bluuebunny/crossref_metadata_2025_split huggingface dataset:
Functional consequences of fast-spiking interneurons in striatum
Authors: Kumar Arvind , Guo Lihao 
Published: September 2024

AbstractThe striatum features a distinct network characterized by a high degree of shared feedforward inhibition (FFI) from a mere 1% of fast-spiking interneurons (FSI). We investigate the potential roles of this extensively shared FFI in striatal function beyond inducing synchrony. Our findings reveal that FSIs increase the acrosstrial variability of striatal responses to cortical stimuli and, combined with recurrent inhibition, lead to a ‘correlation attractor’ of striatal activities, i.e., weakly correlated inputs result in more correlated responses and vice versa. Thus, we uncover a mechanism by which input correlation can be bidirectionally modulated, which is possible only because of high sharing of FSI inputs. We posit that the emergence of a correlation attractor leads to non-zero correlation level and variable rate trajectories of striatal responses across trials, hence beneficial for exploration in learning. However, given their role in across-trial variability, we argue that FSIs should be ‘disengaged’ from the MSNs during performance where stability across trials is required.Significance StatementStriatum is a network of inhibitory neurons. Fast spiking interneurons constitute about 1% of the striatal neural population and provide feedforward inhibition (FSI). Here, we unravel two novel ways in which FSIs may shape striatal function. Given the recurrent inhibition, it is assumed that striatum can only de-correlate inputs. We show that high sharing of FSI also renders the striatum an ability to correlate inputs. Thus, recurrent and shared FSI create a ‘correlation attractor’. Besides, we show that shared FSIs give rise to high across-trial variability. Therefore, we argue that FSIs are more crucial in learning as they provide the neural basis of exploration, but they may impair learned behavior due to high across-trial variability.
Targeting FUS-ALS aggregation with Proteasome Inhibitors
Authors: Younis Amal , Yassen Kanar , Rozales Kinneret , Kadah Tahani , Saida Naseeb , Meller Anatoly , Hazra Joyeeta Dutta , Heinrich Ronit , Levy-Adam Flonia , Berlin Shai , Shalgi Reut 
Published: September 2024

SummaryALS, Amyotrophic lateral sclerosis, a devastating neurodegenerative disease (ND) with no cure, is often caused by abnormal cytosolic aggregation of RNA-binding proteins, the most well-known of which are TDP-43 and FUS. The proteasome is considered one of the major systems that degrades misfolded, including ND-associated, proteins, thereby acting to reduce aggregation, while inhibition of the proteasome increases aggregation. Unexpectedly, we found that proteasome inhibitor treatment significantly reduced ALS-associated mutant FUS aggregation in cells and in primary neurons. This is in sharp contrast to most other ND-associated aggregating proteins, including Huntingtin and TDP-43, for which proteasome inhibitors enhanced aggregation. We further found that this inhibitory effect is dependent on the transcription factor HSF1, suggesting that the underlying mechanism of this effect is transcriptionally-mediated. Since heat shock treatment did not show any effect on FUS aggregation, we hypothesized that proteasome inhibitors elicit a transcriptional program distinct of that of heat shock, which is protective of FUS aggregation. We identified BAG3, a co-chaperone that cooperates with HSP70 in reducing FUS aggregation, as a significant mediator of this effect. We therefore propose BBB-permeable proteasome inhibitors as a potential therapy specific to ALS-FUS.
A neural model for V1 that incorporates dendritic nonlinearities and back-propagating action potentials
Authors: Rentzeperis Ilias , Prandi Dario , Bertalmío Marcelo 
Published: September 2024

AbstractThe groundbreaking work of Hubel and Wiesel has been instrumental in shaping our understanding of V1, leading to modeling neural responses as cascades of linear and nonlinear processes in what has come to be known as the “standard model” of vision. Under this formulation, however, some dendritic properties cannot be represented in a practical manner, while extensive evidence indicates that dendritic processes are an indispensable element of key neural behaviours. As a result, current V1 models fail to explain neural responses in a number of scenarios. In this work, we propose an implicit model for V1 that considers nonlinear dendritic integration and backpropagation of action potentials from the soma to the dendrites. This is a parsimonious scheme that minimizes an energy, allows for a better conceptual understanding of neural processes, and explains several neurophysiological phenomena that have challenged classical approaches.
Sex-specific maladaptive responses to acute stress upon in utero THC exposure are mediated by dopamine
Authors: Valeria Serra , Francesco Traccis , Sonia Aroni , Laura Vidal Palencia , Luca Concas , Marcello Serra , Roberta Leone , Patrizia Porcu , Arnau Busquets Garcia , Roberto Frau , Miriam Melis 
Published: September 2024

