bluuebunny/crossref_metadata_2025 huggingface dataset:
Modelling Microbiome Association with Host Phenotypes Using a Bayesian Dirichlet Process Model
Authors: Awany Denis , Chimusa Emile R.
Published: October 2024

Dysbiosis in the human gut microbiome has been shown to be intimately involved in the pathogenesis of a wide range of communicable and non-communicable diseases. As microbiome wide association study becomes the workhorse for identifying association between microbial taxa and human diseases/traits, proper modelling of microbial taxa abundances is critical. In particular, statistical frameworks need to effectively model correlation among microbial taxa as well as latent heterogeneity across samples. Here, a Bayesian method using the Dirichlet process random effects model is devised for microbiome association study. The proposed method uses a weighted combination of phylogenetic and radial basis function kernels to model taxa effects, and a non-parametrically modelled latent variable to model latent heterogeneity among samples. Using simulated and real microbiome datasets, it is shown that the method has high statistical power for association inference.

Software

The R codes to implement the method has been incorporated into a script phy-loDPM.R, and is available online athttps://github.com/AwanyDenis/phyloDPM.
Analysis of the dynamics of a complex, multipathway reaction: Insulin dimer dissociation
Authors: Jeong Kwanghoon , Guo Spencer C. , Allaw Sammy , Dinner Aaron R.
Published: October 2024

The protein hormone insulin forms a homodimer that must dissociate to bind to its receptor. Understanding the kinetics and mechanism of dissociation is essential for rational design of therapeutic analogs. In addition to its physiological importance, this dissociation process serves as a paradigm for coupled (un)folding and (un)binding. Based on previous free energy simulations, insulin dissociation is thought to involve multiple pathways with comparable free energy barriers. Here, we analyze the mechanism of insulin dimer dissociation using a recently developed computational framework for estimating kinetic statistics from short-trajectory data. These statistics indicate that the likelihood of dissociation (the committor) closely tracks the decrease in the number of (native and nonnative) intermonomer contacts and the increase in the number of water contacts at the dimer interface; the transition state with equal likelihood of association and dissociation corresponds to an encounter complex with relatively few native contacts and many nonnative contacts. We identify four pathways out of the dimer state and quantify their contributions to the rate, as well as their exchange, by computing reactive fluxes. We show that both the pathways and their extents of exchange can be understood in terms of rotations around three axes of the dimer structure. Our results provide insights into the kinetics of insulin analogues and, more generally, how to characterize complex, multipathway processes.
Genetic reduction of the translational repressors FMRP and 4E-BP2 preserves memory in mouse models of Alzheimer’s disease
Authors: Ribeiro Felipe C. , Cozachenco Danielle , Lacaille Jean-Claude , Nader Karim , De Felice Fernanda G. , Lourenco Mychael V. , Aguilar-Valles Argel , Sonenberg Nahum , Ferreira Sergio T.
Published: October 2024

Alzheimer’s disease (AD) is characterized by progressive memory decline. Converging evidence indicates that hippocampal mRNA translation (protein synthesis) is defective in AD. Here, we show that genetic reduction of the translational repressors, Fragile X messenger ribonucleoprotein (FMRP) or eukaryotic initiation factor 4E (eIF4E)-binding protein 2 (4E-BP2), prevented the attenuation of hippocampal protein synthesis and memory impairment induced by AD-linked amyloid-β oligomers (AβOs) in mice. Moreover, genetic reduction of 4E-BP2 rescued memory deficits in aged APPswe/PS1dE9 (APP/PS1) transgenic mouse model of AD. Our findings demonstrate that strategies targeting repressors of mRNA translation correct hippocampal protein synthesis and memory deficits in AD models. Results suggest that modulating pathways controlling brain mRNA translation may confer memory benefits in AD.
A scientific note on “Rapid brood decapping” – a method for assessment of honey bee (Apis mellifera) brood infestation withTropilaelaps mercedesae
Authors: Uzunov Aleksandar , Janashia Irakli , Chen Chao , Costa Cecilia , Kovačić Marin
Published: October 2024

Tropilaelaps mercedesaeis a parasitic mite species that negatively affects the health of theApis melliferacolonies. Recent reports show that it is spreading westwards, through Central Asia into Europe. Several field and laboratory methods have been proposed to detectTropilaelapsspp. inA. melliferacolonies; however, most of them are either laborious, costly or ineffective. Here we introduce a novel method for detectingT. mercedesaebased on the mite’s characteristic biology (reduced feeding as bee pupae mature, brief dispersal phase on adult bees and agility) and the use of wax strips. Sealed worker brood cells at the development stage of white to purple-eyed pupae are swiftly decapped with wax strips to observe and count surfacing adult mites. Our study shows over 90 % detection efficacy and brood survival, and ease of application. Therefore, we recommend the novel “Rapid brood decapping” method as a reliable tool for detecting and monitoringT. mercedesaeinfestation.
Metabolism fine tuning and cardiokines secretion represent adaptative responses of the heart to High Fat and High Sugar Diets in flies
Authors: Khamvongsa-Charbonnier Lucie , Kremmer Laurent , Torres Magali , Krifa Sallouha , Aubert Charis , Corbet Alice , Crespo Loïc , Röder Laurence , Perrin Laurent , Arquier Nathalie
Published: October 2024

