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Key Points At least three different viewpoints have emerged of cerebellar cortical topography, based on the anatomy and physiology of climbing fibre inputs and Purkinje cell outputs, the physiology of mossy fibre inputs, restriction boundaries in gene expression and regional differences in Purkinje cell phenotype. In this Review we consider some of the more commonly used terminology to describe cerebellar cortical organization with a view to providing some clarification. Overarching this, we argue the different terminologies are in fact unnecessary because both developmental and adult studies suggest that the different mapping techniques — anatomical, physiological and molecular — reveal different facets of a common topography. The one-map hypothesis proposes that cerebellar architecture is built around an array of interdigitated transverse zones, each of which is subdivided into a series of rostrocaudally oriented Purkinje cell stripes, defined by the restricted expression of molecular markers, that are symmetrically distributed across the midline, highly reproducible between individuals, and conserved across species. The most comprehensively studied marker is zebrin II, which cloning studies revealed to be the metabolic enzyme aldolase C. The molecular identity of each stripe may already be determined at the time the Purkinje cells become postmitotic, and, at the time a mouse is born, the molecular identity of individual Purkinje cells seems to be set and independent of cerebellar connectivity. The embryonic Purkinje cell clusters are the targets of the developing climbing fibre and mossy fibre afferents and, through this matching, the Purkinje cells form a template around which afferent topography is constructed. Anatomical and physiological studies in adult animals have shown that climbing fibre afferents from different parts of the contralateral inferior olive form longitudinal zones within the cerebellar cortex. In some cases these zones can be subdivided into smaller units called microzones. Investigation of the relationship between longitudinal zones and Purkinje cell stripes has revealed extensive co-localization, consistent with the one-map hypothesis. Anatomical studies have also found that mossy fibre terminal fields align with Purkinje cell stripes and also with climbing fibres associated with individual longitudinal zones, suggesting a common principle of organization. By contrast, other studies support the notion that mossy fibres terminate as patches to form a fractured somatotopical map within the cerebellar cortex. The apparent discrepancy between stripes and patches may be explained by individual Purkinje cell stripes being subdivided into chains of small patches or microzones, which can be revealed by differential gene expression or electrophysiological mapping. The one-map hypothesis therefore proposes that transverse zones are subdivided into stripes (one or more stripes equals a longitudinal zone); and stripes are further segmented longitudinally into microzones that correspond to one or more small patches. The functional significance of this elaborate architecture remains to be determined but may be used for parallel processing of sensorimotor commands, energy efficient information processing, positional coding of sensory inputs and/or molecular fine-tuning of local circuits for specific functions such as motor learning. The connections in the cerebellum are highly complex, and different experimental approaches have resulted in several maps of cerebellar organization. Reviewing anatomical, physiological and molecular studies, Apps and Hawkes show that different maps might represent facets of a common topography. The fundamental architecture of the cerebellum is concealed within a terminological forest — transverse zones and stripes, longitudinal zones and microzones, patches, etc. To make things worse, the same term is used in different contexts to describe quite different patterns of spatial localization. Here we consider the possibility that this complexity hides the fact that the cerebellar cortex contains only one map, which has been charted in various ways.

Key Points A widely held assumption is that the same neural computation is performed throughout a uniform circuitry in the adult mammalian cerebellar cortex, and differences in function can be explained primarily by distinct patterns of input and output connectivity. Anatomical, genetic and physiological evidence suggests, however, that the cerebellar cortex is not uniform. Regional differences include variations in cell type, morphology and expression of various molecular markers, most notably zebrin II expression by Purkinje cells. Purkinje cells are considered to be key players within the cerebellar cortex because they provide the sole signal output from the cortex to the cerebellar nuclei. Differences related to zebrin II expression include variations in intrinsic and synaptic physiology and patterns of activity of simple spikes and complex spikes. Mouse mutant models also show that Purkinje cell death occurs in restricted patterns that are related to both motor and potentially non-motor dysfunction. Variations in gene expression and related anatomical and physiological differences therefore result in an assembly of non-uniform cerebellar cortical microcircuits that have different information processing capabilities. The cerebellar cortex drives smooth goal-directed movement as well as a range of other functions. Apps and colleagues describe studies that have revealed variations in the cytoarchitecture, molecular composition, physiological properties and vulnerability to cell death of different cerebellar cortical regions, and discuss the idea that these underlie different forms of information processing. The adult mammalian cerebellar cortex is generally assumed to have a uniform cytoarchitecture. Differences in cerebellar function are thought to arise primarily through distinct patterns of input and output connectivity rather than as a result of variations in cortical microcircuitry. However, evidence from anatomical, physiological and genetic studies is increasingly challenging this orthodoxy, and there are now various lines of evidence indicating that the cerebellar cortex is not uniform. Here, we develop the hypothesis that regional differences in properties of cerebellar cortical microcircuits lead to important differences in information processing.