AbstractCannabis remains by far the most consumed illicit drug in Europe. The availability of more potent cannabis has raised concerns regarding the enhanced health risks associated with its use, particularly among pregnant women. Growing evidence shows that cannabis use during pregnancy increases the risks of child psychopathology. We have previously shown that male rat offspring prenatally exposed to Δ9-tetrahydrocannabinol (THC), a rat model of prenatal cannabinoid exposure (PCE), display a hyperdopaminergic phenotype associated with a differential susceptibility to acute THC- and stress-mediated effects on sensorimotor gating functions. Here, we explore the contribution of the hypothalamic-pituitary-adrenal (HPA) axis, key regulator of body adaptive stress responses, to the detrimental effects of acute stress on ventral tegmental area (VTA) dopamine neurons and sensorimotor gating function of PCE rats. We report a sex-dependent compromised balance in mRNA levels of genes encoding mineralocorticoid and glucocorticoid receptors in the VTA, alongside with stress-induced pre-pulse inhibition (PPI) deficits. Notably, VTA dopamine neuronal activity is required for the manifestation of stress-dependent deterioration of PPI. Finally, pharmacological manipulations targeting glycogen-synthase-kinase-3-β signaling during postnatal development correct these stress-induced, sex-specific and dopamine-dependent deficits of PPI. Collectively, these results highlight the critical sex-dependent interplay between HPA axis and dopamine system in the regulation of sensorimotor gating functions in rats.
CRISPR/Cas9-induced breaks are insufficient to break linkage drag surrounding the ToMV locus ofSolanum lycopersicum
Authors: Grubben Jillis , Bijsterbosch Gerard , Aktürk Burak , Visser Richard G.F. , Schouten Henk J. 
Published: September 2024

AbstractDespite the success of CRISPR/Cas9 in inducing DNA double-strand breaks (DSBs) for genome editing, achieving targeted recombination in somatic cells remains challenging, particularly at recombination cold spots like the Tomato Mosaic Virus (ToMV) resistance locus inSolanum lycopersicum. We investigated the potential of CRISPR/Cas9-induced targeted recombination in somatic cells to overcome linkage drag surrounding the ToMV locus. We employed two strategies: first, inducing DSBs in both alleles of F1tomato seedlings to promote non-homologous end joining (NHEJ) and homology-directed repair (HDR); second, targeting a single allele in a heterozygous background to induce HDR in seedlings. CRISPR/Cas9 activity was confirmed in F₁ seedlings by detecting NHEJ-mediated mutations at the target sites in ToMV. We developed a bioinformatics pipeline to identify targeted recombinants by analyzing single nucleotide polymorphisms (SNPs) between parental haplotypes, allowing precise tracking of SNP variations. A two-dimensional pooling strategy was employed to distinguish genuine recombination events from PCR artifacts. Despite these advances and the active CRISPR/Cas9 system in F1progeny, no increase in recombination frequency was observed compared to wild-type plants. We extended our research to protoplasts to assess whether CRISPR/Cas9 could induce targeted recombination under different cellular conditions at the same locus. Consistent with our findings in F1plants, we observed no increase in recombinant patterns compared to wild-type controls in protoplasts. Our findings suggest that CRISPR/Cas9-induced DSBs are insufficient to break the genetic linkage at the ToMV locus on chromosome 9 in recombination cold spots within somatic cells.Article SummaryThis research targets plant biologists and geneticists interested in enhancing plant breeding techniques. The study used CRISPR/Cas9 technology to induce DNA breaks in tomato plants. It specifically targeted the Tomato Mosaic Virus (ToMV) resistance gene, which resists natural recombination. The aim was to induce genetic recombination via CRISPR/Cas9. The highly active CRISPR/Cas9 system did not increase the expected genetic changes, indicating challenges in achieving targeted recombination. These findings highlight the challenges in breaking genetic linkages in specific genome regions using current CRISPR methods. These findings are relevant for developing techniques for targeted recombination in plant breeding.
Enhanced conspicuousness of prey in warmer water mitigates the visual constraint of turbidity for predators
Authors: Zanghi Costanza , Troscianko Jolyon , Ioannou Christos C 
Published: September 2024