Cardiopathies are one of the leading causes of death in obese diabetics. Resulting in part from junk food, diabetic cardiomyopathies are notably characterized by contractile dysfunctions. Using theDrosophilamodel for cardiac function in pathophysiological context, we identified a set of candidate genes, expressed by the heart, whose expression is modulated by acute challenge on High Sugar and High Fat regimes. Genes encoding core components of key homeostatic pathways and proteins such as 1C-metabolism homeostasis, the Galactose metabolism pathway and metabolites transporters, were identified and characterized as adaptative factors of cardiac function under nutritional stresses. In addition, putative secreted proteins were found dysregulated, highlighting the heart as a secretory organ in hyperglycemia and hyperlipidemia. In particular, we characterized the Fit satiety hormone as a new fly cardiokine, which autonomously modulates the cardiac function and remotely affects feeding behavior. Overall, our study uncovered new roles for metabolic pathways and cardiokines, and highlights autonomous and systemic adjustable responses of the heart to nutritional stresses.
Whole genome resequencing of a global collection of Napier grass (Cenchrus purpureus) to explore global population structure and QTL governing yield and feed quality traits
Authors: Teshome A. , Lire H. , Higgins J. , Olango T. , Habte E. , Negawo A.T. , Muktar M.S. , Assefa Y. , Pereira J.F. , Azevedo A.S. , Machado J.C. , Nyamongo D.S. , Zhang J. , Qi Y. , Anderson W. , De Vega J. , Jones C.S.
Published: October 2024

Napier grass (Cenchrus purpureus) is a C4perennial grass species native to Sub-Saharan Africa (SSA), primarily used to feed cattle in SSA. In this study, we sequenced the genomes of 450 Napier grass individuals, sourced from 20 different countries. More than 170 million DNA variants (SNPs and Indels) were detected, of which ∼1% informative SNPs were used to assess genetic diversity in the collection. Our resequencing study provided valuable insights into the genetic diversity across a global Napier grass collection. Furthermore, a genome-wide association study on two independent populations, identified multiple quantitative trait loci (QTL) that were significantly associated with desirable agronomic traits, such as biomass yield, nitrogen and cellulose content. Therefore, our results will serve as a valuable resource in safeguarding and unravelling the patterns of Napier grass genetic diversity, in the face of climate change, and spearhead genomics-based breeding programs to develop high-yielding and drought-tolerant varieties suitable for forage and biofuel production.
Human BNST volume is not simply sexually dimorphic
Authors: Berry Samuel C. , Suri Harsimran K. , Lisi Matteo , Aggleton John P. , Hodgetts Carl J.
Published: October 2024

‘The bed nucleus of the stria terminalis (BNST) is a sexually dimorphic basal forebrain region’, is a claim prevalent across rodent and human neuroscience research, with particular emphasis on its substantially larger size in males. Despite the pervasiveness of this claim, with potential implications for understanding sex differences in anxiety and substance use disorders, inspection of prior literature reveals a complex and nuanced picture. Direct evidence for larger male BNST size in humans comes solely from a handful of mostly small-scale post-mortem studies, which show either no, moderate, or very large differences, therefore indicating the need for a larger systematic investigation. Addressing this, we developed a novel 3T T1-weighted (T1w) manual segmentation protocol of the BNST, which was applied to ultra-high resolution T1w structural MRI data in 170 young human adults. Using a Bayesian modelling approach, taking into account existing post-mortem data, and controlling for total brain volume, age, and sibship, we find little evidence for total BNST volume differences between males and females. We recommend that researchers exercise caution when reporting evidence of BNST sexual dimorphism, particularly when translating findings from rodent models in which the BNST may play a different, olfaction-focused, role.
Modeling of transcriptomic variation among subgenomes in 25 accessions of common wheat reveals cis- and trans- regulation architectures
Authors: Nomura Yasuyuki , Okada Moeko , Tameshige Toshiaki , Takenaka Shotaro , Shimizu Kentaro K. , Nasuda Shuhei , Nagano Atsushi J.
Published: October 2024

