Summary Emerging evidence indicates that certain behavioral traits, such as anxiety, are associated with the development of depression-like behaviors after exposure to chronic stress. However, single traits do not explain the wide variability in vulnerability to stress observed in outbred populations. We hypothesized that a combination of behavioral traits might provide a better characterization of an individual's vulnerability to prolonged stress. Here, we sought to determine whether the characterization of relevant behavioral traits in rats could aid in identifying individuals with different vulnerabilities to developing stress-induced depressionlike behavioral alterations. We also investigated whether behavioral traits would be related to the development of alterations in the hypothalamic-pituitary-adrenal axis and in brain activityas measured through phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) -in response to an acute stressor following either sub-chronic (2 weeks) or chronic (4 weeks) unpredictable stress (CUS). Sprague-Dawley rats were characterized using a battery of behavioral tasks, and three principal traits were identified: anxiety, exploration and activity. When combined, the first two traits were found to explain the variability in the stress responses. Our findings confirm the increased risk of animals with high anxiety developing certain depression-like behaviors (e.g., increased floating time in the forced swim test) when progressively exposed to stress. In contrast, the behavioral profile based on combined low anxiety and low exploration was resistant to alterations related to social behaviors, while the high anxiety and low exploration profile displayed a particularly vulnerable pattern of physiological and neurobiological responses after sub-chronic stress exposure. Our findings indicate important differences in

Sleep is essential for optimal brain functioning and health, but the biological substrates through which sleep delivers these beneficial effects remain largely unknown. We used a systems genetics approach in the BXD genetic reference population (GRP) of mice and assembled a comprehensive experimental knowledge base comprising a deep “sleep-wake” phenome, central and peripheral transcriptomes, and plasma metabolome data, collected under undisturbed baseline conditions and after sleep deprivation (SD). We present analytical tools to interactively interrogate the database, visualize the molecular networks altered by sleep loss, and prioritize candidate genes. We found that a one-time, short disruption of sleep already extensively reshaped the systems genetics landscape by altering 60%–78% of the transcriptomes and the metabolome, with numerous genetic loci affecting the magnitude and direction of change. Systems genetics integrative analyses drawing on all levels of organization imply α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor trafficking and fatty acid turnover as substrates of the negative effects of insufficient sleep. Our analyses demonstrate that genetic heterogeneity and the effects of insufficient sleep itself on the transcriptome and metabolome are far more widespread than previously reported.

Besides its role in vision, light impacts physiology and behavior through circadian and direct (aka ‘masking’) mechanisms. In Smith-Magenis syndrome (SMS), the dysregulation of both sleep-wake behavior and melatonin production strongly suggests impaired non-visual light perception. We discovered that mice haploinsufficient for the SMS causal gene, Retinoic acid induced-1 (Rai1), were hypersensitive to light such that light eliminated alert and active-wake behaviors, while leaving time-spent-awake unaffected. Moreover, variables pertaining to circadian rhythm entrainment were activated more strongly by light. At the input level, the activation of rod/cone and suprachiasmatic nuclei (SCN) by light was paradoxically greatly reduced, while the downstream activation of the ventral-subparaventricular zone (vSPVZ) was increased. The vSPVZ integrates retinal and SCN input and, when activated, suppresses locomotor activity, consistent with the behavioral hypersensitivity to light we observed. Our results implicate Rai1 as a novel and central player in processing non-visual light information, from input to behavioral output.DOI: http://dx.doi.org/10.7554/eLife.23292.001

With the aim to uncover the molecular pathways underlying the regulation of sleep, we recently assembled an extensive and comprehensive systems genetics dataset interrogating a genetic reference population of mice at the levels of the genome, the brain and liver transcriptomes, the plasma metabolome, and the sleep-wake phenome. To facilitate a meaningful and efficient re-use of this public resource by others we designed, describe in detail, and made available a Digital Research Object (DRO), embedding data, documentation, and analytics. We present and discuss both the advantages and limitations of our multi-modal resource and analytic pipeline. The reproducibility of the results was tested by a bioinformatician not implicated in the original project and the robustness of results was assessed by re-annotating genetic and transcriptome data from the mm9 to the mm10 mouse genome assembly.

