bioRxiv Subject Collection: Neuroscience's Journal
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Monday, August 5th, 2024
| Time |
Event |
| 7:52a |
Sensory population activity reveals confidence computations in the primate visual system
Perception is fallible1-3. Humans know this4-6, and so do some non-human animals like macaque monkeys7-14. When monkeys report more confidence in a perceptual decision, that decision is more likely to be correct. It is not known how neural circuits in the primate brain assess the quality of perceptual decisions. Here, we test two hypotheses. First, that decision confidence is related to the structure of population activity in sensory cortex. And second, that this relation differs from the one between sensory activity and decision content. We trained macaque monkeys to judge the orientation of ambiguous stimuli and additionally report their confidence in these judgments. We recorded population activity in the primary visual cortex and used decoders to expose the relationship between this activity and the choice-confidence reports. Our analysis validated both hypotheses and suggests that perceptual decisions arise from a neural computation downstream of visual cortex that estimates the most likely interpretation of a sensory response, while decision confidence instead reflects a computation that evaluates whether this sensory response will produce a reliable decision. Our work establishes a direct link between neural population activity in sensory cortex and the metacognitive ability to introspect about the quality of perceptual decisions. | | 10:31a |
Neural representational precision of distance predicts arithmetic performance
Focusing on the distance between magnitudes as the start point to investigate the mechanism of relationship detecting and its contribution to mathematical thinking, this study explores the precision of neural representations of numerical distance and their impact on arithmetic performance. By employing neural decoding techniques and representational similarity analysis, the present study investigate how accurately the brain represents numerical distances and how this precision relates to arithmetic skills. Thirty-two children participated, completing a dot number comparison task during fMRI scanning and an arithmetic fluency test. Results indicated that neural activation patterns in the intra-parietal sulcus decoded the distance between the presented pair of dots, and higher precision in neural distance representation correlates with better arithmetic performance. These findings suggest that the accuracy of neural decoding can serve as an index of the neural representation precision and that the ability to precisely encode numerical distances in the brain is a key factor in mathematical abilities. This provides new insights into the neural basis of mathematical cognition and learning. | | 1:17p |
Modeling impairment of ionic regulation with extended Adaptive Exponential integrate-and-fire models
To model the dynamics of neuron membrane excitability many models can be considered, from the most biophysically detailed to the highest level of phenomenological description. Recent works at the single neuron level have shown the importance of taking into account the evolution of slow variables such as ionic concentration. A reduction of such a model to models of the integrate-and-fire family is interesting to then go to large network models. In this paper, we introduce a way to consider the impairment of ionic regulation by adding a third, slow, variable to the adaptive Exponential integrate-and-fire model (AdEx). We then implement and simulate a network including this model. We find that this network was able to generate normal and epileptic discharges. This model should be useful for the design of network simulations of normal and pathological states. | | 5:36p |
Increased listening effort and cochlear neural degeneration underlie behavioral deficits in speech perception in noise in normal hearing middle-aged adults.