Common wheat is an allohexaploid plant, thus making it difficult to obtain homoeolog-distinguished transcriptome data. Lasy-Seq, a type of 3’ RNA-seq, is efficient for obtaining homoeolog-distinguished transcriptomes and can thus overcome this measurement difficulty. This study obtained transcriptome data from the seedlings, second leaves, and root tips of 25 lines from mainly eastern transmitted area using Lasy-Seq. Roots and seedlings exhibited similar transcriptome profiles; however, they were different from those of the leaves. We determined the effects of subgenomes, lines and their interactions with leaves, roots, and seedlings on the expression levels of each homoeolog triad. Of the 19,805 homoeolog triads, 50.9–55.4%, 24.2–29.5%, and 7.7–9.0% showed significant effects on their expression levels from subgenome, line, and interaction, respectively. 51–55% and 24–30% have genetic variation in thecis- andtrans-regulation. Hierarchical clustering and co-transregulation network analysis of homoeolog triads revealed that the patterns of expression polymorphisms among the lines were shared in different genes. The triads in which the statistical model detected as line effects imply that expression variation between lines is caused by changes in a smaller number of commontrans-factors. We assigned gene ontology (GO) terms of theArabidopsisorthologs to wheat homoeolog triads via reciprocal BLAST between common wheat andArabidopsis, thus improving the percentage of gene-assigned GO terms to all analyzed GO terms from 19.1% to 90.6%. GO term enrichment analysis revealed that GO terms related to each tissue type function were enriched in genes expressed in the leaves and roots. Our information provides fundamental knowledge for the future breeding of plants possessing complex gene regulatory networks such as common wheat.
Osmoregulation affects elimination of microplastics in fish in freshwater and marine environments
Authors: Pratiwi Hilda Mardiana , Takagi Toshiyuki , Rusni Suhaila , Inoue Koji
Published: October 2024

In recent decades, microplastics (MPs) have emerged as one of the biggest environmental challenges in aquatic environments. Ingestion and toxicity of MPs in seawater (SW) and freshwater (FW) fish have been studied extensively both in field and laboratory settings. However, the basic mechanism of how fish deal with MPs in SW and FW remains unclear, although physiological conditions of fish differ significantly in the two environments. In this study, using Javanese medaka (Oryzias javanicus), a euryhaline fish which adapts readily to both SW and FW, we investigated elimination of MPs in fish in SW and FW environments. We exposedO. javanicuslarvae (21 days post-hatching) to 0.25 mg/L of fluorescent polystyrene microspheres (1 µm) for 24 h and then conducted an elimination test for up to 5 days. The results showed that the gut retention time (GRT) of MPs is longer in FW than in SW, indicating that MP elimination occurs more quickly in SW than in FW. However, despite shorter GRTs, higher numbers of MPs tended to be retained for a longer period in SW larvae than FW larvae. Subsequently, using a fluorescent marker, gastrointestinal fluid was found to move more rapidly in the SW group. This finding indicates that water drinking accelerates gastrointestinal fluid movement, which moves MPs through the gut in SW larvae. Beside the difference in physiological conditions, MP elimination was faster when food was available, suggesting that feeding also affects MP elimination in fish. Internal factors such as body size and intestine length were also examined, but indicated no significant difference between SW and FW. Therefore, osmoregulation and feeding both influence MP elimination in fish.
Anatomical and functional organization of the interpeduncular nucleus in larval zebrafish
Authors: Wu You Kure , Petrucco Luigi , Portugues Ruben
Published: October 2024

The habenulo-interpeduncular pathway is a highly conserved neural circuit across vertebrates, but the anatomical and functional architecture of the interpeduncular nucleus (IPN) remains poorly understood. Here, we use a combination of immunohistochemistry, volumetric electron microscopy (EM), and two-photon imaging to provide the first detailed characterization of the internal organization of the IPN in larval zebrafish. We show that the IPN receives extensive projections from the tegmentum, and reveal a strict segregation between the dorsal (dIPN) and ventral (vIPN) subcircuits, with minimal cross-communication. In the dIPN, we characterise in detail the inputs and outputs of r1π neurons, which have been recently identified as representing the animal’s heading direction. In the vIPN, we identify six distinct glomerular structures, each exhibiting specific patterns of reciprocal connections and projection pathways. Finally, we demonstrate that the connectivity and spontaneous activity patterns of habenular axons are shaped by the local anatomical features of the IPN, suggesting a role for the local interneurons in modulating presynaptic dynamics. Together, these results enhance our understanding of the internal organization of the IPN, and provide a framework for future investigations into both its physiology and its involvement in behavior.
Male Dimorphism and Emergence Strategies: A Mathematical Model of Protandry inFabriciana nerippeFelder, 1862
Authors: Kubo Hidaka , Nakaoka Shinji , Yamaguchi Ryo
Published: October 2024

In many butterfly species, males emerge earlier than females as part of a strategy to maximize male reproductive success. Although behavioral ecological studies using mathematical models have been conducted to explain this phenomenon, certain emergence patterns remain unexplained. In the butterfly speciesFabriciana nerippe, some males emerge at the same time as females, in addition to males that emerge earlier than the females. However, it is unclear what emergence patterns occur in populations with male dimorphism, as observed in this species. In this study, we showed the existence of male body size dimorphism inFabriciana nerippeby conducting a comparative analysis of forewing lengths between males and females. In addition, we developed a comprehensive mathematical model to investigate emergence patterns in the presence of dimorphic males. By introducing a trade-off between large size and early emergence, the model considered a scenario where small early-emerging and large late-emerging males could coexist. Numerical analysis demonstrated the emergence patterns of these two male types with a switch in emergence time. Furthermore, the higher the death rate before emergence, the earlier the emergence switch. These findings suggested that the timing of the switch depends on the death rate and is influenced by environmental factors. This work contributes to ecological and theoretical studies on timing dimorphism in life-history strategies across a broader range of species.

Highlights

We confirmed the existence of male body-size dimorphism corresponding to emergence timing inFabriciana nerippe.

