Valerio Zerbi

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Zerbi

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Valerio

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0000-0001-7984-9565

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Publications 1 - 10 of 25

Nanostructure-specific X-ray tomography reveals myelin levels, integrity and axon orientations in mouse and human nervous tissue
Georgiadis, Marios; Schroeter, Aileen; Gao, Zirui; et al. (2021)
Nature Communications
Myelin insulates neuronal axons and enables fast signal transmission, constituting a key component of brain development, aging and disease. Yet, myelin-specific imaging of macroscopic samples remains a challenge. Here, we exploit myelin’s nanostructural periodicity, and use small-angle X-ray scattering tensor tomography (SAXS-TT) to simultaneously quantify myelin levels, nanostructural integrity and axon orientations in nervous tissue. Proof-of-principle is demonstrated in whole mouse brain, mouse spinal cord and human white and gray matter samples. Outcomes are validated by 2D/3D histology and compared to MRI measurements sensitive to myelin and axon orientations. Specificity to nanostructure is exemplified by concomitantly imaging different myelin types with distinct periodicities. Finally, we illustrate the method’s sensitivity towards myelin-related diseases by quantifying myelin alterations in dysmyelinated mouse brain. This non-destructive, stain-free molecular imaging approach enables quantitative studies of myelination within and across samples during development, aging, disease and treatment, and is applicable to other ordered biomolecules or nanostructures.
Functional-based parcellation of the mouse prefrontal cortex for network perturbation analysis
Savvateev, Iurii; Grimm, Christina; Markicevic, Marija; et al. (2025)
Cell Reports
The prefrontal cortex (PFC) is a brain region involved in higher-order cognitive processes such as attention, emotional regulation, and social behavior. However, the delineation of distinct subdivisions within the mouse PFC and their contributions to the broader brain network function remain debated. This study utilizes resting-state functional magnetic resonance imaging (MRI) from a cohort of 100 C57BL/6J wild-type mice to derive the functional connectivity (FC)-based parcellation of the mouse PFC with voxel resolution. Our findings reveal clusters that deviate from the established anatomical subdivisions within the cingulate and prelimbic areas while aligning in infralimbic and orbital cortices. Upon the chemogenetic perturbation of one of the clusters, FC perturbations occur only within the functional network linked to the targeted cluster and do not spread to neighboring anatomical areas or functional clusters. We propose FC-based parcellation as a valuable approach for tracking the site of activation and network impact of neurostimulation strategies.
Concurrent optoacoustic tomography and magnetic resonance imaging of resting-state functional connectivity in the mouse brain
Gezginer, Irmak; Chen, Zhenyue; Yoshihara, Hikari A.I.; et al. (2024)
Nature Communications
Resting-state functional connectivity (rsFC) has been essential to elucidate the intricacy of brain organization, further revealing clinical biomarkers of neurological disorders. Although functional magnetic resonance imaging (fMRI) remains a cornerstone in the field of rsFC recordings, its interpretation is often hindered by the convoluted physiological origin of the blood-oxygen-level-dependent (BOLD) contrast affected by multiple factors. Here, we capitalize on the unique concurrent multiparametric hemodynamic recordings of a hybrid magnetic resonance optoacoustic tomography platform to comprehensively characterize rsFC in female mice. The unique blood oxygenation readings and high spatio-temporal resolution at depths provided by functional optoacoustic (fOA) imaging offer an effective means for elucidating the connection between BOLD and hemoglobin responses. Seed-based and independent component analyses reveal spatially overlapping bilateral correlations between the fMRI-BOLD readings and the multiple hemodynamic components measured with fOA but also subtle discrepancies, particularly in anti-correlations. Notably, total hemoglobin and oxygenated hemoglobin components are found to exhibit stronger correlation with BOLD than deoxygenated hemoglobin, challenging conventional assumptions on the BOLD signal origin.
Rapid Reconfiguration of the Functional Connectome after Chemogenetic Locus Coeruleus Activation
Zerbi, Valerio; Floriou-Servou, Amalia; Markicevic, Marija; et al. (2019)
Neuron
Imaging evolution of the primate brain: the next frontier?
Friedrich, Patrick; Forkel, Stephanie J.; Amiez, Céline; et al. (2021)
NeuroImage
Evolution, as we currently understand it, strikes a delicate balance between animals' ancestral history and adaptations to their current niche. Similarities between species are generally considered inherited from a common ancestor whereas observed differences are considered as more recent evolution. Hence comparing species can provide insights into the evolutionary history. Comparative neuroimaging has recently emerged as a novel subdiscipline, which uses magnetic resonance imaging (MRI) to identify similarities and differences in brain structure and function across species. Whereas invasive histological and molecular techniques are superior in spatial resolution, they are laborious, post-mortem, and oftentimes limited to specific species. Neuroimaging, by comparison, has the advantages of being applicable across species and allows for fast, whole-brain, repeatable, and multi-modal measurements of the structure and function in living brains and post-mortem tissue. In this review, we summarise the current state of the art in comparative anatomy and function of the brain and gather together the main scientific questions to be explored in the future of the fascinating new field of brain evolution derived from comparative neuroimaging.
Emerging imaging methods to study whole-brain function in rodent models
Markicevic, Marija; Savvateev, Iurii; Grimm, Christina; et al. (2021)
Translational Psychiatry
