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ObjectiveGestational diabetes mellitus (GDM) is a condition in which women without diabetes are diagnosed with glucose intolerance during pregnancy, typically in the second or third trimester. Early diagnosis, along with a better understanding of its pathophysiology during the first trimester of pregnancy, may be effective in reducing incidence and associated short-term and long-term morbidities.DesignWe comprehensively profiled the gut microbiome, metabolome, inflammatory cytokines, nutrition and clinical records of 394 women during the first trimester of pregnancy, before GDM diagnosis. We then built a model that can predict GDM onset weeks before it is typically diagnosed. Further, we demonstrated the role of the microbiome in disease using faecal microbiota transplant (FMT) of first trimester samples from pregnant women across three unique cohorts.ResultsWe found elevated levels of proinflammatory cytokines in women who later developed GDM, decreased faecal short-chain fatty acids and altered microbiome. We next confirmed that differences in GDM-associated microbial composition during the first trimester drove inflammation and insulin resistance more than 10 weeks prior to GDM diagnosis using FMT experiments. Following these observations, we used a machine learning approach to predict GDM based on first trimester clinical, microbial and inflammatory markers with high accuracy.ConclusionGDM onset can be identified in the first trimester of pregnancy, earlier than currently accepted. Furthermore, the gut microbiome appears to play a role in inflammation-induced GDM pathogenesis, with interleukin-6 as a potential contributor to pathogenesis. Potential GDM markers, including microbiota, can serve as targets for early diagnostics and therapeutic intervention leading to prevention.

Consumption of dietary lipids, such as cholesterol, modulates the gut microbiome with consequences for host health through the production of microbiome-derived metabolites. Despite the implications for host metabolism, a limited number of specific interactions of the gut microbiome with diet-derived lipids have been characterized. This is partially because obtaining species-level resolution of the responsible taxa can be challenging and additional approaches are needed to identify health-relevant metabolites produced from cholesterol–microbiome interactions. Here we performed bio-orthogonal labelling sort sequence spectrometry, a click chemistry based workflow, to profile cholesterol-specific host–microbe interactions. Mice were exposed to an alkyne-functionalized variant of cholesterol and 16S ribosomal RNA gene amplicon sequencing of faecal samples identified diet-derived cholesterol-interacting microbes from the genera Bacteroides, Bifidobacterium, Enterococcus and Parabacteroides. Shotgun metagenomic analysis provided species-level resolution of diet-derived cholesterol-interacting microbes with enrichment of bile acid-like and sulfotransferase-like activities. Using untargeted metabolomics, we identify that cholesterol is converted to cholesterol sulfate in a Bacteroides-specific manner via the enzyme BT_0416. Mice monocolonized with Bacteroides thetaiotaomicron lacking Bt_0416 showed altered host cholesterol and cholesterol sulfate compared with wild-type mice, identifying a previously uncharacterized microbiome-transformation of cholesterol and a mechanism for microbiome-dependent contributions to host phenotype. Moreover, identification of a cholesterol-responsive sulfotransferase in Bacteroides suggests diet-dependent mechanisms for altering microbiome-specific cholesterol metabolism. Overall, our work identifies numerous cholesterol-interacting microbes with implications for more precise microbiome-conscious regulation of host cholesterol homeostasis.

Inositol lipids are ubiquitous in eukaryotes and have finely tuned roles in cellular signalling and membrane homoeostasis. In Bacteria, however, inositol lipid production is relatively rare. Recently, the prominent human gut bacterium Bacteroides thetaiotaomicron (BT) was reported to produce inositol lipids and sphingolipids, but the pathways remain ambiguous and their prevalence unclear. Here, using genomic and biochemical approaches, we investigated the gene cluster for inositol lipid synthesis in BT using a previously undescribed strain with inducible control of sphingolipid synthesis. We characterized the biosynthetic pathway from myo-inositol-phosphate (MIP) synthesis to phosphoinositol dihydroceramide, determined the crystal structure of the recombinant BT MIP synthase enzyme and identified the phosphatase responsible for the conversion of bacterially-derived phosphatidylinositol phosphate (PIP-DAG) to phosphatidylinositol (PI-DAG). In vitro, loss of inositol lipid production altered BT capsule expression and antimicrobial peptide resistance. In vivo, loss of inositol lipids decreased bacterial fitness in a gnotobiotic mouse model. We identified a second putative, previously undescribed pathway for bacterial PI-DAG synthesis without a PIP-DAG intermediate, common in Prevotella. Our results indicate that inositol sphingolipid production is widespread in host-associated Bacteroidetes and has implications for symbiosis.

