Receptive Field Remodeling Induced by Skin Stimulation in Cerebellar Neurons in vivo.

The receptive field of a neuron reflects its function. For example, for parallel fiber (PF) inputs in C3 zone the cerebellar cortex, the excitatory and inhibitory receptive fields of a Purkinje cell (PC) have different locations, and each location has a specific relationship to the location of the climbing fiber (CF) receptive field of the PC. Previous studies have shown that this pattern of input connectivity to the PC and its afferent inhibitory interneurons can be fundamentally disrupted by applying direct electrical stimulation to the PFs, paired or unpaired with CF activation, with protocols that induce plasticity in these synapses. However, afferent fiber stimulation, which is typically used in experimental studies of plasticity, set up highly artificial input patterns at the level of the recipient cells, raising the issue that these forms of plasticity potentially may not occur under more natural input patterns. Here we used skin stimulation to set up spatiotemporally more realistic afferent input patterns in the PFs to investigate whether these input patterns are also capable of inducing synaptic plasticity using similar protocols that have previously been described for direct PF stimulation. We find that receptive field components can be added to and removed from PCs and interneurons following brief periods of skin stimulation. Following these protocols, the receptive fields of mossy fibers were unchanged. These findings confirm that previously described plasticity protocols may have a functional role also for more normal patterns of afferent input

Probabilistic identification of cerebellar cortical neurones across species.

Despite our fine-grain anatomical knowledge of the cerebellar cortex, electrophysiological studies of circuit information processing over the last fifty years have been hampered by the difficulty of reliably assigning signals to identified cell types. We approached this problem by assessing the spontaneous activity signatures of identified cerebellar cortical neurones. A range of statistics describing firing frequency and irregularity were then used, individually and in combination, to build Gaussian Process Classifiers (GPC) leading to a probabilistic classification of each neurone type and the computation of equi-probable decision boundaries between cell classes. Firing frequency statistics were useful for separating Purkinje cells from granular layer units, whilst firing irregularity measures proved most useful for distinguishing cells within granular layer cell classes. Considered as single statistics, we achieved classification accuracies of 72.5% and 92.7% for granular layer and molecular layer units respectively. Combining statistics to form twin-variate GPC models substantially improved classification accuracies with the combination of mean spike frequency and log-interval entropy offering classification accuracies of 92.7% and 99.2% for our molecular and granular layer models, respectively. A cross-species comparison was performed, using data drawn from anaesthetised mice and decerebrate cats, where our models offered 80% and 100% classification accuracy. We then used our models to assess non-identified data from awake monkeys and rabbits in order to highlight subsets of neurones with the greatest degree of similarity to identified cell classes. In this way, our GPC-based approach for tentatively identifying neurones from their spontaneous activity signatures, in the absence of an established ground-truth, nonetheless affords the experimenter a statistically robust means of grouping cells with properties matching known cell classes. Our approach therefore may have broad application to a variety of future cerebellar cortical investigations, particularly in awake animals where opportunities for definitive cell identification are limited

Parallel fiber receptive fields: a key to understanding cerebellar operation and learning.

In several theories of the function of the cerebellum in motor control, the mossy-fiber-parallel fiber input has been suggested to provide information used in the control of ongoing movements whereas the role of climbing fibers is to induce plastic changes of parallel fiber (PF) synapses on Purkinje cells. From studies of climbing fibers during the last few decades, we have gained detailed knowledge about the zonal and microzonal organization of the cerebellar cortex and the information carried by climbing fibers. However, properties of the PF input to Purkinje cells and inhibitory interneurones have been largely unknown. The present review, which focuses on the C3 zone of the cerebellar anterior lobe, will present and discuss recent data of the cutaneous PF input to Purkinje cells, interneurons and Golgi cells as well as novel forms of PF plasticit

Properties of somatosensory synaptic integration in cerebellar granule cells in vivo.

In decerebrated, nonanesthetized cats, we made intracellular whole-cell recordings and extracellular cell-attached recordings from granule cells in the cerebellar C3 zone. Spontaneous EPSPs had large, relatively constant peak amplitudes, whereas IPSPs were small and did not appear to contribute substantially to synaptic integration at a short time scale. In many cases, the EPSPs of individual mossy fiber synapses appeared to be separable by their peak amplitudes. A substantial proportion of our granule cells had small receptive fields on the forelimb skin. Skin stimulation evoked explosive responses in which the constituent EPSPs were analyzed. In the rising phase of the response, our analyses indicated a participation of three to four different mossy fiber synapses, corresponding to the total number of mossy fiber afferents. The cutaneous receptive fields of the driven EPSPs overlapped, indicating an absence of convergence of mossy fibers activated from different receptive fields. Also in granule cells activated by joint movements did we find indications that different afferents were driven by the same type of input. Regardless of input type, the temporal patterns of granule cell spike activity, both spontaneous and evoked, appeared to primarily follow the activity in the presynaptic mossy fibers, although much of the nonsynchronized mossy fiber input was filtered out. In contrast to the prevailing theories of granule cell function, our results suggest a function of granule cells as signal-to-noise enhancing threshold elements, rather than as sparse coding pattern discriminators or temporal pattern generators

The lateral reticular nucleus : integration of descending and ascending systems regulating voluntary forelimb movements