AbstractChanges in environmental conditions impact predator-prey interactions by altering behaviour through sensory and non-sensory pathways. Elevated water temperature and turbidity are known to alter activity levels and anti-predator responses in prey fish, and are increasing globally as a result of anthropogenic activities. Less is known about how temperature and turbidity impact predators’ ability to detect prey directly, or indirectly via changes to prey behaviour.We quantified the detectability of Trinidadian guppies (Poecilia reticulata) free-swimming in a large arena from the perspective of a stationary visual predator (simulated as an underwater camera). We used a fully factorial experimental design testing the independent and combined effects of increased temperature and turbidity.We found that both stressors had a strong influence on the appearance of prey (objectively quantified as the mean magnitude of the optical flow in the videos). As expected, turbidity reduced the frequency of detection between the guppies and the simulated predator, i.e. the magnitude of optical flow exceeded the threshold for a ‘detection event’ more often in clear water. Events were also shorter in duration in turbid water, reducing the time available for a predator to detect the prey. However, during an event, prey were more detectable in warmer water (i.e. the mean magnitude was greater).Although we found no evidence of interactive effects of turbidity and temperature on the response variables, their cumulative main effects suggest an antagonistic effect on the overall rate of prey capture.
pytom-match-pick: a tophat-transform constraint for automated classification in template matching
Authors: Chaillet Marten L. , Roet Sander , Veltkamp Remco C. , Förster Friedrich 
Published: September 2024

AbstractTemplate matching (TM) in cryo-electron tomography (cryo-ET) enablesin situdetection and localization of known macromolecules. However, TM faces challenges such as interfering features with a high signal-to-noise ratio and the need for manual curation of results. To address these challenges, we introduce pytom-match-pick, a GPU-accelerated, open-source command line interface for enhanced TM in cryo-ET. Using pytom-match-pick, we first quantify the effects of point spread function (PSF) weighting and show that a tilt-weighted PSF outperforms a binary wedge with a single defocus estimate. We also assess previously introduced background normalization methods for classification performance. This indicates that phase randomization is more effective than spectrum whitening in reducing false positives. Furthermore, a novel application of the tophat transform on score maps, combined with a dual-constraint thresholding strategy, reduces false positives and improves precision. We benchmarked pytom-match-pick on public datasets, demonstrating improved classification and localization of macromolecules like ribosomal subunits and proteasomes that led to fewer artifacts in subtomogram averages. This tool promises to advance visual proteomics by improving the efficiency and accuracy of macromolecule detection in cellular contexts.
Astrocyte glucocorticoid receptors mediate sex-specific changes in activity following stress
Authors: Depaauw-Holt Lewis R. , Hamane Sarah , Peyrard Sarah , Rogers Benjamin , Fulton Stephanie , Bosson Anthony , Murphy-Royal Ciaran 
Published: September 2024

AbstractInteractions between orexin neurons and astrocytes in the lateral hypothalamus influence activity levels including circadian and motivated behaviour. These behaviors are disrupted by stress in rodents and form a hallmark of stress-related neuropsychiatric disorders. Here we set out to understand how stress influences activity and the underlying cellular mechanisms. We report that the long-term effects of stress on activity levels correlate with spontaneous firing of orexin neurons with hyperactivity in males and hypoactivity presented by female mice. These neuronal changes were accompanied by extensive astrocyte remodelling. Causal manipulations identified lateral hypothalamic astrocytes as key regulators of activity patterns. In the context of stress, genetic deletion of glucocorticoid receptors in lateral hypothalamic astrocytes rescued the effects of stress on orexin neuron firing, restoring activity to control levels in both males and females. Overall, these data suggest that astrocytic regulation of orexin neuron firing enables the maintenance of activity levels, and their dysfunction drives stress-induced activity dysregulation.Graphical Abstract
Synthesis and mechanical characterization of polyacrylamide (PAAm) hydrogels with different stiffnesses for large-batch cell culture applications
Authors: Cresens Charlotte , Aytekin Samet , Shaghaghi Behrad , Gerrits Lotte , Montero-Calle Ana , Barderas Rodrigo , Kouwer Paul , Rocha Susana 
Published: September 2024