How does the human brain prioritize different visual representations in working memory (WM)? Here, we define the oscillatory mechanisms supporting selection of “where” and “when” features from visual WM storage and investigate the role of pFC in feature selection. Fourteen individuals with lateral pFC damage and 20 healthy controls performed a visuospatial WM task while EEG was recorded. On each trial, two shapes were presented sequentially in a top/bottom spatial orientation. A retro-cue presented mid-delay prompted which of the two shapes had been in either the top/bottom spatial position or first/second temporal position. We found that cross-frequency coupling between parieto-occipital alpha (α; 8–12 Hz) oscillations and topographically distributed gamma (γ; 30–50 Hz) activity tracked selection of the distinct cued feature in controls. This signature of feature selection was disrupted in patients with pFC lesions, despite intact α–γ coupling independent of feature selection. These findings reveal a pFC-dependent parieto-occipital α–γ mechanism for the rapid selection of visual WM representations.

How does the human brain integrate spatial and temporal information into unified mnemonic representations? Building on classic theories of feature binding, we first define the oscillatory signatures of integrating ‘where’ and ‘when’ information in working memory (WM) and then investigate the role of prefrontal cortex (PFC) in spatiotemporal integration. Fourteen individuals with lateral PFC damage and 20 healthy controls completed a visuospatial WM task while electroencephalography (EEG) was recorded. On each trial, two shapes were presented sequentially in a top/bottom spatial orientation. We defined EEG signatures of spatiotemporal integration by comparing the maintenance of two possible where-when configurations: the first shape presented on top and the reverse. Frontal delta-theta (δθ; 2–7 Hz) activity, frontal-posterior δθ functional connectivity, lateral posterior event-related potentials, and mesial posterior alpha phase-to-gamma amplitude coupling dissociated the two configurations in controls. WM performance and frontal and mesial posterior signatures of spatiotemporal integration were diminished in PFC lesion patients, whereas lateral posterior signatures were intact. These findings reveal both PFC-dependent and independent substrates of spatiotemporal integration and link optimal performance to PFC.

The vertebrate stress response comprises a suite of behavioural and physiological traits that must be functionally integrated to ensure organisms cope adaptively with acute stressors. Natural selection should favour functional integration, leading to a prediction of genetic integration of these traits. Despite the implications of such genetic integration for our understanding of human and animal health, as well as evolutionary responses to natural and anthropogenic stressors, formal quantitative genetic tests of this prediction are lacking. Here, we demonstrate that acute stress response components in Trinidadian guppies are both heritable and integrated on the major axis of genetic covariation. This integration could either facilitate or constrain evolutionary responses to selection, depending upon the alignment of selection with this axis. Such integration also suggests artificial selection on the genetically correlated behavioural responses to stress could offer a viable non-invasive route to the improvement of health and welfare in captive animal populations.

Understanding complex human brain functions is critically informed by studying such functions during development. Here, we addressed a major gap in models of human memory by leveraging rare direct electrophysiological recordings from children and adolescents. Specifically, memory relies on interactions between the medial temporal lobe (MTL) and prefrontal cortex (PFC), and the maturation of these interactions is posited to play a key role in supporting memory development. To understand the nature of MTL-PFC interactions, we examined subdural recordings from MTL and PFC in 21 neurosurgical patients aged 5.9-20.5 years as they performed an established scene memory task. We determined signatures of memory formation by comparing the study of subsequently recognized to forgotten scenes in single trials. Results establish that MTL and PFC interact via two distinct theta mechanisms, an ∼3-Hz oscillation that supports amplitude coupling and slows down with age and an ∼7-Hz oscillation that supports phase coupling and speeds up with age. Slow and fast theta interactions immediately preceding scene onset further explained age-related differences in recognition performance. Last, with additional diffusion imaging data, we linked both functional mechanisms to the structural maturation of the cingulum tract. Our findings establish system-level dynamics of memory formation and suggest that MTL and PFC interact via increasingly dissociable mechanisms as memory improves across development.

Johnson et al. show that orbitofrontal cortex (OFC) lesions reduce working memory for temporal order but not spatial position, and individual behavioral deficits are commensurate with lesion size. Findings suggest that OFC supports understanding of the order of events.

Gut microbial metabolites generated through interactions with dietary constituents are important modulators of host metabolism and physiology. Our understanding of diet-microbiome-host interactions is hampered by the limited tools to broadly identify microbial species that take up nutrients and their products. BioOrthogonal labeling-Sort-Sequence-Spectrometry (BOSSS) overcomes these challenges by leveraging orally introduced alkyne-modified lipids that permit identification of gut microbes that take up dietary lipids.

