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van Haren, J.

Publications and source records attributed to van Haren, J..

11 recordsLinked to original sources

Distinct Roles of Deep and Superficial Cortical Layers in Tone Prediction, Comparison, and Adaptation in Human Auditory Cortex

Auditory perception relies on prior sensations both to form expectations about upcoming sounds and to adapt to repeated inputs. Yet, how these processes interact with bottom-up frequency-specific stimulus drive, and how they are organised across cortical depth, remains unclear. Using ultra-high-field functional magnetic resonance imaging (7T fMRI), participants listened to stochastic tone sequences whose repetition structure and predictability varied over time. For each voxel independently, we used computational modelling to estimate responses for stimulus drive, repetition suppression, and expectations. We then partitioned the unique and shared variance of these components to estimate their relative importance in modulating BOLD activity across cortical layers in auditory cortices. Expectation-related signals explained most unique variance in deep (infagranular) layers, in line with accounts that place internal model representations and belief updates in deeper cortical populations. Variance jointly explained by stimulus drive and expectation was instead strongest in superficial layers, consistent with these compartments expressing computations that combine bottom-up input with top-down predictions, such as prediction error signalling. Finally, repetition suppression accounted for variance uniformly across depth, suggesting an adaptation-like mechanism that modulates responsiveness without a clear laminar bias. Together, the data suggest that deep layers contain content-specific predictive models, superficial layers register prediction-input alignment, and repetition suppression provides a depth-invariant, local gain control that complements predictive processing.

neuroscience↗

Dynamic competition between selective attention and spatial prediction during visual search

During visual search, we rely on both selective attention and spatial predictions to guide our behavior. However, whether and how these mechanisms interact is largely unclear. Using a contextual cueing paradigm, we investigated whether learning and exploitation of spatial predictive context can occur outside attentional focus. Repeating search scenes enabled distractor context to serve as a contextual cue predicting target location. Participants searched for a target among distractors in two colors: the same as the target-to-be-searched (attended context) or a different color (ignored context). Halfway through the experiments, we changed the target color, thereby altering the attentional status of distractor contexts while maintaining their spatial predictiveness. In Experiment 1, where participants regularly switched between target colors, we found exploitation of spatial predictive context both within and outside attentional focus. However, in Experiment 2, where attention was more stably focused on one target color, only the attended predictive context was exploited before transfer. Intriguingly, after transfer, previously ignored predictive context showed immediate benefits, revealing latent learning. These findings demonstrate a dynamic competition between selective attention and spatial predictions: while learning occurs independently of attention, exploitation may require attentional selection. Our results suggest that selective attention gates the influence of spatial predictions on behavior, with gating strength determined by the stability of attentional control. Significance statementThis research addresses a fundamental question in cognitive science: can we learn from visual information we are not paying attention to? Our findings reveal a dynamic competition between selective attention and spatial prediction that can explain conflicting findings in the literature. We demonstrate that specifically the ability to exploit predictive spatial context depends critically on attentional stability. When required to flexibly switch attentional sets, we can benefit from both attended and unattended predictive information. However, when attention remains focused, unattended information is learned, but only becomes accessible when it is part of our attentional focus. These results reveal that the filtering operation of selective attention and the utilization of spatial prediction during visual search may actually compete dynamically, with selective attention ultimately constraining predictions influence on behavior. This advances our understanding of how these fundamental cognitive mechanisms interact under competition.

neuroscience↗

Hao-Fountain syndrome protein USP7 controls neuronal differentiation via BCOR-ncPRC1.1

