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  • Transcranial Magnetic Stimulation of the Medial Prefrontal Cortex Decreases Emotional Memory Schemas
    Cereb. Cortex (IF 5.437) Pub Date : 2020-01-10
    Bovy L, Berkers R, Pottkämper J, et al.

    Mood-congruent memory bias is a critical characteristic of depression, but the underlying neural mechanism is largely unknown. Negative memory schemas might enhance encoding and consolidation of negative experiences, thereby contributing to the genesis and perpetuation of depressive pathology. To investigate this relationship, we aimed to perturb medial prefrontal cortex (mPFC) processing, using neuronavigated transcranial magnetic stimulation (TMS) targeting the mPFC. Forty healthy volunteers first underwent a negative mood induction to activate negative schema processing after which they received either active inhibitory (N = 20) or control (N = 20) stimulation to the mPFC. Then, all participants performed the encoding of an emotional false memory task. Recall and recognition performance was tested the following morning. Polysomnographic data were recorded continuously during the night before and after encoding. We observed a significantly lower false recognition of negative critical lures following mPFC inhibition, but no differences in veridical memory. These findings were supported by reaction time data, showing a relative slower response to negative compared with positive critical lures. The current findings support previous causal evidence for a role of the mPFC in schema memory processing and further suggest a role of the mPFC in memory bias.

    更新日期:2020-01-15
  • Hierarchical Action Encoding Within the Human Brain
    Cereb. Cortex (IF 5.437) Pub Date : 2020-01-14
    Turella L, Rumiati R, Lingnau A.

    Humans are able to interact with objects with extreme flexibility. To achieve this ability, the brain does not only control specific muscular patterns, but it also needs to represent the abstract goal of an action, irrespective of its implementation. It is debated, however, how abstract action goals are implemented in the brain. To address this question, we used multivariate pattern analysis of functional magnetic resonance imaging data. Human participants performed grasping actions (precision grip, whole hand grip) with two different wrist orientations (canonical, rotated), using either the left or right hand. This design permitted to investigate a hierarchical organization consisting of three levels of abstraction: 1) “concrete action” encoding; 2) “effector-dependent goal” encoding (invariant to wrist orientation); and 3) “effector-independent goal” encoding (invariant to effector and wrist orientation). We found that motor cortices hosted joint encoding of concrete actions and of effector-dependent goals, while the parietal lobe housed a convergence of all three representations, comprising action goals within and across effectors. The left lateral occipito-temporal cortex showed effector-independent goal encoding, but no convergence across the three levels of representation. Our results support a hierarchical organization of action encoding, shedding light on the neural substrates supporting the extraordinary flexibility of human hand behavior.

    更新日期:2020-01-15
  • Transformation of Event Representations along Middle Temporal Gyrus
    Cereb. Cortex (IF 5.437) Pub Date : 2020-01-14
    Leshinskaya A, Thompson-Schill S.

    When learning about events through visual experience, one must not only identify which events are visually similar but also retrieve those events’ associates—which may be visually dissimilar—and recognize when different events have similar predictive relations. How are these demands balanced? To address this question, we taught participants the predictive structures among four events, which appeared in four different sequences, each cued by a distinct object. In each, one event (“cause”) was predictably followed by another (“effect”). Sequences in the same relational category had similar predictive structure, while across categories, the effect and cause events were reversed. Using functional magnetic resonance imaging data, we measured “associative coding,” indicated by correlated responses between effect and cause events; “perceptual coding,” indicated by correlated responses to visually similar events; and “relational category coding,” indicated by correlated responses to sequences in the same relational category. All three models characterized responses within the right middle temporal gyrus (MTG), but in different ways: Perceptual and associative coding diverged along the posterior to anterior axis, while relational categories emerged anteriorly in tandem with associative coding. Thus, along the posterior–anterior axis of MTG, the representation of the visual attributes of events is transformed to a representation of both specific and generalizable relational attributes.

    更新日期:2020-01-15
  • Active Sleep Promotes Coherent Oscillatory Activity in the Cortico-Hippocampal System of Infant Rats
    Cereb. Cortex (IF 5.437) Pub Date : 2020-01-10
    Del Rio-Bermudez C, Kim J, Sokoloff G, et al.

    Active sleep (AS) provides a unique developmental context for synchronizing neural activity within and between cortical and subcortical structures. In week-old rats, sensory feedback from myoclonic twitches, the phasic motor activity that characterizes AS, promotes coherent theta oscillations (4–8 Hz) in the hippocampus and red nucleus, a midbrain motor structure. Sensory feedback from twitches also triggers rhythmic activity in sensorimotor cortex in the form of spindle bursts, which are brief oscillatory events composed of rhythmic components in the theta, alpha/beta (8–20 Hz), and beta2 (20–30 Hz) bands. Here we ask whether one or more of these spindle-burst components are communicated from sensorimotor cortex to hippocampus. By recording simultaneously from whisker barrel cortex and dorsal hippocampus in 8-day-old rats, we show that AS, but not other behavioral states, promotes cortico-hippocampal coherence specifically in the beta2 band. By cutting the infraorbital nerve to prevent the conveyance of sensory feedback from whisker twitches, cortical-hippocampal beta2 coherence during AS was substantially reduced. These results demonstrate the necessity of sensory input, particularly during AS, for coordinating rhythmic activity between these two developing forebrain structures.

    更新日期:2020-01-10
  • Radial Glial Cell-Derived VCAM1 Regulates Cortical Angiogenesis Through Distinct Enrichments in the Proximal and Distal Radial Processes
    Cereb. Cortex (IF 5.437) Pub Date : 2020-01-06
    Zhang S, Wang H, Li J, et al.

    Angiogenesis in the developing cerebral cortex accompanies cortical neurogenesis. However, the precise mechanisms underlying cortical angiogenesis at the embryonic stage remain largely unknown. Here, we show that radial glia-derived vascular cell adhesion molecule 1 (VCAM1) coordinates cortical vascularization through different enrichments in the proximal and distal radial glial processes. We found that VCAM1 was highly enriched around the blood vessels in the inner ventricular zone (VZ), preventing the ingrowth of blood vessels into the mitotic cell layer along the ventricular surface. Disrupting the enrichment of VCAM1 surrounding the blood vessels by a tetraspanin-blocking peptide or conditional deletion of Vcam1 gene in neural progenitor cells increased angiogenesis in the inner VZ. Conversely, VCAM1 expressed in the basal endfeet of radial glial processes promoted angiogenic sprouting from the perineural vascular plexus (PNVP). In utero, overexpression of VCAM1 increased the vessel density in the cortical plate, while knockdown of Vcam1 accomplished the opposite. In vitro, we observed that VCAM1 bidirectionally affected endothelial cell proliferation in a concentration-dependent manner. Taken together, our findings identify that distinct concentrations of VCAM1 around VZ blood vessels and the PNVP differently organize cortical angiogenesis during late embryogenesis.

    更新日期:2020-01-08
  • WNT5a Regulates Epithelial Morphogenesis in the Developing Choroid Plexus
    Cereb. Cortex (IF 5.437) Pub Date : 2020-01-08
    Langford M, O’Leary C, Veeraval L, et al.

    The choroid plexus (CP) is the predominant supplier of cerebral spinal fluid (CSF) and the site of the blood–CSF barrier and is thus essential for brain development and central nervous system homeostasis. Despite these crucial roles, our understanding of the molecular and cellular processes giving rise to the CPs within the ventricles of the mammalian brain is very rudimentary. Here, we identify WNT5a as an important regulator of CP development, where it acts as a pivotal factor driving CP epithelial morphogenesis in all ventricles. We show that WNT5a is essential for the establishment of a cohesive epithelium in the developing CP. We find that in its absence all CPs are substantially reduced in size and complexity and fail to expand into the ventricles. Severe defects were observed in the epithelial cytoarchitecture of all Wnt5a−/− CPs, exemplified by loss of apicobasally polarized morphology and detachment from the ventricular surface and/or basement membrane. We also present evidence that the WNT5a receptor, RYK, and the RHOA kinase, ROCK, are required for normal CP epithelial morphogenesis. Our study, therefore, reveals important insights into the molecular and cellular mechanisms governing CP development.

    更新日期:2020-01-08
  • Diminished Myoinositol in Ventromedial Prefrontal Cortex Modulates the Endophenotype of Impulsivity
    Cereb. Cortex (IF 5.437) Pub Date : 2020-01-02
    Jupp B, Sawiak S, van der Veen B, et al.

    Maladaptive impulsivity manifests in a variety of disorders, including attention-deficit hyperactivity disorder (ADHD), depression, and substance use disorder. However, the etiological mechanisms of impulsivity remain poorly understood. In the present study, we used in-vivo proton magnetic resonance spectroscopy (1H-MRS) to investigate neurometabolite content in the prefrontal cortex (PFC) and striatum of rats exhibiting low- versus high-impulsive (LI, HI) behavior on a visual attentional task. We validated our 1H-MRS findings using regionally resolved ex-vivo mass spectroscopy, transcriptomics, and site-directed RNA interference in the ventromedial PFC. We report a significant reduction in myoinositol levels in the PFC but not the striatum of HI rats compared with LI rats. Reduced myoinositol content was localized to the infralimbic (IL) cortex, where significant reductions in transcript levels of key proteins involved in the synthesis and recycling of myoinositol (IMPase1) were also present. Knockdown of IMPase1in the IL cortex increased impulsivity in nonimpulsive rats when the demand on inhibitory response control was increased. We conclude that diminished myoinositol levels in ventromedial PFC causally mediate a specific form of impulsivity linked to vulnerability for stimulant addiction in rodents. Myoinositol and related signaling substrates may thus offer novel opportunities for treating neuropsychiatric disorders comorbid with impulsive symptomology.

    更新日期:2020-01-07
  • Anatomy and Physiology of Macaque Visual Cortical Areas V1, V2, and V5/MT: Bases for Biologically Realistic Models
    Cereb. Cortex (IF 5.437) Pub Date : 2020-01-02
    Vanni S, Hokkanen H, Werner F, et al.