Ubiquitous in eukaryotes, inositol lipids have finely tuned roles in cellular signaling and membrane homeostasis. In Bacteria, however, inositol lipid production is rare. Recently, the prominent human gut bacterium Bacteroides thetaiotaomicron (BT) was reported to produce inositol lipids, including inositol sphingolipids, but the pathways remain ambiguous and their prevalence unclear. Here, we investigated the gene cluster responsible for inositol lipid synthesis in BT using a novel strain with inducible control of sphingolipid synthesis. We characterized the biosynthetic pathway from myo-inositol-phosphate (MIP) synthesis to phosphoinositol-dihydroceramide, including structural and kinetic studies of the enzyme MIP synthase (MIPS). We determined the crystal structure of recombinant BT MIPS with bound NAD cofactor at 2.0 Å resolution, and identified the first reported phosphatase for the conversion of bacterially-derived phosphatidylinositol phosphate (PIP) to phosphatidylinositol (PI). Transcriptomic analysis indicated inositol production is nonessential but its loss alters BT capsule expression. Bioinformatic and lipidomic comparisons of Bacteroidetes species revealed a novel second putative pathway for bacterial PI synthesis without a PIP intermediate. Our results indicate that inositol sphingolipid production, via one of the two pathways, is widespread in host-associated Bacteroidetes, and may be implicated in host interactions both indirectly via the capsule and directly through inositol lipid provisioning.

Inositol lipids are ubiquitous in eukaryotes and have finely tuned roles in cellular signalling and membrane homoeostasis. In Bacteria, however, inositol lipid production is relatively rare. Recently, the prominent human gut bacterium Bacteroides thetaiotaomicron (BT) was reported to produce inositol lipids and sphingolipids, but the pathways remain ambiguous and their prevalence unclear. Here, using genomic and biochemical approaches, we investigated the gene cluster for inositol lipid synthesis in BT using a previously undescribed strain with inducible control of sphingolipid synthesis. We characterized the biosynthetic pathway from myo-inositol-phosphate (MIP) synthesis to phosphoinositol dihydroceramide, determined the crystal structure of the recombinant BT MIP synthase enzyme and identified the phosphatase responsible for the conversion of bacterially-derived phosphatidylinositol phosphate (PIP-DAG) to phosphatidylinositol (PI-DAG). In vitro, loss of inositol lipid production altered BT capsule expression and antimicrobial peptide resistance. In vivo, loss of inositol lipids decreased bacterial fitness in a gnotobiotic mouse model. We identified a second putative, previously undescribed pathway for bacterial PI-DAG synthesis without a PIP-DAG intermediate, common in Prevotella. Our results indicate that inositol sphingolipid production is widespread in host-associated Bacteroidetes and has implications for symbiosis.

Microbially-derived gut metabolites are important contributors to host phenotypes, many of which may link microbiome composition to metabolic disease. However, relatively few metabolites with known bioactivity have been traced from specific microbes to host tissues. Here, we use a labeling strategy to characterize and trace bacterial sphingolipids from the gut symbiont Bacteroides thetaiotaomicron to mouse colons and livers. We find that bacterial sphingolipid synthesis rescues excess lipid accumulation in a mouse model of hepatic steatosis and observe the transit of a previously uncharacterized bacterial sphingolipid to the liver. The addition of this sphingolipid to hepatocytes improves respiration in response to fatty-acid overload, suggesting that sphingolipid transfer to the liver could potentially contribute to microbiota-mediated liver function. This work establishes a role for bacterial sphingolipids in modulating hepatic phenotypes and defines a workflow that permits the characterization of other microbial metabolites with undefined functions in host health.

Functions of the gut microbiome have a growing number of implications for host metabolic health, with diet being one of the most significant influences on microbiome composition. Compelling links between diet and the gut microbiome suggest key roles for various macronutrients, including lipids, yet how individual classes of dietary lipids interact with the microbiome remains largely unknown. Sphingolipids are bioactive components of most foods and are also produced by prominent gut microbes. This makes sphingolipids intriguing candidates for shaping diet-microbiome interactions. Here, we used a click chemistry-based approach to track the incorporation of bioorthogonal dietary omega-alkynyl sphinganine [sphinganine alkyne (SAA)] into the murine gut microbial community (bioorthogonal labeling). We identified microbial and SAA-specific metabolic products through fluorescence-based sorting of SAA-containing microbes (Sort), 16S rRNA gene sequencing to identify the sphingolipid-interacting microbes (Seq), and comparative metabolomics to identify products of SAA assimilation by the microbiome (Spec). Together, this approach, termed Bioorthogonal labeling-Sort-Seq-Spec (BOSSS), revealed that SAA assimilation is nearly exclusively performed by gut Bacteroides, indicating that sphingolipid-producing bacteria play a major role in processing dietary sphinganine. Comparative metabolomics of cecal microbiota from SAA-treated mice revealed conversion of SAA to a suite of dihydroceramides, consistent with metabolic activities of Bacteroides and Bifidobacterium. Additionally, other sphingolipid-interacting microbes were identified with a focus on an uncharacterized ability of Bacteroides and Bifidobacterium to metabolize dietary sphingolipids. We conclude that BOSSS provides a platform to study the flux of virtually any alkyne-labeled metabolite in diet-microbiome interactions.

