Biology subjects

Zerbi, V.

Publications and source records attributed to Zerbi, V..

At least 19 recordsLinked to original sources

bioRxiv2026

Cortical excitability inversely modulates fMRI connectivity via low-frequency neuronal coupling

The neural mechanisms supporting fMRI connectivity are poorly understood. Leveraging an aggregated analysis of novel and existing chemogenetic manipulations and electrophysiological recordings in the mouse medial prefrontal cortex (PFC), we show that local cortical excitability inversely modulates large-scale fMRI connectivity. Specifically, we find that bidirectional chemogenetic manipulations of cortical excitability produce opposite effects on fMRI connectivity, resulting in fMRI hypoconnectivity when excitability is enhanced, and fMRI hyperconnectivity when excitability is suppressed, despite corresponding increases or decreases in local neuronal firing. Notably, while each chemogenetic manipulation produces a distinct profile of interareal electrophysiological coherence, only low-frequency (< 4Hz) coherence predicts the direction and magnitude of the ensuing fMRI connectivity changes. Biophysical network modelling shows that the observed electrophysiological coherence profiles can arise from the interaction between direct inter-area communication changes mediated by local firing-rate variations, and shared larger-scale low-frequency covariation of ongoing neuronal activity. Together, our results reveal an inverse relationship between regional cortical excitability and large-scale fMRI connectivity, and indicate that fMRI connectivity is primarily supported by low frequency (<4 Hz) electrophysiological coupling. These findings open new avenues for modeling and interpreting fMRI connectivity in health, and in response to pathological or exogenous perturbations linked to cortical excitability.

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bioRxiv2026

A Conserved Locus Coeruleus fMRI Signature of Brain-State Transitions across Sleep, Anesthesia, and Wakefulness

Neuromodulatory systems dynamically reconfigure large-scale brain networks to support adaptation across behavioral and cognitive states. The locus coeruleus (LC), which broadcasts noradrenaline throughout the forebrain, is a central regulator of arousal and state-dependent dynamics. However, how LC activity manifests in brain-wide organization across physiological contexts, and how it biases fMRI connectivity, remains poorly understood. Using an optogenetically informed cross-species framework, we identify a transient LC-derived spatiotemporal pattern of brain activity accompanying brain-state transitions under progressively naturalistic conditions: controlled LC stimulation and endogenous LC fluctuations in anesthetized mice, sleep-wake transitions in rodents and humans, and resting-state activity in awake humans. This LC-derived signature is conserved across species and contexts, leaving a robust and detectable imprint on the BOLD signal. Critically, the prevalence of LC events systematically biases functional connectivity metrics in human fMRI. These findings establish LC activity as a mechanistically interpretable source of variability in resting-state measurements, with direct implications for the interpretation of fMRI biomarkers in arousal-related disorders.

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bioRxiv2025

Minute- and second-scale hippocampal network dysfunctions in the 3xTgAD mouse model of Alzheimer's disease are prevented by TSPO knockout

The 18kDa translocator protein (TSPO) is widely recognized as a biomarker of neuroinflammation, but recent evidence suggests that it may also play a direct role in the pathophysiology of neurological conditions with an inflammatory component such as Alzheimers disease (AD). In this study, we leveraged functional ultrasound imaging (fUSi) to assess how TSPO knockout influences brain activity and connectivity in the 3xTgAD mouse model of AD. Resting-state scans were performed in 16-month-old male and female mice across four genotypes: WT, TSPO-/-, 3xTgAD or 3xTgAD.TSPO-/-. Using a data-driven approach, we identified key functional networks, including a bilateral hippocampal-amygdala limbic network. Dual regression analysis revealed increased engagement of the ventral hippocampus within the limbic network and elevated hemodynamic variance in 3xTgAD mice compared to WT. Moreover, co-activation patterns (CAPs) analysis showed abnormal activation/deactivation cycles involving the dorsal hippocampus, both of which were prevented by TSPO knockout without affecting amyloid or tau burden. Our findings highlight a functional role for TSPO in shaping network dynamics and suggest that its deletion can mitigate brain dysfunction in AD models.

