33 % for N and 86 % for P due to increased crop yields and reduced inputs. This was accompanied by a reduction of 30-35 % in atmospheric emissions of ammonia and nitrous oxide as well a decline in N and P runoff of 35 and 10 %, respectively, whereas the emission of methane increased with 4 %. Model results compared well with (i) large scale observations of ammonia concentrations in air and nitrate concentrations in upper groundwater and ditch water, (ii) with nitrous oxide emissions and phosphorus adsorption in experiments at field scale and (iii) with metal adsorption in large scale soil datasets. Various mitigation measures were evaluated in view of policy ambitions for climate, soil and environmental quality for 2030, i.e. a reduction of 50 % for NH3, 11-17 % for GHG, 20 % for N runoff and 40 % for P runoff and an ambition of 50 % GHG emission reduction for 2050. The measures focused on a combination of animal feeding, low emission housing and application technologies, improved crop, soil and nutrient management, all being applied with an effectiveness of 100 % and 50 %, respectively. In addition, we evaluated impacts of 50 % livestock reduction, and combination scenarios of measures and livestock reduction. Full implementation of all measures can reduce NH3 emission, N leaching and N runoff by approximately 40-50 % and GHG emissions by approximately 30 %, but there is less potential to reduce P runoff, being <10 %. The combination of a more likely 50 % implementation/effectiveness of measures with 25 % livestock reduction leads to a comparable reduction. Required reductions from Dutch agriculture seem not possible with improved management only, but also requires livestock reduction, especially when the NH3 ambitions at the short term (2030) and the climate ambitions for the long term (2050) should be attained.

Visuomotor cerebellum in human and nonhuman primates.

In this paper, we will review the anatomical components of the visuomotor cerebellum in human and, where possible, in non-human primates and discuss their function in relation to those of extracerebellar visuomotor regions with which they are connected. The floccular lobe, the dorsal paraflocculus, the oculomotor vermis, the uvula-nodulus, and the ansiform lobule are more or less independent components of the visuomotor cerebellum that are involved in different corticocerebellar and/or brain stem olivocerebellar loops. The floccular lobe and the oculomotor vermis share different mossy fiber inputs from the brain stem; the dorsal paraflocculus and the ansiform lobule receive corticopontine mossy fibers from postrolandic visual areas and the frontal eye fields, respectively. Of the visuomotor functions of the cerebellum, the vestibulo-ocular reflex is controlled by the floccular lobe; saccadic eye movements are controlled by the oculomotor vermis and ansiform lobule, while control of smooth pursuit involves all these cerebellar visuomotor regions. Functional imaging studies in humans further emphasize cerebellar involvement in visual reflexive eye movements and are discussed.

Cerebellar zones: a personal history.

Cerebellar zones were there, of course, before anyone noticed them. Their history is that of young people, unhindered by preconceived ideas, who followed up their observations with available or new techniques. In the 1960s of the last century, the circumstances were fortunate because three groups, in Leiden, Lund, and Bristol, using different approaches, stumbled on the same zonal pattern in the cerebellum of the cat. In Leiden, the Häggqvist myelin stain divulged the compartments in the cerebellar white matter that channel the afferent and efferent connections of the zones. In Lund, the spino-olivocerebellar pathways activated from individual spinal funiculi revealed the zonal pattern. In Bristol, charting the axon reflex of olivocerebellar climbing fibers on the surface of the cerebellum resulted in a very similar zonal map. The history of the zones is one of accidents and purposeful pursuit. The technicians, librarians, animal caretakers, students, secretaries, and medical illustrators who made it possible remain unnamed, but their contributions certainly should be acknowledged.

Spatially explicit boundaries for agricultural nitrogen inputs in the European Union to meet air and water quality targets.