Pathogenic variants in the ubiquitin-specific protease 7 (USP7) gene cause a neurodevelopmental disorder called Hao-Fountain syndrome. However, which of USP7s pleiotropic functions are relevant for neurodevelopment remains unclear. Here, we present a combination of quantitative proteomics, transcriptomics and epigenomics to define the USP7 regulatory circuitry during neuronal differentiation. USP7 activity is required for the transcriptional programs that direct both differentiation of embryonic stem cells into neural stem cells, and the neuronal differentiation of SH-SY5Y neuroblastoma cells. USP7 controls the dosage of the Polycomb H2AK119ub1 ubiquitin ligase complexes ncPRC1.1 and ncPRC1.6. Loss-of-function experiments revealed that BCOR-ncPRC1.1, but not ncPRC1.6, is a key effector of USP7 during neuronal differentiation. Indeed, BCOR-ncPRC1.1 mediates a major portion of USP7-dependent gene regulation during this process. Besides providing a detailed map of the USP7 regulome during neurodifferentiation, our results suggest that USP7 and ncPRC1.1-associated neurodevelopmental disorders involve dysregulation of a shared epigenetic network.

molecular biology↗

Doublecortin reinforces microtubules to promote growth cone advance in soft environments

Doublecortin (DCX) is a microtubule-associated protein critical for brain development. Although most highly expressed in the developing central nervous system, the molecular function of DCX in neuron morphogenesis remains unknown and controversial. We demonstrate that DCX function is intimately linked to its microtubule-binding activity. By using human induced pluripotent stem cell (hiPSC)- derived cortical i3Neurons genome engineered to express mEmerald-tagged DCX from the endogenous locus, we find that DCX-MT interactions become highly polarized very early during neuron morphogenesis. DCX becomes enriched only on straight microtubules in advancing growth cones with approximately 120 DCX molecules bound per micrometer of growth cone microtubule. At a similar saturation, microtubule-bound DCX molecules begin to impede lysosome transport, and thus can potentially control growth cone organelle entry. In addition, by comparing control, DCX-mEmerald and knockout DCX -/Y i3Neurons, we find that DCX stabilizes microtubules in the growth cone peripheral domain by reducing the microtubule catastrophe frequency and the depolymerization rate. DCX -/Y i3Neuron morphogenesis was inhibited in soft microenvironments that mimic the viscoelasticity of brain tissue and DCX -/Y neurites failed to grow toward brain-derived neurotrophic factor (BDNF) gradients. Together with high resolution traction force microscopy data, we propose a model in which DCX-decorated, rigid growth cone microtubules provide intracellular mechanical resistance to actomyosin generated contractile forces in soft physiological environments in which weak and transient adhesion-mediated forces in the growth cone periphery may be insufficient for productive growth cone advance. These data provide a new mechanistic understanding of how DCX mutations cause lissencephaly-spectrum brain malformations by impacting growth cone dynamics during neuron morphogenesis in physiological environments.

cell biology↗

Growth cone advance requires EB1 as revealed by genomic replacement with a light-sensitive variant

A challenge in analyzing dynamic intracellular cell biological processes is the dearth of methodologies that are sufficiently fast and specific to perturb intracellular protein activities. We previously developed a light-sensitive variant of the microtubule plus end tracking protein EB1 by inserting a blue light-controlled protein dimerization module between functional domains. Here we describe an advanced method to replace endogenous EB1 with this light-sensitive variant in a single genome editing step enabling this approach in human induced pluripotent stem cells and derived neurons. We demonstrate that acute and local optogenetic EB1 inactivation in developing cortical neurons induces microtubule depolymerization in the growth cone periphery and subsequent neurite retraction. In addition, advancing growth cones are repelled from areas of blue light exposure. These phenotypes were independent of the neuronal EB1 homolog EB3, revealing a direct dynamic role of EB1-mediated microtubule plus end interactions in neuron morphogenesis and neurite guidance.

cell biology↗

Leaf-level metabolic changes in response to drought affect daytime CO2 emission and isoprenoid synthesis

