bluuebunny/crossref_metadata_2025_split huggingface dataset:
Near-field potentials index local neural computations more accurately than population spiking
Authors: Tovar David A. , Westerberg Jacob A. , Cox Michele A. , Dougherty Kacie , Wallace Mark T. , Bastos André M. , Maier Alexander 
Published: May 2023

AbstractLocal field potentials (LFP) are low-frequency extracellular voltage fluctuations thought to primarily arise from synaptic activity. However, unlike highly localized neuronal spiking, LFP is spatially less specific. LFP measured at one location is not entirely generated there due to far-field contributions that are passively conducted across volumes of neural tissue. We sought to quantify how much information within the locally generated, near-field low-frequency activity (nfLFP) is masked by volume-conducted far-field signals. To do so, we measured laminar neural activity in primary visual cortex (V1) of monkeys viewing sequences of multifeatured stimuli. We compared information content of regular LFP and nfLFP that was mathematically stripped of volume-conducted far-field contributions. Information content was estimated by decoding stimulus properties from neural responses via spatiotemporal multivariate pattern analysis. Volume-conducted information differed from locally generated information in two important ways: (1) for stimulus features relevant to V1 processing (orientation and eye-of-origin), nfLFP contained more information. (2) in contrast, the volume-conducted signal was more informative regarding temporal context (relative stimulus position in a sequence), a signal likely to be coming from elsewhere. Moreover, LFP and nfLFP differed both spectrally as well as spatially, urging caution regarding the interpretations of individual frequency bands and/or laminar patterns of LFP. Most importantly, we found that population spiking of local neurons was less informative than either the LFP or nfLFP, with nfLFP containing most of the relevant information regarding local stimulus processing. These findings suggest that the optimal way to read out local computational processing from neural activity is to decode the local contributions to LFP, with significant information loss hampering both regular LFP and local spiking.Author’s ContributionsConceptualization, D.A.T., J.A.W, and A.M.; Data Collection, J.A.W., M.A.C., K.D.; Formal Analysis, D.A.T. and J.A.W.; Data Visualization, D.A.T. and J.A.W.; Original Draft, D.A.T., J.A.W., and A.M.; Revisions and Final Draft, D.A.T., J.A.W., M.A.C., K.D., M.T.W., A.M.B., and A.M.Competing InterestsThe authors declare no conflicts of interest.
Dysregulation of amino acid metabolism upon rapid depletion of cap-binding protein eIF4E
Authors: Diamond Paige D. , McGlincy Nicholas J. , Ingolia Nicholas T. 
Published: May 2023

AbstractProtein synthesis is a crucial but metabolically costly biological process that must be tightly coordinated with cellular needs and nutrient availability. In response to environmental stress, translation initiation is modulated to control protein output while meeting new demands. The cap-binding protein eIF4E—the earliest contact between mRNAs and the translation machinery—serves as one point of control, but its contributions to mRNA-specific translation regulation remain poorly understood. To survey eIF4E-dependent translational control, we acutely depleted eIF4E and determined how this impacts protein synthesis. Despite its essentiality, eIF4E depletion had surprisingly modest effects on cell growth and protein synthesis. Analysis of transcript-level changes revealed that long-lived transcripts were downregulated, likely reflecting accelerated turnover. Paradoxically, eIF4E depletion led to simultaneous upregulation of genes involved in catabolism of aromatic amino acids, which arose as secondary effects of reduced protein biosynthesis on amino acid pools, and genes involved in the biosynthesis of amino acids. These futile cycles of amino acid synthesis and degradation were driven, in part, by translational activation ofGCN4, a transcription factor typically induced by amino acid starvation. Furthermore, we identified a novel regulatory mechanism governing translation ofPCL5,a negative regulator of Gcn4, that provides a consistent protein-to-mRNA ratio under varied translation environments. This translational control was partial dependent on a uniquely long poly-(A) tract in thePCL55’ UTR and on poly-(A) binding protein. Collectively, these results highlight how eIF4E connects translation to amino acid homeostasis and stress responses and uncovers new mechanisms underlying how cells tightly control protein synthesis during environmental challenges.
A ubiquitous GC content signature underlies multimodal mRNA regulation by DDX3X
Authors: Jowhar Ziad , Xu Albert , Venkataramanan Srivats , Dossena Francesco , Hoye Mariah L , Silver Debra L , Floor Stephen N , Calviello Lorenzo 
Published: May 2023

