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Baroness Nicola Blackwood of North Oxford, Parliamentary Under Secretary of State for Innovation, has officially opened the Oxford BioEscalator.
Truthful communication of mental science: pledge to our patients and profession.
Recent changes in US government priorities have serious negative implications for science that will compromise the integrity of mental health research, which focuses on vulnerable populations. Therefore, as editors of mental science journals and custodians of the academic record, we confirm with conviction our collective commitment to communicating the truth.
Increased TMEM106B levels lead to lysosomal dysfunction which affects synaptic signaling and neuronal health
Background: Genetic variation in Transmembrane protein 106B (TMEM106B) is known to influence the risk and presentation in several neurodegenerative diseases and modifies healthy aging. While evidence from human studies suggests that the risk allele is associated with higher levels of TMEM106B, the contribution of elevated levels of TMEM106B to neurodegeneration and aging has not been assessed and it remains unclear how TMEM106B modulates disease risk. Methods: To study the effect of increased TMEM106B levels, we generated Cre-inducible transgenic mice expressing human wild-type TMEM106B. We evaluated lysosomal and neuronal health using in vitro and in vivo assays including transmission electron microscopy, immunostainings, behavioral testing, electrophysiology, and bulk RNA sequencing. Results: We created the first transgenic mouse model that successfully overexpresses TMEM106B, with a 4- to 8-fold increase in TMEM106B protein levels in heterozygous (hTMEM106B(+)) and homozygous (hTMEM106B(++)) animals, respectively. We showed that the increase in TMEM106B protein levels induced lysosomal dysfunction and age-related downregulation of genes associated with neuronal plasticity, learning, and memory. Increased TMEM106B levels led to altered synaptic signaling in 12-month-old animals which further exhibited an anxiety-like phenotype. Finally, we observed mild neuronal loss in the hippocampus of 21-month-old animals. Conclusion: Characterization of the first transgenic mouse model that overexpresses TMEM106B suggests that higher levels of TMEM106B negatively impacts brain health by modifying brain aging and impairing the resilience of the brain to the pathomechanisms of neurodegenerative disorders. This novel model will be a valuable tool to study the involvement and contribution of increased TMEM106B levels to aging and will be essential to study the many age-related diseases in which TMEM106B was genetically shown to be a disease- and risk-modifier.
Phase-dependent closed-loop deep brain stimulation of the fornix provides bidirectional manipulation of hippocampal theta oscillations.
INTRODUCTION: Alzheimer's disease (AD) has very limited treatment options and therapies to prevent or reverse neurodegeneration remain elusive. Deep brain stimulation (DBS), whereby high-frequency pulses of electricity are delivered continuously to a specific part of the brain, has been trialled as an experimental treatment for AD. In AD patients, continuous, high frequency DBS targeted to the fornix (fx-DBS) has been shown to be safe, but not reliably effective across patients. In movement disorders, high-frequency DBS is thought to act as a virtual lesion, disrupting pathophysiological activity. In AD, it may be more advantageous to use stimulation to reinforce or rebuild oscillatory activities that are disrupted by the disease process. A primary candidate for such a target is the hippocampal theta oscillation, which provides a temporal framework for mnemonic processing and is altered in rodent models of AD. MATERIAL AND METHODS: We applied closed-loop electrical stimulation to the fornix of rats traversing a linear track, triggered by different phases of the ongoing theta oscillation in the hippocampal local field potential (LFP) using the OscillTrack algorithm. RESULTS: Stimulation at different target phases could robustly suppress or amplify the theta oscillation, and these effects were significantly larger than those caused by open-loop replay of the same stimulation pattern. Amplification of the theta oscillation could be achieved irrespective of the locomotor speed of the animal, showing that it did not result from a secondary effect of behavioural change. CONCLUSIONS: Our findings demonstrate that closed-loop fx-DBS is a viable method of modulating the amplitude of hippocampal theta oscillations that could be applied in human devices to provide a constructive intervention with the potential to boost memory circuit function in AD.
High-throughput screen of 100 000 small molecules in C9ORF72 ALS neurons identifies spliceosome modulators that mobilize G4C2 repeat RNA into nuclear export and repeat associated non-canonical translation.
