A novel biomechanical model of the mouse forelimb predicts muscle activity in optimal control simulations of reaching movements.

Mice are key model organisms in neuroscience and motor systems physiology. Fine motor control tasks performed by mice have become widely used in assaying neural and biophysical motor system mechanisms. Although fine motor tasks provide useful insights into behaviors which require complex multi-joint motor control, there is no previously developed physiological biomechanical model of the adult mouse forelimb available for estimating kinematics nor muscle activity or kinetics during behaviors.

A dual Purkinje cell rate and synchrony code sculpts reach kinematics.

Cerebellar Purkinje cells (PCs) encode movement kinematics in their population firing rates. Firing rate suppression is hypothesized to disinhibit neurons in the cerebellar nuclei, promoting adaptive movement adjustments. Debates persist, however, about whether a second disinhibitory mechanism, PC simple spike synchrony, is a relevant population code.

Cerebellar associative learning underlies skilled reach adaptation.

The cerebellum is hypothesized to refine movement through online adjustments. We examined how such predictive control may be generated using a mouse reach paradigm, testing whether the cerebellum uses within-reach information as a predictor to adjust reach kinematics. We first identified a population-level response in Purkinje cells that scales inversely with reach velocity, pointing to the cerebellar cortex as a potential site linking kinematic predictors and anticipatory control.

An emergent temporal basis set robustly supports cerebellar time-series learning.

The cerebellum is considered a "learning machine" essential for time interval estimation underlying motor coordination and other behaviors. Theoretical work has proposed that the cerebellum's input recipient structure, the granule cell layer (GCL), performs pattern separation of inputs that facilitates learning in Purkinje cells (P-cells). However, the relationship between input reformatting and learning has remained debated, with roles emphasized for pattern separation features from sparsification to decorrelation.

Diverse inhibitory projections from the cerebellar interposed nucleus.

The cerebellum consists of parallel circuit modules that contribute to diverse behaviors, spanning motor to cognitive. Recent work employing cell-type-specific tracing has identified circumscribed output channels of the cerebellar nuclei (CbN) that could confer tight functional specificity. These studies have largely focused on excitatory projections of the CbN, however, leaving open the question of whether inhibitory neurons also constitute multiple output modules.

Online control of reach accuracy in mice.

Reaching movements, as a basic yet complex motor behavior, are a foundational model system in neuroscience. In particular, there has been a significant recent expansion of investigation into the neural circuit mechanisms of reach behavior in mice. Nevertheless, quantification of mouse reach kinematics remains lacking, limiting comparison to the primate literature.

Presynaptic PRRT2 Deficiency Causes Cerebellar Dysfunction and Paroxysmal Kinesigenic Dyskinesia.

PRRT2 loss-of-function mutations have been associated with familial paroxysmal kinesigenic dyskinesia (PKD), infantile convulsions and choreoathetosis, and benign familial infantile seizures. Dystonia is the foremost involuntary movement disorder manifest by patients with PKD. Using a lacZ reporter and quantitative reverse-transcriptase PCR, we mapped the temporal and spatial distribution of Prrt2 in mouse brain and showed the highest levels of expression in cerebellar cortex.

Monosynaptic inputs to specific cell types of the intermediate and deep layers of the superior colliculus.

The intermediate and deep layers of the midbrain superior colliculus (SC) are a key locus for several critical functions, including spatial attention, multisensory integration, and behavioral responses. While the SC is known to integrate input from a variety of brain regions, progress in understanding how these inputs contribute to SC-dependent functions has been hindered by the paucity of data on innervation patterns to specific types of SC neurons. Here, we use G-deleted rabies virus-mediated monosynaptic tracing to identify inputs to excitatory and inhibitory neurons of the intermediate and deep SC.

Corollary Discharge Signals in the Cerebellum.

The cerebellum is known to make movements fast, smooth, and accurate. Many hypotheses emphasize the role of the cerebellum in computing learned predictions important for sensorimotor calibration and feedforward control of movements. Hypotheses of the computations performed by the cerebellum in service of motor control borrow heavily from control systems theory, with models that frequently invoke copies of motor commands, called corollary discharge.

Cerebellar Control of Reach Kinematics for Endpoint Precision.

The cerebellum is well appreciated to impart speed, smoothness, and precision to skilled movements such as reaching. How these functions are executed by the final output stage of the cerebellum, the cerebellar nuclei, remains unknown. Here, we identify a causal relationship between cerebellar output and mouse reach kinematics and show how that relationship is leveraged endogenously to enhance reach precision.

Pathway-Specific Drive of Cerebellar Golgi Cells Reveals Integrative Rules of Cortical Inhibition.

Cerebellar granule cells (GrCs) constitute over half of all neurons in the vertebrate brain and are proposed to decorrelate convergent mossy fiber (MF) inputs in service of learning. Interneurons within the GrC layer, Golgi cells (GoCs), are the primary inhibitors of this vast population and therefore play a major role in influencing the computations performed within the layer. Despite this central function for GoCs, few studies have directly examined how GoCs integrate inputs from specific afferents, which vary in density to regulate GrC population activity.

Theoretically Sparse, Empirically Dense: New Views on Cerebellar Granule Cells.

Cerebellar granule cells are a popular target of neuroanatomical hyperbole, being so small and so numerous. Early theorists proposed unique roles for this vast cell population, ideas that continue to be tested through contemporary approaches. In 2017, a cluster of empirical and theoretical papers offered a fresh and singular look into the functions of granule cells and the computational advantages of their idiosyncratic circuit organization.