AbstractThe road from transcription to protein synthesis is paved with many obstacles, allowing for several modes of post-transcriptional regulation of gene expression. A fundamental player in mRNA biology is DDX3X, an RNA binding protein that canonically regulates mRNA translation. By monitoring dynamics of mRNA abundance and translation following DDX3X depletion, we observe stabilization of translationally suppressed mRNAs. We use interpretable statistical learning models to uncover GC content in the coding sequence as the major feature underlying RNA stabilization. This result corroborates GC content-related mRNA regulation detectable in other studies, including hundreds of ENCODE datasets and recent work focusing on mRNA dynamics in the cell cycle. We provide further evidence for mRNA stabilization by detailed analysis of RNA-seq profiles in hundreds of samples, including aDdx3xconditional knockout mouse model exhibiting cell cycle and neurogenesis defects. Our study identifies a ubiquitous feature underlying mRNA regulation and highlights the importance of quantifying multiple steps of the gene expression cascade, where RNA abundance and protein production are often uncoupled.
Multi-site identification and generalization of clusters of walking behaviors in individuals with chronic stroke and neurotypical controls
Authors: Sánchez Natalia , Schweighofer Nicolas , Mulroy Sara J. , Roemmich Ryan T. , Kesar Trisha M. , Torres-Oviedo Gelsy , Fisher Beth E. , Finley James M. , Winstein Carolee J. 
Published: May 2023

AbstractBackgroundWalking patterns in stroke survivors are highly heterogeneous, which poses a challenge in systematizing treatment prescriptions for walking rehabilitation interventions.ObjectiveWe used bilateral spatiotemporal and force data during walking to create a multi-site research sample to: 1) identify clusters of walking behaviors in people post-stroke and neurotypical controls, and 2) determine the generalizability of these walking clusters across different research sites. We hypothesized that participants post-stroke will have different walking impairments resulting in different clusters of walking behaviors, which are also different from control participants.MethodsWe gathered data from 81 post-stroke participants across four research sites and collected data from 31 control participants. Using sparse K-means clustering, we identified walking clusters based on 17 spatiotemporal and force variables. We analyzed the biomechanical features within each cluster to characterize cluster-specific walking behaviors. We also assessed the generalizability of the clusters using a leave-one-out approach.ResultsWe identified four stroke clusters: a fast and asymmetric cluster, a moderate speed and asymmetric cluster, a slow cluster with frontal plane force asymmetries, and a slow and symmetric cluster. We also identified a moderate speed and symmetric gait cluster composed of controls and participants post-stroke. The moderate speed and asymmetric stroke cluster did not generalize across sites.ConclusionsAlthough post-stroke walking patterns are heterogenous, these patterns can be systematically classified into distinct clusters based on spatiotemporal and force data. Future interventions could target the key features that characterize each cluster to increase the efficacy of interventions to improve mobility in people post-stroke.
Time-resolved network control analysis links reduced control energy under DMT with the serotonin 2a receptor, signal diversity, and subjective experience
Authors: Singleton S. Parker , Timmermann Christopher , Luppi Andrea I. , Eckernäs Emma , Roseman Leor , Carhart-Harris Robin L. , Kuceyeski Amy 
Published: May 2023