The gut microbiome plays a critical role in neonatal immune development; early-life perturbations to the microbiome have been linked to later susceptibility to respiratory conditions, including asthma and chronic obstructive pulmonary disease. Preterm infants are at higher risk for adverse outcomes to respiratory infections such as respiratory syncytial virus (RSV). The microbiome in premature infants is significantly altered, but it remains unclear how this affects lung immune cell development and susceptibility to RSV infection independent of lung immaturity. In this study, we have generated a biorepository of stool specimens from preterm and term infants during the first weeks of life. Metagenomic sequencing studies indicate significant alterations in the gut microbiome between these two groups, including a lack of fiber-fermenting Bacteroides species in preterm infants. Using these stool specimens, we find that the altered gut microbiome in premature infants induces IL-17/neutrophil-biased immune responses but weaker anti-viral interferon responses in the lung, both at steady state and following RSV infection. Mice colonized with preterm infant stool bacteria produced lower levels of neutralizing antibodies against RSV than mice colonized with term infant stool bacteria. Taken together, our findings suggest that the altered gut microbiome in premature infants dysregulates immune cell development in the lung and impairs the infant’s ability to develop long-term immunity against respiratory infections. These findings might be potentially leveraged in the development of gut bacteria-based interventions to improve the development of protective immunity against respiratory viral pathogens in preterm infants. Supported by grants from NIH/NCATS (TL1-TR-002386) and the Biocodex Microbiota Foundation

By recording neural activity directly from the human brain, researchers gain unprecedented insight into how neurocognitive processes unfold in real time. We first briefly discuss how intracranial electroencephalography (iEEG) recordings, performed for clinical practice, are used to study human cognition with the spatiotemporal and single-trial precision traditionally limited to non-human animal research. We then delineate how studies using iEEG have informed our understanding of issues fundamental to human cognition: auditory prediction, working and episodic memory, and internal cognition. We also discuss the potential of iEEG to infer causality through the manipulation or 'engineering' of neurocognitive processes via spatiotemporally precise electrical stimulation. We close by highlighting limitations of iEEG, potential of burgeoning techniques to further increase spatiotemporal precision, and implications for future research using intracranial approaches to understand, restore, and enhance human cognition.

Functions of the gut microbiome have a growing number of implications for host metabolic health, with diet being one of the most significant influences on microbiome composition. Compelling links between diet and the gut microbiome suggest key roles for various macronutrients, including lipids, yet how individual classes of dietary lipids interact with the microbiome remain largely unknown. A class of lipids known as sphingolipids are bioactive components of most foods and are produced by prominent gut microbes. This makes sphingolipids intriguing candidates for shaping diet-microbiome interactions. Here, we use a click-chemistry based approach to track the incorporation of bioorthogonal dietary omega-alkynyl sphinganine (sphinganine alkyne – SAA) into the gut microbial community (Click). Identification of microbe and SAA-specific metabolic products was achieved by fluorescence-based sorting of SAA containing microbes (Sort), 16S rRNA gene sequencing to identify the sphingolipid-interacting microbes (Seq), and comparative metabolomics to identify products of SAA assimilation by the microbiome (Spec). Together this approach, Click-Sort-Seq-Spec (ClickSSS), revealed that SAA-assimilation was nearly exclusively performed by gutBacteroides, indicating that sphingolipid-producing bacteria play a major role in processing dietary sphinganine. Comparative metabolomics of cecal microbiota from SAA-treated mice showed conversion of SAA to a suite of dihydroceramides, consistent with metabolic activity viaBacteroidesandBifidobacterium. Additionally, other sphingolipid-interacting microbes were identified with a focus on an uncharacterized ability ofBacteroidesandBifidobacteriumto metabolize dietary sphingolipids. Therefore, ClickSSS provides a platform to study the flux of virtually any alkyne-labeled metabolite in diet-microbiome interactions.