We developed a comprehensive model of male emergence patterns incorporateing male dimorphism.

We assumed a trade-off between early emergence and large body size.

The timing of male emergence switching is influenced by death rate and reproductive advantage of large males.
NK cells mediate preventive efficacy of intravenous BCG against lung metastasis in mice
Authors: Guerrero Claudia , Moreo Eduardo , Araujo-Voces Miguel , Uranga Santiago , Gómez Ana Belén , Martín Carlos , Aguiló Nacho
Published: October 2024

Lung metastases frequently arise from primary tumors, including bladder cancer, and represent a critical negative prognostic factor. Natural Killer (NK) cells have shown to play a vital role in controlling metastasis. Consequently, tumor cells have evolved specific mechanisms to evade NK cell-mediated immune surveillance, promoting metastasis and resistance to immunotherapy. In this study, we investigated the prophylactic and therapeutic potential of intravenous Bacillus Calmette–Guérin (BCG) in preventing lung metastases from bladder cancer cells using a murine model. We demonstrated that prophylactic BCG administration significantly reduced tumor burden and prolonged survival, largely through NK cell activation. However, BCG treatment was ineffective when administered over established tumors, likely due to tumor-driven immune evasion mechanisms. Our results revealed the contribution of interferon-gamma (IFN-γ) to tumor resistance. Tumor cells exposed to IFN-γ upregulated were more resistant to BCGin vivo, which correlated with the overexpression of immune checkpoint molecules, whereas disruption of the IFN-γ signaling pathway in tumor cells partially restored the therapeutic efficacy of BCG. Our findings highlight the importance of understanding tumor immune escape mechanisms and suggest that BCG could be a promising treatment for preventing lung metastases in bladder cancer.
Optical coherence tomography enables longitudinal evaluation of cell graft-directed remodeling in stroke lesions
Authors: Adewumi Honour O , Simkulet Matthew G , Küreli Gülce , Giblin John T , Lopez Arnaldo Bisbal , Erdener Şefik Evren , Jiang John , Boas David A , O’Shea Timothy M
Published: October 2024

Stem cell grafting can promote glial repair of adult stroke injuries during the subacute wound healing phase, but graft survival and glial repair outcomes are perturbed by lesion severity and mode of injury. To better understand how stroke lesion environments alter the functions of cell grafts, we employed optical coherence tomography (OCT) to longitudinally image mouse cortical photothrombotic ischemic strokes treated with allogeneic neural progenitor cell (NPC) grafts. OCT angiography, signal intensity, and signal decay resulting from optical scattering were assessed at multiple timepoints across two weeks in mice receiving an NPC graft or an injection of saline at two days after stroke. OCT scattering information revealed pronounced axial lesion contraction that naturally occurred throughout the subacute wound healing phase that was not modified by either NPC or saline treatment. By analyzing OCT signal intensity along the coronal plane, we observed dramatic contraction of the cortex away from the imaging window in the first week after stroke which impaired conventional OCT angiography but which enabled the detection of NPC graft-induced glial repair. There was moderate, but variable, NPC graft survival at photothrombotic strokes at two weeks which was inversely correlated with acute stroke lesion sizes as measured by OCT prior to treatment, suggesting a prognostic role for OCT imaging and reinforcing the dominant effect of lesion size and severity on graft outcome. Overall, our findings demonstrate the utility of OCT imaging for both tracking and predicting natural and treatment-directed changes in ischemic stroke lesion cores.
Explaining decision biases through context-dependent repetition
Authors: Wagner Ben J. , Wolf H. Benedikt , Kiebel Stefan J.
Published: October 2024

Humans are prone to decision biases, which make behavior seemingly irrational. An important cause for decision biases is that the context in which decisions are made can later influence which choices humans prefer in new situations. Current computational models often require extensive environmental knowledge to explain these biases. Here, we tested the hypothesis that decision biases are mainly driven by a tendency to repeat context-specific actions. We implemented a series of nine value-based decision experiments on n = 351 male and female participants and reanalyzed six previously published datasets (n=350 participants). We found that higher within-context repetition of an option was associated with biased choices including higher subjective valuation and lower uncertainty for repeated actions. Next, we used a computational model based on two basic principles, learning by reward and decision repetition and tested it on all datasets. Our results show that the combination of these two basic principles is sufficient to explain biased choices. We demonstrate via hierarchical Bayesian model comparison that our model outperforms all alternative models. These results provide novel insights into human choice behavior and offer a solution to difficulties in current explanations and models.