SummaryThe impact of mechanical cues on cell behavior is increasingly being recognized, rendering hydrogel platforms that mimic the extracellular matrix indispensable inin vitrocell biology research. Here, we present a step-by-step protocol for synthesis and rheological characterization of polyacrylamide (PAAm) hydrogels with varying stiffnesses, produced as large circular unattached gels customizable in shape and size. We outline methods for their use in cell culture and downstream applications involving secretome or cell analysis, and protein visualization by fluorescence microscopy.This protocol is based on the recent work of Shi & Janmey who describe a novel and straightforward method for the production of large PAAm hydrogels for bulk cell culture and mechanobiology studies.1Their procedure results in one large gel that is not attached to a supporting surface and therefore can be transferred and/or stamped to generate PAAm gels of custom shapes and sizes. The aim of this step-by-step procedure is therefore not to improve the reported protocol, but to create a clearly outlined and repeatable protocol that enables a smooth implementation in any lab for a diverse audience. In addition, our protocol describes besides harvesting of cells also the collection of secretome for downstream biochemical analyses, as well as immunofluorescence labeling using antibodies that can readily be multiplexed for optimization of labeling conditions.Graphical abstract
A dopaminergic basis of behavioral control
Authors: Ballard Ian C. , Furman Daniella J. , Berry Anne S. , White Robert L. , Jagust William J. , Kayser Andrew S. , D’Esposito Mark 
Published: September 2024

ABSTRACTBoth goal-directed and automatic processes shape human behavior, but these processes often conflict.Behavioral controlis the decision about which process guides behavior. Despite the importance of behavioral control for adaptive decision-making, its neural mechanisms remain unclear. Critically, it is unknown if there are mechanisms for behavioral control that are distinct from those supporting the formation of goal-relevant knowledge. We performed deep phenotyping of individual dopamine system function by combining multiple PET scans, fMRI, and dopaminergic drug administration in a within-subject, double-blind, placebo-controlled design. Subjects performed a rule-based response time task, with goal-directed and automatic decision-making operationalized as model-based and model-free influences on behavior. We found a double dissociation between two aspects of ventral striatal dopamine physiology: D2/3 receptor availability and dopamine synthesis capacity. Convergent and causal evidence indicated that D2/3 receptors regulate behavioral control by enhancing model-based and blunting model-free influences on behavior but do not affect model-based knowledge formation. In contrast, dopamine synthesis capacity was linked to the formation of model-based knowledge but not behavioral control. D2/3 receptors also modulated frontostriatal functional connectivity, suggesting they regulate behavioral control by gating prefrontal inputs to the striatum. These results identify central mechanisms underlying individual and state differences in behavioral control and point to striatal D2/3 receptors as targets for interventions for improving goal-directed behavior.
High-resolutionin vivokinematic tracking with injectable fluorescent nanoparticles
Authors: Ulutas Emine Zeynep , Pradhan Amartya , Koveal Dorothy , Markowitz Jeffrey E. 
Published: September 2024