In the near future, climate change will cause enhanced frequency and/or severity in terrestrial ecosystems, including tropical forests. Drought responses by tropical trees may affect their carbon use, including production of volatile organic compounds (VOCs), with unpredictable implications for carbon cycling and atmospheric chemistry. It remains unclear how metabolic adjustments by mature tropical trees in response to drought will affect their carbon fluxes associated with daytime CO2 production and VOC emission. To address this gap, we used position-specific 13C-pyruvate labeling to investigate leaf CO2 and VOC fluxes from four tropical species before and during a controlled drought in the enclosed rainforest of Biosphere 2. Overall, plants that were more sensitive to drought had greater reductions in daytime CO2 production. Although daytime CO2 production was always dominated by non-mitochondrial processes, the relative contribution of CO2 from the tricarboxylic acid cycle tended to increase under drought. A notable exception was the legume tree Clitoria fairchildiana, which had less anabolic CO2 production than the other species even under pre-drought conditions, perhaps due to more efficient refixation of CO2 and anaplerotic use for amino acid synthesis. C. fairchildiana was also the only species to allocate detectable amounts of 13C label to VOCs, and was a major source of VOCs in the Biosphere 2 forest. In C. fairchildiana leaves, our data indicate that intermediates from the mevalonic acid pathway are used to produce the volatile monoterpene trans-{beta}-ocimene, but not isoprene. This apparent crosstalk between the mevalonic acid and methylerythritol phosphate pathways for monoterpene synthesis declined with drought. Finally, although trans-{beta}-ocimene emissions increased under drought, it was increasingly sourced from stored intermediates and not de novo synthesis. Unique metabolic responses of legumes may play a disproportionate role in the overall changes in daytime CO2 and VOC fluxes in tropical forests experiencing drought.

plant biology↗

Prediction and preview strongly affect reading times but not skipping during natural reading

In a typical text, readers look much longer at some words than at others and fixate some words multiple times, while skipping others altogether. Historically, researchers explained this variation via low-level visual or oculomotor factors, but today it is primarily explained in terms of cognitive factors, such as how well word identity can be predicted from context or discerned from parafoveal preview. While the existence of these effects has been well established in experiments, the relative importance of prediction, preview and low-level factors for eye movement variation in natural reading is unclear. Here, we address this question in three large datasets (n=104, 1.5 million words), using a deep neural network and Bayesian ideal observer to model linguistic prediction and parafoveal preview from moment to moment in natural reading. Strikingly, neither prediction nor preview was important for explaining word skipping - the vast majority of skipping was explained by a simple oculomotor model. For reading times, by contrast, we found strong but independent contributions of both prediction and preview, with effect sizes matching those from controlled experiments. Together, these results challenge dominant models of eye movements in reading by showing that linguistic prediction and parafoveal preview are not important determinants of word skipping.

neuroscience↗

Optogenetic EB1 inactivation shortens metaphase spindles by disrupting cortical force-producing interactions with astral microtubules

Chromosome segregation is accomplished by the mitotic spindle, a bipolar micromachine built primarily from microtubules. Different microtubule populations contribute to spindle function: Kinetochore microtubules attach and transmit forces to chromosomes, antiparallel interpolar microtubules support spindle structure, and astral microtubules connect spindle poles to the cell cortex [1,2]. In mammalian cells, End Binding (EB) proteins associate with all growing microtubule plus ends throughout the cell cycle and serve as adaptors for a diverse group of +TIPs that control microtubule dynamics and interactions with other intracellular structures [3]. Because binding of many +TIPs to EB1 and thus microtubule-end association is switched off by mitotic phosphorylation [4-6] the mitotic function of EBs remains poorly understood. To analyze how EB1 and associated +TIPs on different spindle microtubule populations contribute to mitotic spindle dynamics, we use a light sensitive EB1 variant, {pi}-EB1, that allows local, acute and reversible inactivation of +TIP association with growing microtubule ends in live cells [7]. We find that acute {pi}-EB1 photoinactivation results in rapid and reversible metaphase spindle shortening and transient relaxation of tension across the central spindle. However, in contrast to interphase, {pi}-EB1 photoinactivation does not inhibit microtubule growth in metaphase, but instead increases astral microtubule length and number. Yet, in the absence of EB1 activity astral microtubules fail to engage the cortical dynein/dynactin machinery and spindle poles move away from regions of {pi}-EB1 photoinactivation. In conclusion, our optogenetic approach reveals mitotic EB1 functions that remain hidden in genetic experiments likely due to compensatory molecular systems regulating vertebrate spindle dynamics.