    The cerebral cortex of primates encompasses multiple anatomically and physiologically distinct areas processing visual information. Areas V1, V2, and V5/MT are conserved across mammals and are central for visual behavior. To facilitate the generation of biologically accurate computational models of primate early visual processing, here we provide an overview of over 350 published studies of these three areas in the genus Macaca, whose visual system provides the closest model for human vision. The literature reports 14 anatomical connection types from the lateral geniculate nucleus of the thalamus to V1 having distinct layers of origin or termination, and 194 connection types between V1, V2, and V5, forming multiple parallel and interacting visual processing streams. Moreover, within V1, there are reports of 286 and 120 types of intrinsic excitatory and inhibitory connections, respectively. Physiologically, tuning of neuronal responses to 11 types of visual stimulus parameters has been consistently reported. Overall, the optimal spatial frequency (SF) of constituent neurons decreases with cortical hierarchy. Moreover, V5 neurons are distinct from neurons in other areas for their higher direction selectivity, higher contrast sensitivity, higher temporal frequency tuning, and wider SF bandwidth. We also discuss currently unavailable data that could be useful for biologically accurate models.

    更新日期:2020-01-07
  • Spatial Attentional Selection Modulates Early Visual Stimulus Processing Independently of Visual Alpha Modulations
    Cereb. Cortex (IF 5.437) Pub Date : 2020-01-06
    Gundlach C, Moratti S, Forschack N, et al.

    The capacity-limited human brain is constantly confronted with a huge amount of sensory information. Selective attention is needed for biasing neural processing towards relevant information and consequently allows meaningful interaction with the environment. Activity in the alpha-band has been proposed to be related to top-down modulation of neural inhibition and could thus represent a viable candidate to control the priority of stimulus processing. It is, however, unknown whether modulations in the alpha-band directly relate to changes in the sensory gain control of the early visual cortex. Here, we used a spatial cueing paradigm while simultaneously measuring ongoing alpha-band oscillations and steady-state visual evoked potentials (SSVEPs) as a marker of continuous early sensory processing in the human visual cortex. Thereby, the effects of spatial attention for both of these signals and their potential interactions were assessed. As expected, spatial attention modulated both alpha-band and SSVEP responses. However, their modulations were independent of each other and the corresponding activity profiles differed across task demands. Thus, our results challenge the view that modulations of alpha-band activity represent a mechanism that directly alters or controls sensory gain. The potential role of alpha-band oscillations beyond sensory processing will be discussed in light of the present results.

    更新日期:2020-01-07
  • Frontal Beta Transcranial Alternating Current Stimulation Improves Reversal Learning
    Cereb. Cortex (IF 5.437) Pub Date : 2020-01-02
    Wischnewski M, Joergensen M, Compen B, et al.

    Electroencephalogram (EEG) studies suggest an association between beta (13–30 Hz) power and reversal learning performance. In search for direct evidence concerning the involvement of beta oscillations in reversal learning, transcranial alternating current stimulation (tACS) was applied in a double-blind, sham-controlled and between-subjects design. Exogenous oscillatory currents were administered bilaterally to the frontal cortex at 20 Hz with an intensity of 1 mA peak-to-peak and the effects on reward-punishment based reversal learning were evaluated in hundred-and-eight healthy volunteers. Pre- and post-tACS resting state EEG recordings were analyzed. Results showed that beta-tACS improved rule implementation during reversal learning and decreases left and right resting-state frontal theta/beta EEG ratios following tACS. Our findings provide the first behavioral and electrophysiological evidence for exogenous 20 Hz oscillatory electric field potentials administered over to the frontal cortex to improve reversal learning.

    更新日期:2020-01-04
  • The Role of the Striatum in Learning to Orthogonalize Action and Valence: A Combined PET and 7 T MRI Aging Study
    Cereb. Cortex (IF 5.437) Pub Date : 2020-01-02
    Perosa V, de Boer L, Ziegler G, et al.

    Pavlovian biases influence instrumental learning by coupling reward seeking with action invigoration and punishment avoidance with action suppression. Using a probabilistic go/no-go task designed to orthogonalize action (go/no-go) and valence (reward/punishment), recent studies have shown that the interaction between the two is dependent on the striatum and its key neuromodulator dopamine. Using this task, we sought to identify how structural and neuromodulatory age-related differences in the striatum may influence Pavlovian biases and instrumental learning in 25 young and 31 older adults. Computational modeling revealed a significant age-related reduction in reward and punishment sensitivity and marked (albeit not significant) reduction in learning rate and lapse rate (irreducible noise). Voxel-based morphometry analysis using 7 Tesla MRI images showed that individual differences in learning rate in older adults were related to the volume of the caudate nucleus. In contrast, dopamine synthesis capacity in the dorsal striatum, assessed using [18F]-DOPA positron emission tomography in 22 of these older adults, was not associated with learning performance and did not moderate the relationship between caudate volume and learning rate. This multiparametric approach suggests that age-related differences in striatal volume may influence learning proficiency in old age.

    更新日期:2020-01-04
  • Temporal Dynam ics of the Neuregulin–ErbB Network in the Murine Prefrontal Cortex across the Lifespan
    Cereb. Cortex (IF 5.437) Pub Date : 2020-01-02
    Paterson C, Cumming B, Law A.

    Neuregulin–ErbB signaling is essential for numerous functions in the developing, adult, and aging brain, particularly in the prefrontal cortex (PFC). Mouse models with disrupted Nrg and/or ErbB genes are relevant to psychiatric, developmental, and age-related disorders, displaying a range of abnormalities stemming from cortical circuitry impairment. Many of these models display nonoverlapping phenotypes dependent upon the gene target and timing of perturbation, suggesting that cortical expression of the Nrg–ErbB network undergoes temporal regulation across the lifespan. Here, we report a comprehensive temporal expression mapping study of the Nrg–ErbB signaling network in the mouse PFC across postnatal development through aging. We find that Nrg and ErbB genes display distinct expression profiles; moreover, splice isoforms of these genes are differentially expressed across the murine lifespan. We additionally find a developmental switch in ErbB4 splice isoform expression potentially mediated through coregulation of the lncRNA Miat expression. Our results are the first to comprehensively and quantitatively map the expression patterns of the Nrg–ErbB network in the mouse PFC across the postnatal lifespan and may help disentangle the pathway’s involvement in normal cortical sequences of events across the lifespan, as well as shedding light on the pathophysiological mechanisms of abnormal Nrg–ErbB signaling in neurological disease.

    更新日期:2020-01-04
  • Beyond the Epileptic Focus: Functional Epileptic Networks in Focal Epilepsy
    Cereb. Cortex (IF 5.437) Pub Date : 2019-12-21
    Gil F, Padilla N, Soria-Pastor S, et al.

    Focal epilepsy can be conceptualized as a network disorder, and the functional epileptic network can be described as a complex system of multiple brain areas that interact dynamically to generate epileptic activity. However, we still do not fully understand the functional architecture of epileptic networks. We studied a cohort of 21 patients with extratemporal focal epilepsy. We used independent component analysis of functional magnetic resonance imaging (fMRI) data. In order to identify the epilepsy-related components, we examined the general linear model-derived electroencephalography-fMRI (EEG–fMRI) time courses associated with interictal epileptic activity as intrinsic hemodynamic epileptic biomarkers. Independent component analysis revealed components related to the epileptic time courses in all 21 patients. Each epilepsy-related component described a network of spatially distributed brain areas that corresponded to the specific epileptic network in each patient. We also provided evidence for the interaction between the epileptic activity generated at the epileptic network and the physiological resting state networks. Our findings suggest that independent component analysis, guided by EEG–fMRI epileptic time courses, have the potential to define the functional architecture of the epileptic network in a noninvasive way. These data could be useful in planning invasive EEG electrode placement, guiding surgical resections, and more effective therapeutic interventions.

    更新日期:2019-12-23
  • The Human Dynamic Clamp Reveals the Fronto-Parietal Network Linking Real-Time Social Coordination and Cognition
    Cereb. Cortex (IF 5.437) Pub Date : 2019-12-23
    Dumas G, Moreau Q, Tognoli E, et al.

    How does the brain allow us to interact with others? Social neuroscience has already provided some answers to these questions but has tended to treat high-level, cognitive interpretations of social behavior separately from the sensorimotor mechanisms upon which they rely. The goal here is to identify the underlying neural processes and mechanisms linking sensorimotor coordination and intention attribution. We combine the human dynamic clamp, a novel paradigm for studyingrealistic social behavior, with high-resolution electroencephalography. The collection of humanness and intention attribution reports, kinematics, and neural data affords an opportunity to relate brain activity to the ongoing social behavior. Behavioral results demonstrate that sensorimotor coordination influences the judgments of cooperativeness and humanness. Analysis of brain dynamics reveals two distinct networks related to the integration of visuo-motor information from self and other which overlap over the right parietal region. Furthermore, judgment of humanness and cooperation of others modulate the functional connectivity between this right parietal hub and the prefrontal cortex. These results reveal how distributed neural dynamics integrates information from “low-level” sensorimotor mechanisms and “high-level” social cognition to support the realistic social behaviors that play out in real time during interactive scenarios.

    更新日期:2019-12-23
  • Profilin1-Dependent F-Actin Assembly Controls Division of Apical Radial Glia and Neocortex Development
    Cereb. Cortex (IF 5.437) Pub Date : 2019-12-23
    Kullmann J, Meyer S, Pipicelli F, et al.

    Neocortex development depends on neural stem cell proliferation, cell differentiation, neurogenesis, and neuronal migration. Cytoskeletal regulation is critical for all these processes, but the underlying mechanisms are only poorly understood. We previously implicated the cytoskeletal regulator profilin1 in cerebellar granule neuron migration. Since we found profilin1 expressed throughout mouse neocortex development, we here tested the hypothesis that profilin1 is crucial for neocortex development. We found no evidence for impaired neuron migration or layering in the neocortex of profilin1 mutant mice. However, proliferative activity at basal positions was doubled in the mutant neocortex during mid-neurogenesis, with a drastic and specific increase in basal Pax6+ cells indicative for elevated numbers of basal radial glia (bRG). This was accompanied by transiently increased neurogenesis and associated with mild invaginations resembling rudimentary neocortex folds. Our data are in line with a model in which profilin1-dependent actin assembly controls division of apical radial glia (aRG) and thereby the fate of their progenies. Via this mechanism, profilin1 restricts cell delamination from the ventricular surface and, hence, bRG production and thereby controls neocortex development in mice. Our data support the radial cone hypothesis” claiming that elevated bRG number causes neocortex folds.