Significance Statement

Human decision-making often deviates from rational choice theory. Understanding how decision biases emerge is essential for interpreting real-world human behavior. Our study shows how repeating decisions shapes decision making in novel situations. We adapt a simple computational model that can explain decision biases based on reward learning and decision repetition. By testing the model across 15 datasets, we demonstrate that it outperforms previous models, also offering new insights into how preferences affect subjective valuation and uncertainty. In sum, these findings provide a deeper understanding of how context-dependent preferences for specific decisions emerge and persist.
The representation of stimulus features during stable fixation and active vision
Authors: Moran Caoimhe , Johnson Philippa A. , Hogendoorn Hinze , Landau Ayelet N.
Published: October 2024

Predictive updating of object spatial coordinates from retinotopic pre-saccadic to post-saccadic positions contributes to stable visual perception. However, whether object features are predictively represented at the remapped location remains contested. Many previous studies showing evidence of feature remapping neglect the spatially invariant representation of features in the visual system. For example, feature-based attention boosts attended features across the entire visual field, potentially contributing to the maintenance of stimulus features across saccades. We set out to characterise the spatiotemporal dynamics of feature processing during stable fixation and active vision. To do so, we applied multivariate decoding methods to electroencephalography (EEG) data collected while participants viewed brief visual stimuli. Stimuli appeared at different locations across the visual field at either high or low spatial frequency (SF). During fixation, classifiers were trained to decode SF presented at one parafoveal location and cross-tested on SF from either the same, adjacent or more peripheral locations. When training and testing on the same location, SF was classified shortly after stimulus onset (~80 ms). Decoding of SF at locations farther from the trained location emerged later (~150-300 ms), with decoding latency modulated by eccentricity. This analysis provides a detailed time course for the spread of feature information across the visual field. Next, we investigated how active vision impacts the emergence of SF information. In the presence of a saccade, the decoding time of peripheral SF at parafoveal locations was accelerated, indicating predictive anticipation of SF due to the saccade. Crucially however, this predictive effect was not limited to the specific remapped location. Rather, peripheral SF was correctly classified, at an accelerated time course, at all parafoveal positions. This indicates a spatially coarse remapping of stimulus features during active vision, likely enabling a smooth transition on saccade landing.
Experimental short-term heatwaves negatively impact body weight gain and survival during larval development in a wild pollinator
Authors: Wögler Laura , Kurze Christoph
Published: October 2024

Climate change-induced heatwaves threaten global biodiversity, including crucial pollinators like bumblebees. Despite alarming projections, little is known about the effects of short-term heatwaves on insect larval development. Hence, we investigated the impact of simulated heatwaves on the development of fourth instar larvae (L4) ofBombus terrestrisL. (Hymenoptera: Apidae) using anin vitrorearing method. Individual larvae were incubated at 37°C and 38°C for a period of 4 days, with a constant rearing temperature of 34°C as the control. We examined body weight gain, developmental duration, survival to adult stage, and adult body size (i.e. dry mass, ITD, and head width). A simulated heatwave of 37°C did not significantly affect larval development, but 38°C impaired larval body mass gain. While developmental duration and adult body size were unaffected, an acute heat stress of 38°C during the L4 stage reduced the probability of pupae reaching adulthood. These findings highlight the potential for heatwaves to negatively affect bee populations by impairing larval growth and reducing survival to the adult stage, which may have severe implication for colony fitness.
Unveiling the latent dynamics in social cognition with multi-agent inverse reinforcement learning
Authors: Chen Yusi , Radulescu Angela , Wu Herbert Zheng
Published: October 2024

Understanding the intentions and beliefs of others, a phenomenon known as “theory of mind”, is a crucial element in social behavior. These beliefs and perceptions are inherently subjective and latent, making them often unobservable for investigation. Social interactions further complicate the matter, as multiple agents can engage in recursive reasoning about each other’s strategies with increasing levels of cognitive hierarchy. While previous research has shown promise in understanding a single agent’s belief of values through inverse reinforcement learning, extending this to model interactions among multiple agents remains an open challenge due to the computational complexity. In this work,we adopted a probabilistic recursive modeling of cognitive levels and joint value decomposition to achieve efficient multi-agent inverse reinforcement learning (MAIRL). We validated our method using simulations of a cooperative foraging task. Our algorithm revealed both the ground truth goal-directed value function and agents’ beliefs about their counter-parts’ strategies. When applied to human behavior in a cooperative hallway task, our method identified meaningful goal maps that evolved with task proficiency and an interaction map that is related to key states in the task without accessing to the task rules. Similarly, in a non-cooperative task performed by monkeys, we identified mutual predictions that correlated with the animals’ social hierarchy, highlighting the behavioral relevance of the latent beliefs we uncovered. Together, our findings demonstrate that MAIRL offers a new framework for uncovering human or animal beliefs in social behavior, thereby illuminating previously opaque aspects of social cognition.
Reward-driven cerebellar climbing fiber activity influences both neural and behavioral learning
Authors: Jin Shuyang , Hull Court
Published: October 2024

