Neuroscience

Evaluation Summary:

A meta-analysis of over 14,000 fMRI studies revealed a principle rostral-caudal gradient in the lateral prefrontal cortex. This gradient reflected an internal/external axis, which helps to organize the LPFC's involvement in widespread processes from affect, to memory, to control, and action. This is an important contribution to the literature, particularly as a meta-analytic approach has not been applied to this axis of organization and can complement the limitations of single studies. The evidence for the conclusions could be strengthened by ruling out bias in the analysis and drawing a clearer relationship to functional networks.

(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 manuscript from Singh and colleagues investigates neural connections between the central amygdala and the zona incerta, two subcortical brain regions previously implicated in pain, and further describes the role of the zona incerta to preclinical pain-related behavior in mice. This study employed anatomical tracing, electrophysiology, optogenetics, chemogenetics, and behavioral assays in various pain modalities to link the zona incerta to pain modulation by providing new evidence for a direct inhibitory connection from the central amygdala to the zona incerta that could explain neuropathic pain hypersensitivity. While rigorous, well written, and well executed, the study in its current form lacked evidence to directly support the PKCδ neurons in the central amygdala projecting to the zona incerta as being explicitly involved in this process.

(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 study will be interesting to a broad audience of neuroscientists, as it reveals for the first time that mutations in klc4, which are known to cause a form of early onset hereditary spastic paraplegia in human, affect specific aspects of neuronal development and nervous system functions. High resolution movies of developing sensory neurons in vivo and behavioral assays support the key findings that klc4 plays an essential role in the control of neuronal morphogenesis and behavior. The data presented in the manuscript are overall of a descriptive nature but provide a foundation for future mechanistic studies aimed at addressing the specific functions of KLC4.

(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 authors made paired recordings from synaptically-connected excitatory and inhibitory neurons in slices of human neocortex and used posthoc molecular methods to identify major classes of the recorded interneurons. The principal finding is that, as found previously in rodent cortex, short-term plasticity of the synaptic connections from excitatory to inhibitory neurons depends on the molecular identity of the inhibitory neurons. This is important, as it suggests that many rodent studies carried out over the past decades are physiologically relevant to humans.

(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 manuscript offers a valuable transcriptomic data set of known types of adult zebrafish photoreceptors (rod and cones). The study further identifies a large set of differentially expressed transcription factors, many of which still have an unidentified function in photoreceptors. Using CRISPR F0 screening, the study shows that the two tbx2 zebrafish paralogues are involved in photoreceptors specification beyond what is currently known. The study uses a solid methodology and the results will be valuable for researchers interested in photoreceptor biology. At present, however, the manuscript has a misleading title and focus: the analysis of adult photoreceptors can hardly offer a scenario of the transcription factors involved in the specification of photoreceptors.

(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:

The authors show that how high-dimensional neural signals can be reduced to low-dimensional models with variables that can be directly linked to behavior. The reduced model can account for long timescales of persistent activity that arise from transisions between metastable model states. The authors further show that the rate of these transitions is modulated by water temperature according to the classic Arrhenius law.

(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:

The capacity to flexibly modify our actions in order to seek goals relies upon specific brain regions and neurochemicals. Cerpa et al identify norepinephrine (but not dopamine) within the ventrolateral orbitofrontal cortex (OFC) as key to updating identity-specific action-outcome associations when environmental conditions change. These conclusions are relatively well supported by the data and will be of interest to behavioural neuroscientists studying the function of OFC or noradrenaline signalling, as well as researchers studying associative learning.

(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 an important paper that uses state of the art technology to address the underlying neurobiology of neuropathic pain, a topic of considerable translational relevance. The study describes changes in gene expression at a single cell resolution in somatosensory neurons following peripheral nerve injury. Bioinformatics analyses were employed to segregate neurons in sub-classes and to derive predictions on potential functions of regulated genes. While the work has considerable strengths, such as the single cell approach, there are also some weaknesses, including the fact that new gene candidates did not undergo functional analysis.

(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:

Mutations in MINAR2 causes deafness in human and mice. Loss of function of Minar2 in mice causes a reduction of stereocilia and subsequent hair cell degeneration but the underlying mechanism is unclear. This zebrafish study demonstrated that the Minar2 protein interacts with cholesterol and is localized to the stereocilia of hair cells. The loss of Minar2 reduces cholesterol enrichment in the stereocilia with concomitant accumulation in lysosomes. Thus, this study provides the mechanistic insight of Minar2 and the first glimpse at the importance of cholesterol homeostasis in hair cell function.

(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:

The authors use high spatial resolution MEG in humans to link two important components (time - transient bursts, space - waves) of neural sensorimotor dynamics by investigating how transient beta bursts propagate in the brain. The authors find two directions of propagating waves during beta bursts. The work links two fundamental aspects of neural dynamics which may yield new insights into the origins of sensorimotor behavior, with wide appeal to neuroscientists and clinicians. The reviewers considered the methodological work largely sound, although concerns were raised by the reviewers to what extent the travelling waves correspond to underlying neural activity or reflect the generative nature of field potentials.

(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.)