    更新日期:2019-12-23
  • Foxg1 Antagonizes Neocortical Stem Cell Progression to Astrogenesis
    Cereb. Cortex (IF 5.437) Pub Date : 2019-03-01
    Falcone C, Santo M, Liuzzi G, et al.

    Neocortical astrogenesis follows neuronogenesis and precedes oligogenesis. Among key factors dictating its temporal articulation, there are progression rates of pallial stem cells (SCs) towards astroglial lineages as well as activation rates of astrocyte differentiation programs in response to extrinsic gliogenic cues. In this study, we showed that high Foxg1 SC expression antagonizes astrocyte generation, while stimulating SC self-renewal and committing SCs to neuronogenesis. We found that mechanisms underlying this activity are mainly cell autonomous and highly pleiotropic. They include a concerted downregulation of 4 key effectors channeling neural SCs to astroglial fates, as well as defective activation of core molecular machineries implementing astroglial differentiation programs. Next, we found that SC Foxg1 levels specifically decline during the neuronogenic-to-gliogenic transition, pointing to a pivotal Foxg1 role in temporal modulation of astrogenesis. Finally, we showed that Foxg1 inhibits astrogenesis from human neocortical precursors, suggesting that this is an evolutionarily ancient trait.

    更新日期:2019-12-19
  • Disrupted AMPA Receptor Function upon Genetic- or Antibody-Mediated Loss of Autism-Associated CASPR2
    Cereb. Cortex (IF 5.437) Pub Date : 2019-03-04
    Fernandes D, Santos S, Coutinho E, et al.

    Neuropsychiatric disorders share susceptibility genes, suggesting a common origin. One such gene is CNTNAP2 encoding contactin-associated protein 2 (CASPR2), which harbours mutations associated to autism, schizophrenia, and intellectual disability. Antibodies targeting CASPR2 have also been recently described in patients with several neurological disorders, such as neuromyotonia, Morvan’s syndrome, and limbic encephalitis. Despite the clear implication of CNTNAP2 and CASPR2 in neuropsychiatric disorders, the pathogenic mechanisms associated with alterations in CASPR2 function are unknown. Here, we show that Caspr2 is expressed in excitatory synapses in the cortex, and that silencing its expression in vitro or in vivo decreases the synaptic expression of α‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionic acid (AMPA) receptors and the amplitude of AMPA receptor-mediated currents. Furthermore, Caspr2 loss of function blocks synaptic scaling in vitro and experience-dependent homoeostatic synaptic plasticity in the visual cortex. Patient CASPR2 antibodies decrease the dendritic levels of Caspr2 and synaptic AMPA receptor trafficking, and perturb excitatory transmission in the visual cortex. These results suggest that mutations in CNTNAP2 may contribute to alterations in AMPA receptor function and homoeostatic plasticity, and indicate that antibodies from anti-CASPR2 encephalitis patients affect cortical excitatory transmission.

    更新日期:2019-12-19
  • Foxg1 Directly Represses Dbx1 to Confine the POA and Subsequently Regulate Ventral Telencephalic Patterning
    Cereb. Cortex (IF 5.437) Pub Date : 2019-03-04
    Du A, Wu X, Chen H, et al.

    During early development, signaling centers, such as the cortical hem and the preoptic area (POA), are critical for telencephalic patterning. However, the mechanisms underlying the maintenance of signal centers are poorly understood. Here, we report that the transcription factor Foxg1 is required to confine the POA, a resource of Sonic Hedgehog (Shh) that is pivotal for ventral telencephalic development. Cell-specific deletion of Foxg1 achieved by crossing Foxg1fl/fl with Dbx1-cre or Nestin-CreER combined with tamoxifen induction results in a dramatic expansion of the POA accompanied by the significantly increased activity of the Shh signaling pathway. Ventral pattern formation was severely impaired. Moreover, we demonstrated that Foxg1 directly represses Dbx1 to restrict the POA. Furthermore, we found that the ventral pallium was expanded, which might also contribute to the observed patterning defects. These findings will improve our understanding of the maintenance of signal centers and help to elucidate the mechanisms underlying ventral telencephalic patterning.

    更新日期:2019-12-19
  • Structural Associations of Cortical Contrast and Thickness in First Episode Psychosis
    Cereb. Cortex (IF 5.437) Pub Date : 2019-03-07
    Makowski C, Lewis J, Lepage C, et al.

    There is growing evidence that psychosis is characterized by brain network abnormalities. Analyzing morphological abnormalities with T1-weighted structural MRI may be limited in discovering the extent of deviations in cortical associations. We assess whether structural associations of either cortical white–gray contrast (WGC) or cortical thickness (CT) allow for a better understanding of brain structural relationships in first episode of psychosis (FEP) patients. Principal component and structural covariance analyses were applied to WGC and CT derived from T1-weighted MRI for 116 patients and 88 controls, to explore sets of brain regions that showed group differences, and associations with symptom severity and cognitive ability in patients. We focused on 2 principal components: one encompassed primary somatomotor regions, which showed trend-like group differences in WGC, and the second included heteromodal cortices. Patients’ component scores were related to general psychopathology for WGC, but not CT. Structural covariance analyses with WGC revealed group differences in pairwise correlations across widespread brain regions, mirroring areas derived from PCA. More group differences were uncovered with WGC compared with CT. WGC holds potential as a proxy measure of myelin from commonly acquired T1-weighted MRI and may be sensitive in detecting systems-level aberrations in early psychosis, and relationships with clinical/cognitive profiles.

    更新日期:2019-12-19
  • Acute Inescapable Stress Rapidly Increases Synaptic Energy Metabolism in Prefrontal Cortex and Alters Working Memory Performance
    Cereb. Cortex (IF 5.437) Pub Date : 2019-03-16
    Musazzi L, Sala N, Tornese P, et al.

    Brain energy metabolism actively regulates synaptic transmission and activity. We have previously shown that acute footshock (FS)-stress induces fast and long-lasting functional and morphological changes at excitatory synapses in prefrontal cortex (PFC). Here, we asked whether FS-stress increased energy metabolism in PFC, and modified related cognitive functions. Using positron emission tomography (PET), we found that FS-stress induced a redistribution of glucose metabolism in the brain, with relative decrease of [18F]FDG uptake in ventro-caudal regions and increase in dorso-rostral ones. Absolute [18F]FDG uptake was inversely correlated with serum corticosterone. Increased specific hexokinase activity was also measured in purified PFC synaptosomes (but not in total extract) of FS-stressed rats, which positively correlated with 2-Deoxy [3H] glucose uptake by synaptosomes. In line with increased synaptic energy demand, using an electron microscopy-based stereological approach, we found that acute stress induced a redistribution of mitochondria at excitatory synapses, together with an increase in their volume. The fast functional and metabolic activation of PFC induced by acute stress, was accompanied by rapid and sustained alterations of working memory performance in delayed response to T-maze test. Taken together, the present data suggest that acute stress increases energy consumption at PFC synaptic terminals and alters working memory.

    更新日期:2019-12-19
  • When Conflict Cannot be Avoided: Relative Contributions of Early Selection and Frontal Executive Control in Mitigating Stroop Conflict
    Cereb. Cortex (IF 5.437) Pub Date : 2019-03-16
    Itthipuripat S, Deering S, Serences J.

    When viewing familiar stimuli (e.g., common words), processing is highly automatized such that it can interfere with the processing of incompatible sensory information. At least two mechanisms may help mitigate this interference. Early selection accounts posit that attentional processes filter out distracting sensory information to avoid conflict. Alternatively, late selection accounts hold that all sensory inputs receive full semantic analysis and that frontal executive mechanisms are recruited to resolve conflict. To test how these mechanisms operate to overcome conflict induced by highly automatized processing, we developed a novel version of the color-word Stroop task, where targets and distractors were simultaneously flickered at different frequencies. We measured the quality of early sensory processing by assessing the amplitude of steady-state visually evoked potentials (SSVEPs) elicited by targets and distractors. We also indexed frontal executive processes by assessing changes in frontal theta oscillations induced by color-word incongruency. We found that target- and distractor-related SSVEPs were not modulated by changes in the level of conflict whereas frontal theta activity increased on high compared to low conflict trials. These results suggest that frontal executive processes play a more dominant role in mitigating cognitive interference driven by the automatic tendency to process highly familiar stimuli.

    更新日期:2019-12-19
  • Phosphodiesterase 1 Bridges Glutamate Inputs with NO- and Dopamine-Induced Cyclic Nucleotide Signals in the Striatum
    Cereb. Cortex (IF 5.437) Pub Date : 2019-03-16
    Betolngar D, Mota É, Fabritius A, et al.

    The calcium-regulated phosphodiesterase 1 (PDE1) family is highly expressed in the brain, but its functional role in neurones is poorly understood. Using the selective PDE1 inhibitor Lu AF64196 and biosensors for cyclic nucleotides including a novel biosensor for cGMP, we analyzed the effect of PDE1 on cAMP and cGMP in individual neurones in brain slices from male newborn mice. Release of caged NMDA triggered a transient increase of intracellular calcium, which was associated with a decrease in cAMP and cGMP in medium spiny neurones in the striatum. Lu AF64196 alone did not increase neuronal cyclic nucleotide levels, but blocked the NMDA-induced reduction in cyclic nucleotides indicating that this was mediated by calcium-activated PDE1. Similar effects were observed in the prefrontal cortex and the hippocampus. Upon corelease of dopamine and NMDA, PDE1 was shown to down-regulate the D1-receptor mediated increase in cAMP. PDE1 inhibition increased long-term potentiation in rat ventral striatum, showing that PDE1 is implicated in the regulation of synaptic plasticity. Overall, our results show that PDE1 reduces cyclic nucleotide signaling in the context of glutamate and dopamine coincidence. This effect could have a therapeutic value for treating brain disorders related to dysfunctions in dopamine neuromodulation.

    更新日期:2019-12-19
  • Corticostriatal Circuits Encode the Subjective Value of Perceived Control
    Cereb. Cortex (IF 5.437) Pub Date : 2019-03-16
    Wang K, Delgado M.