Auditory gamma-band (>30 Hz) activity is a biomarker of cortical excitation/inhibition (E/I) balance in autism, schizophrenia, and bipolar disorder. We provide a comprehensive account of the effects of transcranial alternating current stimulation (tACS) and transcranial direct current stimulation (tDCS) on gamma responses. Forty-five healthy young adults listened to 40-Hz auditory click trains while electroencephalography (EEG) data were collected to measure stimulus-related gamma activity immediately before and after 10 min of 1 mA tACS (40 Hz), tDCS, or sham stimulation to left auditory cortex. tACS, but not tDCS, increased gamma power and phase locking to the auditory stimulus. However, both tACS and tDCS strengthened the gamma phase connectome, and effects persisted beyond the stimulus. Finally, tDCS strengthened the coupling of gamma activity to alpha oscillations after termination of the stimulus. No effects were observed in prestimulus gamma power, the gamma amplitude connectome, or any band-limited alpha measure. Whereas both stimulation techniques synchronize gamma responses between regions, tACS also tunes the magnitude and timing of gamma responses to the stimulus. Results reveal dissociable neurophysiological changes following tACS and tDCS and demonstrate that clinical biomarkers can be altered with noninvasive neurostimulation, especially frequency-tuned tACS.NEW & NOTEWORTHY Gamma frequency-tuned transcranial alternating current stimulation (tACS) adjusts the magnitude and timing of auditory gamma responses, as compared with both sham stimulation and transcranial direct current stimulation (tDCS). However, both tACS and tDCS strengthen the gamma phase connectome, which is disrupted in numerous neurological and psychiatric disorders. These findings reveal dissociable neurophysiological changes following two noninvasive neurostimulation techniques commonly applied in clinical and research settings.

Gut microbes are linked to host metabolism, but specific mechanisms remain to be uncovered. Ceramides, a type of sphingolipid (SL), have been implicated in the development of a range of metabolic disorders from insulin resistance (IR) to hepatic steatosis. SLs are obtained from the diet and generated by de novo synthesis in mammalian tissues. Another potential, but unexplored, source of mammalian SLs is production by Bacteroidetes, the dominant phylum of the gut microbiome. Genomes of Bacteroides spp. and their relatives encode serine palmitoyltransfease (SPT), allowing them to produce SLs. Here, we explore the contribution of SL-production by gut Bacteroides to host SL homeostasis. In human cell culture, bacterial SLs are processed by host SL-metabolic pathways. In mouse models, Bacteroides-derived lipids transfer to host epithelial tissue and the hepatic portal vein. Administration of B. thetaiotaomicron to mice, but not an SPT-deficient strain, reduces de novo SL production and increases liver ceramides. These results indicate that gut-derived bacterial SLs affect host lipid metabolism., Ceramides are a type of sphingolipid (SL) that have been shown to play a role in several metabolic disorders. Here, the authors investigate the effect of SL-production by gut Bacteroides on host SL homeostasis and show that microbiome-derived SLs enter host circulation and alter ceramide production.

Sphingolipids, a lipid class characterized by a long-chain amino alcohol backbone, serve vital structural and signaling roles in eukaryotes. Though eukaryotes produce sphingolipids, this capacity is phylogenetically highly restricted in Bacteria. Intriguingly, bacterial species commonly associated in high abundance with eukaryotic hosts include sphingolipid producers, such as the Bacteroidetes in the mammalian gut. To date, a role for bacterial sphingolipids in immune system maturation has been described, but their fate and impact in host physiology and metabolism remain to be elucidated. The structural conservation of bacterial sphingolipids with those produced by their mammalian hosts offer clues about which aspects of mammalian biology may be modulated by these intriguing lipids.

Studies in mice using germfree animals as controls for microbial colonization have shown that the gut microbiome mediates diet-induced obesity. Such studies use diets rich in saturated fat, however, Western diets in the United States America are enriched in soybean oil, composed of unsaturated fatty acids, either linoleic or oleic acid. Here, we addressed whether the microbiome is a variable in fat metabolism in mice on a soybean oil diet. We used conventionally-raised, low-germ, and germfree mice fed for 10 weeks diets either high or low in high-linoleic-acid soybean oil as the sole source of fat. Conventional and germfree mice gained relative fat weight and all mice consumed more calories on the high fat vs. low fat soybean oil diet. Plasma fatty acid levels were generally dependent on diet, with microbial colonization status affecting iso-C18:0, C20:3n-6, C14:0, and C15:0 levels. Colonization status, but not diet, impacted levels of liver sphingolipids including ceramides, sphingomyelins, and sphinganine. Our results confirm that absorbed fatty acids are mainly a reflection of the diet and that microbial colonization influences liver sphingolipid pools regardless of diet.