An intronic G4C2 repeat expansion in the C9ORF72 gene is the major known cause for Amyotrophic Lateral Sclerosis (ALS), with current evidence for both, loss of function and pathological gain of function disease mechanisms. We screened 96 200 small molecules in C9ORF72 patient iPS neurons for modulation of nuclear G4C2 RNA foci and identified 82 validated hits, including the Brd4 inhibitor JQ1 as well as novel analogs of Spliceostatin-A, a known modulator of SF3B1, the branch point binding protein of the U2-snRNP. Spliceosome modulation by these SF3B1 targeted compounds recruits SRSF1 to nuclear G4C2 RNA, mobilizing it from RNA foci into nucleocytoplasmic export. This leads to increased repeat-associated non-canonical (RAN) translation and ultimately, enhanced cell toxicity. Our data (i) provide a new pharmacological entry point with novel as well as known, publicly available tool compounds for dissection of C9ORF72 pathobiology in C9ORF72 ALS models, (ii) allowing to differentially modulate RNA foci versus RAN translation, and (iii) suggest that therapeutic RNA foci elimination strategies warrant caution due to a potential storage function, counteracting translation into toxic dipeptide repeat polyproteins. Instead, our data support modulation of nuclear export via SRSF1 or SR protein kinases as possible targets for future pharmacological drug discovery.
Contributed Talks I: Information integration in early visual processing revealed by Vernier thresholds.
Vernier acuity thresholds represent minimal detectable spatial offset between two closely placed targets. We previously showed that Vernier thresholds for a Poisson-limited ideal observer with access to the cone excitations are determined jointly by duration and contrast through the quantity duration x contrast squared. Here we measured thresholds in 7 human observers for combinations of stimulus contrast (100%, 50%, 25%, and 12.5%) and duration (16.7 ms, 66.7 ms, 266.7 ms and 1066.7 ms), while fixing other stimulus properties (foveal viewing; two achromatic vertical bars; length 10.98 arcmin; width 4.39 arcmin; vertical gap 0.878 arcmin). The combinations of duration and contrast were chosen to form four groups of constant duration x contrast squared. Thresholds were a decreasing function of duration x contrast squared. A one-way between observers ANOVA does not reject the hypothesis threshold duration and contrast are integrated through the quantity duration x contrast squared, but the residuals obtained by predicting threshold within each of the four groups by its mean varied systematically with duration, indicating that duration x contrast squared does not fully summarize the information integration. This difference between ideal and human performance indicates that post-receptoral factors not included in the ideal observer model, such as temporal filtering, affect human performance. These factors will be included in future modeling.
Contributed Talks I: Fixational eye movements and retinal adaptation: optimizing drift to maximize information acquisition.
Fixational eye movements (FEMs) are small, fluctuating eye motions when fixating on a target. Given our visual system is evolved, we may ask why FEMs are beneficial and whether they are optimal. A possible reason for FEMs is overcoming retinal adaptation (fading perception of a fixed image). We present a simple model system allowing theoretical investigation of FEM influence on information about an external stimulus. The model incorporates temporal stimulus modulation, retinal image motion due to the drift component of FEMs, blurring due to optics and receptor size, uniform sampling by the receptor array, adaptation via a bandpass temporal filter, and added noise. We investigate how elements of the model mediate the information transmitted, via: i) mutual information between visual system response and external stimulus, ii) direct estimation of stimulus from the system response, and iii) contrast threshold for signal detection. For all these we find a common quantity that must be maximized. For each spatial frequency this quantity is a summed power transmitted due to stimulus temporal modulation and phase shifts from FEMs, when passed through the temporal filter. We demonstrate that the information transmitted can be increased by adding local persistence to an underlying diffusive process. We also quantify the contribution of FEMs to signal detection for targets of different size and duration; such predictions provide a qualitative account of human psychophysical performance.
Poster Session: The effect of fixational eye-movements on the temporal summation at detection threshold: A simulation study.