Agricultural production in the EU has increased strongly since the 1940s, partly driven by increased nitrogen (N) fertiliser and manure inputs. Increased N inputs and associated losses, however, adversely affect air and water quality, with widespread impacts on terrestrial and aquatic ecosystems and human health. Managing these impacts requires knowledge on 'safe boundaries' for N inputs, i.e., N flows that do not exceed environmental thresholds. We used a spatially explicit N balance model for the EU to derive boundaries for N losses and associated N inputs for three environmental thresholds: (i) N deposition onto natural areas to protect terrestrial biodiversity (critical N loads), (ii) N concentration in runoff to surface water (2.5 mg N l-1) to protect aquatic ecosystems and (iii) nitrate (NO3-) concentration in leachate to groundwater (50 mg NO l-1) to meet the EU drinking water standard. Critical N losses and inputs were calculated for ~40,000 unique soil-slope-climate combinations and then aggregated at country- and EU-level. To respect thresholds for N deposition, N inputs in the EU need to be reduced by 31% on average, ranging from 0% in several countries to 59% in Ireland and Denmark. The strongest reductions are required in intensive livestock regions, such as Benelux, Brittany and the Po valley. To respect thresholds for N concentration in runoff to surface water, N inputs need to be reduced by 43% on average, ranging from 2% in Estonia to 74% in the Netherlands. Average critical N inputs in view of the threshold for NO3- concentration in leachate to groundwater are close to actual (year 2010) inputs, even though leaching thresholds are exceeded in 18% of agricultural land. Critical N inputs and their exceedances presented in this paper can inform more targeted mitigation policies than flat-rate targets for N loss reductions currently mentioned in EU policies.

Historic notes on anatomic, physiologic, and clinical research on the cerebellum.

This chapter is concerned with ideas on the function, structure, and pathology that shaped our present knowledge of the cerebellum. One of the main themes in its early history is its localization subtentorially, leading to misattributions due to clinical observations in trauma and lesion experiments that caused collateral damage to the brainstem. Improvement of techniques led to the insight that it plays a role in movement control (Rolando) or coordination (Flourens). Purkinje initiated the histology of the cerebellar cortex in 1837. Luciani's experiments in 1891 led him to conclude that the cerebellum has a tonic facilitating effect on central structures. Cajal identified the elements of the cortex and their circuitry (1888-1891). The inhibitory nature of the interneurons and the Purkinje cells, and the excitatory connections of the mossy and climbing afferents and the granule cells were established much later by Eccles and Ito. A functional localization for the coordinating action of the cerebellum of the motor system, based on local expansion of the folial chains, was devised by Bolk in 1906. Babinski and Holmes contributed to anatomoclinical insights. Magnus and coworkers showed the cerebellum does not play an essential role in body posture. The heterogeneity of the Purkinje cells with respect to their connections and histochemistry found its expression in the zonal organization of the cerebellar cortex. The roots of modern developments, like cerebellar learning and its involvement in cognition and emotion, can be traced to the theories of Marr and Albus and the pioneering work of the Leiners and Dow.

A comparison of disaggregated nitrogen budgets for Danish agriculture using Europe-wide and national approaches.

Spatially detailed information on agricultural nitrogen (N) budgets is relevant to identify regions where there is a need for a reduction in inputs in view of various forms of N pollution. However, at the scale of the European Union, there is a lack of consistent, reliable, high spatial resolution data necessary for the calculation of regional N losses. To gain insight in the reduction in uncertainty achieved by using higher spatial resolution input data. This was done by comparing spatially disaggregated agricultural N budgets for Denmark for the period 2000-2010, generated by two versions of the European scale model Integrator, a version using high spatial resolution national data for Denmark (Integrator-DK) and a version using available data at the EU scale (Integrator-EU). Results showed that the national N fluxes in the N budgets calculated by the two versions of the model were within 1-5% for N inputs by fertilizer and manure excretion, but inputs by N fixation and N mineralisation differed by 50-100% and N uptake also differed by ca 25%, causing a difference in N leaching and runoff of nearly 50%. Comparison with an independently derived Danish national budget appeared generally to be better with Integrator-EU results in 2000 but with Integrator-DK results in 2010. However, the spatial distribution of manure distribution and N losses from Integrator-DK were closer to observed distributions than those from Integrator-EU. We conclude that close attention to local agronomic practices is needed when using a leaching fraction approach and that for effective support of environmental policymaking, Member States need to collect or submit high spatial resolution agricultural data to Eurostat.

The basal interstitial nucleus (BIN) of the cerebellum provides diffuse ascending inhibitory input to the floccular granule cell layer.

