14 results on '"Markicevic, Marija"'
Search Results
2. Multimodal measures of spontaneous brain activity reveal both common and divergent patterns of cortical functional organization
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Vafaii, Hadi, Mandino, Francesca, Desrosiers-Grégoire, Gabriel, O’Connor, David, Markicevic, Marija, Shen, Xilin, Ge, Xinxin, Herman, Peter, Hyder, Fahmeed, Papademetris, Xenophon, Chakravarty, Mallar, Crair, Michael C., Constable, R. Todd, Lake, Evelyn M. R., and Pessoa, Luiz
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- 2024
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3. Dysfunctional Autism Risk Genes Cause Circuit-Specific Connectivity Deficits With Distinct Developmental Trajectories
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Zerbi, Valerio, Ielacqua, Giovanna D, Markicevic, Marija, Haberl, Matthias Georg, Ellisman, Mark H, A-Bhaskaran, Arjun, Frick, Andreas, Rudin, Markus, and Wenderoth, Nicole
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Biological Psychology ,Biomedical and Clinical Sciences ,Psychology ,Basic Behavioral and Social Science ,Neurosciences ,Autism ,Pediatric ,Intellectual and Developmental Disabilities (IDD) ,Behavioral and Social Science ,Genetics ,Mental Health ,Brain Disorders ,2.1 Biological and endogenous factors ,Aetiology ,Neurological ,Mental health ,Age Factors ,Animals ,Animals ,Newborn ,Autistic Disorder ,Brain ,Brain Mapping ,Connectome ,Disease Models ,Animal ,Fragile X Mental Retardation Protein ,Image Processing ,Computer-Assisted ,Luminescent Proteins ,Magnetic Resonance Imaging ,Membrane Proteins ,Mice ,Mice ,Inbred C57BL ,Mice ,Knockout ,Nerve Tissue Proteins ,Neural Pathways ,Oxygen ,Transduction ,Genetic ,autism ,brain connectivity ,CNTNAP2 ,FMR1 ,resting-state functional MRI ,Cognitive Sciences ,Experimental Psychology ,Biological psychology ,Cognitive and computational psychology - Abstract
Autism spectrum disorders (ASD) are a set of complex neurodevelopmental disorders for which there is currently no targeted therapeutic approach. It is thought that alterations of genes regulating migration and synapse formation during development affect neural circuit formation and result in aberrant connectivity within distinct circuits that underlie abnormal behaviors. However, it is unknown whether deviant developmental trajectories are circuit-specific for a given autism risk-gene. We used MRI to probe changes in functional and structural connectivity from childhood to adulthood in Fragile-X (Fmr1-/y) and contactin-associated (CNTNAP2-/-) knockout mice. Young Fmr1-/y mice (30 days postnatal) presented with a robust hypoconnectivity phenotype in corticocortico and corticostriatal circuits in areas associated with sensory information processing, which was maintained until adulthood. Conversely, only small differences in hippocampal and striatal areas were present during early postnatal development in CNTNAP2-/- mice, while major connectivity deficits in prefrontal and limbic pathways developed between adolescence and adulthood. These findings are supported by viral tracing and electron micrograph approaches and define 2 clearly distinct connectivity endophenotypes within the autism spectrum. We conclude that the genetic background of ASD strongly influences which circuits are most affected, the nature of the phenotype, and the developmental time course of the associated changes.
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- 2018
4. Emerging imaging methods to study whole-brain function in rodent models
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Markicevic, Marija, Savvateev, Iurii, Grimm, Christina, and Zerbi, Valerio
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- 2021
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5. Inhibiting mGluR5 activity by AFQ056/Mavoglurant rescues circuit-specific functional connectivity in Fmr1 knockout mice
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Zerbi, Valerio, Markicevic, Marija, Gasparini, Fabrizio, Schroeter, Aileen, Rudin, Markus, and Wenderoth, Nicole
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- 2019
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6. Neuromodulation of striatal D1 cells shapes BOLD fluctuations in anatomically connected thalamic and cortical regions.