Despite considerable interest in enhancing, preserving, and rehabilitating working memory (WM), efforts to elicit sustained behavioral improvements have been met with limited success. Here, we paired WM training with transcranial direct current stimulation (tDCS) to the frontoparietal network over four days. Active tDCS enhanced WM performance by modulating interactions between frontoparietal theta oscillations and gamma activity, as measured by pre- and post-training high-density electroencephalography (EEG). Increased phase-amplitude coupling (PAC) between the prefrontal stimulation site and temporo-parietal gamma activity explained behavioral improvements, and was most effective when gamma occurred near the prefrontal theta peak. These results demonstrate for the first time that tDCS-linked WM training elicits lasting changes in behavior by optimizing the oscillatory substrates of prefrontal control.

Levels of Bacteroidetes in the gut microbiome are positively associated with insulin resistance (IR) in humans. Considering that IR is promoted by elevations in hepatic sphingolipids (SL), particularly ceramides, and that Bacteroidetes are the only microbiome phylum possessing genes encoding serine palmitoyltransferase (SPT), which mediates SL synthesis, we investigated a potential link between bacterial SL production, host SL metabolism, and IR.In vitro, bacterial SLs entered colonocytes and were metabolized into complex SL, including ceramides. In mice, administration of WTBacteroides thetaiotaomicron, but not a SPT-deficient mutant, resulted in elevated levels of liver ceramides and reduced responsiveness to exogenously administered insulin. This work establishes bacterial SLs as a new class of microbiome-derived molecule capable of impacting host metabolism.One Sentence SummarySL production by gut Bacteroidetes regulates liver ceramide levels and insulin sensitivity.

Processing of low-level visual information shows robust developmental gains through childhood and adolescence. However, it is unknown whether low-level visual processing in the occipital cortex supports age-related gains in memory for complex visual stimuli. Here, we examined occipital alpha activity during visual scene encoding in 24 children and adolescents, aged 6.2–20.5 years, who performed a subsequent memory task while undergoing electrocorticographic recording. Scenes were classified as high- or low-complexity by the number of unique object categories depicted. We found that recognition of high-complexity, but not low-complexity, scenes increased with age. Age was associated with decreased alpha power and increased instantaneous alpha frequency during the encoding of subsequently recognized high- compared to low-complexity scenes. Critically, decreased alpha power predicted improved recognition of high-complexity scenes in adolescents. These findings demonstrate how the functional maturation of the occipital cortex supports the development of memory for complex visual scenes.

Despite concerted efforts over decades, the etiology of multiple sclerosis (MS) remains unclear. Autoimmunity, environmental-challenges, molecular mimicry and viral hypotheses have proven equivocal because early-stage disease is typically presymptomatic. Indeed, most animal models of MS also lack defined etiologies. We have developed a novel adult-onset oligodendrogliopathy using a delineated metabolic stress etiology in myelinating cells, and our central question is, “how much of the pathobiology of MS can be recapitulated in this model?” The analyses described herein demonstrate that innate immune activation, glial scarring, cortical and hippocampal damage with accompanying electrophysiological, behavioral and memory deficits naturally emerge from disease progression. Molecular analyses reveal neurofilament changes in normal-appearing gray matter that parallel those in cortical samples from MS patients with progressive disease. Finally, axon initial segments of deep layer pyramidal neurons are perturbed in entorhinal/frontal cortex and hippocampus from OBiden mice, and computational modeling provides insight into vulnerabilities of action potential generation during demyelination and early remyelination. We integrate these findings into a working model of corticohippocampal circuit dysfunction to predict how myelin damage might eventually lead to cognitive decline.

Background In response to a wound, fibroblasts are activated to migrate toward the wound, to proliferate and to contribute to the wound healing process. We hypothesize that changes in pre-mRNA processing occurring as fibroblasts enter the proliferative cell cycle are also important for promoting their migration. Results RNA sequencing of fibroblasts induced into quiescence by contact inhibition reveals downregulation of genes involved in mRNA processing, including splicing and cleavage and polyadenylation factors. These genes also show differential exon use, especially increased intron retention in quiescent fibroblasts compared to proliferating fibroblasts. Mapping the 3′ ends of transcripts reveals that longer transcripts from distal polyadenylation sites are more prevalent in quiescent fibroblasts and are associated with increased expression and transcript stabilization based on genome-wide transcript decay analysis. Analysis of dermal excisional wounds in mice reveals that proliferating cells adjacent to wounds express higher levels of cleavage and polyadenylation factors than quiescent fibroblasts in unwounded skin. Quiescent fibroblasts contain reduced levels of the cleavage and polyadenylation factor CstF-64. CstF-64 knockdown recapitulates changes in isoform selection and gene expression associated with quiescence, and results in slower migration. Conclusions Our findings support cleavage and polyadenylation factors as a link between cellular proliferation state and migration. Electronic supplementary material The online version of this article (10.1186/s13059-018-1551-9) contains supplementary material, which is available to authorized users.

