Abstract

Corticotropin-releasing factor (CRF) and its type 1 receptor (CRFR₁) play an important role in the responses to stressful challenges. Despite the well-established expression of CRFR₁ in granular cells (GrCs), its role in procedural motor performance and memory formation remains elusive. To investigate the role of CRFR₁ expression in cerebellar GrCs, we used a mouse model depleted of CRFR₁ in these cells. We detected changes in the cellular learning mechanisms in GrCs depleted of CRFR₁ in that they showed changes in intrinsic excitability and long-term synaptic plasticity. Moreover, male mice depleted of CRFR₁ specifically in GrCs showed accelerated Pavlovian associative eye-blink conditioning, but no differences in baseline motor performance, locomotion or fear and anxiety-related behaviors. Last, we analyzed cerebella transcriptome of KO and control mice and detected prominent alterations in the expression of calcium signaling pathways components. Our findings shed light on the interplay between stress-related central mechanisms and cerebellar motor conditioning, highlighting the role of the CRF system in regulating particular forms of cerebellar learning.

SIGNIFICANCE STATEMENT

Although it is known that CRFR₁ is highly expressed in the cerebellum, little attention has been given to its role in cerebellar functions in the behaving animal. Moreover, most of the attention was directed to the effect of CRF on Purkinje cells at the cellular level, and to this date, almost no data exist on the role of this stress-related receptor in other cerebellar structures. Here, we explored the behavioral and cellular effect of GrCs specific ablation of CRFR₁. We found a profound effect on learning, both at the cellular and behavioral levels, without affecting baseline motor skills.