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Markicevic, Marija, Sturman, Oliver, Bohacek, Johannes, Rudin, Markus, Zerbi, Valerio, Fulcher, Ben D., and Wenderoth, Nicole
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CELL morphology , *NEUROMODULATION , *FUNCTIONAL connectivity , *FUNCTIONAL magnetic resonance imaging , *ANIMAL models in research , *DOPAMINE receptors , *THALAMIC nuclei - Abstract
Understanding how the brain's macroscale dynamics are shaped by underlying microscale mechanisms is a key problem in neuroscience. In animal models, we can now investigate this relationship in unprecedented detail by directly manipulating cellular-level properties while measuring the whole-brain response using resting-state fMRI. Here, we focused on understanding how blood-oxygen-level-dependent (BOLD) dynamics, measured within a structurally well-defined striato-thalamo-cortical circuit in mice, are shaped by chemogenetically exciting or inhibiting D1 medium spiny neurons (MSNs) of the right dorsomedial caudate putamen (CPdm). We characterize changes in both the BOLD dynamics of individual cortical and subcortical brain areas, and patterns of inter-regional coupling (functional connectivity) between pairs of areas. Using a classification approach based on a large and diverse set of time-series properties, we found that CPdm neuromodulation alters BOLD dynamics within thalamic subregions that project back to dorsomedial striatum. In the cortex, changes in local dynamics were strongest in unimodal regions (which process information from a single sensory modality) and weakened along a hierarchical gradient towards transmodal regions. In contrast, a decrease in functional connectivity was observed only for cortico-striatal connections after D1 excitation. Our results show that targeted cellular-level manipulations affect local BOLD dynamics at the macroscale, such as by making BOLD dynamics more predictable over time by increasing its self-correlation structure. This contributes to ongoing attempts to understand the influence of structure-function relationships in shaping inter-regional communication at subcortical and cortical levels. [ABSTRACT FROM AUTHOR]
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- 2023
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7. Cortical Excitation:Inhibition Imbalance Causes Abnormal Brain Network Dynamics as Observed in Neurodevelopmental Disorders.
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Markicevic, Marija, Fulcher, Ben D, Lewis, Christopher, Helmchen, Fritjof, Rudin, Markus, Zerbi, Valerio, and Wenderoth, Nicole
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- 2020
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8. Aberrant Somatosensory Processing and Connectivity in Mice Lacking Engrailed-2.
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Chelini, Gabriele, Zerbi, Valerio, Cimino, Luca, Grigoli, Andrea, Markicevic, Marija, Libera, Francesco, Robbiati, Sergio, Gadler, Mattia, Bronzoni, Silvia, Miorelli, Silvia, Galbusera, Alberto, Gozzi, Alessandro, Casarosa, Simona, Provenzano, Giovanni, and Bozzi, Yuri
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AMYGDALOID body ,WHISKERS ,MICE - Abstract
Overreactivity and defensive behaviors in response to tactile stimuli are common symptoms in autism spectrum disorder (ASD) patients. Similarly, somatosensory hypersensitivity has also been described in mice lacking ASD-associated genes such as Fmrl (fragile X mental retardation protein 1). Fmrl knock-out mice also show reduced functional connectivity between sensory cortical areas, which may represent an endogenous biomarker for their hypersensitivity. Here, we measured whole-brain functional connectivity in Engrailed-2 knock-out (En2
-/- ) adult mice, which show a lower expression of Fmrl and anatomical defects common to Fmrl knock-outs. MRIbased resting-state functional connectivity in adult En2-/- mice revealed significantly reduced synchronization in somatosensoryauditory/associative cortices and dorsal thalamus, suggesting the presence of aberrant somatosensory processing in these mutants. Accordingly, when tested in the whisker nuisance test, En2-/- but not WT mice of both sexes showed fear behavior in response to repeated whisker stimulation. En2-/- mice undergoing this test exhibited decreased c-Fos-positive neurons (a marker of neuronal activity) in layer IV of the primary somatosensory cortex and increased immunoreactive cells in the basolateral amygdala compared with WT littermates. Conversely, when tested in a sensory maze, En2-/- and WT mice spent a comparable time in whisker-guided exploration, indicating that whisker-mediated behaviors are otherwise preserved in En2-/- mutants. Therefore, fearful responses to somatosensory stimuli in En2-/- mice are accompanied by reduced basal connectivity of sensory regions, reduced activation of somatosensory cortex, and increased activation of the basolateral amygdala, suggesting that impaired somatosensory processing is a common feature in mice lacking ASD-related genes. [ABSTRACT FROM AUTHOR]- Published
- 2019
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9. Rapid Reconfiguration of the Functional Connectome after Chemogenetic Locus Coeruleus Activation.
