Peer review process
Revised: This Reviewed Preprint has been revised by the authors in response to the previous round of peer review; the eLife assessment and the public reviews have been updated where necessary by the editors and peer reviewers.
Read more about eLife’s peer review process.Editors
- Reviewing EditorKate WassumUniversity of California, Los Angeles, Los Angeles, United States of America
- Senior EditorKate WassumUniversity of California, Los Angeles, Los Angeles, United States of America
Reviewer #2 (Public review):
Summary:
The authors aimed to explore the role of climbing fibers (CFs) in cerebellar learning, with a focus on optokinetic reflex (OKR) adaptation. Their goal was to understand how CF activity influences memory acquisition, memory consolidation, and memory retrieval by optogenetically suppressing CF inputs at various stages of the learning process.
Strengths:
The study addresses a significant question in the cerebellar field by focusing on the specific role of CFs in adaptive learning. The authors use optogenetic tools to manipulate CF activity. This provides a direct method to test the causal relationship between CF activity and learning outcomes.
Weaknesses:
Despite shedding light on the potential role of CFs in cerebellar learning, the study is hampered by significant methodological issues that question the validity of its conclusions. The absence of detailed evidence on the effectiveness of CF suppression and concerns over tissue damage from optogenetic stimulation weaken the argument that CFs are not essential for memory consolidation. These challenges make it difficult to confirm whether the study's objectives were fully met or if the findings conclusively support the authors' claims. The research commendably attempts to unravel the temporal involvement of CFs in learning but also underscores the difficulties in pinpointing specific neural mechanisms that underlie the phases of learning. Addressing these methodological issues, investigating other signals that might instruct consolidation, and understanding CFs' broader impact on various learning behaviors are crucial steps for future studies.
Comments on revisions:
In this revision, the authors provide new data regarding the effect of eNpHR on CF-evoked complex spiking in vivo but fails to address overall concerns showing the functional effect that explains their causal results. Additionally, the paper has a narrow "CF-or-nothing" framing that leaves unanswered the central question of which signal instructs consolidation if CFs do not. Substantial new experiments and tighter logic are required before the work can serve as a definitive test of CF involvement in different memory processes.
Reviewer #3 (Public review):
Summary:
The authors attempted to study connections with the inferior olive to the cerebellar cortex and analyze impacts on optokinetic reflex using optogenetics to perturb the pathway. This is a commendable effort as these methods are very challenging due to the location of the inferior olive and recording methods.
Strengths:
The authors have shown that climbing fiber activity was altered due to the optogenetic perturbation. They have added an additional figure to show that complex spikes disappear with inhibitory optogenetics and the impacts on behavior are interesting.
Weaknesses:
The images provided to show injection region are difficult to see and specific cell types are not co-labeled. The data and strength of the results would benefit from high-resolution images demonstrating selectivity and expression, in particular for Figure 2A and 3A. In addition, while the processed recording data looks very striking, including the raw data, as done in Figure 2, would again support the conclusions.
One major concern is that the viruses chosen are non-specific to the cell targets and a cre-based approach is lacking to draw conclusions on only the targeted pathway of interest. It is unclear based on the figures provided if the AAVs labeled only the pathway of interest. It would be interesting to know if typical memory acquisition returns in the same animals if inhibition stops and if animal movement was impacted by the perturbation.