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. Here, we find that two recently recognized MLI subtypes, MLI1 and MLI2, have a highly specialized connectivity that allows them to serve distinct functional roles. MLI1s primarily inhibit PCs, are electrically coupled to each other, fire synchronously with other MLI1s on the millisecond timescale in vivo, and synchronously pause PC firing. MLI2s are not electrically coupled, primarily inhibit MLI1s and disinhibit PCs, and are well suited to gating cerebellar-dependent behavior and learning. The synchronous firing of electrically coupled MLI1s and disinhibition provided by MLI2s require a major re-evaluation of cerebellar processing.

A deep-learning strategy to identify cell types across species from high-density extracellular recordings.

High-density probes allow electrophysiological recordings from many neurons simultaneously across entire brain circuits but don't reveal cell type. Here, we develop a strategy to identify cell types from extracellular recordings in awake animals, revealing the computational roles of neurons with distinct functional, molecular, and anatomical properties. We combine optogenetic activation and pharmacology using the cerebellum as a testbed to generate a curated ground-truth library of electrophysiological properties for Purkinje cells, molecular layer interneurons, Golgi cells, and mossy fibers. We train a semi-supervised deep-learning classifier that predicts cell types with greater than 95% accuracy based on waveform, discharge statistics, and layer of the recorded neuron. The classifier's predictions agree with expert classification on recordings using different probes, in different laboratories, from functionally distinct cerebellar regions, and across animal species. Our classifier extends the power of modern dynamical systems analyses by revealing the unique contributions of simultaneously-recorded cell types during behavior.

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 predictions1. Molecular layer interneurons (MLIs) account for approximately 80% of the inhibitory interneurons in the cerebellar cortex2, and are vital to cerebellar processing1,3. MLIs are thought to primarily inhibit PCs and suppress the plasticity of excitatory synapses onto PCs. MLIs also inhibit, and are electrically coupled to, other MLIs4-7, but the functional significance of these connections is not known1,3. Behavioral studies suggest that cerebellar-dependent learning is gated by disinhibition of PCs, but the source of such disinhibition has not been identified8. Here we find that two recently recognized MLI subtypes2, MLI1 and MLI2, have highly specialized connectivity that allows them to serve very different functional roles. MLI1s primarily inhibit PCs, are electrically coupled to each other, fire synchronously with other MLI1s on the millisecond time scale in vivo, and synchronously pause PC firing. MLI2s are not electrically coupled, they primarily inhibit MLI1s and disinhibit PCs, and are well suited to gating cerebellar-dependent learning8. These findings require a major reevaluation of processing within the cerebellum in which disinhibition, a powerful circuit motif present in the cerebral cortex and elsewhere9-17, greatly increases the computational power and flexibility of the cerebellum. They also suggest that millisecond time scale synchronous firing of electrically-coupled MLI1s helps regulate the output of the cerebellar cortex by synchronously pausing PC firing, which has been shown to evoke precisely-timed firing in PC targets18.

Consistency of angular tuning in the rat vibrissa system.

Each region along the rat mystacial vibrissa pathway contains neurons that respond preferentially to vibrissa deflections in a particular direction, a property called angular tuning. Angular tuning is normally defined using responses to deflections of the principal vibrissa, which evokes the largest response magnitude. However, neurons in most brain regions respond to multiple vibrissae and do not necessarily respond to different vibrissae with the same angular tuning. We tested the consistency of angular tuning across the receptive field in several stations along the vibrissa-to-cortex pathway: primary somatosensory (barrel) cortex, ventroposterior medial nucleus of the thalamus (VPM), second somatosensory cortex, and superior colliculus. We found that when averaged across the population, neurons in all of these regions have low (superior colliculus and second somatosensory cortex) or statistically insignificant (barrel cortex and VPM) angular tuning consistencies across vibrissae. Nevertheless, in each region there are a small number of neurons that display consistent angular tuning for at least some vibrissae. We discuss the relevance of these findings for the transformation of inputs along the vibrissa trigeminal pathway and for the detection of sensory cues by whisking animals.

Superior colliculus control of vibrissa movements.

This study tested the role of the superior colliculus in generating movements of the mystacial vibrissae--whisking. First, we compared the kinematics of whisking generated by the superior colliculus with those generated by the motor cortex. We found that in anesthetized rats, microstimulation of the colliculus evoked a sustained vibrissa protraction, whereas stimulation of motor cortex produced rhythmic protractions. Movements generated by the superior colliculus are independent of motor cortex and can be evoked at lower thresholds and shorter latencies than those generated by the motor cortex. Next we tested the hypothesis that the colliculus is acting as a simple reflex loop with the neurons that drive vibrissa movement receiving sensory input evoked by vibrissa contacts. We found that most tecto-facial neurons do not receive sensory input. Not only did these neurons not spike in response to sensory stimulation, but field potential analysis revealed that subthreshold sensory inputs do not overlap spatially with tecto-facial neurons. Together these findings suggest that the superior colliculus plays a pivotal role in vibrissa movement--regulating vibrissa set point and whisk amplitude--but does not function as a simple reflex loop. With the motor cortex controlling the whisking frequency, the superior colliculus control of set point and amplitude would account for the main parameters of voluntary whisking.

Superior sensation: superior colliculus participation in rat vibrissa system.

BACKGROUND: The superior colliculus, usually considered a visuomotor structure, is anatomically positioned to perform sensorimotor transformations in other modalities. While there is evidence for its potential participation in sensorimotor loops of the rodent vibrissa system, little is known about its functional role in vibrissa sensation or movement. In anesthetized rats, we characterized extracellularly recorded responses of collicular neurons to different types of vibrissa stimuli. RESULTS: Collicular neurons had large receptive fields (median = 14.5 vibrissae). Single units displayed responses with short latencies (5.6 +/- 0.2 msec, median = 5.5) and relatively large magnitudes (1.2 +/- 0.1 spikes/stimulus, median = 1.2). Individual neurons could entrain to repetitive vibrissa stimuli delivered at < or = 20 Hz, with little reduction in phase locking, even when response magnitude was decreased. Neurons responded preferentially to vibrissa deflections at particular angles, with 43% of the cells having high (> or = 5) angular selectivity indices. CONCLUSION: Results are consistent with a proposed role of the colliculus in somatosensory-mediated orienting. These properties, together with the connections of the superior colliculus in sensorimotor loops, are consistent with its involvement in orienting, alerting and attentive functions related to the vibrissa system.