The basal interstitial nucleus (BIN) in the white matter of the vestibulocerebellum has been defined more than three decades ago, but has since been largely ignored. It is still unclear which neurotransmitters are being used by BIN neurons, how these neurons are connected to the rest of the brain and what their activity patterns look like. Here, we studied BIN neurons in a range of mammals, including macaque, human, rat, mouse, rabbit, and ferret, using tracing, immunohistological and electrophysiological approaches. We show that BIN neurons are GABAergic and glycinergic, that in primates they also express the marker for cholinergic neurons choline acetyl transferase (ChAT), that they project with beaded fibers to the glomeruli in the granular layer of the ipsilateral floccular complex, and that they are driven by excitation from the ipsilateral and contralateral medio-dorsal medullary gigantocellular reticular formation. Systematic analysis of codistribution of the inhibitory synapse marker VIAAT, BIN axons, and Golgi cell marker mGluR2 indicate that BIN axon terminals complement Golgi cell axon terminals in glomeruli, accounting for a considerable proportion ( > 20%) of the inhibitory terminals in the granule cell layer of the floccular complex. Together, these data show that BIN neurons represent a novel and relevant inhibitory input to the part of the vestibulocerebellum that controls compensatory and smooth pursuit eye movements.

Precise spatial relationships between mossy fibers and climbing fibers in rat cerebellar cortical zones.

Classically, mossy fiber and climbing fiber terminals are regarded as having very different spatial distributions in the cerebellar cortex. However, previous anatomical studies have not studied these two major cerebellar inputs with sufficient resolution to confirm this assumption. Here, we examine the detailed pattern of collateralization of both types of cerebellar afferent using small injections of the bidirectional tracer cholera toxin b subunit into the posterior cerebellum. The cortical and zonal location of these injections was characterized by mapping climbing fiber field potentials, the distribution of retrogradely labeled olivary neurons, and the intrinsic zebrin pattern of Purkinje cells. Labeled climbing fiber collaterals were distributed as longitudinal strips and were always accompanied by clusters of labeled mossy fiber rosettes in the subjacent granular layer. Two- and three-dimensional reconstructions and quantitative analysis showed that mossy fibers also collateralized to other stripe-like regions usually below Purkinje cells with the same zebrin-positive or zebrin-negative characteristics as that of the injection site and associated climbing fiber collaterals. The distribution of retrogradely labeled neurons in two major sources of mossy fibers, the lateral reticular and basilar pontine nuclei, revealed interlobular and some interzonal differences. These data indicate that nonadjacent cerebellar zones, sharing the same climbing fiber input and zebrin identity, also share a common mossy fiber input. Other cerebellar cortical regions that receive collaterals from the same mossy fibers usually also have the same zebrin signature. Together with the distribution of neurons in precerebellar centers, the findings suggest a revision of the modular hypothesis for information processing in the cerebellar cortex.

Zonal organization of the mouse flocculus: physiology, input, and output.

The zones of the flocculus have been mapped in many species with a noticeable exception, the mouse. Here, the functional map of the mouse was constructed via extracellular recordings followed by tracer injections of biotinylated-dextran-amine and immunohistochemistry for heat-shock protein-25. Zones were identified based on the Purkinje cell complex spike modulation occurring in response to optokinetic stimulation. In zones 1 and 3 Purkinje cells responded best to rotation about a horizontal axis oriented at 135 degrees ipsilateral azimuth, whereas in zones 2 and 4 they responded best to rotation about the vertical axis. The tracing experiments showed that Purkinje cells of zone 1 projected to the parvicellular part of lateral cerebellar nucleus and superior vestibular nucleus, while Purkinje cells of zone 3 projected to group Y and the superior vestibular nucleus. Purkinje cells of zones 2 and 4 projected to the magnocellular and parvicellular parts of the medial vestibular nucleus, while some also innervated the lateral vestibular nucleus or nucleus prepositus hypoglossi. The climbing fiber inputs to Purkinje cells in zones 1 and 3 were derived from neurons in the ventrolateral outgrowth of the contralateral inferior olive, whereas those in zones 2 and 4 were derived from the contralateral caudal dorsal cap. Purkinje cells in zones 1 and 2, but not in zones 3 and 4, were positively labeled for heat-shock protein-25. The present study illustrates that Purkinje cells in the murine flocculus are organized in discrete zones with specific functions, specific input - output relations, and a specific histochemical signature.

