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Transient photocurrents in a subthreshold evidence accumulator accelerate perceptual decisions.
Perceptual decisions are complete when a continuously updated score of sensory evidence reaches a threshold. In Drosophila, αβ core Kenyon cells (αβc KCs) of the mushroom bodies integrate odor-evoked synaptic inputs to spike threshold at rates that parallel the speed of olfactory choices. Here we perform a causal test of the idea that the biophysical process of synaptic integration underlies the psychophysical process of bounded evidence accumulation in this system. Injections of single brief, EPSP-like depolarizations into the dendrites of αβc KCs during odor discrimination, using closed-loop control of a targeted opsin, accelerate decision times at a marginal cost of accuracy. Model comparisons favor a mechanism of temporal integration over extrema detection and suggest that the optogenetically evoked quanta are added to a growing total of sensory evidence, effectively lowering the decision bound. The subthreshold voltage dynamics of αβc KCs thus form an accumulator memory for sequential samples of information.
CaV2.1 mediates presynaptic dysfunction induced by amyloid β oligomers.
Synaptic dysfunction is an early pathological phenotype of Alzheimer's disease (AD) that is initiated by oligomers of amyloid β peptide (Aβos). Treatments aimed at correcting synaptic dysfunction could be beneficial in preventing disease progression, but mechanisms underlying Aβo-induced synaptic defects remain incompletely understood. Here, we uncover an epithelial sodium channel (ENaC) - CaV2.3 - protein kinase C (PKC) - glycogen synthase kinase-3β (GSK-3β) signal transduction pathway that is engaged by Aβos to enhance presynaptic CaV2.1 voltage-gated Ca2+ channel activity, resulting in pathological potentiation of action-potential-evoked synaptic vesicle exocytosis. We present evidence that the pathway is active in human APP transgenic mice in vivo and in human AD brains, and we show that either pharmacological CaV2.1 inhibition or genetic CaV2.1 haploinsufficiency is sufficient to restore normal neurotransmitter release. These findings reveal a previously unrecognized mechanism driving synaptic dysfunction in AD and identify multiple potentially tractable therapeutic targets.
Brain aging shows nonlinear transitions, suggesting a midlife "critical window" for metabolic intervention.
Understanding the key drivers of brain aging is essential for effective prevention and treatment of neurodegenerative diseases. Here, we integrate human brain and physiological data to investigate underlying mechanisms. Functional MRI analyses across four large datasets (totaling 19,300 participants) show that brain networks not only destabilize throughout the lifetime but do so along a nonlinear trajectory, with consistent temporal "landmarks" of brain aging starting in midlife (40s). Comparison of metabolic, vascular, and inflammatory biomarkers implicate dysregulated glucose homeostasis as the driver mechanism for these transitions. Correlation between the brain's regionally heterogeneous patterns of aging and gene expression further supports these findings, selectively implicating GLUT4 (insulin-dependent glucose transporter) and APOE (lipid transport protein). Notably, MCT2 (a neuronal, but not glial, ketone transporter) emerges as a potential counteracting factor by facilitating neurons' energy uptake independently of insulin. Consistent with these results, an interventional study of 101 participants shows that ketones exhibit robust effects in restabilizing brain networks, maximized from ages 40 to 60, suggesting a midlife "critical window" for early metabolic intervention.
Characterising human disparity tuning properties using population receptive field mapping.
Our visual percept of small differences in depth is largely informed by binocular stereopsis, the ability to decode depth from the horizontal offset between the retinal images in each eye. While multiple cortical areas are associated with stereoscopic processing, it is unclear how tuning to specific binocular disparities is organised across human visual cortex. We used 3T functional magnetic resonance imaging to generate population receptive fields in response to modulation of binocular disparity to characterise the neural tuning to disparity. We also used psychophysics to measure stereoacuity thresholds compared to backgrounds at different depths (pedestal disparity). Ten human participants (7 female) observed correlated or anticorrelated random-dot stereograms with disparity ranging from -0.3° to 0.3°, and responses were modelled as 1-dimensional tuning curves along the depth dimension. First, we demonstrate that lateral and dorsal visual areas show the greatest proportion of vertices selective for binocular disparity. Second, with binocularly correlated stimuli, we show a polynomial relationship between preferred disparity and tuning curve width, with sharply tuned disparity responses at near-zero disparities, and broader disparity tuning profiles at near or far disparities. This relationship held across visual areas and was not present for anticorrelated stimuli. Finally, the individual thresholds for psychophysical stereoacuity at the 3 different pedestal disparities were broadly related to population receptive field tuning width in area V1, suggesting a possible limit for fine stereopsis at the earliest level of cortical processing. Together, these findings point to heterogeneity of disparity processing across human visual areas, comparable to non-human primates.Significance Statement Binocular disparity arises from the horizonal separation of the two eyes and provides information for determining depth and 3D structure. We used functional magnetic resonance imaging and population receptive field mapping to measure tuning of multiple visual areas to binocular disparity in the human visual cortex. We additionally measured psychophysical thresholds for detecting binocular disparity and correlated these with the neural measures. The width of the disparity tuning was related to the preferred disparity across all visual areas. Disparity tuning widths in V1 were also related to psychophysical thresholds. These findings in the human are broadly comparable to non-human primates.