AbstractPsychedelics offer a profound window into the functioning of the human brain and mind through their robust acute effects on perception, subjective experience, and brain activity patterns. In recent work using a receptor-informed network control theory framework, we demonstrated that the serotonergic psychedelics lysergic acid diethylamide (LSD) and psilocybin flatten the brain’s control energy landscape in a manner that covaries with more dynamic and entropic brain activity. Contrary to LSD and psilocybin, whose effects last for hours, the serotonergic psychedelic N,N-dimethyltryptamine (DMT) rapidly induces a profoundly immersive altered state of consciousness lasting less than 20 minutes, allowing for the entirety of the drug experience to be captured during a single resting-state fMRI scan. Using network control theory, which quantifies the amount of input necessary to drive transitions between functional brain states, we integrate brain structure and function to map the energy trajectories of 14 individuals undergoing fMRI during DMT and placebo. Consistent with previous work, we find that global control energy is reduced following injection with DMT compared to placebo. We additionally show longitudinal trajectories of global control energy correlate with longitudinal trajectories of EEG signal diversity (a measure of entropy) and subjective ratings of drug intensity. We interrogate these same relationships on a regional level and find that the spatial patterns of DMT’s effects on these metrics are correlated with serotonin 2a receptor density (obtained from separately acquired PET data). Using receptor distribution and pharmacokinetic information, we were able to successfully recapitulate the effects of DMT on global control energy trajectories, demonstrating a proof-of-concept for the use of control models in predicting pharmacological intervention effects on brain dynamics.
Activity of brain stem glucagon neurons are modulated by energy state and encode sex and frequency-dependent negative valence and anxiety
Authors: Lopez CB , Duran M , Virkus SA , Yadav E , McMichen K , Singh J , Ramsey V , Stocking S , Habegger KM , Hardaway JA 
Published: May 2023

ABSTRACTThe glucagon-like peptide 1 (GLP-1) system has emerged as an important drug target for the treatment of obesity and diabetes. Preclinical and clinical studies demonstrate that the activation of GLP-1 receptors (GLP-1Rs) directly in the brain through overexpression of GLP-1 or GLP-1R agonists produces potent anorexigenic effects, yet the behavioral role and modulation of theendogenousGLP-1 producing system in the brain by energy status is unclear. In this study, we examined the anatomical, physiological, and behavioral properties of preproglucagon-expressing neurons in the nucleus of the solitary tract,GcgNTSneurons, which serve as the primary source of GLP-1 in the brain. Using transgenic laboratory mice, we observed no sex differences in the density and distribution ofGcgNTSneurons in male and female mice. Fos immunolabeling experiments show thatGcgNTSneurons are not significantly activated after intermittent access to palatable food, but the magnitude of Fos activation was linearly related to the amount of food intake in mice provided withad libitumintermittent access to palatable food. Electrophysiological examination ofGcgNTSneurons revealed that these neurons show energy-status and sex-dependent changes in neuronal firing and intrinsic excitability. Twenty-four hour food deprivation produced a significant reduction in excitability and firing in male, but not female mice. We then used optogenetics to investigate the causal behavioral role ofGcgNTSneurons. High frequency optogenetic activation ofGcgNTSneurons using the red light-gated opsin ChrimsonR produced female-specific anxiety-like behavior and real-time place aversion. For feeding, we observed that reversible optogenetic stimulation at high frequencies produced a significant reduction in homeostatic refeeding that did not differ by sex. Using operant conditioning, we found that reversible optogenetic activation ofGcgNTSneurons at 20 Hz, but not 5, also reduces appetitive behavior. These data demonstrate thatGcgNTSneurons exert control over motivation and food-seeking behavior in addition to consumption.
Top-down modulation of sensory processing and mismatch in the mouse posterior parietal cortex
Authors: Raltschev Constanze , Kasavica Sergej , Leonardon Benjamin , Nevian Thomas , Sachidhanandam Shankar 
Published: May 2023

ABSTRACTAn important function of the neocortex is to compare sensory feedback stimuli with internal predictions of the outside world and evoke mismatch responses to deviations, thus allowing expectations to be updated. The mechanisms behind sensory feedback mismatch and prediction formation however remain unclear. Here we created a learned association of an auditory-tactile stimulus sequence in awake head-fixed mice, where a sound predicted an up-coming whisker stimulus, and introduced mismatches by omitting or altering the whisker stimulus intensity. We showed that layer 2/3 posterior parietal cortex (PPC) neurons could report stimulus sequence mismatches, as well as display neural correlates of expectation. Inhibition of PPC-projecting secondary motor cortex (M2) neurons suppressed these correlates, along with population mismatch responses. Hence, M2 can influence sensory processing in the PPC and potentially provide the prediction of sensory feedback from learned relationships within sequences of sensory stimuli.
The stabilized supralinear network accounts for the contrast dependence of visual cortical gamma oscillations
Authors: Holt Caleb J. , Miller Kenneth D. , Ahmadian Yashar 
Published: May 2023