Behavioural feedback is critical for learning in the cerebral cortex. However, such feedback is often not readily available. How the cerebral cortex learns efficiently despite the sparse nature of feedback remains unclear. Inspired by recent deep learning algorithms, we introduce a systems-level computational model of cerebro-cerebellar interactions. In this model a cerebral recurrent network receives feedback predictions from a cerebellar network, thereby decoupling learning in cerebral networks from future feedback. When trained in a simple sensorimotor task the model shows faster learning and reduced dysmetria-like behaviours, in line with the widely observed functional impact of the cerebellum. Next, we demonstrate that these results generalise to more complex motor and cognitive tasks. Finally, the model makes several experimentally testable predictions regarding cerebro-cerebellar task-specific representations over learning, task-specific benefits of cerebellar predictions and the differential impact of cerebellar and inferior olive lesions. Overall, our work offers a theoretical framework of cerebro-cerebellar networks as feedback decoupling machines. Behavioral feedback is critical for learning, but it is often not available. Here, the authors introduce a deep learning model in which the cerebellum provides the cerebrum with feedback predictions, thereby facilitating learning, reducing dysmetria, and making several experimental predictions.

Increased risk of premature cardiovascular disease (CVD) is well recognized in systemic lupus erythematosus (SLE). Aberrant type I-Interferon (IFN)-neutrophil interactions contribute to this enhanced CVD risk. In lupus animal models, the Janus kinase (JAK) inhibitor tofacitinib improves clinical features, immune dysregulation and vascular dysfunction. We conducted a randomized, double-blind, placebo-controlled clinical trial of tofacitinib in SLE subjects (ClinicalTrials.gov NCT02535689). In this study, 30 subjects are randomized to tofacitinib (5 mg twice daily) or placebo in 2:1 block. The primary outcome of this study is safety and tolerability of tofacitinib. The secondary outcomes include clinical response and mechanistic studies. The tofacitinib is found to be safe in SLE meeting study’s primary endpoint. We also show that tofacitinib improves cardiometabolic and immunologic parameters associated with the premature atherosclerosis in SLE. Tofacitinib improves high-density lipoprotein cholesterol levels ( p  = 0.0006, CI 95%: 4.12, 13.32) and particle number ( p  = 0.0008, CI 95%: 1.58, 5.33); lecithin: cholesterol acyltransferase concentration ( p  = 0.024, CI 95%: 1.1, −26.5), cholesterol efflux capacity ( p  = 0.08, CI 95%: −0.01, 0.24), improvements in arterial stiffness and endothelium-dependent vasorelaxation and decrease in type I IFN gene signature, low-density granulocytes and circulating NETs. Some of these improvements are more robust in subjects with STAT4 risk allele. Increased risk of premature cardiovascular disease in systemic lupus erythematosus (SLE) is not well understood, but in animal models, the Janus kinase inhibitor tofacitinib improves related phenotypes. Here the authors report a Phase 1 double-blind randomized trial that shows tofacitinib is safe and well tolerated in in patients with SLE.