Cell migration is a highly conserved process involving cytoskeletal reorganization and restructuring of the surrounding extracellular matrix. Although there are many studies describing mechanisms underlying cell motility, little has been reported about the contribution of alternative isoform use toward cell migration. Here, we investigated whether alternative isoform use can affect cell migration focusing on reversion-inducing-cysteine-rich protein with Kazal motifs (RECK), an established inhibitor of cell migration. We found that a shorter isoform of RECK is more highly expressed in proliferating fibroblasts, in TGF-β–treated fibroblasts, and in tumors compared with differentiated tissue. Knockdown of this short RECK isoform reduces fibroblast migration through Matrigel. Thus, this short isoform of RECK generated by a combination of alternative splicing and alternative polyadenylation plays an opposing role to the canonical RECK isoform, as knockdown of canonical RECK results in faster cell migration through Matrigel. We show that the short RECK protein competes with matrix metalloprotease 9 (MMP9) for binding to the Kazal motifs of canonical RECK, thus liberating MMP9 from an inactivating interaction with canonical RECK. Our studies provide a new paradigm and a detailed mechanism for how alternative isoform use can regulate cell migration by producing two proteins with opposing effects from the same genetic locus.

Recent advances in human cognitive neuroscience show great promise in extending our understanding of the neural basis of memory development. We briefly review the current state of knowledge, highlighting that most work has focused on describing the neural correlates of memory in cross-sectional studies. We then delineate three examples of the application of innovative methods in addressing questions that go beyond description, towards a mechanistic understanding of memory development. First, structural brain imaging and the harmonization of measurements across laboratories may uncover ways in which the maturation of the brain constrains the development of specific aspects of memory. Second, longitudinal designs and sophisticated modeling of the data may identify age-driven changes and the factors that determine individual developmental trajectories. Third, recording memory-related activity directly from the developing brain presents an unprecedented opportunity to examine how distinct brain structures support memory in real time. Finally, the growing prevalence of data sharing offers additional means to tackle questions that demand large-scale datasets, ambitious designs, and access to rare samples. We propose that the use of such innovative methods will move our understanding of memory development from a focus on describing trends to explaining the causal factors that shape behavior. Keywords: Hippocampus, Prefrontal cortex, Structural MRI, Functional MRI, Longitudinal design, ECoG

Intracranial EEG provides spatiotemporally precise evidence that prefrontal cortex maturation partially drives memory development., Prevailing theories link prefrontal cortex (PFC) maturation to the development of declarative memory. However, the precise spatiotemporal correlates of memory formation in the developing brain are not known. We provide rare intracranial evidence that the spatiotemporal propagation of frontal activity supports memory formation in children. Seventeen subjects (6.2 to 19.4 years) studied visual scenes in preparation for a recognition memory test while undergoing direct cortical monitoring. Earlier PFC activity predicted greater accuracy, and subsecond deviations in activity flow between subregions predicted memory formation. Activity flow between inferior and precentral sites was refined during adolescence, partially explaining gains in memory. In contrast, middle frontal activity predicted memory independent of age. These findings show with subsecond temporal precision that the developing PFC links scene perception and memory formation and underscore the role of the PFC in supporting memory development.

How does the human brain rapidly process incoming information in working memory? In growing divergence from a single-region focus on the prefrontal cortex (PFC), recent work argues for emphasis on how distributed neural networks are rapidly coordinated in support of this central neurocognitive function. Previously, we showed that working memory for everyday "what," "where," and "when" associations depends on multiplexed oscillatory systems, in which signals of different frequencies simultaneously link the PFC to parieto-occipital and medial temporal regions, pointing to a complex web of sub-second, bidirectional interactions. Here, we used direct brain recordings to delineate the frontoparietal oscillatory correlates of working memory with high spatiotemporal precision. Seven intracranial patients with electrodes simultaneously localized to prefrontal and parietal cortices performed a visuospatial working memory task that operationalizes the types of identity and spatiotemporal information we encounter every day. First, task-induced oscillations in the same delta-theta (2-7 Hz) and alpha-beta (9-24 Hz) frequency ranges previously identified using scalp electroencephalography (EEG) carried information about the contents of working memory. Second, maintenance was linked to directional connectivity from the parietal cortex to the PFC. However, presentation of the test prompt to cue identity, spatial, or temporal information changed delta-theta coordination from a unidirectional, parietal-led system to a bidirectional, frontoparietal system. Third, the processing of spatiotemporal information was more bidirectional in the delta-theta range than was the processing of identity information, where alpha-beta connectivity did not exhibit sensitivity to the contents of working memory. These findings implicate a bidirectional delta-theta mechanism for frontoparietal control over the contents of working memory.

