In Vivo Differences in Inputs and Spiking Between Neurons in Lobules VI/VII of Neocerebellum and Lobule X of Archaeocerebellum

The cerebellum plays an important role in the coordination and refinement of movements and cognitive processes. Recently, it has been shown that the main output neuron of the cerebellar cortex, i.e., the Purkinje cell, can show a different firing behavior dependent on its intrinsic electrophysiological properties. Yet, to what extent a different nature of mossy fiber inputs can influence the firing behavior of cerebellar cortical neurons remains to be elucidated. Here, we compared the firing rate and regularity of mossy fibers and neurons in two different regions of cerebellar cortex. One region intimately connected with the cerebral cortex, i.e., lobules VI/VII of the neocerebellum, and another one strongly connected with the vestibular apparatus, i.e., lobule X of the archaeocerebellum. Given their connections, we hypothesized that activity in neurons in lobules VI/VII and lobule X may be expected to be more phasic and tonic, respectively. Using whole-cell and cell-attached recordings in vivo in anesthetized mice, we show that the mossy fiber inputs to these functionally distinct areas of the cerebellum differ in that the irregularity and bursty character of their firing is significantly greater in lobules VI/VII than in lobule X. Importantly, this difference in mossy fiber regularity is propagated through the granule cells at the input stage to the Purkinje cells and molecular layer interneurons, ultimately resulting in different regularity of simple spikes. These data show that the firing behavior of cerebellar cortical neurons does not only reflect particular intrinsic properties but also an interesting interplay with the innate activity at the input stage

Gradients in the mammalian cerebellar cortex enable Fourier-like transformation and improve storing capacity

Cerebellar granule cells (GCs) make up the majority of all neurons in the vertebrate brain, but heterogeneities among GCs and potential functional consequences are poorly understood. Here, we identified unexpected gradients in the biophysical properties of GCs in mice. GCs closer to the white matter (inner-zone GCs) had higher firing thresholds and could sustain firing with larger current inputs than GCs closer to the Purkinje cell layer (outer-zone GCs). Dynamic Clamp experiments showed that inner- and outer-zone GCs preferentially respond to high- and low-frequency mossy fiber inputs, respectively, enabling dispersion of the mossy fiber input into its frequency components as performed by a Fourier transformation. Furthermore, inner-zone GCs have faster axonal conduction velocity and elicit faster synaptic potentials in Purkinje cells. Neuronal network modeling revealed that these gradients improve spike-timing precision of Purkinje cells and decrease the number of GCs required to learn spike-sequences. Thus, our study uncovers biophysical gradients in the cerebellar cortex enabling a Fourier-like transformation of mossy fiber inputs

Role of synchronous activation of cerebellar purkinje cell ensembles in multi-joint movement control

It is a longstanding question in neuroscience how elaborate multi-joint movements are coordinated coherently. Microzones of cerebellar Purkinje cells (PCs) are thought to mediate this coordination by controlling the timing of particular motor domains. However, it remains to be elucidated to what extent motor coordination deficits can be correlated with abnormalities in coherent activity within these microzones and to what extent artificially evoked synchronous activity within PC ensembles can elicit multi-joint motor behavior. To study PC ensemble correlates of limb, trunk, and tail movements, we developed a transparent disk treadmill that allows quantitative readout of locomotion and posture parameters in head-fixed mice and simultaneous cellular-resolution imaging and/or optogenetic manipulation. We show that PC ensembles in the ataxic and dystonic mouse mutant tottering have a reduced level of complex spike co-activation, which is delayed relative to movement onset and co-occurs with prolonged swing duration and reduced phase coupling of limb movements as well as with enlarged deflections of body-axis and tail movements. Using optogenetics to increase simple spike rate in PC ensembles, we find that preferred locomotion and posture patterns can be elicited or perturbed depending on the behavioral state. At rest, preferred sequences of limb movements can be elicited, whereas during locomotion, preferred gait-inhibition patterns are evoked. Our findings indicate that synchronous activation of PC ensembles can facilitate initiation and coordination of limb and trunk movements, presumably by tuning downstream systems involved in the execution of behavioral patterns

Purkinje cell input to cerebellar nuclei in tottering: Ultrastructure and physiology

Homozygous tottering mice are spontaneous ataxic mutants, which carry a mutation in the gene encoding the ion pore of the P/Q-type voltage-gated calcium channels. P/Q-type calcium channels are prominently expressed in Purkinje cell terminals, but it is unknown to what extent these inhibitory terminals in tottering mice are affected at the morphological and electrophysiological level. Here, we investigated the distribution and ultrastructure of their Purkinje cell terminals in the cerebellar nuclei as well as the activities of their target neurons. The densities of Purkinje cell terminals and their synapses were not significantly affected in the mutants. However, the Purkinje cell terminals were enlarged and had an increased number of vacuoles, whorled bodies, and mitochondria. These differences started to occur between 3 and 5 weeks of age and persisted throughout adulthood. Stimulation of Purkinje cells in adult tottering mice resulted in inhibition at normal latencies, but the activities of their postsynaptic neurons in the cerebellar nuclei were abnormal in that the frequency and irregularity of their spiking patterns were enhanced. Thus, although the number of their terminals and their synaptic contacts appear quantitatively intact, Purkinje cells in tottering mice show several signs of axonal damage that may contribute to altered postsynaptic activities in the cerebellar nuclei

Regional functionality of the cerebellum

Over the recent years, advances in brain imaging, optogenetics and viral tracing have greatly advanced our understanding of the cerebellum and its connectivity. It has become clear that the cerebellum can be divided into functional units, each connected with particular brain areas involved in specific tasks, allowing afferent and efferent pathways to process task-specific information. The activity patterns in these pathways can be widely different among cerebellar areas. Therefore, it is expected that each cerebellar module is tailored to interpret inputs with a specific activity profile. In this paper we will review the evidence for region-specific inputs, region-specific connectivity with the rest of the brain, and region-specific processing within the cerebellum