The Mesodiencephalic Junction as a Central Hub for Cerebro-Cerebellar Communication

Most studies investigating the impact of cerebral cortex (CC) onto the cerebellum highlight the role of the pontine mossy fibre system. However, cerebro-cerebellar communication may also be mediated by the olivary climbing fibres via a hub in the mesodiencephalic junction (MDJ). Here, we show that rostromedial and caudal parts of mouse CC predominantly project to the principal olive via the rostroventral MDJ and that more rostrolateral CC regions prominently project to the rostral medial accessory olive via the caudodorsal MDJ. Moreover, transneuronal tracing results show that the cerebellar nuclei innervate the olivary-projecting neurons in the MDJ that receive input from CC, and that they adhere to the same topographical relations. By unravelling these topographic and dense, mono- and disynaptic projections from the CC through the MDJ and inferior olive to the cerebellum, this work establishes that cerebro-cerebellar communication can be mediated by both the mossy fibre and climbing fibre system.

Cerebellar learning using perturbations

The cerebellum aids the learning and execution of fast coordinated movements, with acquired information being stored by plasticity of parallel fibre—Purkinje cell synapses. According to the current consensus, erroneously active parallel fibre synapses are depressed by complex spikes arising when climbing fibres signal movement errors. However, this theory cannot solve the credit assignment problem of using the limited information from a global movement evaluation to optimise behaviour by guiding the plasticity in numerous neurones. We identify the possible implementation of an algorithm solving this problem, whereby spontaneous complex spikes perturb ongoing movements, create an eligibility trace for plasticity and signal resulting error changes to guide plasticity. These error changes are extracted by adaptively cancelling the average error. This framework, stochastic gradient descent with estimated global errors, generates specific predictions for synaptic plasticity rules that contradict the current consensus. However, in vitro plasticity experiments under physiological conditions verified our predictions, highlighting the sensitivity of plasticity studies to unphysiological conditions. Using numerical and analytical approaches we demonstrate the convergence and estimate the capacity of learning in our implementation. Finally, a similar mechanism may operate during optimisation of action sequences by the basal ganglia, where dopamine could both initiate movements and signal rewards, analogously to the dual perturbation and correction role of the climbing fibre outlined here.

The conditioned eyeblink reflex: a potential tool for the detection of cerebellar dysfunction in multiple sclerosis

The delayed conditioned eyeblink reflex, in which an individual learns to close the eyelid in response to a conditioned stimulus (e.g. a tone) relies entirely on the functional integrity of a cerebellar motor circuitry that involves the contingent activation of Purkinje cells by parallel and climbing fibres. Molecular changes that disrupt the function of this circuitry, in particular a loss of type-1 metabotropic glutamate receptors (mGlu1 receptors), occur in Purkinje cells of patients with multiple sclerosis and in mice with experimental autoimmune encephalomyelitis as a result of neuroinflammation. mGlu1 receptors are required for cerebellar motor learning associated with the conditioned eyeblink reflex. We propose that the delayed paradigm of the eyeblink conditioning might be particularly valuable for the detection of subtle abnormalities of cerebellar motor learning that are clinically silent and are not associated with demyelinating lesions or axonal damage. In addition, the test might have predictive value following a clinically isolated syndrome, and might be helpful for the evaluation of the efficacy of drug treatment in multiple sclerosis.

Functional origins of the vertebrate cerebellum from a sensory processing antecedent

The structure of the cerebellar cortex is remarkably similar across vertebrate phylogeny. It is well developed in basal jawed fishes, such as sharks and rays with many of the same cell types and organizational features found in other vertebrate groups, including mammals. In particular, the lattice-like organization of cerebellar cortex (with a molecular layer of parallel fibres, interneurons, spiny Purkinje cell dendrites, and climbing fires) is a common defining characteristic. In addition to the cerebellar cortex, fishes and aquatic amphibians have a variety of cerebellum-like structures in the dorso-lateral wall of the hindbrain. These structures are adjacent to, and in part, contiguous with, the cerebellum. They derive their cerebellum-like name from the presence of a molecular layer of parallel fibers and inhibitory interneurons, which has striking organizational similarities to the molecular layer of the cerebellar cortex. However, these structures also have characteristics which differ from the cerebellum. For example, cerebellum-like structures do not have climbing fibres, and they are clearly sensory. They receive direct afferent input from peripheral sensory receptors and relay their outputs to midbrain sensory areas. As a consequence of this close sensory association, and the ability to characterise their signal processing in a behaviourally relevant context, good progress has been made in determining the fundamental processing algorithm in cerebellar-like structures. In particular, we have come to understand the contribution to signal processing made by the molecular layer, which provides an adaptive filter to cancel self-generated noise in electrosensory and lateral line systems. Given the fundamental similarities of the molecular layer across these structures, coupled with evidence that cerebellum-like structures may have been the evolutionary antecedent of the cerebellum, we address the question: do both share the same functional algorithm?