Cerebellar Learning Properties Are Modulated by the CRF Receptor

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. Analysis of cerebella transcriptome obtained from KO and control mice detected prominent alterations in the expression of calcium signaling pathways components. 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. 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 the corticotropin-releasing factor type 1 receptor (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 at 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 granular cell-specific ablation of CRFR₁. We found a profound effect on learning both at the cellular and behavioral levels without an effect on baseline motor skills.