Cerebellar Circuits for Classical Fear Conditioning

Abstract

Accumulating evidence indicates that the cerebellum is critically involved in modulating non-motor behaviors, including cognition and emotional processing. Both imaging and lesion studies strongly suggest that the cerebellum is a component of the fear memory network. Given the well-established role of the cerebellum in adaptive prediction of movement and cognition, the cerebellum is likely to be engaged in the prediction of learned threats. The cerebellum is activated by fear learning, and fear learning induces changes at multiple synaptic sites in the cerebellum. Furthermore, recent technological advances have enabled the investigation of causal relationships between intra- and extra-cerebellar circuits and fear-related behaviors such as freezing. Here, we review the literature on the mechanisms underlying the modulation of cerebellar circuits in a mammalian brain by fear conditioning at the cellular and synaptic levels to elucidate the contributions of distinct cerebellar structures to fear learning and memory. This knowledge may facilitate a deeper understanding and development of more effective treatment strategies for fear-related affective disorders including post-traumatic stress or anxiety related disorders.

Keywords: cerebellum; emotion; fear conditioning; microcircuits; non-motor cognitive function; synaptic plasticity.

Figure 1

Cerebellar microcircuits. Pontine nuclei send excitatory projections to cerebellar granule cells (GCs) and deep cerebellar nuclei (DCN) via mossy fibers (MFs). GCs, which receive inhibitory inputs from Golgi cells (GoCs) in the granular layer, send excitatory projections to the dendrites of Purkinje cells (PCs) and molecular layer interneurons (MLIs), including stellate cells (SCs) and basket cells (BCs) in the molecular layer. MLIs send inhibitory projections to PC dendrites and have reciprocal inhibitory connections among SCs. The inferior olive (IO) sends excitatory projections to PC dendrites and DCN via climbing fibers (CFs) and their collaterals. PCs send inhibitory projections to the DCN and neighboring PCs. The DCN sends excitatory projections to the extracerebellar regions and inhibitory projections to the IO.

Figure 2

Fear learning-induced changes in cerebellar lobule V-VI microcircuits. Schematic illustration of cerebellar microcircuits regulating conditioned stimulus (CS)-dependent fear learning and memory in lobules V-VI. Each synaptic site is labeled with a number. (1) Postsynaptic long-term potentiation (LTP) occurs at parallel fiber (PF)-pyramidal cell (PC) synapses after auditory fear conditioning, underpinned by basolateral amygdala (BLA) activity during fear learning (Sacchetti et al., ; Zhu et al., 2011). (2) Presynaptic LTP occurs at molecular layer interneuron (MLI)-PC synapses after auditory fear conditioning (Scelfo et al., ; Dubois et al., 2020). PC-driven regulation of endocannabinoid signaling at MLI-PC synapses is involved in fear learning and memory (Dubois et al., 2020). (3) Auditory fear conditioning induces acceleration of depolarization-induced suppression of excitation (DSE) at PF-stellate cell (SC) synapses. (4) Auditory fear conditioning induces presynaptic LTP and accelerated depolarization-induced suppression of inhibition (DSI) at SC-SC synapses. Fear extinction learning induces presynaptic long-term depression (LTD) at SC-SC synapses (Dubois and Liu, 2021).

Figure 3

A hypothetical model for distinct roles of deep cerebellar nuclei (DCN) sub-nuclei in fear conditioning. A schematic illustration of the hypothesis that DCN sub-nuclei including the fastigial nuclei (FN), interpositus nuclei (IpN), and dentate nuclei (DN) play distinct roles in fear processing. (1) The FN innervates dopaminergic interneurons which regulate the freezing-regulating ChX10⁺ neurons in a D2R-dependent manner in the ventrolateral periaqueductal gray (vlPAG; Vaaga et al., 2020). Bi-directional modulation of the FN-vlPAG circuit positively regulates conditioned stimulus (CS)-dependent fear extinction learning (Frontera et al., 2020). vlPAG stimulation evokes inferior olive (IO)-mediated synaptic inputs to pyramidal cells (PCs) in lobule VIII (Koutsikou et al., 2014). Cholera toxin b (CTb)-saporin treatment in lobule VIII abolishes both vlPAG activation-induced facilitation of the H-reflex and freezing behavior in response to an innate fear-evoking stimulus and a CS (Koutsikou et al., 2014). (2) The IpN is necessary for the consolidation of auditory fear memory (Sacchetti et al., 2002). It is hypothesized that the IpN receives PC inputs from lobule V-VI or other hemispheric regions for encoding CS-related signals. (3) The DN may contribute to CS discrimination as well as contextual recognition for fear learning and memory. Crus I/II, which are required for contextual fear memory, are thought to contribute to fear memory processing in the DN (Supple et al., 1988).