bioRxiv Subject Collection: Neuroscience's Journal
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Thursday, March 6th, 2025
| Time |
Event |
| 3:30p |
Temporal attention and oculomotor effects dissociate distinct types of temporal expectation
Temporal expectation-the ability to predict when events occur-relies on probabilistic information within the environment. Two types of temporal expectation, temporal precision, based on the variability of an event's onset, and hazard rate, based on the increasing probability of an event with onset delay, interact with temporal attention-ability to prioritize specific moments- at the performance level: Attentional benefits increase with precision but diminish with hazard rate. Both temporal expectation and temporal attention improve fixational stability; however, the distinct oculomotor effects of temporal precision and hazard rate, as well as their interactions with temporal attention, remain unknown. Investigating microsaccade dynamics, we found that hazard-based expectations were reflected in the oculomotor responses, whereas precision- based expectations emerged only when temporal attention was deployed. We also found perception-eye movement dissociations for both types of temporal expectation, yet attentional benefits in performance coincided with microsaccade rate modulations. These findings reveal an interplay among distinct types of temporal expectation and temporal attention in enhancing and recalibrating fixational stability. | | 3:30p |
Common but different: An ERP study of single- and multi-source interference processing in MSIT
Flexible behavior often requires processing of complex, interfering information. Research has investigated conflict-related brain processes mostly using single tasks which hindered direct comparison of different interference types. Thus, the question if they are resolved by a common mechanism or by a set of different, task-specific mechanisms remains open. In this study, we used event-related potentials (ERPs) to examine the spatio-temporal dynamics of cognitive control across Simon, flanker, multi-source and no-conflict conditions. Our findings reveal that all trial types engaged the same sequence of processing stages, as indicated by common ERP waveforms and consistent number and order of microstates across conditions. However, the intensity and duration of these common stages scaled with difficulty of the conflict task (as measured by RTs and accuracy) from Simon to flanker to multi-source interference. Flanker conflict uniquely influenced early ERP components strongly engaging the dorsal attentional system and visual areas, likely due to demands posed by the presence of flanker distractors. Later ERP components (with sources including ventral attention and somatomotor network areas) were affected by both conflicts. Accordingly, when flanker and Simon conflicts were presented together, early processes lineary summed up, but there was an interaction at the later stage of processing paralleling nonlinear drop of accuracy in a multi-conflict condition. Our study provides novel insights into the neural dynamics underlying cognitive control engaged across different conflict types and their interaction. The use of source analysis allowed us to ground ERP-based findings in the wider context of studies, including those using neuroimaging techniques. | | 3:30p |
Colour desaturation in the periphery is explained by general mechanisms of contrast sensitivity and constancy
Colours appear less saturated in the visual periphery than in the fovea. We revisit this well-known phenomenon by characterising parafoveal perceived contrast as a function of size. Observers (n = 20) matched perceived contrast of a parafoveally presented comparison disc (2{degrees} - 0.33{degrees}) to a standard 2{degrees} disc. For chromatic stimuli, desaturation increased with decreasing size. Unexpectedly, a similar amount of desaturation occurred for luminance-defined discs, once their perceived contrast was adjusted to match the standard chromatic discs. Desaturation was reduced as standard stimulus contrast increased, in line with contrast constancy theory, which predicts constant appearance for stimuli that are sufficiently distant from threshold. Since chromatic contrast sensitivity is reduced away from the fovea, contrast constancy is unachievable within the monitor gamut. In conclusion and somewhat counter-intuitively, the appearance of colour and luminance in the periphery is affected similarly, governed by general laws of contrast sensitivity and constancy. | | 8:01p |
Heterogeneous monotonic and non-monotonic responses to odor in mitral/tufted glomeruli of the mouse olfactory bulb
