Genetically eliminating Purkinje neuron GABAergic neurotransmission increases their response gain to vestibular motion

Abstract

Purkinje neurons in the caudal cerebellar vermis combine semicircular canal and otolith signals to segregate linear and gravitational acceleration, evidence for how the cerebellum creates internal models of body motion. However, it is not known which cerebellar circuit connections are necessary to perform this computation. We first showed that this computation is evolutionarily conserved and represented across multiple lobules of the rodent vermis. Then we tested whether Purkinje neuron GABAergic output is required for accurately differentiating linear and gravitational movements through a conditional genetic silencing approach. By using extracellular recordings from lobules VI through X in awake mice, we show that silencing Purkinje neuron output significantly alters their baseline simple spike variability. Moreover, the cerebellum of genetically manipulated mice continues to distinguish linear from gravitational acceleration, suggesting that the underlying computations remain intact. However, response gain is significantly increased in the mutant mice over littermate controls. Altogether, these data argue that Purkinje neuron feedback regulates gain control within the cerebellar circuit.

Purkinje cell neurotransmission patterns cerebellar basket cells into zonal modules defined by distinct pinceau sizes

“…This particular Pcp2 Cre allele is ideal for our purpose because it expresses Cre during embryogenesis and continues into adulthood ( Lewis et al, 2004 ), which means that even the developing Purkinje cells lack Slc32a1 after recombination occurs with the floxed allele ( Tong et al, 2008 ). In these mutants, Purkinje cells are capable of receiving signals and firing simple spikes and complex spikes, although they cannot communicate their computations downstream via fast neurotransmission using GABA ( White et al, 2014 ; Stay et al, 2019 ). Compared to control Slc32a1 flox/flox mice ( Cre -negative, no Slc32a1 deletion; Figure 7A,C,E ), the mutants that lack Slc32a1 in Purkinje cells do not have a clear distinction of Purkinje cell zones or HCN1 zones, as defined by the basket cell pinceaux ( Figure 7B,D,F ).…”

Simple spike dynamics of Purkinje cells in the macaque vestibulo-cerebellum during passive whole-body self-motion

“…The framework of internal models has been the dominant theory of vestibular processing in the past decades (22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33) and is closely related to the framework used to model motor control and adaptation (54)(55)(56)(57)(58)(59)(60)(61)(62). Initially supported by behavioral studies using passive motion stimuli (34,(63)(64)(65), the implementation of internal models in central vestibular pathways has been confirmed by neurophysiological experiments of tilt/translation discrimination (35)(36)(37)(38)(39)(40)(41)(42)(43) and active head movements (66)(67)(68)(69)(70)(71)(72).…”

“…1B), thus responding identically to translational acceleration and tilt position (units are m/s 2 , or equivalently, degrees of tilt). Theoretical (22)(23)(24)(25)(26)(27)(28)(29)(30)(31)(32)(33) and experimental (34)(35)(36)(37)(38)(39)(40)(41)(42)(43) studies have demonstrated that the brain resolves this ambiguity by using head rotation signals, originating from the vestibular semicircular canals, to track head movements relative to vertical, from which the gravitational component (G) can be estimated.…”

In vivo cerebellar circuit function is disrupted in an mdx mouse model of Duchenne muscular dystrophy

“…For awake recordings, surgical procedures were similar to those we previously reported (White et al, 2016b;Stay et al, 2019), with the following modifications: mice were anesthetized with 3% isoflurane at induction, followed by 1-2% isoflurane for maintenance. After the craniotomy, a custom 2-mm circular plastic recording chamber was secured to the skull with dental acrylic, along with a metal head plate for restraint.…”