© 2017 Vendetti, Starr, Johnson, Modavi and Bunge. Analogical reasoning refers to the process of drawing inferences on the basis of the relational similarity between two domains. Although this complex cognitive ability has been the focus of inquiry for many years, most models rely on measures that cannot capture individuals' thought processes moment by moment. In the present study, we used participants' eye movements to investigate reasoning strategies in real time while solving visual propositional analogy problems (A:B::C:D). We included both a semantic and a perceptual lure on every trial to determine how these types of distracting information influence reasoning strategies. Participants spent more time fixating the analogy terms and the target relative to the other response choices, and made more saccades between the A and B items than between any other items. Participants' eyes were initially drawn to perceptual lures when looking at response choices, but they nonetheless performed the task accurately. We used participants' gaze sequences to classify each trial as representing one of three classic analogy problem solving strategies and related strategy usage to analogical reasoning performance. A project-first strategy, in which participants first extrapolate the relation between the AB pair and then generalize that relation for the C item, was both the most commonly used strategy as well as the optimal strategy for solving visual analogy problems. These findings provide new insight into the role of strategic processing in analogical problem solving.

Have you ever wondered what happens in your brain when you think about your favorite songs? Recent research has revealed an area of the brain that is active when we listen to music that we know. This musical memory area is separate from the parts of your brain you use to remember things you have learned in school or details about events that happen in your life. In this article, we will show you where in the brain the musical memory area is, and why your memory for music is often resistant to brain diseases that cause memory loss.

Background Quiescence, reversible exit from the cell division cycle, is characterized by large-scale changes in steady-state gene expression, yet mechanisms controlling these changes are in need of further elucidation. In order to characterize the effects of post-transcriptional control on the quiescent transcriptome in human fibroblasts, we determined mRNA decay rates for over 10,000 genes using a transcription shut-off time-course. Results We found that ~500 of the genes monitored exhibited significant changes in decay rate upon quiescence induction. Genes involved in RNA processing and ribosome biogenesis were destabilized with quiescence, while genes involved in the developmental process were stabilized with quiescence. Moreover, extracellular matrix genes demonstrated an upregulation of gene expression that corresponded with a stabilization of these transcripts. Additionally, targets of a quiescence-associated microRNA (miR-29) were significantly enriched in the fraction of transcripts that were stabilized during quiescence. Conclusion Coordinated stability changes in clusters of genes with important functions in fibroblast quiescence maintenance are highly correlated with quiescence gene expression patterns. Analysis of miR-29 target decay rates suggests that microRNA-induced changes in RNA stability are important contributors to the quiescence gene expression program in fibroblasts. The identification of multiple stability-related gene clusters suggests that other posttranscriptional regulators of transcript stability may contribute to the coordination of quiescence gene expression. Such regulators may ultimately prove to be valuable targets for therapeutics that target proliferative cells, for instance, in cancer or fibrosis. Electronic supplementary material The online version of this article (doi:10.1186/s12864-017-3521-0) contains supplementary material, which is available to authorized users.

The ability to represent and select information in working memory provides the neurobiological infrastructure for human cognition. For 80 years, dominant views of working memory have focused on the key role of prefrontal cortex (PFC) [1–8]. However, more recent work has implicated posterior cortical regions [9–12], suggesting that PFC engagement during working memory is dependent on the degree of executive demand. We provide evidence from neurological patients with discrete PFC damage that challenges the dominant models attributing working memory to PFC-dependent systems. We show that neural oscillations, which provide a mechanism for PFC to communicate with posterior cortical regions [13], independently subserve communications both to and from PFC – uncovering parallel oscillatory mechanisms for working memory. Fourteen PFC patients and 20 healthy, age-matched controls performed a working memory task where they encoded, maintained, and actively processed information about pairs of common shapes. In controls, the electroencephalogram (EEG) exhibited oscillatory activity in the low-theta range over PFC and directional connectivity from PFC to parieto-occipital regions commensurate with executive processing demands. Concurrent alpha-beta oscillations were observed over parieto-occipital regions, with directional connectivity from parieto-occipital regions to PFC, regardless of processing demands. Accuracy, PFC low-theta activity, and PFC ➔ parieto-occipital connectivity were attenuated in patients, revealing a PFC-independent, alpha-beta system. The PFC patients still demonstrated task proficiency, which indicates that the posterior alpha-beta system provides sufficient resources for working memory. Taken together, our findings reveal neurologically dissociable PFC and parieto-occipital systems, and suggest that parallel, bidirectional oscillatory systems form the basis of working memory.