Neuroscience

Evaluation Summary:

This paper is of interest to a broad range of neuroscientists, particularly those interested in ApoE biology and Alzheimer's disease (AD), as it reveals a novel mechanism that counteracts AD-linked amyloid plaque burden and synapse dysfunction in mice. Overall, the methodology is sound, sophisticated, and employs animal models that more closely mimic human diseases, and the results are interesting and compelling. Whilst the mechanistic hypothesis proposed by the authors is consistent with the data, plausible alternative explanations remain.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #2 agreed to share their name with the authors.)

Evaluation Summary:

This manuscript presents a method to characterize diverse neural activity patterns arising from a small invertebrate circuit. This is of practical interest to invertebrate neuroscientists. The application of unsupervised methods to characterize qualitatively distinct regimes of spiking neural circuits is very interesting. The challenges and lessons learned in this study are therefore of broader interest to those seeking to quantitatively characterize large sets of neural data across many subjects. The survey could be improved by further validation of the derived clusters.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)

Evaluation Summary:

There has been a great deal of recent interest in the neural basis for offset responses given their hypothesised importance to perception. This tests the relevance of offset responses to duration perception in a mouse model in addition to examining the brain basis. The work is thorough and well executed. The work demonstrates offset responses that occurs for the first time in auditory cortex distinct from A1 where prevention of offsets by activating cells causes worsening of behavioural performance.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)

Evaluation Summary:

The manuscript shows an important role for Cav2.3 channels in SNI-mediated allodynia and firing properties of PV-expressing APT neurons. Mechanisms that underlie adaptations in chronic pain models are extremely important for the development of novel therapeutics for chronic pain and this could be a significant contribution in that regard. However, the discussion asserts that these studies are the "first direct evidence that supra-spinal Cav3.2 channels play a fundamental role in pain pathophysiology." This is an overstatement as Chen and colleagues examined the role of these channels in the anterior cingulate cortex in CCI-mediated neuropathic pain (Shen, et al., 2015, Molecular Pain).

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #3 agreed to share their name with the authors.)

Evaluation summary:

This study investigates the neural basis of the hidden causal structure between visual and proprioceptive signals in the primate premotor and parietal circuit during reaching tasks executed in a virtual reality environment, where information between the two modalities can be dissociated. Modelling is used to characterize the proprioceptive drift of the monkeys when integrating bimodal information. The key novel result is that premotor neurons represent the integration of bimodal information for small disparities and the segregation for large disparities between the proprioceptive and visual information, while parietal cells show reaching tuning changes that support the updating sensory uncertainty between tasks. Overall, the experiments are technically sound, and the conclusions are mostly well supported. However, a simpler framing of the paper could make the main message easier to grasp, the analysis of Bayesian models seems to lack major details, the statistical reporting is below standard, and a large part of the extensive literature on the role of premotor and parietal cortex in visuomotor behavior is lacking.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)

Evaluation Summary:

This paper suggests that assembly of CaV2.3 with b2a/b2e splice variants confers biophysical properties that enable these channels to contribute to calcium-dependent pacemaking in dopaminergic neurons. The findings could have implications for why these neurons are vulnerable to degeneration in Parkinson's disease. The work will be of interest to ion channel biophysicists and neuroscientists.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)

Evaluation Summary:

This paper proposes that specializations in the outer hair cells' biophysical properties along the cochlea may allow them to amplify the reduced receptor potentials in a manner sufficient to explain all present experimental results. Moreover, the filtering provided by the hair cells may be beneficial for hearing soft high-frequency sounds because it decreases noise and harmonic distortions. Importantly, the amplitude of the relevant motions, even with the low-pass-filtered attenuation, are as large as those measured in the high frequency regions of the cochlea. The authors provide insights and suggestions but the paper lacks strong supportive experimental data to definitively resolve the claimed "apparent" membrane time constant conundrum.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 and Reviewer #3 agreed to share their name with the authors.)

Evaluation Summary:

The authors report that neurons in V1 and V4 provide multiplex information of simultaneously presented objects. A combination of multi-single unit recordings, statistical modelling of neuronal responses and neuronal correlations analyses argues in favor of their claims. Pairs of neurons having similar object preferences tended to be positively correlated when both objects were presented, while pairs of neurons having different objects preferences tended to be negatively correlated. These patterns and others suggest that information about the two objects is multiplexed in time. There are, however, some unclear points that deserve discussion and further analysis that could more strongly support the claims.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #3 agreed to share their name with the authors.)

Evaluation Summary:

This paper introduces Neuroscout, a new web-based platform for the analysis of fMRI data with a particular focus on naturalistic stimuli. It describes a new tool that will potentially be of great use to the neuroimaging community, and whose development is already quite mature and has a number of datasets ready to use online. Neuroscout as a tool will be of particular interest to neuroimagers and cognitive neuroscientists, but the conclusions drawn using the tool should be of interest to neuroscientists more broadly.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1, Reviewer #2 and Reviewer #3 agreed to share their name with the authors.)

Evaluation Summary:

Mahalingam et al. report on a new software suite, ASAP, the assembly stitching and alignment pipeline, capable of montaging and aligning serial sections at a speed leading to total time shorter than image acquisition time. The software applies to both electron microscopy and array tomography, and more generally to any data set consisting of collections of 2D images in need of in-section montaging and cross-section registration. The result is a coarsely registered volume, ready for refining with existing software suits such as SEAMLESS by Macrina et al. (2021) towards subsequent processing, such as image segmentation and neuronal arbor reconstruction for cellular connectomics. This paper will be of special interest to researchers within the field of connectomics, but also to the broad class of scientists who perform large-scale microscopy. The establishment of fast, reliable and scalable image alignment software to process the millions of images produced by modern microscopes at the same speed as they are acquired is key to accelerate research in neuroscience and other fields. The key claims of the manuscript are well supported by the data, and the approaches used are thoughtful and rigorous.

(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1, Reviewer #2 and Reviewer #3 agreed to share their name with the authors.)