The cerebellum plays a key role in motor coordination and learning. In contrast with classical supervised learning models, recent work has revealed that CFs can signal reward-predictive information in some behaviors. This raises the question of whether CFs may also operate according to principles similar to those described by reinforcement learning models. To test how CFs operate during reward-guided behavior, and evaluate the role of reward-related CF activity in learning, we have measured CF responses in Purkinje cells of the lateral cerebellum during a Pavlovian task using 2-photon calcium imaging. Specifically, we have performed multi-stimulus experiments to determine whether CF activity meets the requirements of a reward prediction error (rPE) signal for transfer from an unexpected reward to a reward-predictive cue. We find that once CF activity is transferred to a conditioned stimulus, and there is no longer a response to reward, CFs cannot generate learned responses to a second conditioned stimulus that carries the same reward prediction. In addition, by expressing the inhibitory opsin GtACR2 in neurons of the inferior olive, and optically inhibiting these neurons across behavioral training at the time of unexpected reward, we find that the transfer of CF signals to the conditioned stimulus is impaired. Moreover, this optogenetic inhibition also impairs learning, resulting in a deficit in anticipatory lick timing. Together, these results indicate that CF signals can exhibit several characteristics in common with rPEs during reinforcement learning, and that the cerebellum can harness these learning signals to generate accurately timed motor behavior.
Cerebellar climbing fibers signal flexible, rapidly adapting reward predictions
Authors: Vignali Carlo , Mutersbaugh Michael , Hull Court
Published: October 2024

Classical models of cerebellar computation posit that climbing fibers (CFs) operate according to supervised learning rules, correcting movements by signaling the occurrence of motor errors. However, recent findings suggest that in some behaviors, CF activity can exhibit features that resemble the instructional signals necessary for reinforcement learning, namely reward prediction errors (rPEs). Despite these initial observations, many key properties of reward-related CF responses remain unclear, thus limiting our understanding of how they operate to guide cerebellar learning. Here, we have measured the postsynaptic responses of CFs onto cerebellar Purkinje cells using two-photon calcium imaging to test how they respond to learned stimuli that either do or do not predict reward. We find that CFs can develop generalized responses to similar cues of the same modality, regardless of whether they are reward predictive. However, this generalization depends on temporal context, and does not extend across sensory modalities. Further, learned CF responses are flexible, and can be rapidly updated according to new reward contingencies. Together these results suggest that CFs can generate learned, reward-predictive responses that flexibly adapt to the current environment in a context-sensitive manner.
Reduced spatial spread of nodes in geometric network models improves topology associated with increased computational capabilities
Authors: Christiansen Nicholas , Sandvig Ioanna , Sandvig Axel
Published: October 2024

Biological neural networks are characterized by short average path lengths, high clustering, and modular and hierarchical architectures. These complex network topologies strike a balance between local specialization and global synchronization via long-range connections, resulting in highly efficient communication. Here, we use a geometric network model with either an intermediate or a long-range connection probability to investigate the effects of wiring cost principles on network complexity for different spatial conformations. We find that both long-range and intermediate wiring probabilities only conform to small-world architectures for neurons in dense spatial clusters due to a decrease in wiring cost within clusters. Furthermore, both small-worldness and modularity were reduced in systems with long-range connections caused by a reduction in network clustering, allowing for novel insight into mechanisms underlying adaptive or maladaptive network alterations. Our findings corroborate previous work showing that both wiring probability and spatial distributions play a key role in neural network development.
Neocortical differentiation and hippocampal integration of non-meaningful items and their spatial location
Authors: Nemecz Zsuzsanna , Homolya István , Ilyés Alex , Kis Hunor , Mező György , Varga Virág Anna , Werkle-Bergner Markus , Keresztes Attila
Published: October 2024

Resolving interference between similar inputs is a critical feature of adaptive memory systems. Computational theories of the medial temporal lobe posit that the dentate gyrus and CA3 (CA3DG) subfields of the hippocampus are ideally suited to reduce interference via a process called pattern separation. Whereas neocortical areas upstream of the hippocampus have been shown to play a role in content-specific (e.g., spatial or object-related) interference reduction, the CA3DG is traditionally viewed as a domain-general pattern separator. Recent work also drew attention to the role of frontal and parietal control areas in allocating resources according to task demands during mnemonic discrimination, exerting top-down control over the medial temporal lobe. However, extant evidence in humans is almost solely based on mnemonic discrimination tasks involving everyday items, potentially confounding retrieval processes with pattern separation. Here, we studied pattern separation in a “process-pure” manner, utilizing non-meaningful fractal images. We acquired full-brain high-resolution functional MRI data of 39 participants (mean age (SD) = 22.6 (2.4) years, 19 females) while they studied fractals with varying degrees of interference in either their spatial or object features. Building upon the idea that the repetition of a stimulus results in a diminished BOLD response in areas involved in the processing of that stimulus (repetition suppression), we expected that regions engaged in pattern separation of objects or locations would decrease their response to repetitions, but not to highly similar (interference-inducing) items. We found that the parahippocampal cortex contributes to interference reduction in the spatial domain, while the perirhinal cortex contributes to interference reduction in the object domain. The frontoparietal control network was recruited during the encoding of both object and location lures, and displayed strengthened within- and cross-network connectivity in response to lures. Contrary to our expectations, the CA3DG showed repetition suppression to both exact repetitions and highly similar lures, indicating a lack of sensitivity to small differences in interfering stimuli. Altogether, these results are in line with content-specific neocortical interference reduction in the medial temporal lobe, possibly orchestrated by the frontoparietal control network, but challenge the view of CA3DG as a universal pattern separator.
Ramping dissociates motor and cognitive sequences in the parietal and prefrontal cortices
Authors: Doyle Hannah , Yewbrey Rhys , Kornysheva Katja , Desrochers Theresa M.
Published: October 2024

