Circadian clocks have evolved to synchronize physiology, metabolism and behaviour to the 24-h geophysical cycles of the Earth. Drosophila melanogaster's rhythmic locomotor behaviour provides the main phenotype for the identification of higher eukaryotic clock genes. Under laboratory light-dark cycles, flies show enhanced activity before lights on and off signals, and these anticipatory responses have defined the neuronal sites of the corresponding morning (M) and evening (E) oscillators. However, the natural environment provides much richer cycling environmental stimuli than the laboratory, so we sought to examine fly locomotor rhythms in the wild. Here we show that several key laboratory-based assumptions about circadian behaviour are not supported by natural observations. These include the anticipation of light transitions, the midday 'siesta', the fly's crepuscular activity, its nocturnal behaviour under moonlight, and the dominance of light stimuli over temperature. We also observe a third major locomotor component in addition to M and E, which we term 'A' (afternoon). Furthermore, we show that these natural rhythm phenotypes can be observed in the laboratory by using realistic temperature and light cycle simulations. Our results suggest that a comprehensive re-examination of circadian behaviour and its molecular readouts under simulated natural conditions will provide a more authentic interpretation of the adaptive significance of this important rhythmic phenotype. Such studies should also help to clarify the underlying molecular and neuroanatomical substrates of the clock under natural protocols.

The blue-light sensitive photoreceptor cryptochrome (CRY) may act as a magneto-receptor through formation of radical pairs involving a triad of tryptophans. Previous genetic analyses of behavioral responses of Drosophila to electromagnetic fields using conditioning, circadian and geotaxis assays have lent some support to the radical pair model (RPM). Here, we describe a new method that generates consistent and reliable circadian responses to electromagnetic fields that differ substantially from those already reported. We used the Schuderer apparatus to isolate Drosophila from local environmental variables, and observe extremely low frequency (3 to 50 Hz) field-induced changes in two locomotor phenotypes, circadian period and activity levels. These field-induced phenotypes are CRY- and blue-light dependent, and are correlated with enhanced CRY stability. Mutational analysis of the terminal tryptophan of the triad hypothesised to be indispensable to the electron transfer required by the RPM reveals that this residue is not necessary for field responses. We observe that deletion of the CRY C-terminus dramatically attenuates the EMF-induced period changes, whereas the N-terminus underlies the hyperactivity. Most strikingly, an isolated CRY C-terminus that does not encode the Tryptophan triad nor the FAD binding domain is nevertheless able to mediate a modest EMF-induced period change. Finally, we observe that hCRY2, but not hCRY1, transformants can detect EMFs, suggesting that hCRY2 is blue light-responsive. In contrast, when we examined circadian molecular cycles in wild-type mouse suprachiasmatic nuclei slices under blue light, there was no field effect. Our results are therefore not consistent with the classical Trp triad-mediated RPM and suggest that CRYs act as blue-light/EMF sensors depending on trans-acting factors that are present in particular cellular environments.

Under standard laboratory conditions of rectangular light/dark cycles and constant warm temperature, Drosophila melanogaster show bursts of morning (M) and evening (E) locomotor activity and a “siesta” in the middle of the day. These M and E components have been critical for developing the neuronal dual oscillator model in which clock gene expression in key cells generates the circadian phenotype. However, under natural European summer conditions of cycling temperature and light intensity, an additional prominent afternoon (A) component that replaces the siesta is observed. This component has been described as an “artifact” of the TriKinetics locomotor monitoring system that is used by many circadian laboratories world wide. Using video recordings, we show that the A component is not an artifact, neither in the glass tubes used in TriKinetics monitors nor in open-field arenas. By studying various mutants in the visual and peripheral and internal thermo-sensitive pathways, we reveal that the M component is predominantly dependent on visual input, whereas the A component requires the internal thermo-sensitive channel transient receptor potential A1 (TrpA1). Knockdown of TrpA1 in different neuronal groups reveals that the reported expression of TrpA1 in clock neurons is unlikely to be involved in generating the summer locomotor profile, suggesting that other TrpA1 neurons are responsible for the A component. Studies of circadian rhythms under seminatural conditions therefore provide additional insights into the molecular basis of circadian entrainment that would otherwise be lost under the usual standard laboratory protocols.

Background Autism presents with similar prevalence and core impairments in diverse populations. We conducted a scoping review of reviews to determine key barriers and innovative strategies which can contribute to attaining universal health coverage (UHC), from early detection to effective interventions for autism in low‐ and middle‐income countries (LAMIC). Methods A systematic literature search of review articles was conducted. Reviews relevant to the study research question were included if they incorporated papers from LAMIC and focused on children (