We explored how fixational eye movements (FEMs) affect threshold temporal summation of increment pulses using realistic simulations of early visual processing. Using the Image Systems Engineering Toolbox for Biology, we assessed performance in a spatial 2AFC increment detection task, where the observer identified whether a stimulus appeared on the left or right. The signal-known-exactly ideal observer was trained on the noise-free photocurrent output of the cone mosaic for both stimulus alternatives, with performance calculated using noisy instances of photocurrents, given FEMs knowledge. The stimuli, modelled as 0.24x2.2 arcmin increments of 543 nm light presented via an AOSLO, included both a single 2 ms flash and pairs of flashes separated by interstimulus intervals (ISI) of 17 ms, 33 ms, 100 ms, or 300 ms. Detection thresholds, defined as the stimulus contrast corresponding to 75% correct, were assessed with and without FEMs. Without FEMs, thresholds for detecting two flashes separated by 17-100 ms slightly increased with ISI but remained lower than those for a single flash. With FEMs, the modelled differences between single- and two-flash thresholds were less pronounced, suggesting that, at the level of photocurrent signals, FEMs reduce the benefits of temporal summation for detection. Future work will quantify this reduction by simulating FEMs with varying velocities and explore if adding a temporal adaptation stage improves effect of FEMs' on performance.
Effects of the Incredible Years parenting program on sibling conduct problems: A latent transition analysis
Background: Behavioral parenting programs are a primary strategy used to reduce children's conduct problems. Although behavior problems in siblings may co-occur, behavioral parenting program trials typically report outcomes for one child per family (the index child), with potential program effects on any non-targeted sibling largely neglected. This study examined co-occurring patterns of index child and non-targeted sibling conduct problems, and how parental participation in the Incredible Years (IY) program changes these patterns. Methods: We used individual participant data pooled across three randomized trials of the IY parenting program in England, Wales, and Ireland, with data for the index child and one non-targeted sibling (N = 240 families, 480 children; index child: M age = 4.73, SD = 1.44, range 2–9 years, 62% male; non-targeted sibling: M age = 5.94 years, SD = 3.15, range 6 months−15 years, 49% male). We used latent transition analysis to identify latent classes at both baseline and posttest based on families' combinations of index child and non-targeted sibling conduct problems. Results: We identified two classes with distinct patterns of co-occurring sibling dyad conduct problems: one with moderate clinical levels of index child conduct problems and non-clinical levels for the non-targeted sibling; and one with severe clinical levels for both children. In terms of the effects of IY, most intervention families maintained their patterns of sibling dyad conduct problems, but with lower levels across classes. Most intervention families reported improvements predominantly for the index child. However, a minority of families with severe baseline levels of conduct problems in both children moved to a class with non-clinical levels for both children. Conclusions: For most families, IY had limited effects on non-targeted sibling disruptive behavior. However, IY may reduce co-occurring sibling conduct problems for a small number of families with initially severe levels in both children.
Thermal constraints on Middle Pleistocene hominin brain evolution and cognition
High latitude habitats are subject to thermally-driven energetic constraints that make their occupation challenging. This is likely to have had a particularly significant impact on energy-expensive tissue like the brain, especially during periods of lower global temperatures during the Mid-Pleistocene Ice Ages. I analyse data on endocranial volumes for archaic humans (Homo heidelbergensis, H. neanderthalensis and allies) to show (1) that cranial volumes were typically smaller at high latitudes than in the tropics and (2) that they declined during cold phases and increased during warm phases of the Middle Pleistocene Ice Ages. Within this broad pattern, there is a significant uplift in cranial volumes after 400 ka that seems to coincide with widespread presence of hearths at high latitudes, suggesting that hominin populations might have gained at least partial release from this constraint through cultural control over fire. While this might pinpoint the time at which hominins first began to cook on a regular basis, fire offers other important benefits (notably warmth and extending the length of the working day) that might have played an equally important role in buffering populations against thermal stresses. The larger brain sizes that this made possible have implications for social cognitive capacities like mentalising, that in turn have implications for language skills, cultural behaviour and social group size.
Multimodal population study reveals the neurobiological underpinnings of chronotype.
The rapid shifts in society have altered human behavioural patterns, with increased evening activities, increased screen time and changed sleep schedules. As an explicit manifestation of circadian rhythms, chronotype is closely intertwined with physical and mental health. Night owls often exhibit unhealthier lifestyle habits, are more susceptible to mood disorders and have poorer physical fitness compared with early risers. Although individual differences in chronotype yield varying consequences, their neurobiological underpinnings remain elusive. Here we conducted a pattern-learning analysis with three brain-imaging modalities (grey matter volume, white-matter integrity and functional connectivity) and capitalized on 976 phenotypes in 27,030 UK Biobank participants. The resulting multilevel analysis reveals convergence on the basal ganglia, limbic system, hippocampus and cerebellum. The pattern derived from modelling actigraphy wearables data of daily movement further highlighted these key brain features. Overall, our population-level study comprehensively investigates chronotype, emphasizing its close connections with habit formation, reward processing and emotional regulation.
