Neuroscience

Summary: This manuscript addresses an interesting question of how octopaminergic neurons regulate locomotor rhythms. Despite the interesting topic, the reviewers raised technical and mechanistic concerns that need to be addressed.

Summary: This study investigates asymmetry in functional gradients in human thalamus, striatum and cerebellum. The authors found that the thalamus and the pallidum of the lenticular nucleus have strongly asymmetric principal functional gradients across the two hemispheres. In the case of the caudate and cerebellum, their 2nd and 3rd gradients were asymmetric. In general, the reviewers and editors found the study to be intriguing, but ultimately, felt that the dichotomous model, while interesting, was too speculative with no direct evidence presented. Considering also the lack of results on the functional significance of the asymmetries, the editors and reviewers felt that the study is better suited for a more specialized audience.

Summary: As you will find below, all three reviewers provided very positive technical reviews - there was a strong consensus that this is a well-executed study. The reviewers highlighted the large cohort of participants, the innovative and versatile use of neuroimaging techniques, and in particular the water-corrected diffusion and tau-PET measures, and the careful analysis. While we acknowledge these methodological strengths, we found it difficult to agree on the validity of the interpretation of the findings, considering the unexpected directionality of the results. In addition, we felt that without additional proof-of-concept (e.g. longitudinal study), the current experimental design does not provide sufficient evidence for an early brain pathology marker. However, it was agreed that the study provides a clear advancement relative to other studies looking at the relationship between different imaging domains in AD. As such, the present findings should be particularly valuable for an audience interested in white-matter pathology in neurodegenerative diseases.

Summary: The reviewers agreed that the paradigm proposed in this work is elegant, and the question timely and important. However, as detailed below, they highlighted several concerns about analysis choices and the interpretation of the data. While some of these can be addressed, it was felt that a major drawback of the present manuscript is that the behaviour and EEG are obtained separately and any links are hence only circumstantial.

Summary: The study describes the properties of inputs from the supramammillary nucleus (SuM) to the CA2 area of the hippocampus. Novel information is presented by the influence of the SuM input on the local hippocampal network in the CA2 and what the effect of this input is on network activity in the CA1. The authors use complementary methods to address this question including patch-clamp recordings and optogenetics. Overall the reviewers found this study important, the experiments well-designed and the data of high quality. However, there are several key points raised by the reviewers to strengthen the data in order to fully support the authors' conclusions, and addressing these will require additional experimental work. The list below summarizes the list of required experiments reviewers agreed would be necessary for having full confidence in the authors' conclusions:

1. The authors would need to show the effect of SuM stimulation on synaptically triggered APs and not only on Aps evoked with a current step.

2. The change in the balance of EPCs and IPSCs in a train should be demonstrated in a single cell.

3. The properties of monosynaptic/disynaptic events should be compared and the lack of direct GABAergic input from the SuM demonstrated. The authors should quantify the delay time to light-evoked IPSCs to address whether the SuM-CA2 inputs are forming monosynaptic or disynaptic GABAergic connections to pyramidal neurons, as it is possible SuM neurons co-release glutamate and GABA to CA2. Given the importance of the mono vs. disynaptic innervation of different types of cells, the authors should go beyond the TTX experiments (as TTX would block a disynaptic EPSC) and also use 4-AP to recover the TTX blocked current to unequivocally prove that they inputs are monosynaptic.

4. The preferential role of PV+ cells should be shown with a more selective pharmacological approach.

5. The authors should elaborate on how SuM stimulation influences theta/gamma rhythms in the CA1 area.

This manuscript is under revision at eLife.

Summary: This is an interesting manuscript suggesting that ultrasound stimuli induce movements of the extracellular matrix and the cytoskeleton to cause mechanical activation of ASIC1a in cortical neurons. This is a novel finding.

Summary: All three reviewers are highly enthusiastic about the study reporting the acute effects of retinoic acid on excitatory synaptic transmission and its underlying mechanisms. The experiments are well executed and the results convincing. Aside from some minor comments that require minimal additional experiments or further clarification, the reviewers expressed one major concern regarding the dentate gyrus LTP data. Although further experiments are required to clarify the concerns, the reviewers recommended removing the LTP figure from the present study as it is not well connected with the rest of the study.

Summary: The manuscript examined the role of the lateral habenula (LHb) on contextual and cued fear conditioning with tests occurring at different time points since acquisition. The investigation provided important controls and systematic examination of testing and training conditions in places. The findings are interesting and likely of broad significance. However, the reviewers felt that the investigation lacked focus; that is, a more hypothesis-driven examination of the potential role of the LHb in the differential disruption of contextual and cued fear was viewed as necessary to make a major impact on a broad range of readers. Currently, there is not a clear and strong interpretation of the data, and more studies are necessary to further explore some of the options put forward by the authors.

Summary: The paper tackles an important aspect of neuroanatomical and language research concerning the lateralization differences related to functional lateralization of language. No clear cut results are currently available nowadays and methodological limitations of previous approaches are here addressed with a new angle in the tractography analysis. This is certainly of interest, the methodology is sound and the results deserve to be published. However, as you will see all the reviews highlighted that the novelty of this work both in terms of the methodology and results is somewhat limited, in addition to concerns about the nature of the task used. This makes it seem better suited to a more specialized readership.

Summary: Overall, this technically challenging and well executed study provides a nice description of the effects of aging, high activity (induced by higher temperature), and loss of SOD function on the neurophysiology of the GF system in Drosophila. However, most of the effects described have been observed in other systems. The authors have not adequately controlled for genetic background in their observations and have not carefully considered development effects. At this stage, the study does not provide insight into the mechanisms underlying the age-dependent alterations of the examined neurons.