Background: Assessment of cognitive development is essential to identify children with faltering developmental attainment and monitor the impact of interventions. A key barrier to achieving these goals is the lack of standardized, scalable tools to assess cognitive abilities.Objective: This study aimed to develop a tablet-based gamified assessment of cognitive abilities of 3-year-old children which can be administered by non-specialist field workers.Methods: Workshops among domain experts, literature search for established and gamified paradigms of cognitive assessments and rapid review of mobile games for 3-year-old children was done to conceptualize games for this study. Formative household visits (N = 20) informed the design and content of the games. A cross-sectional pilot study (N = 100) was done to assess feasibility of the tool and check if increasing levels of difficulty and the expected variability between children were evident in game metrics. In-depth interviews (N = 9) were conducted with mothers of participating children to assess its acceptability.Results: Six cognitive domains were identified as being integral to learning – divided attention, response inhibition, reasoning, visual form perception and integration and memory. A narrative, musical soundtrack and positive reinforcement were incorporated into the tool to enhance participant engagement. Child performance determined level timers and difficulty levels in each game. Pilot data indicate that children differ in their performance profile on the tool as measured by the number of game levels played and their accuracy and completion time indicating that it might be possible to differentiate children based on these metrics. Qualitative data suggest high levels of acceptability of the tool amongst participants.Conclusions: A DEvelopmental assessment on an E-Platform (DEEP) has been created comprising distinct games woven into a narrative, which assess six cognitive domains, and shows high levels of acceptability and generates metrics which may be used for validation against gold standard cognitive assessments.

Huntington's disease (HD) is an inherited neurodegenerative disorder caused by abnormal expansion of glutamine repeats in the protein huntingtin. In HD brain, mutant huntingtin undergoes proteolytic processing, and its N-terminal fragment containing poly-glutamine repeats accumulate as insoluble aggregates leading to the defect in cellular protein quality control system and heat shock response (HSR). Here we demonstrate that the defective HSR in the brain is due to the down-regulation of heat shock factor 1 (HSF1) in both mice and fly models of HD. Interestingly, treatment of dexamethasone (a synthetic glucocorticoid) to HD mice or flies significantly increased the expression and transactivation of HSF1 and induction of HSR and these effects are mediated through the down-regulation of HSP90. Dexamethasone treatment also significantly decreased the aggregate load and transient recovery of HD-related behavioural phenotypes in both disease models. These results suggest that dexamethasone could be a potential therapeutic molecule for the treatment of HD and related poly-glutamine disorders.

Smaller, more affordable, and more portable MRI brain scanners offer exciting opportunities to address unmet research needs and long-standing health inequities in remote and resource-limited international settings. Field-based neuroimaging research in low- and middle-income countries (LMICs) can improve local capacity to conduct both structural and functional neuroscience studies, expand knowledge of brain injury and neuropsychiatric and neurodevelopmental disorders, and ultimately improve the timeliness and quality of clinical diagnosis and treatment around the globe. Facilitating MRI research in remote settings can also diversify reference databases in neuroscience, improve understanding of brain development and degeneration across the lifespan in diverse populations, and help to create reliable measurements of infant and child development. These deeper understandings can lead to new strategies for collaborating with communities to mitigate and hopefully overcome challenges that negatively impact brain development and quality of life. Despite the potential importance of research using highly portable MRI in remote and resource-limited settings, there is little analysis of the attendant ethical, legal, and social issues (ELSI). To begin addressing this gap, this paper presents findings from the first phase of an envisioned multi-staged and iterative approach for creating ethical and legal guidance in a complex global landscape. Section 1 provides a brief introduction to the emerging technology for field-based MRI research. Section 2 presents our methodology for generating plausible use cases for MRI research in remote and resource-limited settings and identifying associated ELSI issues. Section 3 analyzes core ELSI issues in designing and conducting field-based MRI research in remote, resource-limited settings and offers recommendations. We argue that a guiding principle for field-based MRI research in these contexts should be including local communities and research participants throughout the research process in order to create sustained local value. Section 4 presents a recommended path for the next phase of work that could further adapt these use cases, address ethical and legal issues, and co-develop guidance in partnership with local communities.

Background Early identification of preschool children who are at risk of faltering in their development is essential to ensuring that all children attain their full potential. Electroencephalography (EEG) has been used to measure neural correlates of cognitive and social development in children for decades. Effective portable and low-cost EEG devices increase the potential of its use to assess neurodevelopment in children at scale and particularly in low-resource settings. We conducted a systematic review aimed to synthesise EEG measures of cognitive and social development in 2-5-year old children. Our secondary aim was to identify how these measures differ across a) the course of development within this age range, b) gender and c) socioeconomic status (SES). Methods and findings A systematic literature search identified 51 studies for inclusion in this review. Data relevant to the primary and secondary aims was extracted from these studies and an assessment for risk of bias was done, which highlighted the need for harmonisation of EEG data collection and analysis methods across research groups and more detailed reporting of participant characteristics. Studies reported on the domains of executive function (n = 22 papers), selective auditory attention (n = 9), learning and memory (n = 5), processing of faces (n = 7) and emotional stimuli (n = 8). For papers investigating executive function and selective auditory attention, the most commonly reported measures were alpha power and the amplitude and latency of positive (P1, P2, P3) and negative (N1, N2) deflections of event related potential (ERPs) components. The N170 and P1 ERP components were the most commonly reported neural responses to face and emotional faces stimuli. A mid-latency negative component and positive slow wave were used to index learning and memory, and late positive potential in response to emotional non-face stimuli. While almost half the studies described changes in EEG measures across age, only eight studies disaggregated results based on gender, and six included children from low income households to assess the impact of SES on neurodevelopment. No studies were conducted in low- and middle-income countries. Conclusion This review has identified power across the EEG spectrum and ERP components to be the measures most commonly reported in studies in which preschool children engage in tasks indexing cognitive and social development. It has also highlighted the need for additional research into their changes across age and based on gender and SES.