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Review
. 2023 Apr 21:17:1166166.
doi: 10.3389/fnsys.2023.1166166. eCollection 2023.

The cerebellum and fear extinction: evidence from rodent and human studies

Alice Doubliez #  1 , Enzo Nio #  1 , Fernando Senovilla-Sanz #  2 , Vasiliki Spatharioti #  2 , Richard Apps  2 , Dagmar Timmann  1 , Charlotte L Lawrenson  2
Affiliations
Review

The cerebellum and fear extinction: evidence from rodent and human studies

Alice Doubliez et al. Front Syst Neurosci. .

Erratum in

Abstract

The role of the cerebellum in emotional control has gained increasing interest, with studies showing it is involved in fear learning and memory in both humans and rodents. This review will focus on the contributions of the cerebellum to the extinction of learned fear responses. Extinction of fearful memories is critical for adaptive behaviour, and is clinically relevant to anxiety disorders such as post-traumatic stress disorder, in which deficits in extinction processes are thought to occur. We present evidence that supports cerebellar involvement in fear extinction, from rodent studies that investigate molecular mechanisms and functional connectivity with other brain regions of the known fear extinction network, to fMRI studies in humans. This evidence is considered in relation to the theoretical framework that the cerebellum is involved in the formation and updating of internal models of the inner and outer world by detecting errors between predicted and actual outcomes. In the case of fear conditioning, these internal models are thought to predict the occurrence of an aversive unconditioned stimulus (US), and when the aversive US is unexpectedly omitted during extinction learning the cerebellum uses prediction errors to update the internal model. Differences between human and rodent studies are highlighted to help inform future work.

Keywords: cerebellum; cerebro-cerebellar circuits; electrophysiology; fMRI; fear behaviour; fear extinction; prediction error.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
FIGURE 1
Neurocircuitry underlying adaptive cerebellar fear processes. In classical pavlovian conditioning, the inferior olive (IO) signals the US, while the mossy fibre-parallel fibre pathway (MF-PF) signals the unconditional stimulus. (1) During the acquisition of a fear memory, there is an upregulation of AMPA receptors at the PF-PC synapse, resulting in post-synaptic long-term potentiation (LTP; Sacchetti et al., 2004; Zhu et al., 2007), as well as an increase of GABAergic signalling onto Purkinje cells from molecular layer interneurons/stellate cells (SC) (Scelfo et al., 2008). Various cerebellar lobules in rodents have been associated with fear learning, but the underlying mechanisms relating to LTP have focused primarily on lobules V/VI. (2) In contrast, NMDAR-mediated long-term depression (LTD) at SC-SC synapses has been associated with extinction (Dubois and Liu, 2021). (3) The medial cerebellar nuclei (MCN) have also been directly associated with fear extinction (Frontera et al., 2020), via projections to dopaminergic, GABAergic and glutamatergic neurons in the vlPAG, Vaaga et al. (2020). MCN projections are capable of modulating glutamatergic neurons that express the transcription factor Chx10 in the vlPAG (Vaaga et al., 2020) which have previously been associated with freezing behaviour through their projection to the magnocellular reticular nucleus. This in turn is directly connected to motor neurons of the spinal cord (Tovote et al., 2016). (4) The cerebellar nuclei also project to the VTA; an area associated with the enhancement of fear extinction learning (Carta et al., 2019). (5) Finally, the cerebellum also projects either directly (thalamus, hypothalamus) or indirectly (amygdala, anterior cingulate cortex, hippocampus, striatum) to multiple other areas that could be related to the fear network (Apps and Strata, 2015). PC: Purkinje Cell, MCN: Medial Cerebellar Nuclei, SC: Stellate Cell, GC: Granule Cell, CS: Conditioned Stimulus, US: Unconditioned Stimulus, VTA: Ventral Tegmental Area, vlPAG: VentroLateral PeriAqueductal Grey.
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Grants and funding

This work has received funding from the European Union’s Horizon 2020 Research and Innovation Programme under the Marie Skłodowska-Curie grant agreement No. 956414. This work was also supported by a grant from the German Research Foundation (DFG; project number: 316,803,389—SFB 1280) to DT (subproject A05), and the UKRI Medical Research Council (MRC; project number: MR/T019484/1).

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