Humans complete different types of sequences as a part of everyday life. These sequences can be divided into two important categories: those that are abstract, in which the steps unfold according to a rule at super-second to minute time scale, and those that are motor, defined solely by individual movements and their order which unfold at the sub-second to second timescale. For example, the sequence of making spaghetti consists of abstract tasks (preparing the sauce and cooking the noodles) and nested motor actions (stir pasta water). Previous work shows neural activity increases (ramps) in the rostrolateral prefrontal (RLPFC) during abstract sequence execution (Desrochers et al., 2015, 2019). During motor sequence production, activity occurs in regions of the prefrontal cortex (Yewbrey et al., 2023). However, it remains unknown if ramping is a signature of motor sequence production as well or solely an attribute of abstract sequence monitoring and execution. We tested the hypothesis that significant ramping activity occurs during motor sequence production in the RLPFC. Contrary to our hypothesis, we did not observe significant ramping activity in the RLPFC during motor sequence production, but we found significant ramping activity in bilateral inferior parietal cortex, in regions distinct from those observed during an abstract sequence task. Our results suggest different prefrontal-parietal circuitry may underlie abstract versus motor sequence execution.
Causal discovery from ecological time-series with one timestamp and multiple observations
Authors: Bystrova Daria , Assaad Charles K. , Si-moussi Sara , Thuiller Wilfried
Published: October 2024

Ecologists frequently seek to establish causal relations between entities of an ecological system, such as species interactions, ecosystem functions or ecosystem services, using observational data. Despite this, many studies still primarily rely on correlation-based methods, which lack the capability for causal interpretation. Recently, causal discovery methods have gained traction in analysing ecological time-series. However, the scarcity of ecological time-series data presents a challenge due to the demanding and time-consuming nature of collecting consistent measurements over extended periods. In this paper, we delve into the applicability of causal discovery methods when applied to point-in-time (or snapshot-like) observational data obtained from ecological dynamic systems. Specifically, we examine the PC algorithm, which holds theoretical validity assuming the causal Markov condition, faithfulness and causal sufficiency. Additionally, we explore the FCI algorithm, an extension of the PC algorithm designed to handle cases where causal sufficiency is violated. Through a combination of theoretical reasoning and simulation experiments, we elucidate the scenarios in which both algorithms are expected to yield meaningful results. We demonstrate that even in situations where causal sufficiency is not satisfied, the PC algorithm - characterized by its comparatively simpler interpretability - can still deduce specific types of relationships between ecological entities. Furthermore, we illustrate our theoretical findings on simulated data as well as on real data containing records of the abundance of various bird species as well as climatic and land-cover conditions.
CRISPR/Cas9-based somatic knock-in of reporters in the avian embryo in ovo
Authors: Vargas Alciades Petit , Mida Baptiste , Goïame Rosette , Alegria-Prevot Olinda , Djelic Bojana , Fischer Evelyne , Tozer Samuel , Gros Jérôme , Manceau Marie , Morin Xavier
Published: October 2024

Gene editing and protein tagging are at the heart of modern developmental and cell biology. The advent of CRISPR/Cas9 based methods offers the possibility to develop customized approaches for genomic manipulations in non-classical experimental models. Here, we show that highly efficient somatic knock-ins of long DNA fragments can be achieved in the developing chick neural tube in ovo. We compare different types of repair matrices and different methods for the delivery of the CRISPR/Cas9 machinery, and find that an all plasmid-based approach and short arms of homology provide an easy and efficient method to achieve high frequencies of knock-in insertions with virtually no background signal. We use this method to target fluorescent reporters and dynamically monitor the subcellular distribution of endogenously expressed tagged proteins, as well as to insert the Gal4-VP16 transcription factor or the Cre recombinase at specific loci to label neural sub-populations in the chick embryonic spinal cord. Finally, we show that the method can also be applied to target the epiblast and somitic mesoderm.
A low-level Cdkn1c/p57kip2expression in spinal progenitors drives the transition from proliferative to neurogenic modes of division
Authors: Mida Baptiste , Lehman Nathalie , Coulpier Fanny , Bouhali Kamal , Goiame Rosette , Thomas-Chollier Morgane , Fischer Evelyne , Morin Xavier
Published: October 2024

During vertebrate neurogenesis, a progressive transition from symmetric proliferative to asymmetric neurogenic divisions is critical to balance growth and differentiation. Using single-cell RNA-seq data from chick embryonic neural tube, we identify the cell cycle regulator Cdkn1c as a key regulator of this transition. While Cdkn1 is classically associated with neuronal cell cycle exit, we show that its expression initiates at low levels in neurogenic progenitors. Functionally targeting the onset of this expression impacts the course of neurogenesis: Cdkn1c knockdown impairs neuron production by favoring proliferative symmetric divisions. Conversely, inducing a low-level CDKN1c misexpression in self-expanding progenitors forces them to prematurely undergo neurogenic divisions. CDKN1c exerts this effect primarily by inhibiting the cyclin D-CDK complex and lengthening G1 phase duration. We propose that Cdkn1c acts as a dual driver of the neurogenic transition whose low level of expression first controls the progressive entry of progenitors into neurogenic modes of division before a higher expression mediates cell cycle exit in daughter cells. This highlights that the precise control of neurogenesis regulators’ expression levels sequentially imparts distinct functions, and is essential for proper neural development.
Regional associations of sleep architecture and Alzheimer’s disease pathology
Authors: Buchal Antonia , Elmenhorst David , Doering Elena , Dzialas Verena , Giehl Kathrin , Bischof Gérard N , van Eimeren Thilo , Drzezga Alexander , Hoenig Merle C. ,   the T-POT study group
Published: October 2024