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bioRxiv2025

Complementary BOLD- and ADC-fMRI explore the role of lateral superior colliculus in flicker fusion frequency

The transition from static to dynamic vision is encoded in the superior colliculus, as recently shown using blood-oxygen-level-dependent functional MRI (BOLD-fMRI) of the rat brain. Visual stimulation at higher frequency than the flicker fusion frequency threshold leads to continuity illusion and is associated with negative BOLD response in the visual cortex, triggered by the superior colliculus. In this paper, we explored this mechanism using fMRI of the rat brain with visual stimulation at low (1Hz) and high (25Hz) frequency. We compared responses between different brain regions (the dorsolateral geniculate nucleus of the thalamus, the medial and lateral parts of the superior colliculus, and the visual cortex), sexes, and field strengths (9.4T and 14T, with varying contributions from large vessels). Results confirmed distinct neural responses to low and high frequency stimulation and highlighted the role of the lateral part of the superior colliculus in the transition from static to dynamic vision. Finally, we evaluated the ability of apparent diffusion coefficient (ADC)-fMRI to detect response to visual stimulation without vascular contribution. We found significant ADC-fMRI response in the medial and lateral parts of the superior colliculus but also in the corpus callosum. Our results highlight the ADC-fMRI high spatial specificity and high sensitivity to white matter.

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bioRxiv2025

Biological subtyping of autism via cross-species fMRI

It is frequently assumed that the phenotypic heterogeneity in autism spectrum disorder reflects underlying pathobiological variation. However, direct evidence in support of this hypothesis is lacking. Here, we leverage cross-species functional neuroimaging to examine whether variability in brain functional connectivity reflects distinct biological mechanisms. We find that fMRI connectivity alterations in 20 distinct mouse models of autism (n=549 individual mice) can be clustered into two prominent hypo- and hyperconnectivity subtypes. We show that these connectivity profiles are linked to distinct signaling pathways, with hypoconnectivity being associated with synaptic dysfunction, and hyperconnectivity reflecting transcriptional and immune-related alterations. Extending these findings to humans, we identify analogous hypo- and hyperconnectivity subtypes in a large, multicenter resting state fMRI dataset of n=940 autistic and n=1036 neurotypical individuals. Remarkably, hypo- and hyperconnectivity autism subtypes are replicable across independent cohorts (accounting for 25.1% of all autism data), exhibit distinct functional network architecture, are behaviorally dissociable, and recapitulate synaptic and immune mechanisms identified in corresponding mouse subtypes. Our cross-species investigation, thus, decodes the heterogeneity of fMRI connectivity in autism into distinct pathway-specific etiologies, offering a new empirical framework for targeted subtyping of autism.

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bioRxiv2024

Canonical time-series features for characterizing biologically informative dynamical patterns in fMRI

The interdisciplinary time-series analysis literature encompasses thousands of statistical features for quantifying interpretable properties of dynamical data. But for any given application, it is likely that just a small subset of informative time-series features is required to capture the dynamical quantities of interest. So, while comprehensive libraries of time-series features have been developed, it is useful to construct reduced and computationally efficient subsets for specific applications. In this work, we demonstrate a systematic process to deduce such a reduced set, focused on the problem of distinguishing changes to functional Magnetic Resonance Imaging (fMRI) time series caused by a range of experimental manipulations of excitatory and inhibitory neural activity in mouse cortical circuits. We reduce a comprehensive library of over 7000 candidate time-series features down to a subset of 16 features, which we call catchaMouse16, that aims to both: (i) accurately characterize biologically relevant properties of fMRI time series; and (ii) minimize inter-feature redundancy. The catchaMouse16 feature set accurately classifies experimental perturbations of neuronal activity from fMRI recordings, and also shows strong generalization performance on an unseen mouse and human resting-state fMRI data where it tracks spatial variations in excitatory and inhibitory cortical cell densities, often with greater statistical power than the full hctsa feature set. We provide an efficient, open-source implementation of the catchaMouse16 feature set in C (achieving an approximately 60 times speed-up relative to the native Matlab code of the same features), with wrappers for Python and Matlab. This work demonstrates a procedure to reduce a large candidate time-series feature set down to the key statistical properties of mouse fMRI dynamics that can be used to efficiently quantify and interpret informative dynamical patterns in neural time series.