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Zerbi, Valerio, Floriou-Servou, Amalia, Markicevic, Marija, Vermeiren, Yannick, Sturman, Oliver, Privitera, Mattia, von Ziegler, Lukas, Ferrari, Kim David, Weber, Bruno, De Deyn, Peter Paul, Wenderoth, Nicole, and Bohacek, Johannes
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LOCUS coeruleus , *ADRENERGIC receptors - Abstract
The locus coeruleus (LC) supplies norepinephrine (NE) to the entire forebrain and regulates many fundamental brain functions. Studies in humans have suggested that strong LC activation might shift network connectivity to favor salience processing. To causally test this hypothesis, we use a mouse model to study the effect of LC stimulation on large-scale functional connectivity by combining chemogenetic activation of the LC with resting-state fMRI, an approach we term "chemo-connectomics." We show that LC activation rapidly interrupts ongoing behavior and strongly increases brain-wide connectivity, with the most profound effects in the salience and amygdala networks. Functional connectivity changes strongly correlate with transcript levels of alpha-1 and beta-1 adrenergic receptors across the brain, and functional network connectivity correlates with NE turnover within select brain regions. We propose that these changes in large-scale network connectivity are critical for optimizing neural processing in the context of increased vigilance and threat detection. • Chemo-connectomics combines chemogenetics (DREADDs) with resting-state fMRI • Locus coeruleus (LC) activation rapidly increases brain-wide functional connectivity • Connectivity changes correlate positively with adrenergic receptor distribution • LC activation shifts large-scale network connectivity toward salience processing Zerbi et al. selectively activate the mouse locus coeruleus , which provides norepinephrine to the brain. This induces anxiety and rapidly shifts network connectivity toward salience and fear processing. This appears to be mediated by the spatial distribution of adrenergic receptors. [ABSTRACT FROM AUTHOR]
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- 2019
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10. Prenatal interleukin 6 elevation increases glutamatergic synapse density and disrupts hippocampal connectivity in offspring.
