Characterization of Comments About bioRxiv and medRxiv Preprints.

Importance: Preprints have been increasingly used in biomedical science, and a key feature of many platforms is public commenting. The content of these comments, however, has not been well studied, and it is unclear whether they resemble those found in journal peer review. Objective: To describe the content of comments on the bioRxiv and medRxiv preprint platforms. Design, Setting, and Participants: In this cross-sectional study, preprints posted on the bioRxiv and medRxiv platforms in 2020 were accessed through each platform's application programming interface on March 29, 2021, and a random sample of preprints containing between 1 and 20 comments was evaluated independently by 3 evaluators using an instrument to assess their features and general content. Main Outcome and Measures: The numbers and percentages of comments from authors or nonauthors were assessed, and the comments from nonauthors were assessed for content. These nonauthor comments were assessed to determine whether they included compliments, criticisms, corrections, suggestions, or questions, as well as their topics (eg, relevance, interpretation, and methods). Nonauthor comments were also analyzed to determine whether they included references, provided a summary of the findings, or questioned the preprint's conclusions. Results: Of 52 736 preprints, 3850 (7.3%) received at least 1 comment (mean [SD] follow-up, 7.5 [3.6] months), and the 1921 assessed comments (from 1037 preprints) had a median length of 43 words (range, 1-3172 words). The criticisms, corrections, or suggestions present in 694 of 1125 comments (61.7%) were the most prevalent content, followed by compliments (n = 428 [38.0%]) and questions (n = 393 [35.0%]). Criticisms usually regarded interpretation (n = 286), methodological design (n = 267), and data collection (n = 238), while compliments were mainly about relevance (n = 111) and implications (n = 72). Conclusions and Relevance: In this cross-sectional study of preprint comments, topics commonly associated with journal peer review were frequent. However, only a small percentage of preprints posted on the bioRxiv and medRxiv platforms in 2020 received comments on these platforms. A clearer taxonomy of peer review roles would help to describe whether postpublication peer review fulfills them.

Memory Consolidation Depends on Endogenous Hippocampal Levels of Anandamide: CB1 and M4, but Possibly not TRPV1 Receptors Mediate AM404 effects.

The endocannabinoid system is involved in the fine-tuning of local synaptic plasticity in the hippocampus during the initial steps of memory formation/transformation. In spite of extensive studies, endocannabinoid modulation of these processes is still poorly understood. Here we studied the effects of intra-CA1 infused AM404, an anandamide (AEA) transport/metabolism inhibitor, upon an aversive memory consolidation with or without prior systemic administration of metyrapone, as well the concomitant intra-CA1 administration of AM404 plus AM251 (CB1 receptor inverse-agonist), capsazepine (TRPV1 receptor antagonist) or tropicamide (M4 receptor antagonist). We also investigated the effect of AM404 on memory retrieval and Long-Term Potentiation induction. Adult male Wistar rats were trained in the Contextual Fear Conditioning task and tested 48 h later. AM404 disrupted both memory consolidation and retrieval, and abolished LTP induction. The post-training effect, however, was reverted by metyrapone - which was amnestic by itself - corroborating the known co-dependency between glucocorticoids and endocannabinoids, and suggesting that some level of aversiveness is necessary for an adequate consolidation. In the coadministration experiments, while AM251 and tropicamide were able to revert the AM404 amnestic effect, capsazepine had no effect. This confirms that CB1 actually mediate the amnestic effect caused by the augmented AEA pool, but TRPV1 does not. The tropicamide result suggests an interesting comodulatory interaction between the endocannabinoid and the cholinergic systems. We propose a steady-state model centered in the idea of an optimal, stable extracellular concentration of anandamide as a necessary condition to ensure the consolidation of a stable memory trace in the CA1 area.

Enhancement of extinction memory by pharmacological and behavioral interventions targeted to its reactivation.

Extinction is a process that involves new learning that inhibits the expression of previously acquired memories. Although temporarily effective, extinction does not erase an original fear association. Since the extinction trace tends to fade over time, the original memory can resurge. On the other hand, strengthening effects have been described in several reconsolidation studies using different behavioral and pharmacological manipulations. In order to know whether an extinction memory can be strengthened by reactivation-based interventions in the contextual fear conditioning task, we began by replicating the classic phenomenon of spontaneous recovery to show that brief reexposure sessions can prevent the decay of the extinction trace over time in a long-lasting way. This fear attenuation was shown to depend both on L-type calcium channels and protein synthesis, which suggests a reconsolidation process behind the reactivation-induced strengthening effect. The extinction trace was also susceptible to enhancement by a post-reactivation infusion of a memory-enhancing drug (NaB), which was also able to prevent rapid fear reacquisition (savings). These findings point to new reactivation-based approaches able to strengthen an extinction memory to promote its persistence. The constructive interactions between extinction and reconsolidation may represent a promising novel approach in the realm of fear-related disorder treatments.