Neuroscience

Evaluation Summary:

Opioids are widely used as pain killers, but present the severe side-effect of respiratory depression. The study from Baertsch et al. provides a mechanistic understanding of the actions of opioids on breathing by elucidating some of the biophysical and synaptic mechanisms by which opioids depress breathing with the goal of identifying therapeutic strategies. The data suggest that opioid-induced respiratory depression (OIRD) is due to both presynaptic hyperpolarization, and reduction of synaptic efficacy. The paper is generally well written and the data presented for the most part advances understanding of the mechanisms of OIRD at the level of central respiratory neural circuits.

(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 names with the authors.)

Evaluation Summary:

Martín-Fernández et al. show that Nrp1 acts within the primary somatosensory cortex to control the refinement of axons and the topography of contralateral targeting, particularly with regards to homotopic "matching" of gradients. While this action of Nrp1 has already been discovered between cortical areas, this work elucidates its role within a cortical area, with further insight into the developmental dynamics of projection and refinement also reported. This is impactful to the field of cortical axon guidance and corpus callosum development. The data analysis is rigorous and most conclusions are justified by the data.

(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 study investigates the relationship between neuronal spiking and local field potential (LFP) activity recorded on micro-electrodes, and intracranial EEG activity recorded on macro-electrodes using a data from human patients with epilepsy. The dataset is rare and unique in that it is from the human brain and recording neural activity from multiple scales (single neuron, LFP, iEEG) within the same subjects. The study tackles important questions with regards to how ripples relate to broadband LFP activity as well as single neurons in the human brain. This results will be of interest to a broad audience of neuroscientists, and particularly to readers in the field of memory as well as those who perform electrophysiology.

(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 excellent manuscript combines molecular, anatomical and behavioral methods to characterize neuron types in the mouse superior colliculus. It will likely be a significant resource to those who study how these circuits integrate sensory information to promote motor output. A diverse set of experiments supports the conclusion that the superior colliculus includes separate circuit modules involved in distinct behaviors: prey capture and predator escape.

(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 is a careful and systematic simulation study that convincingly illustrates a role for intrinsic resonance properties in suppressing the effects of cellular and network heterogeneities in a continuous attractor network model of grid cell firing patterns. The study shows that overly simplified models of neurons can lead to fragility in important network level behaviour and that intrinsic neuronal properties strongly influence relevant network level dynamics. This an important result that likely applies to a broad range of network models. Further investigation into the mechanism, possibly using a simplified model, would substantiate the simulation results and fully exploit the power of models in providing intuition and illustrating the generality of the observations.

(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:

After more than 20 years of intensive research the molecular machinery of Resurgent Currents (INaR), a non-canonical identity of currents mediated by voltage-activated sodium channels is still a mystery. In this paper, Ransdell and colleagues advance the conceptual framework with new experimental insight and a new kinetic model of INaR.

(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 is of interest to neuroscientists and psychologists working on perceptual decision-making and metacognition. Using a novel task varying the timing of covert decisions, together with sophisticated computational modelling, allowed identifying neural correlates of latent states related to confidence. The conclusions are in line with other papers identifying a dissociation between brain activity supporting performance and confidence, but provide a novel lens through which to understand these differences by focusing on confidence noise. An open issue is how to interpret conclusions about neural correlates of deviations from an ideal-observer model.

(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 provides further evidence for hemispheric asymmetry in the cortical control of manual actions based on intracranial (ECoG) recordings in human participants. Specifically, based a linear encoding model, the authors argue that movement encoding is more bilateral in the left hemisphere than the right hemisphere. The paper is well-written and the analyses are largely appropriate for addressing the primary hypothesis, though it would be helpful to detail the variability of electrode placement across individuals (which arises for the clinical intervention being undertaken) and incorporate this variability into the statistical analysis. Given the novelty of this type of human data and the well established question being addressed, this paper will be of interest to both basic and clinical researchers in motor neuroscience.

(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 #2 agreed to share their names with the authors.)

Evaluation Summary:

This manuscript uses viral tracing to identify interneurons, throughout the spinal cord, which synapse onto motoneurons innervating pairs of flexor and extensor hindlimb muscles. Importantly, the data identifies single premotor interneurons which travel to, and presumably regulate the activity of, multiple motor pools. It is possible that these premotor neurons are involved in regulating muscle stiffness across a joint.

(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 work clearly demonstrates an important role for two specific sodium-permeable ion channels for maintaining the pacemaker-like firing of midbrain dopamine neurons. These neurons have a key role in motivation, reinforcement and locomotion, and have been implicated in Parkinson's disease and multiple neuropsychiatric disorders. The authors also find that the regular firing of these cells is robustly maintained even when one of the two channels is knocked out, through upregulation of the level of the other channel.

(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.)