13More and more researchers make use of multi-omics approaches to tackle complex cellular 14 and organismal systems. It has become apparent that the potential for re-use and integrate data 15 generated by different labs can enhance knowledge. However, a meaningful and efficient re-16 use of data generated by others is difficult to achieve without in depth understanding of how 17 these datasets were assembled. We therefore designed and describe in detail a digital research 18 object embedding data, documentation and analytics on mouse sleep regulation. The aim of 19 this study was to bring together electrophysiological recordings, sleep-wake behavior, 20 metabolomics, genetics, and gene regulatory data in a systems genetics model to investigate 21 sleep regulation in the BXD panel of recombinant inbred lines. We here showcase both the 22 Experiment 1 and Experiment 2 ( Figure 1) were approved by the veterinary authorities of the 95 state of Vaud, Switzerland (SCAV authorization #2534). 96 97 Animal, breeding, and housing conditions 98 34 BXD lines originating from the University of Tennessee Health Science Center (Memphis, 99 TN, United States of America) were selected for Experiment 1 and Experiment 2. These lines 100 were randomly chosen from the newly generated advanced recombinant inbred line (ARIL) 101 RwwJ panel 4 , although lines with documented poor breeding performance were not 102 considered. 4 additional BXD RI strains were chosen from the older TyJ panel for 103 reproducibility purposes and were obtained directly from the Jackson Laboratory (JAX, Bar 104Harbor, Maine). The names used for some of the BXD lines have been modified over time to 105 reflect genetic proximity. Table 1 lists the BXD line names we used in our files alongside the 106 corresponding current JAX names and IDs. In our analyses, we discarded the BXD63/RwwJ 107 line for quality reasons (see Technical Validation) as well as the 4 older BXD strains that were 108 derived from a different DBA/2 sub-strains, i.e. DBA/2Rj instead of DBA/2J for RwwJ lines 109 21 . The methods below describe the remaining 33 BXD lines, F1 and parental strains. 110 Two breeding trios per BXD strain were purchased from a local facility (EPFL-SV, Lausanne, 111 Switzerland) and bred in-house until sufficient offspring was obtained. The parental strains 112 DBA/2J (D2), C57BL6/J (B6) and their reciprocal F1 offspring (B6D2F1 [BD-F1] and 113 D2B6F1 [DB-F1]) were bred and phenotyped alongside. Suitable (age and sex) offspring was 114 transferred to our sleep-recording facility, where they were singly housed, with food and 115 water available ad libitum, at a constant temperature of 25°C and under a 12 h light/12 h dark 116 cycle (LD12:12, fluorescent lights, intensity 6.6 cds/m 2 , with ZT0 and ZT12 designating light 117 and dark onset, respectively). Male mice aged 11-14 week at the time of experiment were 118 used for phenotyping, with a mean of 12 animals per BXD line among all experiments. Note 119 that 3 BXD lines had a lower replicate number (n), with respect...

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Since the revised Medical Devices Ordinance (MedDO) and the new Ordinance on Clinical Trials with Medical Devices (ClinO-MD) entered into force in Switzerland in May 2021, clinical investigators have encountered challenges in correctly categorising their research projects and identifying whether their projects pertain to the category of clinical studies with medical devices (governed by the ClinO-MD) or are considered human research other than clinical trials (governed by Chapter 2 of the Human Research Ordinance (HRO)). In this article, we discuss the PES-SLEEP project in order to illustrate a practical approach to this categorisation challenge between the lighter HRO regulatory framework and the more demanding ClinO-MD pathway. We also present the important points that were considered by the ethics committee for the canton of Vaud (EC Vaud) in order for the study to be approved as an HRO research project.