Current models of olfactory sensory processing in the olfactory bulb (OB) posit that both intra- and interglomerular inhibitory circuits are involved in transforming sensory input. However, the impact of these circuits on different olfactory receptor neuron (ORNs) inputs remains poorly understood. We generated a model of the OB input-output transformation in which the output of each glomerulus is a function of its ORN input, local feed-forward intraglomerular inhibition and interglomerular normalization in which activity of each glomerulus is divided by the population response. The output of the model included linear and non-linear concentration-response relationships that depended on the input ORN Hill coefficient and half-activation value. The concentration-response relationships could be broadly categorized into four groups based on how the output response was influenced by increasing the concentration. Increasing concentration evoked monotonic increases (I) or decreases (D) in some glomeruli. Other glomeruli responded with non-monotonic decreases then increases (DI) or increased then decreased (ID). The non-monotonic ID glomeruli required interglomerular inhibition in our model, were most common in glomeruli with higher affinity ORN input and were heterogeneous in the magnitude of their drop. In vivo 2-photon Ca2+ imaging from MTC glomeruli in awake mice revealed qualitatively similar response types. Increasing levels of excitation drove higher levels of suppression in subsets of glomeruli, and nearly half of the recorded MTC glomeruli could be classified as ID. Additionally, the sensitivity of individual glomeruli was significantly correlated with the degree to which it was non-monotonic. Our results demonstrate that nonlinear responses of MTC to changes in odor concentration are not unusual, but indeed are typical, and that they can be explained by intra- and interglomerular inhibition. | | 8:36p |
Amyloid beta is released by lysosomal exocytosis from hiPSC-derived neurons
The endosomal-lysosomal system has long been linked to the production of amyloid beta (A{beta}), but the specific intracellular compartments involved in A{beta} secretion remain contentious. While lysosomes are typically associated with A{beta} degradation, studies have also shown that lysosomes also serve as site of A{beta} accumulation in cells, mouse models, and human tissues. Lysosomal exocytosis is a major secretory pathway in non-neuronal cells, but few studies have investigated this pathway in neurons. Here, we examined the potential role and mechanism of lysosomal exocytosis in human induced pluripotent stem cell (hiPSC)-derived neurons, and we hypothesized that lysosomal exocytosis is a pathway for A{beta} secretion from these neurons. Using total internal reflection fluorescence (TIRF) microscopy, lysosomes filled with fluorescently labelled amyloid were seen approaching and fusing with the plasma membrane in real-time. The number and composition of the released particles were characterized using nanoscale flow cytometry. Silencing two proteins, Rab27b and munc13-4, significantly reduced these events and blocked the release of amyloid into the extracellular space. Our results provide direct evidence for the involvement of lysosomal exocytosis in the release of A{beta} from neurons and highlight its potential as a target for therapeutic intervention in Alzheimer's disease. | | 8:36p |
C9orf72-ALS mutation drives mitophagy impairments in iNeurons
Introduction: ALS is a neurodegenerative disorder characterised by progressive upper and lower motor neuron loss. A GGGGCC hexanucleotide repeat expansion (HRE) in the C9orf72 gene is the most common mutation found in populations of European descent. Mitochondrial dysfunction has been observed in C9orf72-ALS patients and models of the disease, however reports on mitochondrial clearance via mitophagy in C9orf72-ALS are limited. Results: iNeurons from C9orf72-ALS patients displayed reduced mitochondrial membrane potential and reduced mitophagy, due to reductions in autophagosome production and reduced ULK1 recruitment to mitochondria. No consistent changes to PINK1/Parkin or BNIP3 mitophagy pathways were observed. Conclusions: Our data show that mitochondrial function is impaired in C9orf72-ALS patient iNeurons. An in-depth characterisation of mitophagy suggests that a deficit in autophagosome production is responsible and provides further evidence that toxic gain-of-function mechanisms in C9orf72-ALS are responsible for autophagy deficits. | | 8:36p |
Parabrachial Calca neurons influence aversive and appetitive taste function
