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Deficient synaptic neurotransmission results in a persistent sleep-like cortical activity across vigilance states in mice.
Growing evidence suggests that brain activity during sleep, as well as sleep regulation, are tightly linked with synaptic function and network excitability at the local and global levels. We previously reported that a mutation in synaptobrevin 2 (Vamp2) in restless (rlss) mice results in a marked increase of wakefulness and suppression of sleep, in particular REM sleep (REMS), as well as increased consolidation of sleep and wakefulness. In this study, using finer-scale in vivo electrophysiology recordings, we report that spontaneous cortical activity in rlss mice during NREM sleep (NREMS) is characterized by an occurrence of abnormally prolonged periods of complete neuronal silence (OFF-periods), often lasting several seconds, similar to the burst suppression pattern typically seen under deep anesthesia. Increased incidence of prolonged network OFF-periods was not specific to NREMS but also present in REMS and wake in rlss mice. Slow-wave activity (SWA) was generally increased in rlss mice relative to controls, while higher frequencies, including theta-frequency activity, were decreased, further resulting in diminished differences between vigilance states. The relative increase in SWA after sleep deprivation was attenuated in rlss mice, suggesting either that rlss mice experience persistently elevated sleep pressure or, alternatively, that the intrusion of sleep-like patterns of activity into the wake state attenuates the accumulation of sleep drive. We propose that a deficit in global synaptic neurotransmitter release leads to "state inertia," reflected in an abnormal propensity of brain networks to enter and remain in a persistent "default state" resembling coma or deep anesthesia.
Hypotheses in light detection by vertebrate ancient opsin in the bird brain.
Extra-retinal photoreception is common across fish and avian species. In birds, the hypothalamus contains non-visual photoreceptors that detect light and regulate multiple endocrine systems. To date, light-dependent control of seasonal reproduction is one of the most well-studied systems that require deep brain photoreception. However, the precise photoreceptor(s) that detect light and the neuroendocrine connection between opsin-expressing cells and the gonadotropin-releasing hormone-1 (GnRH1) system remain poorly defined. In the past couple of decades, two opsin molecules have been proposed to link light detection with seasonal reproduction in birds: neuropsin (Opn5) and vertebrate ancient opsin (VA opsin). Only VA opsin is expressed in GnRH1 cells and has an absorption spectrum that matches the action spectrum of the avian photoperiodic reproductive response. This perspective describes how the annual change in daylength, referred to as photoperiod, regulates the neuroendocrine control of seasonal reproduction. The opsin genes are then outlined, and the cellular phototransduction cascade is described, highlighting the common feature of hyperpolarization in response to light stimulation. We then discuss the latest evidence using short-hairpin RNA to temporarily knock down VA opsin and Opn5 on transcripts involved in the neuroendocrine regulation of reproduction. Based on emerging data, we outline three theoretical scenarios in which VA opsin might regulate GnRH1 synthesis and release in birds. The models proposed provide a series of testable hypotheses that can be used to improve our understanding of avian light detection by VA opsin or other opsin-expressing cells in the brain.
Photoreceptors and Circadian Clocks
The possession of a circadian timing system allows an organism to anticipate rhythmic phenomena. Rather than passively responding to 24h changes in the environment, an internal clock allows an organism to anticipate these changes. Thus physiology and behavior can be fine-tuned in advance of the altered conditions and no time will be lost in the adjustment process. In mammals, the suprachiasmatic nuclei (SCN) of the hypothalamus are the site of a master circadian pacemaker, coordinating rhythms throughout the body, including sleep–wake cycles. The primary input into the SCN is light, and the light–dark cycle produced by the rotation of the Earth provides a robust signal enabling internal and external cycles to be synchronized (entrained). The influence of light upon this central clock is mediated by photoreceptors within the eye, but until recently it remained unclear which ocular cells provided dawn/dusk information for photoentrainment. Research into the mechanisms of mammalian photoentrainment resulted in the identification of a third class of ocular photoreceptor, quite different from the rods and cones. This system is composed of a subset of ‘blue-light’-photosensitive retinal ganglion cells expressing the photopigment melanopsin. Subsequent studies have shown that these cells not only regulate the circadian system but also mediate a broad range of other irradiance-detection tasks, including pineal melatonin suppression and pupil constriction.