    The ability to perceive and exercise control over an outcome is both desirable and beneficial to our well-being. It has been shown that animals and humans alike exhibit behavioral bias towards seeking control and that such bias recruits the ventromedial prefrontal cortex (vmPFC) and striatum. Yet, this bias remains to be quantitatively captured and studied neurally. Here, we employed a behavioral task to measure the preference for control and characterize its neural underpinnings. Participants made a series of binary choices between having control and no-control over a game for monetary reward. The mere presence of the control option evoked activity in the ventral striatum. Importantly, we manipulated the expected value (EV) of each choice pair to extract the pairing where participants were equally likely to choose either option. The difference in EV between the options at this point of equivalence was inferred as the subjective value of control. Strikingly, perceiving control inflated the reward value of the associated option by 30% and this value inflation was tracked by the vmPFC. Altogether, these results capture the subjective value of perceived control inherent in decision making and highlight the role of corticostriatal circuitry in the perception of control.

    更新日期:2019-12-19
  • Reduced Hippocampal Dendrite Branching, Spine Density and Neurocognitive Function in Premature Rabbits, and Reversal with Estrogen or TrkB Agonist Treatment
    Cereb. Cortex (IF 5.437) Pub Date : 2019-03-16
    Klebe D, Tibrewal M, Sharma D, et al.

    Preterm-born children suffer from neurological and behavioral disorders. Herein, we hypothesized that premature birth and non-maternal care of preterm newborns might disrupt neurobehavioral function, hippocampal dendritic arborization, and dendritic spine density. Additionally, we assessed whether 17β-estradiol (E2) replacement or the TrkB receptor agonist, 7,8-dihydroxyflavone (DHF), would reverse compromised dendritic development and cognitive function in preterm newborns. These hypotheses were tested by comparing preterm (E28.5) rabbit kits cared and gavage-fed by laboratory personnel and term-kits reared and breast-fed by their mother doe at an equivalent postconceptional age. Neurobehavioral tests showed that both premature-birth and formula-feeding with non-maternal care led to increased anxiety behavior, poor social interaction, and lack of novelty preference compared with term-kits. Dendritic branching and number of total or mushroom dendritic spines were reduced in the CA1 field of preterm-kits compared with term controls. While CDC42 and Rac1/2/3 expression levels were lower, RhoA-activity was higher in preterm-kits compared with term controls. Both E2 and DHF treatment reversed prematurity-induced reduction in spine density, reduced total RhoA-GTPase levels, and enhanced cognitive function. Hence, prematurity and non-maternal care result in cognitive deficits, and reduced dendritic arbors and spines in CA1. E2 replacement or DHF treatment might reverse changes in dendritic spines and improve neurodevelopment in premature infants.

    更新日期:2019-12-19
  • Prefrontal Cortical and Behavioral Adaptations to Surgical Delivery Mediated by Metabolic Principles
    Cereb. Cortex (IF 5.437) Pub Date : 2019-03-16
    Taylor-Giorlando M, Scheinost D, Ment L, et al.

    We previously observed an association between mode of delivery and brain mitochondrial mechanisms in pups. We also showed that mitochondrial processes impact adult behavior. However, no experimental data is available to causally connect mode of delivery with cellular processes of neurons in the cerebral cortex and adult behavior. Here we show that surgical delivery of pups alters mitochondrial dynamics and spine synapses of layer 3 pyramidal neurons of the prefrontal cortex compared to the values of mice delivered vaginally. These alterations in ultrastructure seen in adult mice delivered surgically were associated with the development of behavioral phenotypes resembling those characteristic of animal models of psychiatric illness. This included impaired performance in prepulse inhibition as well as hyperlocomotion in the open field and elevated plus maze tests. Knocking out a mitochondria-related gene, UCP-2, blocked cellular and behavioral adaptations induced by surgical delivery. These results highlight a crucial role for brain mitochondrial adaptations in the process of birth to affect neuronal circuitry in support of normal and altered adult behaviors. Further, these findings were supported with neuroimaging data from human neonates delivered vaginally and surgically, suggesting that the murine findings have human clinical relevance.

    更新日期:2019-12-19
  • The Role of Redox Dysregulation in the Effects of Prenatal Stress on Embryonic Interneuron Migration
    Cereb. Cortex (IF 5.437) Pub Date : 2019-03-16
    Bittle J, Menezes E, McCormick M, et al.

    Maternal stress during pregnancy is associated with increased risk of psychiatric disorders in offspring, but embryonic brain mechanisms disrupted by prenatal stress are not fully understood. Our lab has shown that prenatal stress delays inhibitory neural progenitor migration. Here, we investigated redox dysregulation as a mechanism for embryonic cortical interneuron migration delay, utilizing direct manipulation of pro- and antioxidants and a mouse model of maternal repetitive restraint stress starting on embryonic day 12. Time-lapse, live-imaging of migrating GAD67GFP+ interneurons showed that normal tangential migration of inhibitory progenitor cells was disrupted by the pro-oxidant, hydrogen peroxide. Interneuron migration was also delayed by in utero intracerebroventricular rotenone. Prenatal stress altered glutathione levels and induced changes in activity of antioxidant enzymes and expression of redox-related genes in the embryonic forebrain. Assessment of dihydroethidium (DHE) fluorescence after prenatal stress in ganglionic eminence (GE), the source of migrating interneurons, showed increased levels of DHE oxidation. Maternal antioxidants (N-acetylcysteine and astaxanthin) normalized DHE oxidation levels in GE and ameliorated the migration delay caused by prenatal stress. Through convergent redox manipula-tions, delayed interneuron migration after prenatal stress was found to critically involve redox dysregulation. Redox biology during prenatal periods may be a target for protecting brain development.

    更新日期:2019-12-19
  • Premotor Cortex Provides a Substrate for the Temporal Transformation of Information During the Planning of Gait Modifications
    Cereb. Cortex (IF 5.437) Pub Date : 2019-03-16
    Nakajima T, Fortier-Lebel N, Drew T.

    We tested the hypothesis that the premotor cortex (PMC) in the cat contributes to the planning and execution of visually guided gait modifications. We analyzed single unit activity from 136 cells localized within layer V of cytoarchitectonic areas 6iffu and that part of 4δ within the ventral bank of the cruciate sulcus while cats walked on a treadmill and stepped over an obstacle that advanced toward them. We found a rich variety of discharge patterns, ranging from limb-independent cells that discharged several steps in front of the obstacle to step-related cells that discharged either during steps over the obstacle or in the steps leading up to that step. We propose that this population of task-related cells within this region of the PMC contributes to the temporal evolution of a planning process that transforms global information of the presence of an obstacle into the precise spatio-temporal limb adjustment required to negotiate that obstacle.

    更新日期:2019-12-19
  • Switching From Fear to No Fear by Different Neural Ensembles in Mouse Retrosplenial Cortex
    Cereb. Cortex (IF 5.437) Pub Date : 2019-03-19
    Wang G, Xie H, Wang L, et al.

    Fear extinction is generally considered a form of new learning that inhibits previously acquired fear memories. Here, by tracking immediate early gene expression in vivo, we found that contextual fear extinction training evoked distinct neural ensembles in mouse retrosplenial cortex (RSC). The optogenetic reactivation of these extinction-activated neurons in the RSC was sufficient to suppress a fear response, while the reactivation of conditioning-activated neurons in the same area promoted a fear response. The generation of such an extinction-memory-related neural ensemble was associated with adult neurogenesis, as abolishing newborn neurons in the adult hippocampus via X-ray irradiation eliminated both the extinction-activated neurons in the RSC and the optogenetic-reactivation-induced suppression of contextual fear memory. Therefore, switching from fear to no fear in response to the same context is modulated by the RSC through an extinction-activated neural ensemble, the generation of which might require adult neurogenesis in the hippocampus.

    更新日期:2019-12-19
  • Thalamic Inputs to Posterior Parietal Cortical Areas Involved in Skilled Forelimb Movement and Tool Use in the Capuchin Monkey
    Cereb. Cortex (IF 5.437) Pub Date : 2019-03-19
    Mayer A, Lewenfus G, Bittencourt-Navarrete R, et al.

    The posterior parietal cortex (PPC) is a central hub for the primate forebrain networks that control skilled manual behavior, including tool use. Here, we quantified and compared the sources of thalamic input to electrophysiologically-identified hand/forearm-related regions of several PPC areas, namely areas 5v, AIP, PFG, and PF, of the capuchin monkey (Sapajus sp). We found that these areas receive most of their thalamic connections from the Anterior Pulvinar (PuA), Lateral Posterior (LP) and Medial Pulvinar (PuM) nuclei. Each PPC area receives a specific combination of projections from these nuclei, and fewer additional projections from other nuclei. Moreover, retrograde labeling of the cells innervating different PPC areas revealed substantial intermingling of these cells within the thalamus. Differences in thalamic input may contribute to the different functional properties displayed by the PPC areas. Furthermore, the observed innervation of functionally-related PPC domains from partly intermingled thalamic cell populations accords with the notion that higher-order thalamic inputs may dynamically regulate functional connectivity between cortical areas.

    更新日期:2019-12-19
  • Evolution of Brain Connections: Integrating Diffusion MR Tractography With Gene Expression Highlights Increased Corticocortical Projections in Primates
    Cereb. Cortex (IF 5.437) Pub Date : 2019-03-30
    Charvet C, Palani A, Kabaria P, et al.

    Diffusion MR tractography permits investigating the 3D structure of cortical pathways as interwoven paths across the entire brain. We use high-resolution scans from diffusion spectrum imaging and high angular resolution diffusion imaging to investigate the evolution of cortical pathways within the euarchontoglire (i.e., primates, rodents) lineage. More specifically, we compare cortical fiber pathways between macaques (Macaca mulatta), marmosets (Callithrix jachus), and rodents (mice, Mus musculus). We integrate these observations with comparative analyses of Neurofilament heavy polypeptide (NEFH) expression across the cortex of mice and primates. We chose these species because their phylogenetic position serves to trace the early evolutionary history of the human brain. Our comparative analysis from diffusion MR tractography, cortical white matter scaling, and NEFH expression demonstrates that the examined primates deviate from mice in possessing increased long-range cross-cortical projections, many of which course across the anterior to posterior axis of the cortex. Our study shows that integrating gene expression data with diffusion MR data is an effective approach in identifying variation in connectivity patterns between species. The expansion of corticocortical pathways and increased anterior to posterior cortical integration can be traced back to an extension of neurogenetic schedules during development in primates.