The parabrachial (PB) nucleus participates in taste processing and integration with other senses. PB neurons that express the Calca gene support sensory-integrative responses, albeit only limited data have addressed their influence on taste. Here we studied how chemogenetic dampening of PB-Calca neurons impacted mouse orosensory preferences for diverse taste stimuli in brief-access fluid exposure tests, which capture oral sensory/tongue control of licking behavior. Intracranial delivery of Cre-dependent viruses in female and male CalcaCre/+ mice induced expression of the inhibitory designer receptor hM4Di:mCherry (hM4Di mice) or fluorophore mCherry alone (mCherry mice) in PB-Calca neurons. Several weeks later, hM4Di and mCherry mice entered brief-access tests where they could lick taste solutions on discrete seconds-long trials. Stimuli included the behaviorally avoided, but functionally different, bitter taste stimuli quinine (0 [water], 0.1, 0.3, and 1.0 mM) and cycloheximide (0, 0.001, 0.003, and 0.01 mM), and the appetitive sugar sucrose (0, 100, 300, 500, and 1000 mM). Both hM4Di and mCherry mice received the hM4Di ligand clozapine-N-oxide (CNO, 5 mg/kg, i.p.) prior to daily tests performed by blinded experimenters. With CNO, hM4Di mice displayed greater average licking (i.e., less avoidance) of quinine (p < 0.05), but not cycloheximide (p > 0.3), than mCherry mice, implying PB-Calca neurons variably influence orosensory responses across bitter stimuli. Moreover, male hM4Di mice selectively showed reduced mean licking preferences for sucrose under CNO (p < 0.05). These data suggest that PB-Calca neurons participate in both aversive and appetitive taste-guided behaviors, with their role in appetitive taste dependent on sex. | | 8:36p |
Peripheral Beta-Blockade Differentially Enhances Cardiac and Respiratory Interoception
Interoception, the perception of internal visceral states, arises from complex brain-body interactions across the central and peripheral nervous systems. Despite noradrenaline's key role in these interactions, its specific contribution to interoceptive processes remains unclear. In a placebo-controlled, randomised, within-subject study, we employed computational modelling of interoceptive psychophysics to determine how pharmacological beta-adrenoceptor antagonism controls interoception across cardiac and respiratory domains. Both cardio-selective bisoprolol and non-selective propranolol improved cardiac perceptual sensitivity, with bisoprolol exerting an enhanced effect on cardiac metacognition. In contrast, both beta-blockers increased respiratory perceptual precision, with no corresponding changes in sensitivity or metacognition. These findings reveal a novel dissociation between central and peripheral beta-adrenergic mechanisms in interoception, highlighting the pivotal role of peripheral noradrenaline in regulating multi-organ brain-body interactions. Our results suggest that beta-blockers may provide promising routes for modulating distinct facets of interoception, potentially opening new avenues for intervention in conditions characterised by disrupted bodily self-awareness. | | 8:36p |
Phase separation drives SNARE complexes formation
Background: Neuronal exocytosis is mainly driven by the assembly of the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complexes. However, little is known about the organization principle of the SNARE complex. Methods: Protein condensates formed by SNARE complex were imaged by confocal microscope. Fluorescence recovery after photobleaching (FRAP) assay together with fusion and division assays at the cellular level and in vitro studies with purified proteins were performed to characterize the dynamic properties of protein condensates. The effect of SNARE complex phase separation on the recruitment of synaptic vesicles was detected by immunofluorescence. Results: We discover that phase separation drives SNARE complex formation and aggregation; in addition, nonintrinsically disordered regions (non-IDRs) of the syntaxin1 protein is necessary for the formation of these biological condensates. Functionally, phase separation of the SNARE complex can be regulated by the major cofactors of the fusion machinery and has the ability to recruit synaptic vesicles in neurons. Conclusions: Our study here establishes that phase separation is a promising way to mediate the formation and aggregation of the SNARE complex, and further identified that the non-IDRs of syntaxin1 is necessary for the phase separation of the SNARE complex. Our work answers an vital scientific question: does the SNARE complex function as multiple copies that are dispersed or clustered together to ensure sustained neurotransmitter release. In sum, phase separation provides an ideal working model for SNARE complex-mediated membrane fusion and neurotransmitter release. |
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