Enabling SENSE accelerated 2D CSI for hyperpolarized carbon-13 imaging.
As hyperpolarized (HP) carbon-13 (13C) metabolic imaging is clinically translated, there is a need for easy-to-implement, fast, and robust imaging techniques. However, achieving high temporal resolution without decreasing spatial and/or spectral resolution, whilst maintaining the usability of the imaging sequence is challenging. Therefore, this study looked to accelerate HP 13C MRI by combining a well-established and robust sequence called two-dimensional Chemical Shift Imaging (2D CSI) with prospective under sampling and SENSitivity Encoding (SENSE) reconstruction. Due to the low natural abundance of 13C, the sensitivity maps cannot be pre-acquired for the reconstruction. As such, the implementation of sodium (23Na) sensitivity maps for SENSE reconstructed 13C CSI was demonstrated in a phantom and in vivo in the pig kidney. Results showed that SENSE reconstruction using 23Na sensitivity maps corrected aliased images with a four-fold acceleration. With high temporal resolution, the kidney spectra produced a detailed metabolic arrival and decay curve, useful for further metabolite kinetic modelling or denoising. Metabolic ratio maps were produced in three pigs demonstrating the technique's ability for repeat metabolic measurements. In cases with unknown metabolite spectra or limited HP MRI specialist knowledge, this robust acceleration method ensures comprehensive capture of metabolic signals, mitigating the risk of missing spectral data.
The Nuffield Early Language Intervention (NELI) programme is associated with lasting improvements in children's language and reading skills.
BACKGROUND: Oral language skills are a critical foundation for education and psychosocial development. Learning to read, in particular, depends heavily on oral language skills. The Nuffield Early Language Intervention (NELI) has been shown to improve the language of 4-5-year-old children entering school with language weaknesses in four robust trials. To date, however, there is limited evidence on the durability of the gains produced by the intervention, and some have argued that the effects of such educational interventions typically fade-out quite rapidly. METHODS: A large-scale effectiveness trial of the NELI intervention implemented under real-world conditions produced educationally meaningful improvements in children's language and reading abilities. Here, we report follow-up testing of children from this study conducted approximately 2 years after the completion of the intervention. RESULTS: At 2-year follow-up, children who had received NELI had better oral language (d = 0.22 or d = 0.33 for children with lower language ability), reading comprehension (d = 0.16 or d = 0.24 for children with lower language ability) and single-word reading skills (d = 0.16 or d = 0.22 for children with lower language ability) than the control group. CONCLUSIONS: Our data show that, although fade-out effects are common in educational research, a widely used language intervention produces durable improvements in language and reading skills, with educationally important effect sizes. These findings have important theoretical and practical implications.
Adopting Quality for School Readiness (AQSR): A Heuristic Framework using Recommended Practice and Professional Knowledge to Support Oral Language in Multilingual Classrooms
Quality oral language interventions support children’s readiness for formal literacy instruction and yet a framework for multilingual classrooms is not available. To address this gap, we drew on the empirical literature on linguistically diverse learners, classroom linguistic environments, and usage-based theories to identify principles for recommended pedagogical practices. We next examined how teachers explained their oral language teaching and what they said after delivering an intervention based on recommended practice. Using a reflexive approach to qualitative interview and questionnaire data, we found some convergence but also areas of limited overlap between recommended practice and teacher professional knowledge. Supporting child talk was seen to serve a motivational-affective purpose more than the cognitive-linguistic purposes implicit in research-informed recommended practices. Based on insights from specialized literature and distillations of professional knowledge, we propose a heuristic framework named Adopting Quality for School Readiness (AQSR). We also discuss uses for the AQSR framework and outstanding questions for future research.
