Neuroscience

Evaluation Summary:

This is an innovative and important paper with interest to basic and translational neuroscientists that demonstrates the power of experimental models to advance our understanding of human disease. The authors focus on early-life epilepsy, a devastating and common disorder, and specifically on genetic epilepsies generated via pathological sequence variations in the hyperpolarization-activated nonspecific cation (HCN) channel subtype 1. They delineate the epileptic phenotype and demonstrate some of the potential mechanisms leading to the generation of spontaneous seizures in genetically engineered mice.

(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:

Brodbeck and colleagues make a strong contribution to the field of neurolinguistics by asking whether speech comprehension uses local (e.g., sublexical) or global (e.g., sentences) contextual probabilities. To tackle this, they recorded participants with magnetoencephalography while they listened to a story. The authors assessed which of three possible speech models best explained brain activity using state-of-the-art analyses and information-theoretic measures. The authors report strong and valuable evidence for both local and global contextual analyses supporting the coexistence of both hierarchical and parallel speech processing in the human brain.

(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:

All-trans retinoic acid (atRA) is a potent regulator of synaptic function known to be critical for certain forms of homeostatic plasticity. Previous work by the Vlachos group established that atRA also modulates synaptic function in human cortex and linked the synaptic effects of atRA to the spine apparatus protein synaptopodin. As a follow up study, the present work investigated the effect of atRA in the hippocampus. The authors found that atRA can play a key role in modulating enduring forms of synaptic plasticity in the dentate gyrus of the hippocampus even when it does not seem to drive overt changes in basal synaptic function, and this "metaplasticity"-related effects also require synaptopodin. Together, these studies establish a critical role of atRA in modulating synaptic transmission and plasticity at multiple regions of the human brain.

(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:

In mammals the cellular retinaldehyde binding protein, CRALBP, is expressed in the pigment epithelium (RPE) and in Müller glial cells (MGCs) in the retina. Zebrafish has two copies of the gene, each expressed in one of the cell types. By knocking out each gene with CRISPR/Cas9, the authors could show that it is the copy expressed in the RPE that is essential for turnover of retinal and for cone function. Thus, the zebrafish gene duplication suggests that the RPE role of CRALBP is the important one also in humans, implying the RPE as target for future gene therapy in humans with mutations in CRALBP.

(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:

The authors demonstrate that selective inactivation of carnitine acetyltransferase (Crat) – a key metabolic enzyme – in AgRP neurons attenuates the response of AgRP neurons to peanut butter (PB) chips, the release of dopamine in the nucleus accumbens, and the motivation to work for food when mice are fasted. The strength of this study is the demonstration that metabolic sensing by AgRP neurons is somehow linked to dopamine release in the nucleus accumbens, but a weakness is that it is unclear how the lack of Crat in AgRP neurons affects their responsiveness to PB chips or how AgRP neurons regulate dopamine release.

Evaluation Summary:

This manuscript is of considerable interest to neuroendocrinologists and other neuroscientists because it provides important insights into mechanisms controlling the synchronous activity of a specific subpopulation of hypothalamic neurons. Luteinizing hormone is secreted from the pituitary gland in pulses which vary over the estrous cycle. The pulses arise by patterned secretion of a hypothalamic 'releasing factor', the secretion of which is itself governed by a population of hypothalamic neurons that express the neuropeptide kisspeptin. The paper by Voliotis et al. combines novel experimental evidence from transgenic mice with an elegant mathematical model to analyze how the kisspeptin neurons generate the varying pulsatile patterns.

(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 paper will be of interest to the large class of neuroscientists who perform network analyses and are interested in the processing of visual information. It sets a new standard in connectomic analysis because is combines EM data of a whole fly brain with fluorescent labeling of specific neurons. 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 and Reviewer #2 agreed to share their names with the authors.)

Evaluation Summary:

This manuscript investigates the plastic properties of synapses impinging on pyramidal neurons in the piriform cortex from the lateral olfactory tract (LOT) and intracortical inputs. Their findings uncover some of the location and pathway-dependent plasticity rules and challenge the notion that LOT inputs (carrying direct odor information from the bulb) become "hardwired" after the critical period. The results provide novel information about how activity and experience alter synaptic communication in the olfactory circuit in a synapse-type specific manner.

(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 describes a novel tool for tracking synaptic plasticity at the single synapse resolution with a SEP-tagged GluA1 receptor expressed in a transgenic mouse. The authors rather convincingly demonstrate that this tool does not disturb synaptic physiology or mouse behavior. They also show that this tool can be used to measure the distribution of synaptic weights and its variation during a plasticity protocol in barrel cortex. This tool is useful for more quantitative measurements of synaptic strength in vivo, although some revisions would help making a convincing case of the usefulness of this tool with respect to previous methods. Genetic specificity of the expression of the construct is also a concern.

(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:

Hwang et al. address the important question about whether specific thalamic sub-regions serve as essential "hubs" for interconnecting diverse cognitive processes. Using a group of patients with isolated thalamic lesions (n=20), and a group of size-matched lesions outside the thalamus (n=42), they report that lesions to the anterior-medio-dorsal thalamus are most likely to cause widespread cognitive deficit. Evidence from existing task-based and resting-state fMRI data sets, as well as data sets on gene expression further provide evidence the importance of these regions as a network hub for domain general cognitive functions.

(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.)