    更新日期:2019-12-19
  • Maturational Changes in Human Dorsal and Ventral Visual Networks
    Cereb. Cortex (IF 5.437) Pub Date : 2019-03-30
    Ciesielski K, Stern M, Diamond A, et al.

    Developmental neuroimaging studies report the emergence of increasingly diverse cognitive functions as closely entangled with a rise-fall modulation of cortical thickness (CTh), structural cortical and white-matter connectivity, and a time-course for the experience-dependent selective elimination of the overproduced synapses. We examine which of two visual processing networks, the dorsal (DVN; prefrontal, parietal nodes) or ventral (VVN; frontal-temporal, fusiform nodes) matures first, thus leading the neuro-cognitive developmental trajectory. Three age-dependent measures are reported: (i) the CTh at network nodes; (ii) the matrix of intra-network structural connectivity (edges); and (iii) the proficiency in network-related neuropsychological tests. Typically developing children (age ~6 years), adolescents (~11 years), and adults (~21 years) were tested using multiple-acquisition structural T1-weighted magnetic resonance imaging (MRI) and neuropsychology. MRI images reconstructed into a gray/white/pial matter boundary model were used for CTh evaluation. No significant group differences in CTh and in the matrix of edges were found for DVN (except for the left prefrontal), but a significantly thicker cortex in children for VVN with reduced prefrontal ventral-fusiform connectivity and with an abundance of connections in adolescents. The higher performance in children on tests related to DVN corroborates the age-dependent MRI structural connectivity findings. The current findings are consistent with an earlier maturational course of DVN.

    更新日期:2019-12-19
  • Children Use Regions in the Visual Processing and Executive Function Networks during a Subsequent Memory Reading Task
    Cereb. Cortex (IF 5.437) Pub Date : 2019-03-30
    Farah R, Coalson R, Petersen S, et al.

    Memory encoding is a critical process for memory function, which is foundational for cognitive functioning including reading, and has been extensively studied using subsequent memory tasks. Research in adults using such tasks indicates the participation of visual and cognitive-control systems in remembered versus forgotten words. However, given the known developmental trajectories of these systems, the functional neuroanatomy of memory encoding in children may be different than in adults. We examined brain activation for silent word reading and checkerboard viewing during an event-related reading task in 8–12 year-old children. Results indicate greater activation for checkerboard viewing than lexical processing in early visual regions, as well as for lexical processing versus checkerboard viewing in regions in left sensorimotor mouth, cingulo-opercular and dorsal-attention networks. Greater activation for remembered than forgotten words was observed in bilateral visual system and left lateralized regions within the ventral- and dorsal-attention, cingulo-opercular and fronto-parietal networks. These findings suggest a relatively mature reliance on the cognitive-control system, but greater reliance on the visual system in children when viewing words subsequently remembered. The location of regions with greater activity for remembered words reinforces the involvement of the attention and cognitive-control systems in subsequent memory in reading.

    更新日期:2019-12-19
  • The Attentional Blink is Related to the Microsaccade Rate Signature
    Cereb. Cortex (IF 5.437) Pub Date : 2019-04-03
    Roberts M, Lange G, Van Der Veen T, et al.

    The reduced detectability of a target T2 following discrimination of a preceding target T1 in the attentional blink (AB) paradigm is classically interpreted as a consequence of reduced attention to T2 due to attentional allocation to T1. Here, we investigated whether AB was related to changes in microsaccade rate (MSR). We found a pronounced MSR signature following T1 onset, characterized by MSR suppression from 200 to 328 ms and enhancement from 380 to 568 ms. Across participants, the magnitude of the MSR suppression correlated with the AB effect such that low T2 detectability corresponded to reduced MSR. However, in the same task, T1 error trials coincided with the presence of microsaccades. We discuss this apparent paradox in terms of known neurophysiological correlates of MS whereby cortical excitability is suppressed both during the microsaccade and MSR suppression, in accordance to poor T1 performance with microsaccade occurrence and poor T2 performance with microsaccade absence. Our data suggest a novel low-level mechanism contributing to AB characterized by reduced MSR, thought to cause suppressed visual cortex excitability. This opens the question of whether attention mediates T2 performance suppression independently from MSR, and if not, how attention interacts with MSR to produce the T2 performance suppression.

    更新日期:2019-12-19
  • Local and Volume-Conducted Contributions to Cortical Field Potentials
    Cereb. Cortex (IF 5.437) Pub Date : 2019-04-03
    Torres D, Makarova J, Ortuño T, et al.

    Brain field potentials (FPs) can reach far from their sources, making difficult to know which waves come from where. We show that modern algorithms efficiently segregate the local and remote contributions to cortical FPs by recovering the generator-specific spatial voltage profiles. We investigated experimentally and numerically the local and remote origin of FPs in different cortical areas in anesthetized rats. All cortices examined show significant state, layer, and region dependent contribution of remote activity, while the voltage profiles help identify their subcortical or remote cortical origin. Co-activation of different cortical modules can be discriminated by the distinctive spatial features of the corresponding profiles. All frequency bands contain remote activity, thus influencing the FP time course, in cases drastically. The reach of different FP patterns is boosted by spatial coherence and curved geometry of the sources. For instance, slow cortical oscillations reached the entire brain, while hippocampal theta reached only some portions of the cortex. In anterior cortices, most alpha oscillations have a remote origin, while in the visual cortex the remote theta and gamma even surpass the local contribution. The quantitative approach to local and distant FP contributions helps to refine functional connectivity among cortical regions, and their relation to behavior.

    更新日期:2019-12-19
  • Changes in Functional Connectivity Predict Outcome of Repetitive Transcranial Magnetic Stimulation Treatment of Major Depressive Disorder
    Cereb. Cortex (IF 5.437) Pub Date : 2019-04-06
    Corlier J, Wilson A, Hunter A, et al.

    Repetitive transcranial magnetic stimulation (rTMS) treatment of major depressive disorder (MDD) is associated with changes in brain functional connectivity (FC). These changes may be related to the mechanism of action of rTMS and explain the variability in clinical outcome. We examined changes in electroencephalographic FC during the first rTMS treatment in 109 subjects treated with 10 Hz stimulation to left dorsolateral prefrontal cortex. All subjects subsequently received 30 treatments and clinical response was defined as ≥40% improvement in the inventory of depressive symptomatology-30 SR score at treatment 30. Connectivity change was assessed with coherence, envelope correlation, and a novel measure, alpha spectral correlation (αSC). Machine learning was used to develop predictive models of outcome for each connectivity measure, which were compared with prediction based upon early clinical improvement. Significant connectivity changes were associated with clinical outcome (P < 0.001). Machine learning models based on αSC yielded the most accurate prediction (area under the curve, AUC = 0.83), and performance improved when combined with early clinical improvement measures (AUC = 0.91). The initial rTMS treatment session produced robust changes in FC, which were significant predictors of clinical outcome of a full course of treatment for MDD.

    更新日期:2019-12-19
  • FMRP Modulates Activity-Dependent Spine Plasticity by Binding Cofilin1 mRNA and Regulating Localization and Local Translation
    Cereb. Cortex (IF 5.437) Pub Date : 2019-04-06
    Feuge J, Scharkowski F, Michaelsen-Preusse K, et al.

    Multiple variants of intellectual disability, e.g., the Fragile X Syndrome are associated with alterations in dendritic spine morphology, thereby pointing to dysregulated actin dynamics during development and processes of synaptic plasticity. Surprisingly, although the necessity of spine actin remodeling was demonstrated repeatedly, the importance and precise role of actin regulators is often undervalued. Here, we provide evidence that structural and functional plasticity are severely impaired after NMDAR-dependent LTP in the hippocampus of Fmr1 KO mice. We can link these defects to an aberrant activity-dependent regulation of Cofilin 1 (cof1) as activity-dependent modulations of local cof1 mRNA availability, local cof1 translation as well as total cof1 expression are impaired in the absence of FMRP. Finally, we can rescue activity-dependent structural plasticity in KO neurons by mimicking the regulation of cof1 observed in WT cells, thereby illustrating the potential of actin modulators to provide novel treatment strategies for the Fragile X Syndrome.

    更新日期:2019-12-19
  • The Glutamine Transporter Slc38a1 Regulates GABAergic Neurotransmission and Synaptic Plasticity
    Cereb. Cortex (IF 5.437) Pub Date : 2019-05-03
    Qureshi T, Sørensen C, Berghuis P, et al.

    GABA signaling sustains fundamental brain functions, from nervous system development to the synchronization of population activity and synaptic plasticity. Despite these pivotal features, molecular determinants underscoring the rapid and cell-autonomous replenishment of the vesicular neurotransmitter GABA and its impact on synaptic plasticity remain elusive. Here, we show that genetic disruption of the glutamine transporter Slc38a1 in mice hampers GABA synthesis, modifies synaptic vesicle morphology in GABAergic presynapses and impairs critical period plasticity. We demonstrate that Slc38a1-mediated glutamine transport regulates vesicular GABA content, induces high-frequency membrane oscillations and shapes cortical processing and plasticity. Taken together, this work shows that Slc38a1 is not merely a transporter accumulating glutamine for metabolic purposes, but a key component regulating several neuronal functions.

    更新日期:2019-12-19
  • In utero Exposure to Anesthetics Alters Neuronal Migration Pattern in Developing Cerebral Cortex and Causes Postnatal Behavioral Deficits in Rats
    Cereb. Cortex (IF 5.437) Pub Date : 2019-04-11
    Gluncic V, Moric M, Chu Y, et al.

    During fetal development, cerebral cortical neurons are generated in the proliferative zone along the ventricles and then migrate to their final positions. To examine the impact of in utero exposure to anesthetics on neuronal migration, we injected pregnant rats with bromodeoxyuridine to label fetal neurons generated at embryonic Day (E) 17 and then randomized these rats to 9 different groups receiving 3 different means of anesthesia (oxygen/control, propofol, isoflurane) for 3 exposure durations (20, 50, 120 min). Histological analysis of brains from 54 pups revealed that significant number of neurons in anesthetized animals failed to acquire their correct cortical position and remained dispersed within inappropriate cortical layers and/or adjacent white matter. Behavioral testing of 86 littermates pointed to abnormalities that correspond to the aberrations in the brain areas that are specifically developing during the E17. In the second set of experiments, fetal brains exposed to isoflurane at E16 had diminished expression of the reelin and glutamic acid decarboxylase 67, proteins critical for neuronal migration. Together, these results call for cautious use of anesthetics during the neuronal migration period in pregnancy and more comprehensive investigation of neurodevelopmental consequences for the fetus and possible consequences later in life.