Harmonising flavours: How arousing music and sound influence food perception and emotional responses
This study aims to provide a novel understanding of how music and sound varying in arousal can affect temporal changes in food perception and the corresponding emotional responses, measured through both subjective and objective (i.e., electrophysiological) methods. Exciting conditions are associated with low valence and high arousal, whereas calm conditions are associated with high valence and low arousal. Calm music (CM), calm sound (CS), and a combination of calm music and sound (CMCS) evoked emotions such as joy, relaxation, calmness, pleasantness, and at ease, and were correlated with the perception of sweetness and creaminess. Conversely, exciting music (EM) increased arousal, evoked emotions such as, activity, enthusiasm, energy, and excitement, and amplified the perception of roasted and bitter flavours. Exciting sounds (ES) and combined exciting music and exciting sound (EMES) conditions were positively correlated with anxiety, fatigue, unease, unhappiness, difficulty concentrating, irritation, and restlessness, as well as enhancing the perception of roasted and bitter flavours. Furthermore, the EM and EMES conditions gave rise to significantly higher skin conductance and respiration rate, with corresponding correlations with the perception of roasted and bitter flavours. The ES and EMES conditions demonstrated significantly higher heart rate and respiration rate. The CM condition showed significantly higher heart rate and emotional responses while the CS condition showed significantly higher skin conductance. The findings of this study indicate that sensory attributes are closely associated with the emotions and physiological responses evoked when consuming ice cream under different music and sound conditions.
Audiovisual Associations in Saint-Saëns’ Carnival of the Animals: A Cross-Cultural Investigation on the Role of Timbre
Several studies have investigated crossmodal associations involving audiovisual stimuli. To date, however, far fewer studies have explored the relationship between musical timbre and visual features (e.g., soft/harsh timbres with blue/red colours). To fill this gap in the literature, 249 participants were invited to judge the match between different coloured images and musical excerpts. The images depicted seven characters from Saint-Saëns’ “Carnival of the Animals”; the audio stimuli consisted of the music the composer created to represent each character. To test the effect of timbre and culture, the audio stimuli were presented either in the original orchestral version or in the piano transcription, while the participants were recruited from various countries, encompassing both Western and non-Western nationalities. The results demonstrate that timbre influences crossmodal associations between musical excerpts and drawings, while these associations remain consistent across cultures, languages, and levels of musical background.
Single extracellular vesicle detection assay identifies membrane-associated α-synuclein as an early-stage biomarker in Parkinson's disease.
Accurate diagnosis of early Parkinson's disease requires platforms suitable for detecting minute amounts of neuronally derived biomarkers in the massive protein excess of easily accessible biofluids such as blood. Here, we describe an on-chip droplet-confined fluorescence reporting assay that identified α-synuclein on the membrane of L1CAM+ extracellular vesicles (EVs) immunocaptured from human serum and corroborate this finding by super-resolution direct stochastic optical reconstruction microscopy (dSTORM) microscopy. Using conditioned media from neuroblastoma cells expressing α-synuclein mutants or patient-derived induced pluripotent stem cell (iPSC) neurons with α-synuclein gene triplication, we found that association of α-synuclein with the L1CAM+ EV surface is increased under pathological conditions. Accordingly, this readout, as measured by the droplet-based assay, is an improved predictive biomarker in the prodromal phase (area under the receiver operating characteristic curve [AUC] = 0.93) or diagnostic biomarker in the clinical phase (AUC = 0.95) of Parkinson's disease. More broadly, our platform will simplify the assessment of EV membrane proteins and facilitate their application as diagnostic biomarkers across diverse clinical indications.