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Mirabella, Filippo, Desiato, Genni, Mancinelli, Sara, Fossati, Giuliana, Rasile, Marco, Morini, Raffaella, Markicevic, Marija, Grimm, Christina, Amegandjin, Clara, Termanini, Alberto, Peano, Clelia, Kunderfranco, Paolo, di Cristo, Graziella, Zerbi, Valerio, Menna, Elisabetta, Lodato, Simona, Matteoli, Michela, and Pozzi, Davide
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SYNAPSES , *MATERNAL immune activation , *ENCEPHALITIS , *TRANSCRIPTION factors , *STAT proteins , *HIPPOCAMPUS (Brain) , *NEURAL development - Abstract
Early prenatal inflammatory conditions are thought to be a risk factor for different neurodevelopmental disorders. Maternal interleukin-6 (IL-6) elevation during pregnancy causes abnormal behavior in offspring, but whether these defects result from altered synaptic developmental trajectories remains unclear. Here we showed that transient IL-6 elevation via injection into pregnant mice or developing embryos enhanced glutamatergic synapses and led to overall brain hyperconnectivity in offspring into adulthood. IL-6 activated synaptogenesis gene programs in glutamatergic neurons and required the transcription factor STAT3 and expression of the RGS4 gene. The STAT3-RGS4 pathway was also activated in neonatal brains during poly(I:C)-induced maternal immune activation, which mimics viral infection during pregnancy. These findings indicate that IL-6 elevation at early developmental stages is sufficient to exert a long-lasting effect on glutamatergic synaptogenesis and brain connectivity, providing a mechanistic framework for the association between prenatal inflammatory events and brain neurodevelopmental disorders. [Display omitted] • Prenatal IL-6 causes increases in excitatory synapses and brain connectivity in adults • IL-6 activates genetic programs of synaptogenesis in developing neurons • Transcription factor STAT3 is activated in neurons upon IL-6 elevation • The STAT3 downstream gene Rgs4 is responsible for the increase in excitatory synapses Prenatal inflammation is a risk factor for different neurodevelopmental disorders, but the mechanisms by which brain connectivity is affected remain unclear. Mirabella et al. demonstrate that transient maternal elevation of IL-6 induces an abnormal, long-lasting increase of excitatory synapses and brain connectivity in the offspring, providing a mechanistic link between maternal immune activation and defects in newborn brain development. [ABSTRACT FROM AUTHOR]
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- 2021
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11. The Microglial Innate Immune Receptor TREM2 Is Required for Synapse Elimination and Normal Brain Connectivity.
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Filipello, Fabia, Morini, Raffaella, Corradini, Irene, Zerbi, Valerio, Canzi, Alice, Michalski, Bernadeta, Erreni, Marco, Markicevic, Marija, Starvaggi-Cucuzza, Chiara, Otero, Karel, Piccio, Laura, Cignarella, Francesca, Perrucci, Fabio, Tamborini, Matteo, Genua, Marco, Rajendran, Lawrence, Menna, Elisabetta, Vetrano, Stefania, Fahnestock, Margaret, and Paolicelli, Rosa Chiara
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NATURAL immunity , *MICROGLIA , *SYNAPSES , *NEURAL transmission , *NEURAL circuitry - Abstract
Summary The triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial innate immune receptor associated with a lethal form of early, progressive dementia, Nasu-Hakola disease, and with an increased risk of Alzheimer’s disease. Microglial defects in phagocytosis of toxic aggregates or apoptotic membranes were proposed to be at the origin of the pathological processes in the presence of Trem2 inactivating mutations. Here, we show that TREM2 is essential for microglia-mediated synaptic refinement during the early stages of brain development. The absence of Trem2 resulted in impaired synapse elimination, accompanied by enhanced excitatory neurotransmission and reduced long-range functional connectivity. Trem2 −/− mice displayed repetitive behavior and altered sociability. TREM2 protein levels were also negatively correlated with the severity of symptoms in humans affected by autism. These data unveil the role of TREM2 in neuronal circuit sculpting and provide the evidence for the receptor’s involvement in neurodevelopmental diseases. [ABSTRACT FROM AUTHOR]
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- 2018
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12. Repetitive Mild Closed-Head Injury Induced Synapse Loss and Increased Local BOLD-fMRI Signal Homogeneity.