Collaborative care for pregnant women with eye conditions.
The management of ophthalmic conditions in pregnancy presents unique challenges that demand a nuanced approach. Significant knowledge gaps and practice variations persist, likely as a result of the infrequent nature of these issues in pregnancy, as well as the lack of crossover in the specialty training curriculum for both specialties. This commentary explores how multidisciplinary team (MDT) working can address these uncertainties to support shared decision-making and potentially improve outcomes in this vulnerable patient population. We highlight the need to involve ophthalmologists in obstetric MDTs, where appropriate, and the importance of establishing clear communication channels and referral pathways between both specialties and across hospitals in the region. We also share our experience of establishing these pathways locally, the feedback we have received from interdisciplinary educational initiatives to improve knowledge sharing, and possible future directions for this collaborative approach to help fill the evidence gap.
Structures of the human adult muscle-type nicotinic receptor in resting and desensitized states.
Muscle-type nicotinic acetylcholine receptor (AChR) is the key signaling molecule in neuromuscular junctions. Here, we present the structures of full-length human adult receptors in complex with Fab35 in α-bungarotoxin (αBuTx)-bound resting states and ACh-bound desensitized states. In addition to identifying the conformational changes during recovery from desensitization, we also used electrophysiology to probe the effects of eight previously unstudied AChR genetic variants found in patients with congenital myasthenic syndrome (CMS), revealing they cause either slow- or fast-channel CMS characterized by prolonged or abbreviated ion channel bursts. The combined kinetic and structural data offer a better understanding of both the AChR state transition and the pathogenic mechanisms of disease variants.
Neuroimaging-based data-driven subtypes of spatiotemporal atrophy due to Parkinson's disease.
Parkinson's disease is the second most common neurodegenerative disease. Despite this, there are no robust biomarkers to predict progression, and understanding of disease mechanisms is limited. We used the Subtype and Stage Inference algorithm to characterize Parkinson's disease heterogeneity in terms of spatiotemporal subtypes of macroscopic atrophy detectable on T1-weighted MRI-a successful approach used in other neurodegenerative diseases. We trained the model on covariate-adjusted cortical thicknesses and subcortical volumes from the largest known T1-weighted MRI dataset in Parkinson's disease, Enhancing Neuroimaging through Meta-Analysis consortium Parkinson's Disease dataset (n = 1100 cases). We tested the model by analyzing clinical progression over up to 9 years in openly-available data from people with Parkinson's disease from the Parkinson's Progression Markers Initiative (n = 584 cases). Under cross-validation, our analysis supported three spatiotemporal atrophy subtypes, named for the location of the earliest affected regions as: 'Subcortical' (n = 359, 33%), 'Limbic' (n = 237, 22%) and 'Cortical' (n = 187, 17%). A fourth subgroup having sub-threshold/no atrophy was named 'Sub-threshold atrophy' (n = 317, 29%). Statistical differences in clinical scores existed between the no-atrophy subgroup and the atrophy subtypes, but not among the atrophy subtypes. This suggests that the prime T1-weighted MRI delineator of clinical differences in Parkinson's disease is atrophy severity, rather than atrophy location. Future work on unravelling the biological and clinical heterogeneity of Parkinson's disease should leverage more sensitive neuroimaging modalities and multimodal data.
Discovery of active mouse, plant and fungal cytochrome P450s in endogenous proteomes and upon expression in planta.
Eukaryotes produce a large number of cytochrome P450s that mediate the synthesis and degradation of diverse endogenous and exogenous metabolites. Yet, most of these P450s are uncharacterized and global tools to study these challenging, membrane-resident enzymes remain to be exploited. Here, we applied activity profiling of plant, mouse and fungal P450s with chemical probes that become reactive when oxidized by P450 enzymes. Identification by mass spectrometry revealed labeling of a wide range of active P450s, including six plant P450s, 40 mouse P450s and 13 P450s of the fungal wheat pathogen Zymoseptoria tritici. We next used transient expression of GFP-tagged P450s by agroinfiltration to show ER-targeting and NADPH-dependent, activity-based labeling of plant, mouse and fungal P450s. Both global profiling and transient expression can be used to detect a broad range of active P450s to study e.g. their regulation and discover selective inhibitors.