Cyclic nucleotide phosphodiesterases as drug targets.
Cyclic nucleotides are synthesized by adenylyl and/or guanylyl cyclase, and downstream of this synthesis, the cyclic nucleotide phosphodiesterase families (PDEs) specifically hydrolyze cyclic nucleotides. PDEs control cyclic adenosine-3',5'monophosphate (cAMP) and cyclic guanosine-3',5'-monophosphate (cGMP) intracellular levels by mediating their quick return to the basal steady state levels. This often takes place in subcellular nanodomains. Thus, PDEs govern short-term protein phosphorylation, long-term protein expression, and even epigenetic mechanisms by modulating cyclic nucleotide levels. Consequently, their involvement in both health and disease is extensively investigated. PDE inhibition has emerged as a promising clinical intervention method, with ongoing developments aiming to enhance its efficacy and applicability. In this comprehensive review, we extensively look into the intricate landscape of PDEs biochemistry, exploring their diverse roles in various tissues. Furthermore, we outline the underlying mechanisms of PDEs in different pathophysiological conditions. Additionally, we review the application of PDE inhibition in related diseases, shedding light on current advancements and future prospects for clinical intervention. SIGNIFICANCE STATEMENT: Regulating PDEs is a critical checkpoint for numerous (patho)physiological conditions. However, despite the development of several PDE inhibitors aimed at controlling overactivated PDEs, their applicability in clinical settings poses challenges. In this context, our focus is on pharmacodynamics and the structure activity of PDEs, aiming to illustrate how selectivity and efficacy can be optimized. Additionally, this review points to current preclinical and clinical evidence that depicts various optimization efforts and indications.
Recent developments in gene therapy for Parkinson's disease.
Parkinson's disease (PD) is a progressive, neurodegenerative disorder for which there is currently no cure. Gene therapy has emerged as a novel approach offering renewed hope for the development of treatments that meaningfully alter the course of the disease. In this review we explore various gene therapy strategies currently being developed targeting key aspects of PD pathogenesis: the restoration of the dopamine system by delivering genes involved in dopamine biosynthesis; reinforcing the inhibitory signalling pathways through glutamic acid decarboxylase (GAD) delivery to increase GABA production; enhancing neuronal survival and development by introducing various neurotrophic factors; delivery of genes to complement recessive familial PD mutations to correct mitochondrial dysfunction; restoring lysosomal function through delivery of GBA1 to increase glucocerebrosidase (GCase) activity; and reducing alpha-synuclein levels by reducing or silencing SNCA expression. Despite promising early work, challenges remain in developing safe, effective, and long-lasting gene therapies. Key considerations include optimizing viral vectors for targeted delivery, achieving controlled and sustained gene expression using different promoters, minimizing immune responses and increasing transgene delivery capacity. Future prospects may involve combinatory strategies targeting multiple pathways, such as multi-gene constructs delivered via high-capacity viral systems.
Addressing the speed-accuracy simulation trade-off for adaptive spiking neurons
The adaptive leaky integrate-and-fire (ALIF) model is fundamental within computational neuroscience and has been instrumental in studying our brains in silico. Due to the sequential nature of simulating these neural models, a commonly faced issue is the speed-accuracy trade-off: either accurately simulate a neuron using a small discretisation time-step (DT), which is slow, or more quickly simulate a neuron using a larger DT and incur a loss in simulation accuracy. Here we provide a solution to this dilemma, by algorithmically reinterpreting the ALIF model, reducing the sequential simulation complexity and permitting a more efficient parallelisation on GPUs. We computationally validate our implementation to obtain over a 50× training speedup using small DTs on synthetic benchmarks. We also obtained a comparable performance to the standard ALIF implementation on different supervised classification tasks - yet in a fraction of the training time. Lastly, we showcase how our model makes it possible to quickly and accurately fit real electrophysiological recordings of cortical neurons, where very fine sub-millisecond DTs are crucial for capturing exact spike timing.
Evaluating the transcriptional regulators of arterial gene expression via a catalogue of characterized arterial enhancers.
