Realistic mossy fiber input patterns to unipolar brush cells evoke a continuum of temporal responses comprised of components mediated by different glutamate receptors.

Unipolar brush cells (UBCs) are excitatory interneurons in the cerebellar cortex that receive mossy fiber (MF) inputs and excite granule cells. The UBC population responds to brief burst activation of MFs with a continuum of temporal transformations, but it is not known how UBCs transform the diverse range of MF input patterns that occur in vivo. Here, we use cell-attached recordings from UBCs in acute cerebellar slices to examine responses to MF firing patterns that are based on in vivo recordings.

Specialized connectivity of molecular layer interneuron subtypes leads to disinhibition and synchronous inhibition of cerebellar Purkinje cells.

Molecular layer interneurons (MLIs) account for approximately 80% of the inhibitory interneurons in the cerebellar cortex and are vital to cerebellar processing. MLIs are thought to primarily inhibit Purkinje cells (PCs) and suppress the plasticity of synapses onto PCs. MLIs also inhibit, and are electrically coupled to, other MLIs, but the functional significance of these connections is not known.

Implications of variable synaptic weights for rate and temporal coding of cerebellar outputs.

Purkinje cell (PC) synapses onto cerebellar nuclei (CbN) neurons allow signals from the cerebellar cortex to influence the rest of the brain. PCs are inhibitory neurons that spontaneously fire at high rates, and many PC inputs are thought to converge onto each CbN neuron to suppress its firing. It has been proposed that PCs convey information using a rate code, a synchrony and timing code, or both.

A Purkinje cell to parabrachial nucleus pathway enables broad cerebellar influence over the forebrain.

In addition to its motor functions, the cerebellum is involved in emotional regulation, anxiety and affect. We found that suppressing the firing of cerebellar Purkinje cells (PCs) rapidly excites forebrain areas that contribute to such functions (including the amygdala, basal forebrain and septum), but that the classic cerebellar outputs, the deep cerebellar nuclei, do not directly project there. We show that PCs directly inhibit parabrachial nuclei (PBN) neurons that project to numerous forebrain regions.

Cerebellar circuits for disinhibition and synchronous inhibition.

The cerebellar cortex contributes to diverse behaviors by transforming mossy fiber inputs into predictions in the form of Purkinje cell (PC) outputs, and then refining those predictions. Molecular layer interneurons (MLIs) account for approximately 80% of the inhibitory interneurons in the cerebellar cortex, and are vital to cerebellar processing. MLIs are thought to primarily inhibit PCs and suppress the plasticity of excitatory synapses onto PCs.

A Continuum of Response Properties across the Population of Unipolar Brush Cells in the Dorsal Cochlear Nucleus.

Unipolar brush cells (UBCs) in the cerebellum and dorsal cochlear nucleus (DCN) perform temporal transformations by converting brief mossy fiber bursts into long-lasting responses. In the cerebellar UBC population, mixing inhibition with graded mGluR-dependent excitation leads to a continuum of temporal responses. In the DCN, it has been thought that mGluR contributes little to mossy fiber responses and that there are distinct excitatory and inhibitory UBC subtypes.

Implications of variable synaptic weights for rate and temporal coding of cerebellar outputs.

Purkinje cell (PC) synapses onto cerebellar nuclei (CbN) neurons convey signals from the cerebellar cortex to the rest of the brain. PCs are inhibitory neurons that spontaneously fire at high rates, and many uniform sized PC inputs are thought to converge onto each CbN neuron to suppress or eliminate firing. Leading theories maintain that PCs encode information using either a rate code, or by synchrony and precise timing.

Cerebellar granule cell signaling is indispensable for normal motor performance.

Within the cerebellar cortex, mossy fibers (MFs) excite granule cells (GCs) that excite Purkinje cells (PCs), which provide outputs to the deep cerebellar nuclei (DCNs). It is well established that PC disruption produces motor deficits such as ataxia. This could arise from either decreases in ongoing PC-DCN inhibition, increases in the variability of PC firing, or disruption of the flow of MF-evoked signals.

Structured cerebellar connectivity supports resilient pattern separation.

The cerebellum is thought to help detect and correct errors between intended and executed commands and is critical for social behaviours, cognition and emotion. Computations for motor control must be performed quickly to correct errors in real time and should be sensitive to small differences between patterns for fine error correction while being resilient to noise. Influential theories of cerebellar information processing have largely assumed random network connectivity, which increases the encoding capacity of the network's first layer.

Unusually Slow Spike Frequency Adaptation in Deep Cerebellar Nuclei Neurons Preserves Linear Transformations on the Subsecond Timescale.

Purkinje cells (PCs) are spontaneously active neurons of the cerebellar cortex that inhibit glutamatergic projection neurons within the deep cerebellar nuclei (DCN) that provide the primary cerebellar output. Brief reductions of PC firing rapidly increase DCN neuron firing. However, prolonged reductions of PC inhibition, as seen in some disease states, certain types of transgenic mice, during optogenetic suppression of PC firing, and in acute slices of the cerebellum, do not lead to large, sustained increases in DCN firing.

The Cerebellar Cortex.

The cerebellar cortex is an important system for relating neural circuits and learning. Its promise reflects the longstanding idea that it contains simple, repeated circuit modules with only a few cell types and a single plasticity mechanism that mediates learning according to classical Marr-Albus models. However, emerging data have revealed surprising diversity in neuron types, synaptic connections, and plasticity mechanisms, both locally and regionally within the cerebellar cortex.