Persistence of training-induced visual improvements after occipital stroke
Damage to the primary visual cortex causes homonymous visual impairments that appear to benefit from visual discrimination training. However, whether improvements persist without continued training remains to be determined and was the focus of the present study. After a baseline assessment visit, 20 participants trained twice daily in their blind-field for a minimum of six months (median=155 sessions), using a motion discrimination and integration task. At the end of training, a return study visit was used to assess recovery. Three months later, 14 of the participants returned for a third study visit to assess persistence of recovery. At each study visit, motion discrimination and integration thresholds, Humphrey visual fields, and structural MRI scans were collected. Immediately after training, all but four participants showed improvements in the trained discrimination task, and shrinkage of the perimetrically-defined visual defect. While these gains were sustained in seven out of eleven participants who improved with training, four participants lost their improvement in motion discrimination thresholds at the follow-up visit. Persistence of recovery was not related to age, time since lesion, number of training sessions performed, proportion of V1 damaged, deficit size, or optic tract degeneration measured from structural MRI scans. The present findings underscore the potential of extended visual training to induce long-term improvements in stroke-induced vision loss. However, they also highlight the need for further investigations to better understand the mechanisms driving recovery, its persistence post-training, and especially heterogeneity among participants.
Investigating the impact of electroconvulsive therapy on brain networks and sleep: an observational study protocol.
INTRODUCTION: Electroconvulsive therapy (ECT) is a highly effective treatment for refractory depression, but it may also cause cognitive side effects. Despite decades of use, the mechanisms by which ECT exerts both its antidepressant and cognitive effects are still poorly understood, with the latter substantially limiting referral and adherence to therapy. ECT induces changes in correlated neural activity-functional connectivity-across various brain networks, which may underlie both its clinical efficacy and associated cognitive side effects. Electroencephalography (EEG) could address these knowledge gaps by identifying biomarkers that predict therapeutic outcomes or cognitive side effects. Such developments could ultimately improve patient selection and adherence. Such markers likely span large-scale functional brain networks or temporal dynamics of brain activity during sleep. We hypothesise that enhancement in slow wave sleep mediates the relationship between antidepressant effects and changes in functional connectivity throughout the course of ECT. METHODS AND ANALYSIS: Disruptions of Brain Networks and Sleep by Electroconvulsive Therapy (DNS-ECT) is an ongoing observational study investigating the impact of ECT on large-scale brain functional networks and their relationships to sleep slow waves, an EEG marker linked to synaptic plasticity. The novelty of this study stems from our focus on the assessment of EEG markers during sleep, wakefulness and ECT-induced seizures over the course of therapy. Graph-based network analyses of high-density EEG signals allow characterisation of functional networks locally in specific subnetworks and globally over large-scale functional networks. Longitudinal assessments of EEG alongside clinical and cognitive outcomes provide a unique opportunity to improve our understanding of the circuit mechanisms underlying the development of cognitive impairments and antidepressant effects incurred during ECT. ETHICS AND DISSEMINATION: Recruitment for this 5-year study started in March 2023. Dissemination plans include presentations at scientific conferences and peer-reviewed publications. This study has been registered with ClinicalTrials.gov registry under identifier. TRIAL REGISTRATION NUMBER: NCT05905705.
Ablation of CCL17-positive hippocampal neurons induces inflammation-dependent epilepsy.