cell biology↗

The E3 ligase TRIM1 ubiquitinates LRRK2 and controls its localization, degradation, and toxicity

Missense mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial Parkinsons Disease (PD); however, pathways regulating LRRK2 subcellular localization, function, and turnover are not fully defined. We performed quantitative mass spectrometry-based interactome studies to identify 48 novel LRRK2 interactors, including the microtubule-associated E3 ubiquitin ligase TRIM1 (Tripartite Motif Family 1). TRIM1 recruits LRRK2 to the microtubule cytoskeleton for ubiquitination and proteasomal degradation by binding LRRK2911-920, a nine amino acid segment within a flexible interdomain region (LRRK2853-981), which we designate the "Regulatory Loop" (RL). Phosphorylation of LRRK2 Ser910/Ser935 within LRRK2 RL serves as a molecular switch controlling LRRK2s association with cytoplasmic 14-3-3 versus microtubule-bound TRIM1. Association with TRIM1 modulates LRRK2s interaction with Rab29 and prevents upregulation of LRRK2 kinase activity by Rab29 in an E3-ligase-dependent manner. Finally, TRIM1 rescues neurite outgrowth deficits caused by PD-driving mutant LRRK2 G2019S. Our data suggest that TRIM1 is a critical regulator of LRRK2, controlling its degradation, localization, binding partners, kinase activity, and cytotoxicity.

molecular biology↗

Rainforest-to-pasture conversion stimulates soil methanogenesis across the Brazilian Amazon

The Amazon rainforest is a biodiversity hotspot and large terrestrial carbon sink that is threatened by agricultural conversion. Rainforest-to-pasture conversion leads to the release of a potent greenhouse gas by converting soil from a methane sink into a source. The biotic methane cycle is driven by microorganisms; therefore, this study focused on active methane-cycling microorganisms and their functions across land-use types. We collected intact soil cores from three land use types (primary rainforest, pasture, and secondary rainforest) of two geographically distinct areas of the Brazilian Amazon (Santarem, Para and Ariquemes, Rondonia) and performed DNA stable-isotope probing coupled with metagenomics to identify the active methanotrophs and methanogens. At both locations, we observed a significant change in the composition of the isotope-labeled methane-cycling microbial community across land use types, specifically an increase in the abundance and diversity of active methanogens in pastures. We conclude that a significant increase in the abundance and activity of methanogens in pasture soils could explain the greater methane flux. Furthermore, we found that secondary rainforests recovered as methane sinks, indicating the potential for reforestation to offset greenhouse gas emissions in the tropics. These findings are critical for informing land management practices and global tropical rainforest conservation.

microbiology↗

Local Control of Intracellular Microtubule Dynamics by End Binding Protein 1 (EB1) Photo-Dissociation

Dynamic remodelling of the microtubule cytoskeleton and local interactions with intracellular targets are central to many polarized cell biological processes, an idea first formalized as search-and-capture hypothesis three decades ago1. However, because of the rapid timescale of microtubule polymerization dynamics, it is difficult to directly ask how, when and where dynamic microtubules participate in specific biological processes. Here, we employ a blue light-sensitive interaction with the oat phototropin LOV2 domain2 to generate a photo-inactivated variant of the microtubule end-binding protein EB1, a small adaptor that is central to the interaction of functionally and structurally diverse proteins with growing microtubule ends3,4, that can replace endogenous EB1 function. Acute and reversible blue light-mediated n-EB1 photo-dissociation allows spatially and temporally precise control of intracellular microtubule polymerization dynamics. In addition to demonstrating that neither the GTP cap nor the MT polymerase CKAP5 are sufficient to sustain persistent MT polymerization at physiological growth rates, our data illustrate accurate subcellular control of a freely diffusible, cytoplasmic protein at the second and micrometer scale. This novel design may serve as a template for precise control of many other intracellular protein activities.

cell biology↗