Bidirectional control of fear memories by the cerebellum through the ventrolateral periaqueductal grey

Abstract

10Fear conditioning is a form of associative learning that is known to involve brain areas, notably the 11 amygdala, the prefrontal cortex and the periaqueductal grey (PAG). Here, we describe the functional 12 role of pathways that link the cerebellum with the fear network. We found that the cerebellar 13 fastigial nucleus (FN) sends glutamatergic projections to vlPAG that synapse onto glutamatergic and 14 GABAergic vlPAG neurons. Chemogenetic and optogenetic manipulations revealed that the FN-vlPAG 15 pathway controls bi-directionally the strength of the fear memory, indicating a role in the association 16 of the conditioned and unconditioned stimuli, a function consistent with vlPAG encoding of fear 17 prediction error. In addition, we found that a FN -thalamic parafascicular nucleus pathway, which 18 may relay cerebellar influence to the amygdala, is involved in anxiety and fear expression but not in 19 fear memory. Our results reveal the contributions to the emotional system of the cerebellum, which 20 exerts a potent control on the strength of the fear memory through excitatory FN-vlPAG projections. 21 22 23 Keywords: cerebellum; limbic circuits; fear memory, chemogenetics, electrophysiology 24 vermis, in relation to negative emotions (e.g. during recall of self-generated emotional episodes 20 ). 50 Consistent with this, localized cerebellar lesions, principally in the midline vermis, account in large 51 part for the emotional disturbances, inappropriate behavior and changes in affect, which are 52 collectively termed the "cerebellar cognitive affective syndrome" 21 and reported in cerebellar 53 patients. Several studies have shown that the cerebellum has functional connections from fear-54 related areas including the PAG, the amygdala, and the prefrontal cortex [22][23][24][25] . In accordance with the 55 existence of such connections, Pavlovian fear conditioning affects cerebellar plasticity 26 , post-56 conditioning cerebellar inactivation affects memory consolidation 27 , and cerebellar lesions -or 57 inactivation-modulate freezing 24,28 ; however, the pathways by which the cerebellum participates to 58 fear learning or expression remain undefined. 59. The cerebellar vermis, which is most consistently associated with emotional pathologies and fear 60 expression 20,24,29 , projects to the fastigial nucleus (FN), a deep cerebellar nucleus (DCN) which 61 projects to many targets from the spinal cord to the diencephalon 22 . The purpose of the present 62 study is to study the contribution of specific FN output pathways to fear learning. Using 63 neuroanatomical tracings, chemogenetic modulation of the cerebellar input to the vlPAG and to the 64 BLA during fear conditioning, optogenetics and extracellular electrophysiological recordings in awake 65 freely moving animals, we demonstrate the contribution of the cerebellum to fear learning through 66 its inputs to the vlPAG. 67 68 4 69 70Results 71 Neuroanatomical link between the cerebellum and vlPAG 72In order to examine cerebellar projections to areas involve...

Ablation of STAT3 in Purkinje Cells Reorganizes Cerebellar Synaptic Plasticity in Long-Term Fear Memory Network

“…In this sense, STAT3 deletion in the PCs could induce the hypoactivity of PCs, sending the hyperactivity of DCN to the closed-loop circuitry of the cerebellum or to other fear-related regions while processing fear memory storage. For instance, cerebellar fastigial nucleus (FN) sends glutamatergic projections to ventrolateral periaqueductal grey (vlPAG), controlling the strength of the fear memory (Frontera et al, 2020). Thus, PC activity suppression led by LTD-like synaptic plasticity in the STAT3 PKO mice may contribute to increased fear memory.…”

Systemic pharmacological suppression of neural activity reverses learning impairment in a mouse model of Fragile X syndrome

“…This specificity enhances its therapeutic potential. At the same time, this approach of suppressing neural activity during a pre-training period may be generally applicable to any learning task, motor or cognitive (Rochefort et al, 2013;Badura et al, 2018;Ashburn et al, 2020;Frontera et al, 2020;Stoodley and Tsai, 2021;Hwang et al, 2022), that is impaired by enhanced associative LTD.…”

“…In other words, diazepam rescued the learning impairment with no apparent side effects on other, closely related functions of the same neural circuitry. At the same time, there is reason to expect that this approach of suppressing neural activity during a pre-training period may be generally applicable to any learning task, motor or cognitive, that is impaired by enhanced associative LTD (Rochefort et al, 2013;Badura et al, 2018;Ashburn et al, 2019;Frontera et al, 2020;Stoodley and Tsai, 2021;Hwang et al, 2022). Pharmacological suppression of neural activity should suppress PF-Purkinje cell LTD throughout the cerebellum, and hence may have the general effect of restoring all regions of the cerebellum to a state compatible with new LTD-dependent learning.…”