Modeled changes of cerebellar activity in mutant mice are predictive of their learning impairments.

Aleksandra Badura,Claudia Clopath,Martijn Schonewille,Chris I. De Zeeuw

doi:10.1038/srep36131

Abstract

Translating neuronal activity to measurable behavioral changes has been a long-standing goal of systems neuroscience. Recently, we have developed a model of phase-reversal learning of the vestibulo-ocular reflex, a well-established, cerebellar-dependent task. The model, comprising both the cerebellar cortex and vestibular nuclei, reproduces behavioral data and accounts for the changes in neural activity during learning in wild type mice. Here, we used our model to predict Purkinje cell spiking as well as behavior before and after learning of five different lines of mutant mice with distinct cell-specific alterations of the cerebellar cortical circuitry. We tested these predictions by obtaining electrophysiological data depicting changes in neuronal spiking. We show that our data is largely consistent with the model predictions for simple spike modulation of Purkinje cells and concomitant behavioral learning in four of the mutants. In addition, our model accurately predicts a shift in simple spike activity in a mutant mouse with a brainstem specific mutation. This combination of electrophysiological and computational techniques opens a possibility of predicting behavioral impairments from neural activity.

Highlights

Both use the same pathways to convey the visual, vestibular and oculomotor input signals as well as the same oculomotor pathways to control the oculomotor output[15,17,18]
When we looked at the Purkinje cell (PC) SS firing patterns in the mutant mice that underwent VOR phase-reversal training, we saw a significant increase in the amplitude of SS modulation (n = 3; n of PCs = 10; peak-to-peak amplitude = 20.2 ± 4.5 Hz; p = 0.03 when compared to SS modulation before training) (Fig. 4f and Table 4), which was reflected in an overall increase in SS firing frequency (44.9 ± 3.6 Hz and 58.2 ± 3.7 Hz, before and after training, respectively; p = 0.01)
When we looked at the PC SS firing patterns in the mutant mice that were subjected to VOR phase-reversal training, we saw a significant increase in the amplitude of SS modulation similar to that found in the PC-Δγ2 (n = 3; n of PCs = 12; peak-to-peak amplitude = 14.5 ± 2.9 Hz; p = 0.05 when compared to SS modulation before training)

Summary

Introduction

Both use the same pathways to convey the visual, vestibular and oculomotor input signals as well as the same oculomotor pathways to control the oculomotor output[15,17,18]. In order to have a complete picture of the cerebellar circuit and test the limits of our model we investigate the PCs spiking behavior in two additional mutant mice with Purkinje cell specific lesions These include the PC-ΔKCC2 mice[20], in which the GABAergic inhibition of MLIs on PCs is significantly reduced, and the PC-ΔPP2B mice, in which long-term potentiation (LTP) at the PF-PC synapse is abolished and intrinsic excitability of PCs is reduced[21]. We tested to what extent our model reproduces motor learning deficits resulting from major reduction of input from the granule cell layer, using a granule cell specific mutant GC-ΔCACNA1A, in which the majority of granule cells is silenced[19] This mouse model utilizes an imperfect Cre-lox system together with a cerebellar GC-specific promoter[31,32], resulting in a loss of GC output in an estimated ~75% of the GC population[19]. These data highlight the role of SS modulation amplitude in cerebellar cortex dynamics during phase-shift paradigms

Methods

Results

Conclusion