SummaryWhen stimulated, neural populations in the visual cortex exhibit fast rhythmic activity with frequencies in the gamma band (30-80 Hz). The gamma rhythm manifests as a broad resonance peak in the powerspectrum of recorded local field potentials, which exhibits various stimulus dependencies. In particular, in macaque primary visual cortex (V1), the gamma peak frequency increases with increasing stimulus contrast. Moreover, this contrast dependence is local: when contrast varies smoothly over visual space, the gamma peak frequency in each cortical column is controlled by the local contrast in that column’s receptive field. No parsimonious mechanistic explanation for these contrast dependencies of V1 gamma oscillations has been proposed. The stabilized supralinear network (SSN) is a mechanistic model of cortical circuits that has accounted for a range of visual cortical response nonlinearities and contextual modulations, as well as their contrast dependence. Here, we begin by showing that a reduced SSN model without retinotopy robustly captures the contrast dependence of gamma peak frequency, and provides a mechanistic explanation for this effect based on the observed non-saturating and supralinear input-output function of V1 neurons. Given this result, the local dependence on contrast can trivially be captured in a retinotopic SSN which however lacks horizontal synaptic connections between its cortical columns. However, long-range horizontal connections in V1 are in fact strong, and underlie contextual modulation effects such as surround suppression. We thus explored whether a retinotopically organized SSN model of V1 with strong excitatory horizontal connections can exhibit both surround suppression and the local contrast dependence of gamma peak frequency. We found that retinotopic SSNs can account for both effects, but only when the horizontal excitatory projections are composed of two components with different patterns of spatial fall-off with distance: a short-range component that only targets the source column, combined with a long-range component that targets columns neighboring the source column. We thus make a specific qualitative prediction for the spatial structure of horizontal connections in macaque V1, consistent with the columnar structure of cortex.
Reliability of resting-state EEG modulation by continuous and intermittent theta burst stimulation of the primary motor cortex: A sham-controlled study
Authors: Rodionov Andrei , Ozdemir Recep A. , Benwell Christopher S.Y. , Fried Peter J. , Boucher Pierre , Momi Davide , Ross Jessica M. , Santarnecchi Emiliano , Pascual-Leone Alvaro , Shafi Mouhsin M. 
Published: May 2023

ABSTRACTTheta burst stimulation (TBS) is a form of repetitive transcranial magnetic stimulation designed to induce changes of cortical excitability that outlast the period of TBS application. In this study, we explored the effects of continuous TBS (cTBS) and intermittent TBS (iTBS) versus sham TBS stimulation, applied to the primary motor cortex, on modulation of resting state electroencephalography (rsEEG) power. We first conducted hypothesis-driven region-of-interest (ROI) analyses examining changes in alpha (8-12 Hz) and beta (13-21 Hz) bands over the left and right motor cortex. Additionally, we performed data-driven whole-brain analyses across a wide range of frequencies (1-50 Hz) and all electrodes. Finally, we assessed the reliability of TBS effects across two sessions approximately 1 month apart. None of the protocols produced significant group-level effects in the ROI. Whole-brain analysis revealed that cTBS significantly enhanced relative power between 19-43 Hz over multiple sites in both hemispheres. However, these results were not reliable across visits. There were no significant differences between EEG modulation by active and sham TBS protocols. Between-visit reliability of TBS-induced neuromodulatory effects was generally low-to-moderate. We discuss confounding factors and potential approaches for improving the reliability of TBS-induced rsEEG modulation.
Metabolic response of microglia to amyloid deposition during Alzheimer’s disease progression in a mouse model
Authors: Marino Kaitlyn M. , Squirrell Jayne M. , Chacko Jenu V. , Watters Jyoti W. , Eliceiri Kevin W. , Ulland Tyler K. 
Published: May 2023