Objective

Recent evidence suggests that disturbances of sleep architecture are linked to Alzheimer’s disease (AD) pathology. Here, we assessed the association between sleep architecture and regional amyloid and tau pathology employing a portable sleep-monitoring device in addition to PET imaging.

Methods

18 cognitively normal adults (CN; M(Age) = 64.06 (8.63), Sex (M/F) =6/12) and 18 patients with MCI/early AD (M(Age) = 67.33 (8.25), Sex (M/F) =9/9) were included from the “Tau Propagation Over Time” (T-POT) study. All subjects underwent amyloid ([11C]-PiB) and tau ([18F]-AV1451) PET imaging. PET images were normalized to MNI-space and intensity standardized to the whole cerebellum ([11C]-PiB) or the inferior cerebellum ([18F]-AV1451). Sleep monitoring was performed at home using the portable “Dreem” EEG-headband (Beacon Biosignal), which is a reliable and comfortable wireless alternative to the gold-standard polysomnography (PSG). Sleep recordings were performed within six months of the PET acquisitions. At least, one sufficient night had to be acquired, which was used to assess the sleep macrostructure for each individual. Total duration of sleep phases per minutes (i.e. REM, N1, N2, N3) and total sleep time were extracted. In a first step, a linear mixed model (LMM) was used to compare the groups in terms of duration of the different sleep stages across the nightly recordings. Given the results of this comparison, mean N1 and N3 duration were subsequently correlated with regional amyloid and tau pathology SUVRs of 34 cortical regions using Spearman’s correlation. The reported results are based on one-tailed tests. All analyses were corrected for age.

Results

Patients with MCI/AD showed reduced N3 duration (p= .007) compared to the CN group. A trend was observed indicating that patients with MCI/AD exhibited longer N1 durations (p= .094); however, this difference did not reach statistical significance. Shorter N3 duration was associated with higher regional amyloid load in the paracentral lobe and the posterior cingulate gyrus, whereas longer N1 duration was linked to higher amyloid pathology in several regions, including the medial temporal lobe, cingulate cortex and the occipital lobe. Moreover, associations were observed between longer N1 duration and greater tau burden in regions comprising the temporal lobe, cingulate cortex, and medial-frontal areas of the brain.

Conclusion

Differences in sleep architecture between healthy controls and MCI/AD may arise from regionally-specific accumulation patterns of AD pathologies. Although it remains unknown whether disruptions in sleep architecture are a cause or a consequence, a complex relationship between AD-aggregation pathology in specific brain regions and the different phases of sleep appears to emerge.
hMT+ Activity Predicts the Effect Of Spatial Attention On Surround Suppression
Authors: Kiniklioglu Merve , Boyaci Huseyin
Published: October 2024

Surround suppression refers to the decrease in behavioral sensitivity and neural response to a central stimulus due to the presence of surrounding stimuli. Several aspects of surround suppression in human motion perception have been studied in detail, including its atypicality in some clinical populations. However, how the extent of spatial attention affects the strength of surround suppression has not been systematically studied before. To address this question, we presented human participants with ‘center’ and ‘surround’ drifting gratings and sought to find whether attending only to the center (‘narrow attention’) versus both to the center and surround (‘wide attention’) modulates the suppression strength in motion processing. Using psychophysics and functional magnetic resonance imaging (fMRI), we measured motion direction discrimination thresholds and cortical activity in the primary visual cortex (V1) and middle temporal complex (hMT+). We found increased perceptual thresholds and, thus, stronger surround suppression under the wide attention condition. We also found that the pattern of hMT+ activity was consistent with the behavioral results. Furthermore, a mathematical model that combines spatial attention and divisive normalization was able to explain the pattern in the behavioral and fMRI results. These findings provide a deeper understanding of how attention affects center-surround interactions and suggest possible neural mechanisms with relevance to both basic and clinical vision science.

Significance Statement

Our sensitivity to the drift direction of a grating decreases when it is surrounded by an iso-oriented high-contrast surround. Here, we report the first systematic neuroimaging study on how the extent of spatial attention modulates the strength of this ‘surround suppression’. We found that the strength of surround suppression increases as the extent of spatial attention increases, and, pointing to its critical role, hMT+ activity predicts these results. Furthermore, a mathematical model combining spatial interactions and attention could explain the results. In addition to their relevance to basic vision science, these findings have clinical implications because they suggest that the atypical surround suppression observed in some populations could be related to abnormal spatial attention mechanisms.