Middle-age is a critical period of rapid changes in brain function that presents an opportunity for early diagnostics and intervention for neurodegenerative conditions later in life. Hearing loss is one such early indicator linked to many comorbidities later in life. However, current clinical tests fail to capture hearing difficulties for ~10% of middle-aged adults seeking help at hearing clinics. Cochlear neural degeneration (CND) could play a role in these hearing deficits, but our current understanding is limited by the lack of objective diagnostics and uncertainty regarding its perceptual consequences. Here, using a cross-species approach, we measured envelope following responses (EFRs) - neural ensemble responses to sound originating from the peripheral auditory pathway - in young and middle-aged adults with normal audiometric thresholds, and compared these responses to young and middle-aged Mongolian gerbils, where CND was histologically confirmed. We observed near identical changes in EFRs across species that were associated with CND. Perceptual effects measured as behavioral readouts showed deficits in the most challenging listening conditions and were associated with CND. Additionally, pupil-indexed listening effort increased even at moderate task difficulties where behavioral outcomes were matched. Our results reveal perceptual deficits in middle-aged adults driven by CND and increases in listening effort, which may result in increased listening fatigue and conversational disengagement. | | 6:47p |
Nanoscale volumetric fluorescence imaging via photochemical sectioning
Optical nanoscopy of intact biological specimens has been transformed by recent advancements in hydrogel-based tissue clearing and expansion, enabling the imaging of cellular and subcellular structures with molecular contrast. However, existing high-resolution fluorescence microscopes have limited imaging depth, which prevents the study of whole-mount specimens without physical sectioning. To address this challenge, we developed "photochemical sectioning," a spatially precise, light-based sample sectioning process. By combining photochemical sectioning with volumetric lattice light-sheet imaging and petabyte-scale computation, we imaged and reconstructed axons and myelination sheaths across entire mouse olfactory bulbs at nanoscale resolution. An olfactory-bulb-wide analysis of myelinated and unmyelinated axons revealed distinctive patterns of axon degeneration and de-/dysmyelination in the neurodegenerative mouse, highlighting the potential for peta- to exabyte-scale super-resolution studies using this approach. | | 8:46p |
Synapse weakening-induced caspase-3 activity confers specificity to microglia-mediated synapse elimination
During brain development, synapses are initially formed in excess and are later eliminated in an activity-dependent manner, with weak synapses being preferentially removed. Previous studies identified glia as mediators of synapse removal, but it is unclear how glia specifically target weak synapses. Here we show that, in the developing mouse visual pathway, inhibiting synaptic transmission induces postsynaptic activation of caspase-3. Caspase-3 is essential for synapse elimination driven by both spontaneous and experience-dependent neural activity. Synapse weakening-induced caspase-3 activation determines the specificity of synapse elimination mediated by microglia but not astrocytes. Furthermore, in a mouse model of Alzheimers disease, caspase-3 deficiency protects against synapse loss induced by amyloid-{beta} deposition. Our results reveal caspase-3 activation as a key step in activity-dependent synapse elimination during development and synapse loss in neurodegeneration. | | 8:46p |
Patient-specific therapeutic benefit of MuSK agonist antibody ARGX-119 in MuSK myasthenia gravis passive transfer models
Muscle-specific kinase (MuSK) orchestrates establishment and maintenance of neuromuscular synapses, which enable muscle contraction. Autoantibodies targeting MuSK cause myasthenia gravis (MG), a disease characterized by fatigable skeletal muscle weakness which requires chronic immunosuppressive treatment and ventilatory support at some point in ~30% of patients. MuSK autoantibodies are predominantly IgG4 and are bispecific, functionally monovalent antibodies due to Fab-arm exchange. Through monovalent binding, MuSK IgG4 autoantibodies act as antagonists on the MuSK signalling pathway, impairing neuromuscular synaptic function. In contrast, bivalent MuSK antibodies act as agonists of the MuSK signalling pathway. Since symptoms in MuSK MG are largely caused by antagonistic monovalent MuSK antibodies, we hypothesized that a bivalent MuSK agonist could rescue MuSK MG, bypassing the need for generalized immunosuppression. In this study, we investigated whether an agonist antibody targeting the Frizzled- like domain of MuSK, ARGX-119, can ameliorate disease in MuSK MG models induced by passive transfer of polyclonal IgG4 from unrelated patients. For each patient material we first established the minimal dose for a progressive MG phenotype based on muscle function tests. ARGX-119 significantly improved survival and muscle weakness in a mouse model induced by one patient material, but not by three others. Mechanistically, this patient-specific efficacy could not be explained by autoantibody epitope specificity, titer or competition for ARGX-119 binding, but rather correlated to the presence of MuSK activating antibodies in some patients. We further provide evidence that an in vitro assay may predict which patients potentially benefit from ARGX-119 and that this treatment, when effective in MuSK MG mice, follows a bell-shaped dose-effect curve. These results provide first proof of concept of a MuSK agonist in a clinically relevant model for MuSK MG. We anticipate this to be a starting point for investigating the therapeutic benefit of ARGX-119 in MuSK MG and other neuromuscular diseases hallmarked by neuromuscular synaptic dysfunction. |
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