Norton, A. | bioRxiv Science

bioRxiv2024

Processing reliant on granule cells is essential for motor learning but dispensable for many cerebellar-dependent behaviors

Cerebellar dysfunction leads to motor, learning, emotional, and social deficits. It is assumed that these deficits arise from impaired processing of mossy fiber inputs that activate granule cells (GCs) that in turn excite Purkinje cells (PCs). However, high-frequency spontaneous PC firing might also influence behaviors. To clarify how the cerebellum regulates behaviors, we compared the effects of disrupting either GC signaling, which selectively perturbs cerebellar processing, or PC signaling, which disrupts cerebellar processing and spontaneous PC firing. We find that both GC and PC signaling are required for eyeblink conditioning and vestibulo-ocular reflex (VOR) learning. However, disrupting PC signaling impairs baseline VOR, anxiety, and social behaviors, but abolishing GC signaling does not. This establishes that cerebellar processing is essential for motor learning, but is not required for many cerebellum-dependent behaviors. This suggests that such behaviors could be rescued by elevating firing in downstream targets, as shown previously for social deficits.

neuroscience↗

bioRxiv2023

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.

neuroscience↗