Cerebellar control of movements is dependent on mossy fiber input conveying information about sensory and premotor activity in the spinal cord. While much is known about spino-cerebellar systems, which provide the cerebellum with detailed sensory information, much less is known about systems conveying motor information. Individual motoneurones do not have projections to spino-cerebellar neurons. Instead, the fastest route is from last order spinal interneurons. In order to identify the networks that convey ascending premotor information from last order interneurons, we have focused on the lateral reticular nucleus (LRN), which provides the major mossy fiber input to cerebellum from spinal interneuronal systems. Three spinal ascending systems to the LRN have been investigated: the C3-C4 propriospinal neurones (PNs), the ipsilateral forelimb tract (iFT) and the bilateral ventral flexor reflex tract (bVFRT). Voluntary forelimb movements involve reaching and grasping together with necessary postural adjustments and each of these three interneuronal systems likely contribute to specific aspects of forelimb motor control. It has been demonstrated that the command for reaching can be mediated via C3-C4 PNs, while the command for grasping is conveyed via segmental interneurons in the forelimb segments. Our results reveal convergence of ascending projections from all three interneuronal systems in the LRN, producing distinct combinations of excitation and inhibition. We have also identified a separate descending control of LRN neurons exerted via a subgroup of cortico-reticular neurones. The LRN projections to the deep cerebellar nuclei exert a direct excitatory effect on descending motor pathways via the reticulospinal, vestibulospinal, and other supraspinal tracts, and might play a key role in cerebellar motor control. Our results support the hypothesis that the LRN provides the cerebellum with highly integrated information, enabling cerebellar control of complex forelimb movements

The lateral reticular nucleus : integration of descending and ascending systems regulating voluntary forelimb movements

Cerebellar control of movements is dependent on mossy fiber input conveying information about sensory and premotor activity in the spinal cord. While much is known about spino-cerebellar systems, which provide the cerebellum with detailed sensory information, much less is known about systems conveying motor information. Individual motoneurones do not have projections to spino-cerebellar neurons. Instead, the fastest route is from last order spinal interneurons. In order to identify the networks that convey ascending premotor information from last order interneurons, we have focused on the lateral reticular nucleus (LRN), which provides the major mossy fiber input to cerebellum from spinal interneuronal systems. Three spinal ascending systems to the LRN have been investigated: the C3-C4 propriospinal neurones (PNs), the ipsilateral forelimb tract (iFT) and the bilateral ventral flexor reflex tract (bVFRT). Voluntary forelimb movements involve reaching and grasping together with necessary postural adjustments and each of these three interneuronal systems likely contribute to specific aspects of forelimb motor control. It has been demonstrated that the command for reaching can be mediated via C3-C4 PNs, while the command for grasping is conveyed via segmental interneurons in the forelimb segments. Our results reveal convergence of ascending projections from all three interneuronal systems in the LRN, producing distinct combinations of excitation and inhibition. We have also identified a separate descending control of LRN neurons exerted via a subgroup of cortico-reticular neurones. The LRN projections to the deep cerebellar nuclei exert a direct excitatory effect on descending motor pathways via the reticulospinal, vestibulospinal, and other supraspinal tracts, and might play a key role in cerebellar motor control. Our results support the hypothesis that the LRN provides the cerebellum with highly integrated information, enabling cerebellar control of complex forelimb movements

Synaptic Integration in Cerebellar Granule Cells

To understand the function of cerebellar granule cells, we need detailed knowledge about the information carried by their afferent mossy fibers and how this information is integrated by the granule cells. Recently, we made whole cell recordings from granule cells in the non-anesthetized, decerebrate cats. All recordings were made in the forelimb area of the C3 zone for which the afferent and efferent connections and functional organization have been investigated in detail. Major findings of the study were that the mossy fiber input to single granule cells was modality- and receptive field-specific and that simultaneous activity in two and usually more of the afferent mossy fibers were required to activate the granule cell spike. The high threshold for action potentials and the convergence of afferents with virtually identical information suggest that an important function of granule cells is to increase the signal-to-noise ratio of the mossy fiber-parallel fiber information. Thus a high-sensitivity, noisy mossy fiber input is transformed by the granule cell to a high-sensitivity, low-noise signal

Receptive field plasticity profoundly alters the cutaneous parallel fiber synaptic input to cerebellar interneurons in vivo

The cutaneous parallel fiber (PF) receptive fields of cerebellar stellate and basket cells in the cerebellar C3 zone in vivo are normally very small but can be dramatically enlarged by climbing fiber (CF)-dependent plasticity. To analyze the effects of this receptive field plasticity, we present for the first time whole-cell patch-clamp recordings from these interneurons during natural and electrical activation of cutaneously driven synaptic input. In "naive" interneurons, peripheral input nearly exclusively activated a few (two to eight) large PF EPSPs from a specific small skin area that overlapped the receptive field of the local CF input. After conjunctive PF and CF stimulation, numerous small and large EPSPs and ramp-like depolarizations could be activated from the entire forelimb skin. These findings therefore confirm previous suggestions that conjunctive PF and CF activation leads to a long-lasting potentiation of PF synaptic input to interneurons. The CF response, which is crucial for the induction of the PF synaptic potentiation, was strong but variable and very different from the conventional EPSPs evoked by PFs

Reciprocal bidirectional plasticity of parallel fiber receptive fields in cerebellar Purkinje cells and their afferent interneurons.

The highly specific relationships between parallel fiber (PF) and climbing fiber (CF) receptive fields in Purkinje cells and interneurons suggest that normal PF receptive fields are established by CF-specific plasticity. To test this idea, we used PF stimulation that was either paired or unpaired with CF activity. Conspicuously, unpaired PF stimulation that induced long-lasting, very large increases in the receptive field sizes of Purkinje cells induced long-lasting decreases in receptive field sizes of their afferent interneurons. In contrast, PF stimulation paired with CF activity that induced long-lasting decreases in the receptive fields of Purkinje cells induced long-lasting, large increases in the receptive fields of interneurons. These properties, and the fact the mossy fiber receptive fields were unchanged, suggest that the receptive field changes were due to bidirectional PF synaptic plasticity in Purkinje cells and interneurons