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Markicevic M, Mandino F, Toyonaga T, Cai Z, Fesharaki-Zadeh A, Shen X, Strittmatter SM, and Lake EMR
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Repeated mild head injuries due to sports, or domestic violence and military service are increasingly linked to debilitating symptoms in the long term. Although symptoms may take decades to manifest, potentially treatable neurobiological alterations must begin shortly after injury. Better means to diagnose and treat traumatic brain injuries requires an improved understanding of the mechanisms underlying progression and means through which they can be measured. Here, we employ a repetitive mild traumatic brain injury (rmTBI) and chronic variable stress mouse model to investigate emergent structural and functional brain abnormalities. Brain imaging is achieved with [
18 F]SynVesT-1 positron emission tomography, with the synaptic vesicle glycoprotein 2A ligand marking synapse density and BOLD (blood-oxygen-level-dependent) functional magnetic resonance imaging (fMRI). Animals were scanned six weeks after concluding rmTBI/Stress procedures. Injured mice showed widespread decreases in synaptic density coupled with an i ncrease in local BOLD-fMRI synchrony detected as regional homogeneity. Injury-affected regions with higher synapse density showed a greater increase in fMRI regional homogeneity. Taken together, these observations may reflect compensatory mechanisms following injury. Multimodal studies are needed to provide deeper insights into these observations.- Published
- 2024
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13. Multimodal identification of the mouse brain using simultaneous Ca 2+ imaging and fMRI.
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Mandino F, Horien C, Shen X, Desrosiers-Gregoire G, Luo W, Markicevic M, Constable RX, Papademetris X, Chakravarty MM, Betzel RF, and Lake EMR
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Individual differences in neuroimaging are of interest to clinical and cognitive neuroscientists based on their potential for guiding the personalized treatment of various heterogeneous neurological conditions and diseases. Despite many advantages, the workhorse in this arena, BOLD (blood-oxygen-level-dependent) functional magnetic resonance imaging (fMRI) suffers from low spatiotemporal resolution and specificity as well as a propensity for noise and spurious signal corruption. To better understand individual differences in BOLD-fMRI data, we can use animal models where fMRI, alongside complementary but more invasive contrasts, can be accessed. Here, we apply simultaneous wide-field fluorescence calcium imaging and BOLD-fMRI in mice to interrogate individual differences using a connectome-based identification framework adopted from the human fMRI literature. This approach yields high spatiotemporal resolution cell-type specific signals (here, from glia, excitatory, as well as inhibitory interneurons) from the whole cortex. We found mouse multimodal connectome- based identification to be successful and explored various features of these data.
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- 2024
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14. Intrinsic excitation-inhibition imbalance affects medial prefrontal cortex differently in autistic men versus women.
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Trakoshis S, Martínez-Cañada P, Rocchi F, Canella C, You W, Chakrabarti B, Ruigrok AN, Bullmore ET, Suckling J, Markicevic M, Zerbi V, Baron-Cohen S, Gozzi A, Lai MC, Panzeri S, and Lombardo MV
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- Adult, Animals, England, Female, Humans, Inhibition, Psychological, Language, Magnetic Resonance Imaging, Male, Mice, Middle Aged, Sex Factors, Young Adult, Autistic Disorder physiopathology, Communication, Mice, Inbred C57BL physiology, Prefrontal Cortex physiopathology
- Abstract
Excitation-inhibition (E:I) imbalance is theorized as an important pathophysiological mechanism in autism. Autism affects males more frequently than females and sex-related mechanisms (e.g., X-linked genes, androgen hormones) can influence E:I balance. This suggests that E:I imbalance may affect autism differently in males versus females. With a combination of in-silico modeling and in-vivo chemogenetic manipulations in mice, we first show that a time-series metric estimated from fMRI BOLD signal, the Hurst exponent (H), can be an index for underlying change in the synaptic E:I ratio. In autism we find that H is reduced, indicating increased excitation, in the medial prefrontal cortex (MPFC) of autistic males but not females. Increasingly intact MPFC H is also associated with heightened ability to behaviorally camouflage social-communicative difficulties, but only in autistic females. This work suggests that H in BOLD can index synaptic E:I ratio and that E:I imbalance affects autistic males and females differently., Competing Interests: ST, PM, FR, CC, WY, BC, AR, JS, MM, VZ, SB, AG, ML, SP, ML No competing interests declared, EB is employed half-time by the University of Cambridge and half-time at GlaxoSmithKline plc (GSK); he holds stock in GSK. All other authors have no conflict of interests to declare., (© 2020, Trakoshis et al.)
- Published
- 2020
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