OBJECTIVE: Neuronal cell death and neuroinflammation are characteristic features of epilepsy, but it remains unclear whether neuronal cell death as such is causative for the development of epileptic seizures. To test this hypothesis, we established a novel mouse line permitting inducible ablation of pyramidal neurons by inserting simian diphtheria toxin (DT) receptor (DTR) cDNA into the Ccl17 locus. The chemokine CCL17 is expressed in pyramidal CA1 neurons in adult mice controlling microglial quiescence. METHODS: Seizure activity in CCL17-DTR mice was analyzed by electroencephalographic recordings following treatment with DT for 3 consecutive days. Neuroinflammation and neuronal cell death were evaluated by (immuno)histochemistry. Pharmacological inhibition of TNFR1 signaling was achieved by treatment with XPro1595, a dominant-negative inhibitor of soluble tumor necrosis factor. RESULTS: Neuronal cell death was detectable 7 days (d7) after the first DT injection in heterozygous CCL17-DTR mice. Spontaneous epileptic seizures were observed in the vast majority of mice, often with an initial peak at d6-9, followed by a period of reduced activity and a gradual increase during the 1-month observation period. Microglial reactivity was overt from d5 after DT administration not only in the CA1 region but also in the CA2/CA3 area, shortly followed by astrogliosis. Reactive microgliosis and astrogliosis persisted until d30 and, together with neuronal loss and stratum radiatum shrinkage, reflected important features of human hippocampal sclerosis. Granule cell dispersion was detectable only 3 months after DT treatment. Application of XPro1595 significantly reduced chronic seizure burden without affecting the development of hippocampal sclerosis. SIGNIFICANCE: In conclusion, our data demonstrate that sterile pyramidal neuronal death is sufficient to cause epilepsy in the absence of other pathological processes. The CCL17-DTR mouse line may thus be a valuable model for further mechanistic studies on epilepsy and assessment of antiseizure medication.
Modifiable risk factors of vaccine hesitancy: insights from a mixed methods multiple population study combining machine learning and thematic analysis during the COVID-19 pandemic.
BACKGROUND: Vaccine hesitancy, the delay in acceptance or reluctance to vaccinate, ranks among the top threats to global health. Identifying modifiable factors contributing to vaccine hesitancy is crucial for developing targeted interventions to increase vaccination uptake. METHODS: This mixed-methods multiple population study utilized gradient boosting machines and thematic analysis to identify modifiable predictors of vaccine hesitancy during the COVID-19 pandemic. Predictors of vaccine hesitancy were investigated in 2926 Norwegian adults (Mage = 37.91, 79.69% female), before the predictive utility of these variables was investigated in an independent sample of 734 adults in the UK (Mage = 40.34, 57.08% female). Two independent teams of authors conducted the machine learning and thematic analyses, blind to each other's analytic procedures and results. RESULTS: The machine learning model performed well in discerning vaccine hesitant (n = 248, 8.48% and n = 109, 14.85%, Norway and UK, respectively) from vaccine uptaking individuals (n = 2678, 91.52% and n = 625, 85.15%), achieving an AUC of 0.94 (AUPRC: 0.72; balanced accuracy: 86%; sensitivity = 0.81; specificity = 0.98) in the Norwegian sample, and an AUC of 0.98 (AUPRC: 0.89; balanced accuracy: 89%; sensitivity = 0.83; specificity = 0.97) in the out-of-sample replication in the UK. The mixed methods investigation identified five categories of modifiable risk tied to vaccine hesitancy, including illusion of invulnerability, doubts about vaccine efficacy, mistrust in official entities, minimization of the societal impact of COVID-19, and health-related fears tied to vaccination. The portrayal of rare incidents across alternative media platforms as fear amplifiers, and the mainstream media's stigmatizing presentation of unvaccinated individuals, were provided as additional motives underlying vaccine reluctance and polarization. The thematic analysis further revealed information overload, fear of needles, previous negative vaccination experiences, fear of not getting healthcare follow-up after vaccination if needed, and vaccine aversion due to underlying (psychiatric) illness (e.g., eating disorders) as motives underlying vaccine hesitance. CONCLUSIONS: The identified influential predictors were consistent across two European samples, highlighting their generalizability across European populations. These predictors offer insights about modifiable factors that could be adapted by public health campaigns in mitigating misconceptions and fears related to vaccination toward increasing vaccine uptake. Moreover, the results highlight the media's responsibility, as mediators of the public perception of vaccines, to minimize polarization and provide accurate portrayals of rare vaccine-related incidents, reducing the risk aggravating fear and reactance to vaccination.