Feedback inhibition underlies new computational functions of cerebellar interneurons

Abstract
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Abstract

The function of a feedback inhibitory circuit between cerebellar Purkinje cells and molecular layer interneurons (MLIs) was defined by combining optogenetics, neuronal activity recordings both in cerebellar slices and in vivo, and computational modeling. Purkinje cells inhibit a subset of MLIs in the inner third of the molecular layer. This inhibition is non-reciprocal, short-range (less than 200 mm) and is based on convergence of 1-2 Purkinje cells onto MLIs. During learning-related eyelid movements in vivo, the activity of a subset of MLIs progressively increases as Purkinje cell activity decreases, with Purkinje cells usually leading the MLIs. Computer simulations indicate that these relationships are best explained by the feedback circuit from Purkinje cells to MLIs and that this feedback circuit plays a central role in making cerebellar learning efficient.

Data availability

All data generated or analysed during this study are included in the manuscript and supporting file; Source Data files have been provided as Excel files. Source code is available at https://github.com/mauk-lab-utexas/CBMSim

Article and author information

Author details

Hunter E Halverson

Center for Learning and Memory, The University of Texas at Austin, Austin, United States

Competing interests
The authors declare that no competing interests exist.
Jinsook Kim

Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-6487-6608
Andrei Khilkevich

Center for Learning and Memory, The University of Texas at Austin, Austin, United States

Competing interests
The authors declare that no competing interests exist.
Michael D Mauk

Center for Learning and Memory, The University of Texas at Austin, Austin, United States

Competing interests
The authors declare that no competing interests exist.
George J Augustine

Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore

For correspondence
george.augustine@ntu.edu.sg

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-7408-7485

Funding

Ministry of Education - Singapore (MOE2016-T2-1-097)

George J Augustine

Ministry of Education - Singapore (MOE2017-T3-1-002)

George J Augustine

National Institute of Mental Health (MH46904)

Michael D Mauk

National Institute of Mental Health (MH74006)

Michael D Mauk

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All mice procedures were conducted according to the Institutional Animal Care and Use Committee guidelines of the Biopolis Biological Resource Center (# AUP 18095). Treatment of rabbits and surgical procedures were in accordance with National Institutes of Health guidelines and an institutionally approved animal welfare protocol (AUP 2015-00137). All surgery was performed under anesthesia and every effort was made to minimize suffering.

Copyright

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.