In the past decade, the idea that single populations of neurons support cognition and behavior has gradually given way to the realization that connectivity matters and that complex behavior results from interactions between remote yet anatomically connected areas that form specialized networks. In parallel, innovation in brain imaging techniques has led to the availability of a broad set of imaging tools to characterize the functional organization of complex networks. However, each of these tools poses significant technical challenges and faces limitations, which require careful consideration of their underlying anatomical, physiological, and physical specificity. In this review, we focus on emerging methods for measuring spontaneous or evoked activity in the brain. We discuss methods that can measure large-scale brain activity (directly or indirectly) with a relatively high temporal resolution, from milliseconds to seconds. We further focus on methods designed for studying the mammalian brain in preclinical models, specifically in mice and rats. This field has seen a great deal of innovation in recent years, facilitated by concomitant innovation in gene-editing techniques and the possibility of more invasive recordings. This review aims to give an overview of currently available preclinical imaging methods and an outlook on future developments. This information is suitable for educational purposes and for assisting scientists in choosing the appropriate method for their own research question. [Figure not available: see fulltext.]
Tonic and burst-like locus coeruleus stimulation distinctly shift network activity across the cortical hierarchy
Grimm, Christina; Duss, Sian N.; Privitera, Mattia; et al. (2024)
Nature Neuroscience
Noradrenaline (NA) release from the locus coeruleus (LC) changes activity and connectivity in neuronal networks across the brain, modulating multiple behavioral states. NA release is mediated by both tonic and burst-like LC activity. However, it is unknown whether the functional changes in target areas depend on these firing patterns. Using optogenetics, photometry, electrophysiology and functional magnetic resonance imaging in mice, we show that tonic and burst-like LC firing patterns elicit brain responses that hinge on their distinct NA release dynamics. During moderate tonic LC activation, NA release engages regions associated with associative processing, while burst-like stimulation biases the brain toward sensory processing. These activation patterns locally couple with increased astrocytic and inhibitory activity and change the brain's topological configuration in line with the hierarchical organization of the cerebral cortex. Together, these findings reveal how the LC-NA system achieves a nuanced regulation of global circuit operations.
On the use of preclinical imaging to explore the principles of brain function in rodent models and their relevance for illnesses of the human mind
Zerbi, Valerio (2022)
Translational Psychiatry
Brain mapping across 16 autism mouse models reveals a spectrum of functional connectivity subtypes
Zerbi, Valerio; Pagani, Marco; Markicevic, Marija; et al. (2021)
Molecular Psychiatry
Autism Spectrum Disorder (ASD) is characterized by substantial, yet highly heterogeneous abnormalities in functional brain connectivity. However, the origin and significance of this phenomenon remain unclear. To unravel ASD connectopathy and relate it to underlying etiological heterogeneity, we carried out a bi-center cross-etiological investigation of fMRI-based connectivity in the mouse, in which specific ASD-relevant mutations can be isolated and modeled minimizing environmental contributions. By performing brain-wide connectivity mapping across 16 mouse mutants, we show that different ASD-associated etiologies cause a broad spectrum of connectional abnormalities in which diverse, often diverging, connectivity signatures are recognizable. Despite this heterogeneity, the identified connectivity alterations could be classified into four subtypes characterized by discrete signatures of network dysfunction. Our findings show that etiological variability is a key determinant of connectivity heterogeneity in ASD, hence reconciling conflicting findings in clinical populations. The identification of etiologically-relevant connectivity subtypes could improve diagnostic label accuracy in the non-syndromic ASD population and paves the way for personalized treatment approaches.
CDKL5 sculpts functional callosal connectivity to promote cognitive flexibility
Awad, Patricia Nora; Zerbi, Valerio; Johnson-Venkatesh, Erin M.; et al. (2024)
Molecular Psychiatry
Functional and structural connectivity alterations in short- and long-range projections have been reported across neurodevelopmental disorders (NDD). Interhemispheric callosal projection neurons (CPN) represent one of the major long-range projections in the brain, which are particularly important for higher-order cognitive function and flexibility. However, whether a causal relationship exists between interhemispheric connectivity alterations and cognitive deficits in NDD remains elusive. Here, we focused on CDKL5 Deficiency Disorder (CDD), a severe neurodevelopmental disorder caused by mutations in the X-linked Cyclin-dependent kinase-like 5 (CDKL5) gene. We found an increase in homotopic interhemispheric connectivity and functional hyperconnectivity across higher cognitive areas in adult male and female CDKL5-deficient mice by resting-state functional MRI (rs-fMRI) analysis. This was accompanied by an increase in the number of callosal synaptic inputs but decrease in local synaptic connectivity in the cingulate cortex of juvenile CDKL5-deficient mice, suggesting an impairment in excitatory synapse development and a differential role of CDKL5 across excitatory neuron subtypes. These deficits were associated with significant cognitive impairments in CDKL5 KO mice. Selective deletion of CDKL5 in the largest subtype of CPN likewise resulted in an increase of functional callosal inputs, without however significantly altering intracortical cingulate networks. Notably, such callosal-specific changes were sufficient to cause cognitive deficits. Finally, when CDKL5 was selectively re-expressed only in this CPN subtype, in otherwise CDKL5-deficient mice, it was sufficient to prevent the cognitive impairments of CDKL5 mutants. Together, these results reveal a novel role of CDKL5 by demonstrating that it is both necessary and sufficient for proper CPN connectivity and cognitive function and flexibility, and further validates a causal relationship between CPN dysfunction and cognitive impairment in a model of NDD.

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Valerio Zerbi

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