Key Points The cerebellum is crucial for the coordination of movement. Here, we present a model of the cerebellar paravermis, a region concerned with the control of voluntary limb movements through its interconnections with the spinal cord. We particularly focus on the olivo–cerebellar climbing fibre system. Climbing fibres are proposed to convey motor error signals (signals that convey information about inappropriate movements) related to elementary limb movements that result from the contraction of single muscles. The actual encoding of motor error signals is suggested to depend on sensorimotor transformations carried out by spinal modules that mediate nociceptive withdrawal reflexes. The termination of the climbing fibre system in the cerebellar cortex subdivides the paravermis into distinct microzones. Functionally similar but spatially separate microzones converge onto a common group of cerebellar nuclear neurons. The processing units formed as a consequence are termed 'multizonal microcomplexes' (MZMCs), and are each related to a specific spinal reflex module. The distributed nature of microzones that belong to a given MZMC is proposed to enable similar climbing fibre inputs to integrate with mossy fibre inputs that arise from different sources. Anatomical results consistent with this notion have been obtained. Within an individual MZMC, the skin receptive fields of climbing fibres, mossy fibres and cerebellar cortical inhibitory interneurons appear to be similar. This indicates that the inhibitory receptive fields of Purkinje cells within a particular MZMC result from the activation of inhibitory interneurons by local granule cells. On the other hand, the parallel fibre-mediated excitatory receptive fields of the Purkinje cells in the same MZMC differ from all of the other receptive fields, but are similar to those of mossy fibres in another MZMC. This indicates that the excitatory input to Purkinje cells in a given MZMC originates in non-local granule cells and is mediated over some distance by parallel fibres. The output from individual MZMCs often involves two or three segments of the ipsilateral limb, indicative of control of multi-joint muscle synergies. The distal-most muscle in this synergy seems to have a roughly antagonistic action to the muscle associated with the climbing fibre input to the MZMC. Our model indicates that the cerebellar paravermis system could provide the control of both single- and multi-joint movements. Agonist–antagonist activity associated with single-joint movements might be controlled within a particular MZMC, whereas coordination across multiple joints might be governed by interactions between MZMCs, mediated by parallel fibres. A coordinated movement is easy to recognize, but we know little about how it is achieved. In search of the neural basis of coordination, we present a model of spinocerebellar interactions in which the structure–functional organizing principle is a division of the cerebellum into discrete microcomplexes. Each microcomplex is the recipient of a specific motor error signal — that is, a signal that conveys information about an inappropriate movement. These signals are encoded by spinal reflex circuits and conveyed to the cerebellar cortex through climbing fibre afferents. This organization reveals salient features of cerebellar information processing, but also highlights the importance of systems level analysis for a fuller understanding of the neural mechanisms that underlie behaviour.

Time perception is an essential element of conscious and subconscious experience, coordinating our perception and interaction with the surrounding environment. In recent years, major technological advances in the field of neuroscience have helped foster new insights into the processing of temporal information, including extending our knowledge of the role of the cerebellum as one of the key nodes in the brain for this function. This consensus paper provides a state-of-the-art picture from the experts in the field of the cerebellar research on a variety of crucial issues related to temporal processing, drawing on recent anatomical, neurophysiological, behavioral, and clinical research.The cerebellar granular layer appears especially well-suited for timing operations required to confer millisecond precision for cerebellar computations. This may be most evident in the manner the cerebellum controls the duration of the timing of agonist-antagonist EMG bursts associated with fast goal-directed voluntary movements. In concert with adaptive processes, interactions within the cerebellar cortex are sufficient to support sub-second timing. However, supra-second timing seems to require cortical and basal ganglia networks, perhaps operating in concert with cerebellum. Additionally, sensory information such as an unexpected stimulus can be forwarded to the cerebellum via the climbing fiber system, providing a temporally constrained mechanism to adjust ongoing behavior and modify future processing. Patients with cerebellar disorders exhibit impairments on a range of tasks that require precise timing, and recent evidence suggest that timing problems observed in other neurological conditions such as Parkinson’s disease, essential tremor, and dystonia may reflect disrupted interactions between the basal ganglia and cerebellum.The complex concepts emerging from this consensus paper should provide a foundation for further discussion, helping identify basic research questions required to understand how the brain represents and utilizes time, as well as delineating ways in which this knowledge can help improve the lives of those with neurological conditions that disrupt this most elemental sense. The panel of experts agrees that timing control in the brain is a complex concept in whom cerebellar circuitry is deeply involved. The concept of a timing machine has now expanded to clinical disorders.

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.

Many common disorders of pregnancy are attributed to insufficient invasion of the uterine lining by trophoblast, fetal cells that are the major cell type of the placenta. Interactions between fetal trophoblast and maternal uterine NK (uNK) cells--specifically interactions between HLA-C molecules expressed by the fetal trophoblast cells and killer Ig-like receptors (KIRs) on the maternal uNK cells--influence placentation in human pregnancy. Consistent with this, pregnancies are at increased risk of preeclampsia in mothers homozygous for KIR haplotype A (KIR AA). In this study, we have demonstrated that trophoblast expresses both paternally and maternally inherited HLA-C surface proteins and that maternal KIR AA frequencies are increased in affected pregnancies only when the fetus has more group 2 HLA-C genes (C2) than the mother. These data raise the possibility that there is a deleterious allogeneic effect stemming from paternal C2. We found that this effect also occurred in other pregnancy disorders (fetal growth restriction and recurrent miscarriage), indicating a role early in gestation for these receptor/ligand pairs in the pathogenesis of reproductive failure. Notably, pregnancy disorders were less frequent in mothers that possessed the telomeric end of the KIR B haplotype, which contains activating KIR2DS1. In addition, uNK cells expressed KIR2DS1, which bound specifically to C2+ trophoblast cells. These findings highlight the complexity and central importance of specific combinations of activating KIR and HLA-C in maternal-fetal immune interactions that determine reproductive success.

