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. We mapped output and input patterns to intersectionally restricted cell types of the interposed and adjacent interstitial nuclei in mice. In contrast to the widespread assumption of primarily excitatory outputs and restricted inferior olive-targeting inhibitory output, we found that inhibitory neurons from this region ramified widely within the brainstem, targeting both motor- and sensory-related nuclei, distinct from excitatory output targets. Despite differences in output targeting, monosynaptic rabies tracing revealed largely shared afferents to both cell classes. We discuss the potential novel functional roles for inhibitory outputs in the context of cerebellar theory.

Widespread inhibitory projections from the interposed cerebellar nucleus

The cerebellum consists of parallel parasagittal modules that contribute to diverse behaviors, spanning motor to cognitive. Recent work illustrating a role for the anterior interposed nucleus (IntA) in reach control in mice raised questions of its anatomical organization that could confer functional specificity. We employed intersectional cell- and projection- specific labeling methods to map IntA inputs and outputs. In contrast to long-standing dogma of primarily excitatory outputs and restricted inferior olive targeting inhibitory output, we found that inhibitory IntA neurons ramified widely within the brainstem, targeting both motor- and sensory-related nuclei, suggesting potential functional roles in disinhibitory control or predictive sensory cancellation. Using monosynaptic rabies tracing, we then found that excitatory output neurons receive fewer and more precisely organized inputs than inhibitory neurons, which may set them up for distinct computations. Together these data suggest IntA contains at least two distinct output circuits and promise advances in identifying parallel computations of the cerebellum.

A FN-MdV pathway and its role in cerebellar multimodular control of sensorimotor behavior

The cerebellum is crucial for various associative sensorimotor behaviors. Delay eyeblink conditioning (DEC) depends on the simplex lobule-interposed nucleus (IN) pathway, yet it is unclear how other cerebellar modules cooperate during this task. Here, we demonstrate the contribution of the vermis-fastigial nucleus (FN) pathway in controlling DEC. We found that task-related modulations in vermal Purkinje cells and FN neurons predict conditioned responses (CRs). Coactivation of the FN and the IN allows for the generation of proper motor commands for CRs, but only FN output fine-tunes unconditioned responses. The vermis-FN pathway launches its signal via the contralateral ventral medullary reticular nucleus, which converges with the command from the simplex-IN pathway onto facial motor neurons. We propose that the IN pathway specifically drives CRs, whereas the FN pathway modulates the amplitudes of eyelid closure during DEC. Thus, associative sensorimotor task optimization requires synergistic modulation of different olivocerebellar modules each provide unique contributions.

A Novel FN-MdV Pathway and Its Role in Cerebellar Multimodular Control of Sensorimotor Behavior

The cerebellum is crucial for various associative sensorimotor behaviors. Delay eyeblink conditioning (DEC) depends on the simplex lobule-interposed nucleus (IN) pathway, yet it is unclear how other cerebellar modules cooperate during this task. Here, we demonstrate the contribution of the vermis-fastigial nucleus (FN) pathway in controlling DEC. We found that task-related modulations in vermal Purkinje cells and FN neurons predict conditioned responses (CRs). Coactivation of the FN and the IN allows for the generation of proper motor commands for CRs, but only FN output fine-tunes unconditioned responses. The vermis-FN pathway launches its signal via the contralateral ventral medullary reticular nucleus, which converges with the command from the simplex-IN pathway onto facial motor neurons. We propose that the IN pathway specifically drives CRs whereas the FN pathway modulates the amplitudes of eyelid closure during DEC. Thus, associative sensorimotor task optimization requires synergistic modulation of different olivocerebellar modules that provide unique contributions.

Graded and bidirectional control of real-time reach kinematics by the cerebellum

The rules governing the relationship between cerebellar output and movement production remain unknown despite the well-recognized importance of the cerebellum in motor learning and precision. In this study, we investigated how cerebellar output sculpts reach behavior in mice by manipulating neural activity in the anterior interposed nucleus (IntA) in closed-loop with ongoing behavior. Optogenetic modulation of cerebellar output revealed monotonically graded and bidirectional control of real-time reach velocity by IntA. Furthermore, kinematic effects were relatively context invariant, suggesting that cerebellar output summates with ongoing motor commands generated elsewhere throughout the reaching movement. These results characterize the relationship between cerebellar output modulation and reach behavior as a bidirectional and scalable kinematic command signal. Our findings illustrate how learned, predictive coding in the cerebellar cortex could be actuated through the cerebellar nuclei to contribute in real time to purposive motor control.

Muscimol inactivation of caudal fastigial nucleus and posterior interposed nucleus in monkeys with strabismus

Previously, we showed that neurons in the supraoculomotor area (SOA), known to encode vergence angle in normal monkeys, encode the horizontal eye misalignment in strabismic monkeys. The SOA receives afferent projections from the caudal fastigial nucleus (cFN) and the posterior interposed nucleus (PIN) in the cerebellum. The objectives of the present study were to investigate the potential roles of the cFN and PIN in 1) conjugate eye movements and 2) binocular eye alignment in strabismic monkeys. We used unilateral injections of the GABAA agonist muscimol to reversibly inactivate the cFN (4 injections in exotropic monkey S1 with ∼4° of exotropia; 5 injections in esotropic monkey S2 with ∼34° of esotropia) and the PIN (3 injections in monkey S1). cFN inactivation induced horizontal saccade dysmetria in all experiments (mean 39% increase in ipsilesional saccade gain and 26% decrease in contralesional gain). Also, mean contralesional smooth-pursuit gain was decreased by 31%. cFN inactivation induced a divergent change in eye alignment in both monkeys, with exotropia increasing by an average of 9.8° in monkey S1 and esotropia decreasing by an average of 11.2° in monkey S2 ( P < 0.001). Unilateral PIN inactivation in monkey S1 resulted in a mean increase in the gain of upward saccades by 13% and also induced a convergent change in eye alignment, reducing exotropia by an average of 2.7° ( P < 0.001). We conclude that cFN/PIN influences on conjugate eye movements in strabismic monkeys are similar to those postulated in normal monkeys and cFN/PIN play important and complementary roles in maintaining the steady-state misalignment in strabismus.