SummaryAlzheimer’s disease (AD) drives metabolic changes in the central nervous system (CNS). In AD microglia are activated and proliferate in response to amyloid β plaques. To further characterize the metabolic changes in microglia associated with plaque depositionin situ, we examined cortical tissue from 2, 4, and 8-month-old wild type and 5XFAD mice, a mouse model of plaque deposition. 5XFAD mice exhibited progressive microgliosis and plaque deposition as well as changes in microglial morphology and neuronal dystrophy. Multiphoton-based fluorescent lifetime imaging microscopy (FLIM) metabolic measurements showed that older mice had an increased amount of free NAD(P)H, indicative of a shift towards glycolysis. Interestingly in 5XFAD mice, we also found an abundant previously undescribed third fluorescence component that suggests an alternate NAD(P)H binding partner associated with pathology. This work demonstrates that FLIM in combination with other quantitative imaging methods, is a promising label-free tool for understanding the mechanisms of AD pathology.
A new fluorescence-based approach for direct visualization of coat formation during sporulation inBacillus cereus
Authors: Lablaine Armand , Chamot Stéphanie , Serrano Mónica , Billaudeau Cyrille , Bornard Isabelle , Carballido-Lopez Rut , Carlin Frédéric , Henriques Adriano O. , Broussolle Véronique 
Published: May 2023

AbstractThe pathogenic bacteriaBacillus cereus,Bacillus anthracisandBacillus thuringiensisform spores encased in a protein coat surrounded by a balloon-like exosporium. These structures mediate spore interactions with its environment, including the host immune system, control the transit of molecules that trigger germination and thus are essential for the spore life cycle. Formation of the coat and exosporium has been traditionally visualized by transmission electronic microscopy on fixed cells. Recently, we showed that assembly of the exosporium can be directly observed in liveB. cereuscells by super resolution-structured illumination microscopy (SR-SIM) using the membrane MitoTrackerGreen (MTG) dye. Here, we demonstrate that the different steps of coat formation can also be visualized by SR-SIM using MTG and SNAP-cell TMR-star dyes duringB. cereussporulation. We used these markers to characterize a subpopulation of engulfment-defectiveB. cereuscells that develops at a suboptimal sporulation temperature. Importantly, we predicted and confirmed that synthesis and accumulation of coat material, as well as synthesis of the σK-dependent protein BxpB, occur in cells arrested during engulfment. These results suggest that, unlike the well-studied model organismBacillus subtilis, the activity of σKis not strictly linked to the state of forespore development inB. cereus.
Regulation of coronavirus nsp15 cleavage specificity by RNA structure
Authors: Salukhe Indranil , Choi Ryan , Voorhis Wesley Van , Barrett Lynn , Hyde Jennifer L. 
Published: May 2023

AbstractSARS-CoV-2, the etiologic agent of the COVID-19 pandemic, has had an enduring impact on global public health. However, SARS-CoV-2 is only one of multiple pathogenic human coronaviruses (CoVs) to have emerged since the turn of the century. CoVs encode for several nonstructural proteins (NSPS) that are essential for viral replication and pathogenesis. Among them is nsp15, a uridine-specific viral endonuclease that is important in evading the host immune response and promoting viral replication. Despite the established function of nsp15 as a uridine-specific endonuclease, little is known about other determinants of its cleavage specificity. In this study we investigate the role of RNA secondary structure in SARS-CoV-2 nsp15 endonuclease activity.Using a series ofin vitroendonuclease assays, we observed that thermodynamically stable RNA structures were protected from nsp15 cleavage relative to RNAs lacking stable structure. We leveraged the s2m RNA from the SARS 3’UTR as a model for our structural studies as it adopts a well-defined structure with several uridines, two of which are unpaired and thus high probably targets for nsp15 cleavage. We found that SARS-CoV-2 nsp15 specifically cleaves s2m at the unpaired uridine within the GNRNA pentaloop of the RNA. Further investigation revealed that the position of uridine within the pentaloop also impacted nsp15 cleavage efficiency, suggesting that positioning within the pentaloop is necessary for optimal presentation of the scissile uridine and alignment within the nsp15 catalytic pocket. Our findings indicate that RNA secondary structure is an important determinant of nsp15 cleavage and provides insight into the molecular mechanisms of recognition of RNA by nsp15.