The pivotal role of the periaqueductal grey (PAG) in fear learning is reinforced by the identification of neurons in male rat ventrolateral PAG (vlPAG) that encode fear memory through signalling the onset and offset of an auditory-conditioned stimulus during presentation of the unreinforced conditioned tone (CS+) during retrieval. Some units only display CS+ onset or offset responses, and the two signals differ in extinction sensitivity, suggesting that they are independent of each other. In addition, understanding cerebellar contributions to survival circuits is advanced by the discovery that (i) reversible inactivation of the medial cerebellar nucleus (MCN) during fear consolidation leads in subsequent retrieval to (a) disruption of the temporal precision of vlPAG offset, but not onset responses to CS+, and (b) an increase in duration of freezing behaviour. And (ii) chemogenetic manipulation of the MCN-vlPAG projection during fear acquisition (a) reduces the occurrence of fear-related ultrasonic vocalisations, and (b) during subsequent retrieval, slows the extinction rate of fear-related freezing. These findings show that the cerebellum is part of the survival network that regulates fear memory processes at multiple timescales and in multiple ways, raising the possibility that dysfunctional interactions in the cerebellar-survival network may underlie fear-related disorders and comorbidities. Anxiety disorders are a cluster of mental health conditions characterised by persistent and excessive amounts of fear and worry. They affect millions of people worldwide, but treatments can sometimes be ineffective and have unwanted side effects. Understanding which brain regions are involved in fear and anxiety-related behaviours, and how those areas are connected, is the first step towards designing more effective treatments. A region known as the periaqueductal grey (or PAG) sits at the centre of the brain’s fear and anxiety network, regulating pain, encoding fear memories and responding to threats and stressors. It also controls survival behaviours such as the ‘freeze’ response, when an animal is frightened. A more recent addition to the fear and anxiety network is the cerebellum, which sits at the base of the brain. Two-way connections between this region and the PAG have been well described, but how the cerebellum might influence fear and anxiety-related behaviours remains unclear. To explore this role, Lawrenson, Paci et al. investigated whether the cerebellum modulates brain activity within the PAG and if so, how this relates to fear behaviours. Rats had electrodes implanted in their brains to record the activity of nerve cells within the PAG. A common fear-conditioning task was then used to elicit ‘freeze’ responses: a sound was paired with mild foot shocks until the animals learned to fear the auditory signal. In the rats, a subset of neurons within the PAG responded to the tone, consistent with those cells encoding a fear memory. But when a drug blocked the cerebellum’s output during fear conditioning, the timing of the PAG response was less precise and the rats’ freeze response lasted longer. Lawrenson, Paci et al. concluded that the cerebellum, through its interactions with the brain’s fear and anxiety network, might be responsible for coordinating the most appropriate behavioural response to fear, and how long ‘freezing’ lasts. In summary, these findings show that the cerebellum is a part of the brain’s survival network which regulates fear-memory processes. It raises the possibility that disruption of the cerebellum might underlie anxiety and other fear-related disorders, thereby providing a new target for future therapies.

Cerebellar damage during posterior fossa surgery in children can lead to ataxia and risk of cerebellar mutism syndrome. Compartmentalisation of sensorimotor and cognitive functions within the cerebellum have been demonstrated in animal electrophysiology and human imaging studies. Electrophysiological monitoring was carried out under general anaesthesia to assess the limb sensorimotor representation within the human cerebellum for assessment of neurophysiological integrity to reduce the incidence of surgical morbidities. Thirteen adult and paediatric patients undergoing posterior fossa surgery were recruited. Sensory evoked field potentials were recorded in response to mapping (n = 8) to electrical stimulation of limb nerves or muscles. For motor mapping (n = 5), electrical stimulation was applied to the surface of the cerebellum and evoked EMG responses were sought in facial and limb muscles. Sensory evoked potentials were found in two patients (25%). Responses were located on the surface of the right inferior posterior cerebellum to stimulation of the right leg in one patient, and on the left inferior posterior lobe in another patient to stimulation of left forearm. No evoked EMG responses were found for the motor mapping. The present study identifies challenges with using neurophysiological methods to map functional organization within the human cerebellum and considers ways to improve success.