Morphological Constraints on Cerebellar Granule Cell Combinatorial Diversity.

Combinatorial expansion by the cerebellar granule cell layer (GCL) is fundamental to theories of cerebellar contributions to motor control and learning. Granule cells (GrCs) sample approximately four mossy fiber inputs and are thought to form a combinatorial code useful for pattern separation and learning. We constructed a spatially realistic model of the cerebellar GCL and examined how GCL architecture contributes to GrC combinatorial diversity.

Rubrocerebellar Feedback Loop Isolates the Interposed Nucleus as an Independent Processor of Corollary Discharge Information in Mice.

Understanding cerebellar contributions to motor coordination requires deeper insight into how the output structures of the cerebellum, the cerebellar nuclei, integrate their inputs and influence downstream motor pathways. The magnocellular red nucleus (RNm), a brainstem premotor structure, is a major target of the interposed nucleus (IN), and has also been described in previous studies to send feedback collaterals to the cerebellum. Because such a pathway is in a key position to provide motor efferent information to the cerebellum, satisfying predictions about the use of corollary discharge in cerebellar computations, we studied it in mice of both sexes.

Recurrent Feedback Loops in Associative Learning.

In this issue of Neuron, Gao et al. (2016) report on a little-studied feedback pathway from the cerebellar nuclei back to the cerebellar cortex. They find that it contributes to associative conditioning and execution of learned movements, highlighting a role for local feedback loops in the brain.

Cerebellar Premotor Output Neurons Collateralize to Innervate the Cerebellar Cortex.

Motor commands computed by the cerebellum are hypothesized to use corollary discharge, or copies of outgoing commands, to accelerate motor corrections. Identifying sources of corollary discharge, therefore, is critical for testing this hypothesis. Here we verified that the pathway from the cerebellar nuclei to the cerebellar cortex in mice includes collaterals of cerebellar premotor output neurons, mapped this collateral pathway, and identified its postsynaptic targets.

Cerebellar loops: a review of the nucleocortical pathway.

Feedback pathways are a common circuit motif in vertebrate brains. Reciprocal interconnectivity is seen between the cerebral cortex and thalamus as well as between basal ganglia structures, for example. Here, we review the literature on the nucleocortical pathway, a feedback pathway from the cerebellar nuclei to the cerebellar cortex, which has been studied anatomically but has remained somewhat obscure.

The neuronal code(s) of the cerebellum.

Understanding how neurons encode information in sequences of action potentials is of fundamental importance to neuroscience. The cerebellum is widely recognized for its involvement in the coordination of movements, which requires muscle activation patterns to be controlled with millisecond precision. Understanding how cerebellar neurons accomplish such high temporal precision is critical to understanding cerebellar function.

Synchrony and neural coding in cerebellar circuits.

The cerebellum regulates complex movements and is also implicated in cognitive tasks, and cerebellar dysfunction is consequently associated not only with movement disorders, but also with conditions like autism and dyslexia. How information is encoded by specific cerebellar firing patterns remains debated, however. A central question is how the cerebellar cortex transmits its integrated output to the cerebellar nuclei via GABAergic synapses from Purkinje neurons.

Purkinje neuron synchrony elicits time-locked spiking in the cerebellar nuclei.

An unusual feature of the cerebellar cortex is that its output neurons, Purkinje cells, release GABA (γ-aminobutyric acid). Their high intrinsic firing rates (50 Hz) and extensive convergence predict that their target neurons in the cerebellar nuclei would be largely inhibited unless Purkinje cells pause their spiking, yet Purkinje and nuclear neuron firing rates do not always vary inversely. One indication of how these synapses transmit information is that populations of Purkinje neurons synchronize their spikes during cerebellar behaviours.

Deactivation of L-type Ca current by inhibition controls LTP at excitatory synapses in the cerebellar nuclei.

Long-term potentiation (LTP) of mossy fiber EPSCs in the cerebellar nuclei is controlled by synaptic inhibition from Purkinje neurons. EPSCs are potentiated by a sequence of excitation, inhibition, and disinhibition, raising the question of how these stimuli interact to induce plasticity. Here, we find that synaptic excitation, inhibition, and disinhibition couple to different calcium-dependent signaling pathways.

Millisecond timescale disinhibition mediates fast information transmission through an avian basal ganglia loop.

Avian song learning shares striking similarities with human speech acquisition and requires a basal ganglia (BG)-thalamo-cortical circuit. Information processing and transmission speed in the BG is thought to be limited by synaptic architecture of two serial inhibitory connections. Propagation speed may be critical in the avian BG circuit given the temporally precise control of musculature during vocalization.

Organization of the songbird basal ganglia, including area X.

Area X is a songbird basal ganglia nucleus that is required for vocal learning. Both Area X and its immediate surround, the medial striatum (MSt), contain cells displaying either striatal or pallidal characteristics. We used pathway-tracing techniques to compare directly the targets of Area X and MSt with those of the lateral striatum (LSt) and globus pallidus (GP).

A novel basal ganglia pathway forms a loop linking a vocal learning circuit with its dopaminergic input.

Dopamine has been implicated in mediating contextual modulation of motor behaviors and learning in many species. In songbirds, dopamine may act on the basal ganglia nucleus Area X to influence the neural activity that contributes to vocal learning and contextual changes in song variability. Neurons in midbrain dopamine centers, the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA), densely innervate Area X and show singing-related changes in firing rate.