Candelabrum cells are ubiquitous cerebellar cortex interneurons with specialized circuit properties.

To understand how the cerebellar cortex transforms mossy fiber (MF) inputs into Purkinje cell (PC) outputs, it is vital to delineate the elements of this circuit. Candelabrum cells (CCs) are enigmatic interneurons of the cerebellar cortex that have been identified based on their morphology, but their electrophysiological properties, synaptic connections and function remain unknown. Here, we clarify these properties using electrophysiology, single-nucleus RNA sequencing, in situ hybridization and serial electron microscopy in mice.

Graded heterogeneity of metabotropic signaling underlies a continuum of cell-intrinsic temporal responses in unipolar brush cells.

Many neuron types consist of populations with continuously varying molecular properties. Here, we show a continuum of postsynaptic molecular properties in three types of neurons and assess the functional correlates in cerebellar unipolar brush cells (UBCs). While UBCs are generally thought to form discrete functional subtypes, with mossy fiber (MF) activation increasing firing in ON-UBCs and suppressing firing in OFF-UBCs, recent work also points to a heterogeneity of response profiles.

A transcriptomic atlas of mouse cerebellar cortex comprehensively defines cell types.

The cerebellar cortex is a well-studied brain structure with diverse roles in motor learning, coordination, cognition and autonomic regulation. However,  a complete inventory of cerebellar cell types is currently lacking. Here, using recent advances in high-throughput transcriptional profiling, we molecularly define cell types across individual lobules of the adult mouse cerebellum.

Introduction of synaptotagmin 7 promotes facilitation at the climbing fiber to Purkinje cell synapse.

Synaptotagmin 7 (Syt7) is a high-affinity calcium sensor that is implicated in multiple aspects of synaptic transmission. Here, we study the influence of Syt7 on the climbing fiber (CF) to Purkinje cell (PC) synapse. We find that small facilitation and prominent calcium-dependent recovery from depression at this synapse do not rely on Syt7 and that Syt7 is not normally present in CFs.

Purkinje cell outputs selectively inhibit a subset of unipolar brush cells in the input layer of the cerebellar cortex.

Circuitry of the cerebellar cortex is regionally and functionally specialized. Unipolar brush cells (UBCs), and Purkinje cell (PC) synapses made by axon collaterals in the granular layer, are both enriched in areas that control balance and eye movement. Here, we find a link between these specializations in mice: PCs preferentially inhibit metabotropic glutamate receptor type 1 (mGluR1)-expressing UBCs that respond to mossy fiber (MF) inputs with long lasting increases in firing, but PCs do not inhibit mGluR1-lacking UBCs.

Presynaptic Short-Term Plasticity Persists in the Absence of PKC Phosphorylation of Munc18-1.

Post-tetanic potentiation (PTP) is a form of short-term plasticity that lasts for tens of seconds following a burst of presynaptic activity. It has been proposed that PTP arises from protein kinase C (PKC) phosphorylation of Munc18-1, an SM (Sec1/Munc-18 like) family protein that is essential for release. To test this model, we made a knock-in mouse in which all Munc18-1 PKC phosphorylation sites were eliminated through serine-to-alanine point mutations (Munc18-1SA mice), and we studied mice of either sex.

Cerebellar and vestibular nuclear synapses in the inferior olive have distinct release kinetics and neurotransmitters.

The inferior olive (IO) is composed of electrically-coupled neurons that make climbing fiber synapses onto Purkinje cells. Neurons in different IO subnuclei are inhibited by synapses with wide ranging release kinetics. Inhibition can be exclusively synchronous, asynchronous, or a mixture of both.

Cerebellum-Specific Deletion of the GABA Receptor δ Subunit Leads to Sex-Specific Disruption of Behavior.

Granule cells (GCs) of the cerebellar input layer express high-affinity δ GABA subunit-containing GABA receptors (δGABARs) that respond to ambient GABA levels and context-dependent neuromodulators like steroids. We find that GC-specific deletion of δGABA (cerebellar [cb] δ knockout [KO]) decreases tonic inhibition, makes GCs hyperexcitable, and in turn, leads to differential activation of cb output regions as well as many cortical and subcortical brain areas involved in cognition, anxiety-like behaviors, and the stress response. Cb δ KO mice display deficits in many behaviors, but motor function is normal.

Climbing fiber synapses rapidly and transiently inhibit neighboring Purkinje cells via ephaptic coupling.

Climbing fibers from the inferior olive make strong excitatory synapses onto cerebellar Purkinje cell (PC) dendrites and trigger distinctive responses known as complex spikes. We found that, in awake mice, a complex spike in one PC suppressed conventional simple spikes in neighboring PCs for several milliseconds. This involved a new ephaptic coupling, in which an excitatory synapse generated large negative extracellular signals that nonsynaptically inhibited neighboring PCs.

Meissner corpuscles and their spatially intermingled afferents underlie gentle touch perception.

Meissner corpuscles are mechanosensory end organs that densely occupy mammalian glabrous skin. We generated mice that selectively lacked Meissner corpuscles and found them to be deficient in both perceiving the gentlest detectable forces acting on glabrous skin and fine sensorimotor control. We found that Meissner corpuscles are innervated by two mechanoreceptor subtypes that exhibit distinct responses to tactile stimuli.