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J Neurosci. 2018 Jul 25;38(30):6751-6765. doi: 10.1523/JNEUROSCI.3106-15.2018. Epub 2018 Jun 22.

Cerebellar Learning Properties Are Modulated by the CRF Receptor.

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Department of Neurobiology, Weizmann Institute of Science, Rehovot, 76100, Israel.
Department of Stress Neurobiology and Behavioral Neurogenetics, Max Planck Institute of Psychiatry, Munich, 80804, Germany.
Department of Brain and Behavioral Sciences, University of Pavia, 27100 Pavia, Italy.
Museo Storico della Fisica e Centro Studi e Ricerche Enrico Fermi, 00184 Rome, Italy.
Department of Neuroscience, Erasmus MC, 3000 DR Rotterdam, The Netherlands.
Department of Biology and Biotechnology L. Spallanzani, University of Pavia, 27100 Pavia, Italy.
Department of Biological Services.
Department of Veterinary Resources, Weizmann Institute of Science, Rehovot, 76100, Israel.
Brain Connectivity Center, Istituto Di Ricovero e Cura a Carattere Scientifico C. Mondino, 27100 Pavia, Italy, and.
Department of Neuroscience, Erasmus MC, 3000 DR Rotterdam, The Netherlands,
Netherlands Institute for Neuroscience, Royal Dutch Academy of Arts and Science, 1105 BA Amsterdam, The Netherlands.
Department of Neurobiology, Weizmann Institute of Science, Rehovot, 76100, Israel,


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.


CRF; CRFR1; cerebellum; eyeblink conditioning; granule cells

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