Bidirectional control of fear memories by cerebellar neurons projecting to the ventrolateral periaqueductal grey

Jimena Laura Frontera,Hind Baba Aissa,Romain William Sala,Clément Léna,Daniela Popa,Caroline Mailhes-Hamon,Ioana Antoaneta Georgescu

doi:10.1038/s41467-020-18953-0

Abstract

Fear conditioning is a form of associative learning that is known to involve different brain areas, notably the amygdala, the prefrontal cortex and the periaqueductal grey (PAG). Here, we describe the functional role of pathways that link the cerebellum with the fear network. We found that the cerebellar fastigial nucleus (FN) sends glutamatergic projections to vlPAG that synapse onto glutamatergic and GABAergic vlPAG neurons. Chemogenetic and optogenetic manipulations revealed that the FN-vlPAG pathway controls bi-directionally the strength of the fear memories, indicating an important role in the association of the conditioned and unconditioned stimuli, a function consistent with vlPAG encoding of fear prediction error. Moreover, FN-vlPAG projections also modulate extinction learning. We also found a FN-parafascicular thalamus pathway, which may relay cerebellar influence to the amygdala and modulates anxiety behaviors. Overall, our results reveal multiple contributions of the cerebellum to the emotional system.

Highlights

Fear conditioning is a form of associative learning that is known to involve different brain areas, notably the amygdala, the prefrontal cortex and the periaqueductal grey (PAG)
Combining a vglut2-cre mice line with the infusion of AAV-DIO-tdTom in fastigial nucleus (FN), and retrograde AAV-GFP in ventrolateral PAG (vlPAG) allowed us to determine that the FN–vlPAGprojecting neurons correspond to vesicular glutamate transporter 2 expressing neurons (85.4 ± 4.0% of GFP-expressing cells co-localized with vGluT2+ neurons, n = 4; Fig. 1j–l)
These results indicate that FN–vlPAG projections contribute to the formation of conditioned fear memories, in which the activation of this pathway during the fear conditioning decreases the strength of the fear memory formation, while the inhibition of this pathway increases it

Summary

Introduction

Fear conditioning is a form of associative learning that is known to involve different brain areas, notably the amygdala, the prefrontal cortex and the periaqueductal grey (PAG). Chemogenetic and optogenetic manipulations revealed that the FN-vlPAG pathway controls bi-directionally the strength of the fear memories, indicating an important role in the association of the conditioned and unconditioned stimuli, a function consistent with vlPAG encoding of fear prediction error. The cerebellum is strongly recruited in aversive emotional states: in humans, neuroimaging studies have revealed changes in cerebellar activation, mainly in the vermis, in relation to negative emotions (e.g., during recall of self-generated emotional episodes[20]). Chemogenetic modulation of the cerebellar input to the vlPAG during fear conditioning and extinction, optogenetics and extracellular electrophysiological recordings in awake freely moving animals, we demonstrate the contribution of the cerebellum to fear learning through its inputs to the vlPAG

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Conclusion