The distribution of climbing and mossy fiber collateral branches from the copula pyramidis and the paramedian lobule: congruence of climbing fiber cortical zones and the pattern of zebrin banding within the rat cerebellum.

Individual cerebellar cortical zones defined by the somatotopy of climbing fiber responses and by their olivo-cortico-nuclear connections located in the paramedian lobule and the copula pyramidis of the rat cerebellum were microinjected with cholera toxin B subunit. Collateral branches of climbing and mossy fibers were mapped and related to the pattern of zebrin-positive and -negative bands of Purkinje cells. Climbing fiber collaterals from the copula distribute to the anterior lobe: from the paramedian lobule mainly to lobulus simplex and rostral crus I. Climbing fibers terminating in particular zones (X, A2, C1, CX, C2, C3, D1, and D2) in the paramedian lobule or the copula collateralize to one or two corresponding zones in lobulus simplex, crus I and II, the paraflocculus, and/or the anterior lobe. These zones can be defined by their relationship to the pattern of zebrin banding. Collaterals from mossy fibers, labeled from the same injection sites in the copula and paramedian lobule, often distribute bilaterally in a symmetrical pattern of multiple but ill-defined longitudinal strips in the anterior lobe and/or lobulus simplex. One or more of these longitudinal aggregates of mossy fiber collaterals was always found subjacent to the strip(s) of labeled climbing fiber collaterals arising from the same locus in the paramedian lobule or the copula. Corticonuclear projections focused on the target nucleus of each zone, although a bilateral plexus of thinner axons, presumably of mossy fiber collateral origin, was sometimes also present in several other regions of the cerebellar nuclei. Overall, these results suggest that climbing fiber zones and zebrin banding reflect a common organizational scheme within the cerebellar cortex.

Topography of olivo-cortico-nuclear modules in the intermediate cerebellum of the rat.

This study provides a detailed anatomical description of the relation between olivo-cortico-nuclear modules of the intermediate cerebellum of the rat and the intrinsic zebrin pattern of the Purkinje cells. Strips of climbing fibers were labeled using small injections of biotinylated dextran amine into either the medial or dorsal accessory olives, while, in some cases, simultaneous retrograde labeling of Purkinje cells was obtained using gold-lectin injections into selected parts of the interposed nuclei. Our data are represented in a new, highly detailed, cortical surface reconstruction of the zebrin pattern and in relation to the collateral labeling of the climbing fibers to the cerebellar nuclei. We show that the somatotopic regions of the dorsal accessory olive behave differently in their projections to essentially zebrin-negative regions that represent the C1 and C3 zones of the anterior and posterior parts of the cortex. The rostral part of the medial accessory olive projects to zebrin-positive areas, in particular to the P4+ band of the anterior lobe and lobule VI and to the P5+ band of the posterior lobe, indicating that C2 has two noncontiguous representations in the SL and crus 1. By relating the areas of overlap that resulted from the injections in the accessory olives, i.e., labeling of climbing fiber strips and patches of climbing fiber nuclear collaterals, with the results from the injections in the interposed nuclei, i.e., retrograde labeling of Purkinje cells and of inferior olivary neurons, direct verification of the concept of modular cerebellar connections was obtained.

The human cerebellum.

This short review deals with observations on the gross morphology and internal structure of the human cerebellum, and with studies of cerebellar fiber connections in non-human primates. Attention is focussed on its gross anatomy, the zonal organization of the primate cerebellum, the brain stem, thalamic and cortical connections of the cerebellar nuclei and on the cortico-ponto-cerebellar pathway. The presence of important reciprocal nucleo-mesencephalo-olivary loops as part of the circuitry of the dentate and globose (posterior interposed) nuclei and their absence among the connections of other cerebellar nuclei is emphasized.

What we do not know about cerebellar systems neuroscience.

Our knowledge of the modular organization of the cerebellum and the sphere of influence of these modules still presents large gaps. Here I will review these gaps against our present anatomical and physiological knowledge of these systems.