The establishment and growth of the arterial endothelium requires the coordinated expression of numerous genes. However, regulation of this process is not yet fully understood. Here, we combined in silico analysis with transgenic mice and zebrafish models to characterize arterial-specific enhancers associated with eight key arterial identity genes (Acvrl1/Alk1, Cxcr4, Cxcl12, Efnb2, Gja4/Cx37, Gja5/Cx40, Nrp1 and Unc5b). Next, to elucidate the regulatory pathways upstream of arterial gene transcription, we investigated the transcription factors binding each arterial enhancer compared to a similar assessment of non-arterial endothelial enhancers. These results found that binding of SOXF and ETS factors was a common occurrence at both arterial and pan-endothelial enhancers, suggesting neither are sufficient to direct arterial specificity. Conversely, FOX motifs independent of ETS motifs were over-represented at arterial enhancers. Further, MEF2 and RBPJ binding was enriched but not ubiquitous at arterial enhancers, potentially linked to specific patterns of behaviour within the arterial endothelium. Lastly, there was no shared or arterial-specific signature for WNT-associated TCF/LEF, TGFβ/BMP-associated SMAD1/5 and SMAD2/3, shear stress-associated KLF4 or venous-enriched NR2F2. This cohort of well characterized and in vivo-verified enhancers can now provide a platform for future studies into the interaction of different transcriptional and signalling pathways with arterial gene expression.
From Cadavers to Neural Networks: A Narrative Review on Artificial Intelligence Tools in Anatomy Teaching
The application of artificial intelligence (AI) in anatomy teaching is gaining attention due to its potential to support personalized learning and its ability to provide customized, real-time feedback. While the potential impact of complete AI integration in medical education remains unclear, there is a suspicion that it could revolutionize pedagogical and assessment practices. Traditional anatomy teaching strategies that use donated human resources hinder continuous learning due to accessibility and ethical challenges. Existing resources, such as anatomy atlases, may not provide knowledge of spatial relationships. AI-powered applications enable students to access more flexible and accessible learning material beyond physical classrooms. This review critically evaluates current advances and the possible impacts of AI in learning anatomy based on the reported empirical original studies. Additionally, it recognizes the challenges and provides possible solutions for them. Most of the initiatives to integrate AI in anatomy teaching are directed towards the development of customized anatomy chatbots and their integration with virtual reality (VR). Although the crucial role of medical imaging in the anatomy curriculum is recognized, currently, no AI application has been developed to target this field. This review discusses the currently available AI tools for anatomy teaching. Additionally, the knowledge gaps and future directions of AI in medical education, especially anatomy education, are also discussed. With the present advances in AI technologies, their application in anatomical education is still deficient. This review paper provides an overview of recent tools used in anatomy teaching and learning.
Circulating neuropeptide Y dynamics and performance during exercise in heart failure patients with contemporary medical and device therapy.
High cardiac sympathetic drive and release of the sympathetic cotransmitter neuropeptide Y (NPY) are significant features of congestive heart failure (CHF), in which resting venous NPY levels are known to be associated with mortality. However, whether circulating NPY levels increase during exercise in CHF when they are already elevated is controversial. We sought to establish the dynamics of circulating NPY levels in CHF patients treated with contemporary medical therapy and devices in relationship to indices of performance linked to long-term prognosis. CHF patients (n = 15) underwent cardiopulmonary exercise testing with venous blood sampling at rest, peak exercise and recovery. These patients had significantly higher resting venous NPY levels compared with an age- and sex-matched control group of patients (n = 16) with normal left ventricular function (40 ± 6.9 vs. 9.0 ± 4.6 pg/mL, respectively; P
Nanoscale Biodegradable Printing for Designed Tuneability of Vaccine Delivery Kinetics.
Two-photon polymerization (2PP) 3D printing enables top-down biomaterial synthesis with nanoscale spatial resolution for de novo design of monodisperse injectable drug delivery systems. Spatiotemporal Controlled Release Inks of Biocompatible polyEsters (SCRIBE) is a novel poly(lactic-co-glycolic acid)-triacrylate resin family with sub-micron resolution and tuneable hydrolysis that addresses the limitations of current 2PP resins. SCRIBE enables the direct printing of hollow microparticles with tuneable chemistry and complex geometries inaccessible to molding techniques, which are used to engineer controlled protein release in vitro and in vivo. SCRIBE microparticles are used to modulate antibody titers and class switching as a function of antigen release rate and extend these findings to enable a single-injection vaccine formulation with extended antibody induction kinetics. Demonstrating how the chemistry and computer-aided design of 2PP-printed microparticles can be used to tune responses to biomacromolecule release in vivo opens significant opportunities for a new generation of drug delivery vehicles.