    更新日期:2019-12-19
  • Diversity of Feature Selectivity in Macaque Visual Cortex Arising from a Limited Number of Broadly Tuned Input Channels
    Cereb. Cortex (IF 5.437) Pub Date : 2019-04-10
    Mohan Y, Jayakumar J, Lloyd E, et al.

    Spike (action potential) responses of most primary visual cortical cells in the macaque are sharply tuned for the orientation of a line or an edge, and neurons preferring similar orientations are clustered together in cortical columns. The preferred stimulus orientation of these columns span the full range of orientations, as observed in recordings of spikes and in classical optical imaging of intrinsic signals. However, when we imaged the putative thalamic input to striate cortical cells that can be seen in imaging of intrinsic signals when they are analyzed on a larger spatial scale, we found that the orientation domain map of the primary visual cortex did not show the same diversity of orientations. This map was dominated by just the one orientation that is most commonly preferred by neurons in the retina and the lateral geniculate nucleus. This supports cortical feature selectivity and columnar architecture being built upon feed-forward signals transmitted from the thalamus in a very limited number of broadly tuned input channels.

    更新日期:2019-12-19
  • KCC2 Manipulation Alters Features of Migrating Interneurons in Ferret Neocortex
    Cereb. Cortex (IF 5.437) Pub Date : 2019-04-06
    Djankpa F, Lischka F, Chatterjee M, et al.

    KCC2 is a brain specific chloride–potassium cotransporter affecting neuronal development including migration and cellular maturation. It modulates chloride homeostasis influencing the switch of GABA from depolarizing to hyperpolarizing, which contributes to the cues that influence the termination of neuronal migration. The expression of KCC2 during migration of interneurons, therefore, correlates with the ability of these cells to respond to GABA as a stop signal. Manipulation of KCC2 in development can affect various aspects of migrating neurons, including the speed. We describe the effect of KCC2 downregulation and inhibition on features of migrating interneurons of normal ferret kits and those treated with methylazoxymethanol acetate, which increases KCC2. Treatment of organotypic cultures with Bisphenol A, an environmental toxin that alters gene expression, also downregulates KCC2 protein. In organotypic slices treated with the KCC2 antagonist VU0240551, chloride imaging shows inhibition of KCC2 via blockade of chloride flux. Time-lapse video imaging of organotypic cultures treated with either drug, shows a significant increase in the average speed, step size, and number of turns made by migrating neurons leaving the ganglionic eminence. Our findings demonstrate the harmful effect of environmental toxins on brain development and potential consequences in the pathogenesis of neurodevelopmental disorders.

    更新日期:2019-12-19
  • Altered Cortical Brain Structure and Increased Risk for Disease Seen Decades After Perinatal Exposure to Maternal Smoking: A Study of 9000 Adults in the UK Biobank
    Cereb. Cortex (IF 5.437) Pub Date : 2019-07-04
    Salminen L, Wilcox R, Zhu A, et al.

    Secondhand smoke exposure is a major public health risk that is especially harmful to the developing brain, but it is unclear if early exposure affects brain structure during middle age and older adulthood. Here we analyzed brain MRI data from the UK Biobank in a population-based sample of individuals (ages 44–80) who were exposed (n = 2510) or unexposed (n = 6079) to smoking around birth. We used robust statistical models, including quantile regressions, to test the effect of perinatal smoke exposure (PSE) on cortical surface area (SA), thickness, and subcortical volumes. We hypothesized that PSE would be associated with cortical disruption in primary sensory areas compared to unexposed (PSE−) adults. After adjusting for multiple comparisons, SA was significantly lower in the pericalcarine (PCAL), inferior parietal (IPL), and regions of the temporal and frontal cortex of PSE+ adults; these abnormalities were associated with increased risk for several diseases, including circulatory and endocrine conditions. Sensitivity analyses conducted in a hold-out group of healthy participants (exposed, n = 109, unexposed, n = 315) replicated the effect of PSE on SA in the PCAL and IPL. Collectively our results show a negative, long term effect of PSE on sensory cortices that may increase risk for disease later in life.

    更新日期:2019-12-19
  • Structural Covariance Reveals Alterations in Control and Salience Network Integrity in Chronic Schizophrenia
    Cereb. Cortex (IF 5.437) Pub Date : 2019-05-08
    Spreng R, DuPre E, Ji J, et al.

    Schizophrenia (SCZ) is recognized as a disorder of distributed brain dysconnectivity. While progress has been made delineating large-scale functional networks in SCZ, little is known about alterations in grey matter integrity of these networks. We used a multivariate approach to identify the structural covariance of the salience, default, motor, visual, fronto-parietal control, and dorsal attention networks. We derived individual scores reflecting covariance in each structural image for a given network. Seed-based multivariate analyses were conducted on structural images in a discovery (n = 90) and replication (n = 74) sample of SCZ patients and healthy controls. We first validated patterns across all networks, consistent with well-established functional connectivity reports. Next, across two SCZ samples, we found reliable and robust reductions in structural integrity of the fronto-parietal control and salience networks, but not default, dorsal attention, motor and sensory networks. Well-powered exploratory analyses failed to identify relationships with symptoms. These findings provide evidence of selective structural decline in associative networks in SCZ. Such decline may be linked with recently identified functional disturbances in associative networks, providing more sensitive multi-modal network-level probes in SCZ. Absence of symptom effects suggests that identified disturbances may underlie a trait-type marker in SCZ.

    更新日期:2019-12-19
  • How Task Interactivity Shapes Action Observation
    Cereb. Cortex (IF 5.437) Pub Date : 2019-10-07
    Sacheli L, Verga C, Arcangeli E, et al.

    Action observation triggers imitation, a powerful mechanism permitting interpersonal coordination. Coordination, however, also occurs when the partners’ actions are nonimitative and physically incongruent. One influential theory postulates that this is achieved via top-down modulation of imitation exerted by prefrontal regions. Here, we rather argue that coordination depends on sharing a goal with the interacting partner: this shapes action observation, overriding involuntary imitation, through the predictive activity of the left ventral premotor cortex (lvPMc). During functional magnetic resonance imaging (fMRI), participants played music in turn with a virtual partner in interactive and noninteractive conditions requiring 50% of imitative/nonimitative responses. In a full-factorial design, both perceptual features and low-level motor requirements were kept constant throughout the experiment. Behaviorally, the interactive context minimized visuomotor interference due to the involuntary imitation of physically incongruent movements. This was paralleled by modulation of neural activity in the lvPMc, which was specifically recruited during the interactive task independently of the imitative/nonimitative nature of the social exchange. This lvPMc activity reflected the predictive decoding of the partner’s actions, as revealed by multivariate pattern analysis. This demonstrates that, during interactions, we process our partners’ behavior to prospectively infer their contribution to the shared goal achievement, generating motor predictions for cooperation beyond low-level imitation.

    更新日期:2019-12-19
  • Motor and Limbic System Contribution to Emotional Laughter across the Lifespan
    Cereb. Cortex (IF 5.437) Pub Date : 2019-12-17
    Talami F, Vaudano A, Meletti S.

    Laughter is a universal human behavior generated by the cooperation of different systems toward the construction of an expressive vocal pattern. Given the sensitivity of neuroimaging techniques to movements, the neural mechanisms underlying laughter expression remain unclear. Herein, we characterized the neural correlates of emotional laughter using the onsets and the duration of laughter bursts to inform functional magnetic resonance imaging. Laughter-related blood oxygen level-dependent (BOLD) increases involved both the motor (motor cortex, supplementary motor area, frontal operculum) and the emotional/limbic (anterior cingulate cortex, amygdala, n. accumbens, hippocampus) systems, as well as modulatory circuitries encompassing the basal ganglia, thalamus, and cerebellum. BOLD changes related to the 2 s preceding the laughter outbreak were selectively observed at the temporo-occipital junction and the periaqueductal gray matter, supporting the role of the former in the detection of incongruity and the gating role of the latter in the initiation of spontaneous laughter. Moreover, developmental changes were identified in laughter processing, consisting in a greater engagement of the reward circuitry in younger subjects; conversely, the default mode network appears more activated in older participants. Our findings contribute valuable information about the processing of real-life humorous materials and suggest a close link between laughter-related motor, affective, and cognitive elements, confirming its complex and multi-faceted nature.

    更新日期:2019-12-19
  • Heritability and Cognitive Relevance of Structural Brain Controllability
    Cereb. Cortex (IF 5.437) Pub Date : 2019-12-14
    Lee W, Rodrigue A, Glahn D, et al.

    Cognition and behavior are thought to emerge from the connections and interactions among brain regions. The precise nature of these relationships remains elusive. Here we use tools provided by network control theory to determine how the structural connectivity profile of brain regions may shape individual variation in cognition. In a cohort of healthy young adults (n = 1066), we computed two fundamental brain regional control patterns, average and modal controllability, which index the degree of influence of a region over others. We first established that regional brain controllability measures were both reproducible and heritable. Regions with controllability profiles theoretically conducive to facilitating multiple cognitive operations were over-represented in higher-order resting-state networks. Finally, variation in regional controllability accounted for about 50% of interindividual variability in multiple cognitive domains. We conclude that controllability is a biologically plausible property of the structural connectome and provides a mechanistic explanation for how brain structural architecture may influence cognitive functions.

    更新日期:2019-12-18
  • Subjective Uncontrollability over Aversive Events Reduces Working Memory Performance and Related Large-Scale Network Interactions
    Cereb. Cortex (IF 5.437) Pub Date : 2019-12-14
    Wanke N, Schwabe L.