AbstractBehavioral quantification is a cornerstone of many neuroscience experiments. Recent advances in motion tracking have streamlined the study of behavior in small laboratory animals and enabled precise movement quantification on fast (millisecond) timescales. This includes markerless keypoint trackers, which utilize deep network systems to label positions of interest on the surface of an animal (e.g., paws, snout, tail,etc.). These approaches mark a major technological achievement. However, they have a high error rate relative to motion capture in humans and are yet to be benchmarked against ground truth datasets in mice. Moreover, the extent to which they can be used to track joint or skeletal kinematics remains unclear. As the primary output of the motor system is the activation of muscles that, in turn, exert forces on the skeleton rather than the skin, it is important to establish potential limitations of techniques that rely on surface imaging. This can be accomplished by imaging implanted fiducial markers in freely moving mice. Here, we present a novel tracking method called QD-Pi (QuantumDot-basedPose estimationin vivo), which employs injectable near-infrared fluorescent nanoparticles (quantum dots, QDs) immobilized on microbeads. We demonstrate that the resulting tags are biocompatible and can be imaged non-invasively using commercially available camera systems when injected into fatty tissue beneath the skin or directly into joints. Using this technique, we accurately capture 3D trajectories of up to ten independent internal positions in freely moving mice over multiple weeks. Finally, we leverage this technique to create a large-scale ground truth dataset for benchmarking and training the next generation of markerless keypoint tracker systems.
Sparsity of population activity in the hippocampus is task-invariant across the trisynaptic circuit and dorsoventral axis
Authors: Lee J. Quinn , Nielsen Matt , McHugh Rebecca , Morgan Erik , Hong Nancy S. , Sutherland Robert J. , McDonald Robert J. 
Published: September 2024

AbstractEvidence from neurophysiological and genetic studies demonstrates thatactivity sparsity– the proportion of neurons that are active at a given time in a population – systematically varies across the canonical trisynaptic circuit of the hippocampus. Recent work has also shown that sparsity varies across the hippocampal dorsoventral (long) axis, wherein activity is sparser in ventral than dorsal regions. While the hippocampus has a critical role in long-term memory (LTM), whether sparsity across the trisynaptic circuit and hippocampal long axis is task-dependent or invariant remains unknown. Importantly, representational sparsity has significant implications for neural computation and theoretical models of learning and memory within and beyond the hippocampus. Here we used functional molecular imaging to quantify sparsity in the rat hippocampus during performance of the Morris water task (MWT) and contextual fear discrimination (CFD) – two popular and distinct assays of LTM. We found that activity sparsity is highly reliable across memory tasks, wherein activity increases sequentially across the trisynaptic circuit (DG < CA3 < CA1) and decreases across the long axis (ventral < dorsal). These results have important implications for models of hippocampal function and suggest that activity sparsity is a preserved property in the hippocampal system across cognitive settings.
Lateral prefrontal cortex controls interplay between working memory and actions
Authors: Kiyonaga Anastasia , Miller Jacob A. , D’Esposito Mark 
Published: September 2024

ABSTRACTHumans must often keep multiple task goals in mind, at different levels of priority and immediacy, while also interacting with the environment. We might need to remember information for an upcoming task while engaged in more immediate actions. Consequently, actively maintained working memory (WM) content may bleed into ongoing but unrelated motor behavior. Here, we experimentally test the impact of WM maintenance on action execution, and we transcranially stimulate lateral prefrontal cortex (PFC) to parse its functional contributions to WM-motor interactions. We first created a task scenario wherein human participants (both sexes) executed cued hand movements during WM maintenance. We manipulated the compatibility between WM and movement goals at the trial level and the statistical likelihood that the two would be compatible at the block level. We found that remembering directional words (e.g., ‘left’, ‘down’) biased the trajectory and speed of hand movements that occurred during the WM delay, but the bias was dampened in blocks when WM content predictably conflicted with movement goals. Then we targeted left lateral PFC with two different transcranial magnetic stimulation (TMS) protocols before participants completed the task. We found that an intermittent theta-burst protocol, which is thought to be excitatory, dampened sensitivity to block-level control demands (i.e., proactive control), while a continuous theta-burst protocol, which is thought to be inhibitory, dampened adaptation to trial-by- trial conflict (i.e., reactive control). Therefore, lateral PFC is involved in controlling the interplay between WM content and manual action, but different PFC mechanisms may support different time-scales of adaptive control.Significance StatementWorking memory (WM) allows us to keep information active in mind to achieve our moment-to-moment goals. However, WM maintenance may sometimes unintentionally shape our externally-geared actions. This study formalizes the everyday “action slips” humans commit when we type out or say the wrong word in conversation because it was held in mind for a different goal. The results show that internally maintained content can influence ongoing hand movements, but this interplay between WM and motor behavior depends on the cortical excitability state of the lateral PFC. Neural perturbation with transcranial magnetic stimulation (TMS) shows that temporarily increasing or decreasing PFC excitability can make participants more or less susceptible to the impact of WM on actions.