    Lack of control over significant events may induce a state of learned helplessness that is characterized by cognitive, motivational, and affective deficits. Although highly relevant in the pathogenesis of several mental disorders, the extent of the cognitive deficits induced by experiences of uncontrollability and the neural mechanisms underlying such deficits in humans remain poorly understood. Using functional magnetic resonance imaging (fMRI), we tested here whether uncontrollability over aversive events impairs subsequent working memory performance and, if so, which neural processes are involved in such deficits. We assessed working memory and the involved neurocircuitry in the MRI scanner before and after participants underwent a task in which they could either learn to avoid electric shocks or had no instrumental control over shocks. Our results show that subjective, but not objective, uncontrollability over aversive events impaired working memory performance. This impact of subjective uncontrollability was linked to altered prefrontal and parahippocampal activities and connectivity as well as decreased crosstalk between frontoparietal executive and salience networks. Our findings show that the perceived uncontrollability over aversive events, rather than the aversive events themselves or the actual, objective control over them, disrupts subsequent working memory processes, most likely through altered crosstalk between prefrontal, temporal, and parietal areas.

    更新日期:2019-12-18
  • Brain Morphological Dynamics of Procrastination: The Crucial Role of the Self-Control, Emotional, and Episodic Prospection Network
    Cereb. Cortex (IF 5.437) Pub Date : 2019-12-16
    Chen Z, Liu P, Zhang C, et al.

    Globally, about 17% individuals are suffering from the maladaptive procrastination until now, which impacts individual’s financial status, mental health, and even public policy. However, the comprehensive understanding of neuroanatomical understructure of procrastination still remains gap. 688 participants including 3 independent samples were recruited for this study. Brain morphological dynamics referred to the idiosyncrasies of both brain size and brain shape. Multilinear regression analysis was utilized to delineate brain morphological dynamics of procrastination in Sample 1. In the Sample 2, cross-validation was yielded. Finally, prediction models of machine learning were conducted in Sample 3. Procrastination had a significantly positive correlation with the gray matter volume (GMV) in the left insula, anterior cingulate gyrus (ACC), and parahippocampal gyrus (PHC) but was negatively correlated with GMV of dorsolateral prefrontal cortex (dlPFC) and gray matter density of ACC. Furthermore, procrastination was positively correlated to the cortical thickness and cortical complexity of bilateral orbital frontal cortex (OFC). In Sample 2, all the results were cross-validated highly. Predication analysis demonstrated that these brain morphological dynamic can predict procrastination with high accuracy. This study ascertained the brain morphological dynamics involving in self-control, emotion, and episodic prospection brain network for procrastination, which advanced promising aspects of the biomarkers for it.

    更新日期:2019-12-18
  • Loss of Dmrt5 Affects the Formation of the Subplate and Early Corticogenesis
    Cereb. Cortex (IF 5.437) Pub Date : 2019-12-16
    Ratié L, Desmaris E, García-Moreno F, et al.

    Dmrt5 (Dmrta2) and Dmrt3 are key regulators of cortical patterning and progenitor proliferation and differentiation. In this study, we show an altered apical to intermediate progenitor transition, with a delay in SP neurogenesis and premature birth of Ctip2+ cortical neurons in Dmrt5−/− mice. In addition to the cortical progenitors, DMRT5 protein appears present in postmitotic subplate (SP) and marginal zone neurons together with some migrating cortical neurons. We observed the altered split of preplate and the reduced SP and disturbed radial migration of cortical neurons into cortical plate in Dmrt5−/− brains and demonstrated an increase in the proportion of multipolar cells in primary neuronal cultures from Dmrt5−/− embryonic brains. Dmrt5 affects cortical development with specific time sensitivity that we described in two conditional mice with slightly different deletion time. We only observed a transient SP phenotype at E15.5, but not by E18.5 after early (Dmrt5lox/lox;Emx1Cre), but not late (Dmrt5lox/lox;NestinCre) deletion of Dmrt5. SP was less disturbed in Dmrt5lox/lox;Emx1Cre and Dmrt3−/− brains than in Dmrt5−/− and affects dorsomedial cortex more than lateral and caudal cortex. Our study demonstrates a novel function of Dmrt5 in the regulation of early SP formation and radial cortical neuron migration. Summary StatementOur study demonstrates a novel function of Dmrt5 in regulating marginal zone and subplate formation and migration of cortical neurons to cortical plate.

    更新日期:2019-12-18
  • Temporal Differences in Interneuron Invasion of Neocortex and Piriform Cortex during Mouse Cortical Development
    Cereb. Cortex (IF 5.437) Pub Date : 2019-12-14
    Hsing H, Zhuang Z, Niou Z, et al.

    Establishing a balance between excitation and inhibition is critical for brain functions. However, how inhibitory interneurons (INs) generated in the ventral telencephalon integrate with the excitatory neurons generated in the dorsal telencephalon remains elusive. Previous studies showed that INs migrating tangentially to enter the neocortex (NCx), remain in the migratory stream for days before invading the cortical plate during late corticogenesis. Here we show that in developing mouse cortices, INs in the piriform cortex (PCx; the major olfactory cortex) distribute differently from those in the NCx. We provide evidence that during development INs invade and mature earlier in PCx than in NCx, likely owing to the lack of CXCR4 expression in INs from PCx compared to those in NCx. We analyzed IN distribution patterns in Lhx2 cKO mice, where projection neurons in the lateral NCx are re-fated to generate an ectopic PCx (ePCx). The PCx-specific IN distribution patterns found in ePCx suggest that properties of PCx projection neurons regulate IN distribution. Collectively, our results show that the timing of IN invasion in the developing PCx fundamentally differs from what is known in the NCx. Further, our results suggest that projection neurons instruct the PCx-specific pattern of IN distribution.

    更新日期:2019-12-17
  • Motion Perception in the Common Marmoset
    Cereb. Cortex (IF 5.437) Pub Date : 2019-12-11
    Cloherty S, Yates J, Graf D, et al.

    Visual motion processing is a well-established model system for studying neural population codes in primates. The common marmoset, a small new world primate, offers unparalleled opportunities to probe these population codes in key motion processing areas, such as cortical areas MT and MST, because these areas are accessible for imaging and recording at the cortical surface. However, little is currently known about the perceptual abilities of the marmoset. Here, we introduce a paradigm for studying motion perception in the marmoset and compare their psychophysical performance with human observers. We trained two marmosets to perform a motion estimation task in which they provided an analog report of their perceived direction of motion with an eye movement to a ring that surrounded the motion stimulus. Marmosets and humans exhibited similar trade-offs in speed versus accuracy: errors were larger and reaction times were longer as the strength of the motion signal was reduced. Reverse correlation on the temporal fluctuations in motion direction revealed that both species exhibited short integration windows; however, marmosets had substantially less nondecision time than humans. Our results provide the first quantification of motion perception in the marmoset and demonstrate several advantages to using analog estimation tasks.

    更新日期:2019-12-13
  • Altered Sex Chromosome Dosage Induces Coordinated Shifts in Cortical Anatomy and Anatomical Covariance
    Cereb. Cortex (IF 5.437) Pub Date : 2019-12-11
    Xenophontos A, Seidlitz J, Liu S, et al.

    Sex chromosome dosage (SCD) variation increases risk for neuropsychiatric impairment, which may reflect direct SCD effects on brain organization. Here, we 1) map cumulative X- and Y-chromosome dosage effects on regional cortical thickness (CT) and investigate potential functional implications of these effects using Neurosynth, 2) test if this map is organized by patterns of CT covariance that are evident in health, and 3) characterize SCD effects on CT covariance itself. We modeled SCD effects on CT and CT covariance for 308 equally sized regions of the cortical sheet using structural neuroimaging data from 301 individuals with varying numbers of sex chromosomes (169 euploid, 132 aneuploid). Mounting SCD increased CT in the rostral frontal cortex and decreased CT in the lateral temporal cortex, bilaterally. Regions targeted by SCD were associated with social functioning, language processing, and comprehension. Cortical regions with a similar degree of SCD-sensitivity showed heightened CT covariance in health. Finally, greater SCD also increased covariance among regions similarly affected by SCD. Our study both 1) develops novel methods for comparing typical and disease-related structural covariance networks in the brain and 2) uses these techniques to resolve and identify organizing principles for SCD effects on regional cortical anatomy and anatomical covariance.

    更新日期:2019-12-13
  • The Neural Basis for Response Latency in a Sensory-Motor Behavior
    Cereb. Cortex (IF 5.437) Pub Date : 2019-12-11
    Lee J, Darlington T, Lisberger S.

    We seek a neural circuit explanation for sensory-motor reaction times. In the smooth eye movement region of the frontal eye fields (FEFSEM), the latencies of pairs of neurons show trial-by-trial correlations that cause trial-by-trial correlations in neural and behavioral latency. These correlations can account for two-third of the observed variation in behavioral latency. The amplitude of preparatory activity also could contribute, but the responses of many FEFSEM neurons fail to support predictions of the traditional “ramp-to-threshold” model. As a correlate of neural processing that determines reaction time, the local field potential in FEFSEM includes a brief wave in the 5–15-Hz frequency range that precedes pursuit initiation and whose phase is correlated with the latency of pursuit in individual trials. We suggest that the latency of the incoming visual motion signals combines with the state of preparatory activity to determine the latency of the transient response that controls eye movement. Impact statementThe motor cortex for smooth pursuit eye movements contributes to sensory-motor reaction time through the amplitude of preparatory activity and the latency of transient, visually driven responses.

    更新日期:2019-12-13
  • Multiple Morphological Factors Underlie Experience-Dependent Cross-Modal Plasticity in the Developing Sensory Cortices
    Cereb. Cortex (IF 5.437) Pub Date : 2019-12-11
    Wang M, Yu Z, Li G, et al.

    Sensory experience regulates the structural and functional wiring of sensory cortices. In previous work, we showed that whisker deprivation (WD) from birth not only reduced excitatory synaptic transmission of layer (L) 2/3 pyramidal neurons of the correspondent barrel cortex in mice, but also cross-modally reduced synaptic transmission of L2/3 pyramidal neurons in other sensory cortices. Here, we used in utero electroporation, in combination with optical clearing, to examine the main morphological components regulating neural circuit wiring, namely presynaptic bouton density, spine density, as well as dendrite and axon arbor lengths. We found that WD from P0 to P14 reduced presynaptic bouton density in both L4 and L2/3 inputs to L2/3 pyramidal neurons, as well as spine density across the dendritic tree of L2/3 pyramidal neurons, in the barrel field of the primary somatosensory cortex. The cross-modal effects in the primary auditory cortex were manifested mostly as reduced dendrite and axon arbor size, as well as reduced bouton density of L2/3 inputs. Increasing sensory experience by rearing mice in an enriched environment rescued the effects of WD. Together, these results demonstrate that multiple morphological factors contribute to experience-dependent structural plasticity during early wiring of the sensory cortices.

    更新日期:2019-12-13
  • Two Distinct Systems Represent Contralateral and Ipsilateral Sensorimotor Processes in the Human Premotor Cortex: A Dense TMS Mapping Study
    Cereb. Cortex (IF 5.437) Pub Date : 2019-12-11
    Lega C, Chelazzi L, Cattaneo L.

    Animal brains contain behaviorally committed representations of the surrounding world, which integrate sensory and motor information. In primates, sensorimotor mechanisms reside in part in the premotor cortex (PM), where sensorimotor neurons are topographically clustered according to functional specialization. Detailed functional cartography of the human PM is still under investigation. We explored the topographic distribution of spatially dependent sensorimotor functions in healthy volunteers performing left or right, hand or foot, responses to visual cues presented in the left or right hemispace, thus combining independently stimulus side, effector side, and effector type. Event-related transcranial magnetic stimulation was applied to single spots of a dense grid of 10 points on the participants’ left hemiscalp, covering the whole PM. Results showed: (1) spatially segregated hand and foot representations, (2) focal representations of contralateral cues and movements in the dorsal PM, and (3) distributed representations of ipsilateral cues and movements in the ventral and dorso-medial PM. The present novel causal information indicates that (1) the human PM is somatotopically organized and (2) the left PM contains sensory-motor representations of both hemispaces and of both hemibodies, but the hemispace and hemibody contralateral to the PM are mapped on a distinct, nonoverlapping cortical region compared to the ipsilateral ones.

    更新日期:2019-12-13
  • Adolescent Decision-Making Under Risk: Neural Correlates and Sex Differences
    Cereb. Cortex (IF 5.437) Pub Date : 2019-12-11
    Korucuoglu O, Harms M, Kennedy J, et al.

    An increased propensity for risk taking is a hallmark of adolescent behavior with significant health and social consequences. Here, we elucidated cortical and subcortical regions associated with risky and risk-averse decisions and outcome evaluation using the Balloon Analog Risk Task in a large sample of adolescents (n = 256, 56% female, age 14 ± 0.6), including the level of risk as a parametric modulator. We also identified sex differences in neural activity. Risky decisions engaged regions that are parts of the salience, dorsal attention, and frontoparietal networks, but only the insula was sensitive to increasing risks in parametric analyses. During risk-averse decisions, the same networks covaried with parametric levels of risk. The dorsal striatum was engaged by both risky and risk-averse decisions, but was not sensitive to escalating risk. Negative-outcome processing showed greater activations than positive-outcome processing. Insula, lateral orbitofrontal cortex, middle, rostral, and superior frontal areas, rostral and caudal anterior cingulate cortex were activated only by negative outcomes, with a subset of regions associated with negative outcomes showing greater activation in females. Taken together, these results suggest that safe decisions are predicted by more accurate neural representation of increasing risk levels, whereas reward-related processes play a relatively minor role.

    更新日期:2019-12-13
  • Cortical Surfaces Mediate the Relationship Between Polygenic Scores for Intelligence and General Intelligence
    Cereb. Cortex (IF 5.437) Pub Date : 2019-12-11
    Lett T, Vogel B, Ripke S, et al.

    Recent large-scale, genome-wide association studies (GWAS) have identified hundreds of genetic loci associated with general intelligence. The cumulative influence of these loci on brain structure is unknown. We examined if cortical morphology mediates the relationship between GWAS-derived polygenic scores for intelligence (PSi) and g-factor. Using the effect sizes from one of the largest GWAS meta-analysis on general intelligence to date, PSi were calculated among 10 P value thresholds. PSi were assessed for the association with g-factor performance, cortical thickness (CT), and surface area (SA) in two large imaging-genetics samples (IMAGEN N = 1651; IntegraMooDS N = 742). PSi explained up to 5.1% of the variance of g-factor in IMAGEN (F1,1640 = 12.2–94.3; P < 0.005), and up to 3.0% in IntegraMooDS (F1,725 = 10.0–21.0; P < 0.005). The association between polygenic scores and g-factor was partially mediated by SA and CT in prefrontal, anterior cingulate, insula, and medial temporal cortices in both samples (PFWER-corrected < 0.005). The variance explained by mediation was up to 0.75% in IMAGEN and 0.77% in IntegraMooDS. Our results provide evidence that cumulative genetic load influences g-factor via cortical structure. The consistency of our results across samples suggests that cortex morphology could be a novel potential biomarker for neurocognitive dysfunction that is among the most intractable psychiatric symptoms.

    更新日期:2019-12-13
  • Absence of TRIM32 Leads to Reduced GABAergic Interneuron Generation and Autism-like Behaviors in Mice via Suppressing mTOR Signaling
    Cereb. Cortex (IF 5.437) Pub Date : 2019-12-11
    Zhu J, Zou M, Li Y, et al.

    Mammalian target of rapamycin (mTOR) signaling plays essential roles in brain development. Hyperactive mTOR is an essential pathological mechanism in autism spectrum disorder (ASD). Here, we show that tripartite motif protein 32 (TRIM32), as a maintainer of mTOR activity through promoting the proteasomal degradation of G protein signaling protein 10 (RGS10), regulates the proliferation of medial/lateral ganglionic eminence (M/LGE) progenitors. Deficiency of TRIM32 results in an impaired generation of GABAergic interneurons and autism-like behaviors in mice, concomitant with an elevated autophagy, which can be rescued by treatment embryonically with 3BDO, an mTOR activator. Transplantation of M/LGE progenitors or treatment postnatally with clonazepam, an agonist of the GABAA receptor, rescues the hyperexcitability and the autistic behaviors of TRIM32−/− mice, indicating a causal contribution of GABAergic disinhibition. Thus, the present study suggests a novel mechanism for ASD etiology in that TRIM32 deficiency-caused hypoactive mTOR, which is linked to an elevated autophagy, leads to autism-like behaviors via impairing generation of GABAergic interneurons. TRIM32−/− mouse is a novel autism model mouse.

    更新日期:2019-12-13
  • Differential Effects of Open- and Closed-Loop Intracortical Microstimulation on Firing Patterns of Neurons in Distant Cortical Areas
    Cereb. Cortex (IF 5.437) Pub Date : 2019-12-11
    Averna A, Pasquale V, Murphy M, et al.

    Intracortical microstimulation can be used successfully to modulate neuronal activity. Activity-dependent stimulation (ADS), in which action potentials recorded extracellularly from a single neuron are used to trigger stimulation at another cortical location (closed-loop), is an effective treatment for behavioral recovery after brain lesion, but the related neurophysiological changes are still not clear. Here, we investigated the ability of ADS and random stimulation (RS) to alter firing patterns of distant cortical locations. We recorded 591 neuronal units from 23 Long-Evan healthy anesthetized rats. Stimulation was delivered to either forelimb or barrel field somatosensory cortex, using either RS or ADS triggered from spikes recorded in the rostral forelimb area (RFA). Both RS and ADS stimulation protocols rapidly altered spike firing within RFA compared with no stimulation. We observed increase in firing rates and change of spike patterns. ADS was more effective than RS in increasing evoked spikes during the stimulation periods, by producing a reliable, progressive increase in stimulus-related activity over time and an increased coupling of the trigger channel with the network. These results are critical for understanding the efficacy of closed-loop electrical microstimulation protocols in altering activity patterns in interconnected brain networks, thus modulating cortical state and functional connectivity.

    更新日期:2019-12-13
  • Distinct Laminar Requirements for NMDA Receptors in Experience-Dependent Visual Cortical Plasticity
    Cereb. Cortex (IF 5.437) Pub Date : 2019-12-12
    Fong M, Finnie P, Kim T, et al.

    Primary visual cortex (V1) is the locus of numerous forms of experience-dependent plasticity. Restricting visual stimulation to one eye at a time has revealed that many such forms of plasticity are eye-specific, indicating that synaptic modification occurs prior to binocular integration of thalamocortical inputs. A common feature of these forms of plasticity is the requirement for NMDA receptor (NMDAR) activation in V1. We therefore hypothesized that NMDARs in cortical layer 4 (L4), which receives the densest thalamocortical input, would be necessary for all forms of NMDAR-dependent and input-specific V1 plasticity. We tested this hypothesis in awake mice using a genetic approach to selectively delete NMDARs from L4 principal cells. We found, unexpectedly, that both stimulus-selective response potentiation and potentiation of open-eye responses following monocular deprivation (MD) persist in the absence of L4 NMDARs. In contrast, MD-driven depression of deprived-eye responses was impaired in mice lacking L4 NMDARs, as was L4 long-term depression in V1 slices. Our findings reveal a crucial requirement for L4 NMDARs in visual cortical synaptic depression, and a surprisingly negligible role for them in cortical response potentiation. These results demonstrate that NMDARs within distinct cellular subpopulations support different forms of experience-dependent plasticity.

    更新日期:2019-12-13
  • Pain-Evoked Reorganization in Functional Brain Networks
    Cereb. Cortex (IF 5.437) Pub Date : 2019-12-09
    Zheng W, Woo C, Yao Z, et al.

    Recent studies indicate that a significant reorganization of cerebral networks may occur in patients with chronic pain, but how immediate pain experience influences the organization of large-scale functional networks is not yet well characterized. To investigate this question, we used functional magnetic resonance imaging in 106 participants experiencing both noxious and innocuous heat. Painful stimulation caused network-level reorganization of cerebral connectivity that differed substantially from organization during innocuous stimulation and standard resting-state networks. Noxious stimuli increased somatosensory network connectivity with (a) frontoparietal networks involved in context representation, (b) “ventral attention network” regions involved in motivated action selection, and (c) basal ganglia and brainstem regions. This resulted in reduced “small-worldness,” modularity (fewer networks), and global network efficiency and in the emergence of an integrated “pain supersystem” (PS) whose activity predicted individual differences in pain sensitivity across 5 participant cohorts. Network hubs were reorganized (“hub disruption”) so that more hubs were localized in PS, and there was a shift from “connector” hubs linking disparate networks to “provincial” hubs connecting regions within PS. Our findings suggest that pain reorganizes the network structure of large-scale brain systems. These changes may prioritize responses to painful events and provide nociceptive systems privileged access to central control of cognition and action during pain.

    更新日期:2019-12-11
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