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bioRxiv2024

Functional-based parcellation of the mouse prefrontal cortex for network perturbation analysis

The prefrontal cortex (PFC) is a region of the brain involved in higher-order cognitive processes such as attention, emotional regulation, and social behavior, making it a hotspot for an ongoing clinical and fundamental research. Importantly, its functionality is intricately interconnected within a wide array of functional networks encompassing multiple other brain areas. However, the delineation of distinct subdivisions within the mouse PFC and their contributions to the broader brain network function remain topics of ongoing debate. In the current study, we used resting-state functional magnetic resonance imaging (rsfMRI) from a large cohort of wildtype animals to derive the functional-connectivity (FC) based parcellation of the mouse PFC with voxel resolution. Our findings indicate the presence of FC-based clusters that deviate from the established anatomical subdivisions within the cingulate and prelimbic areas, while they align in infralimbic and orbital cortices. To further underscore the association of these FC-based clusters with distinct functional networks, we performed network-specific perturbations using chemogenetics in the identified clusters in dorsal PFC and monitor the elicited effects with fMRI (chemo-fMRI). Our recordings revealed that FC perturbations were observed only within the functional networks linked to the targeted clusters and did not spread to neighbouring anatomical areas or functional clusters. We propose that FC-based parcellation is a valuable approach for tracking the impact of external activations and confirming the precise site of activation. O_FIG O_LINKSMALLFIG WIDTH=127 HEIGHT=200 SRC="FIGDIR/small/586664v1_ufig1.gif" ALT="Figure 1"> View larger version (19K): org.highwire.dtl.DTLVardef@11d4042org.highwire.dtl.DTLVardef@165cb5forg.highwire.dtl.DTLVardef@b0a4aorg.highwire.dtl.DTLVardef@d093c9_HPS_FORMAT_FIGEXP M_FIG C_FIG

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bioRxiv2023

Multipair phase-modulated temporal interference electrical stimulation combined with fMRI.

Temporal Interference stimulation (TIS) is a promising non-invasive brain stimulation technique exploiting frequency-shifted kHz fields to modulate oscillatory neural activity without invasive procedures. While human studies suggest TIS efficacy in targeting relatively deep brain structures, recent computational modeling and animal studies indicate potential off-target stimulations via the application of standard TIS protocols. Here, we computationally optimized TIS targeting for the prefrontal cortex (PFC) in mice. Combining in vivo electrophysiological recordings, intracellular calcium dynamics with fiber photometry, and functional MRI, we confirmed TIS-induced amplitude modulation, neuronal entrainment and hemodynamic responses in the PFC, while also identifying off-target modulations. To mitigate off-target effects, we propose a novel configuration with three electrode pairs, one of which is actively phase-shifted by 180 degrees. This cancelling field significantly enhanced TIS focality, reducing off-target effects without compromising the TIS efficacy in the target area. This work effectively addresses one of TIS most critical shortcomings and opens new avenues for research and clinical applications. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=178 SRC="FIGDIR/small/571679v2_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@b04067org.highwire.dtl.DTLVardef@154549aorg.highwire.dtl.DTLVardef@17e63c3org.highwire.dtl.DTLVardef@c7a341_HPS_FORMAT_FIGEXP M_FIG C_FIG

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bioRxiv2023

Simultaneous single-cell calcium imaging of neuronal population activity and brain-wide BOLD fMRI

Blood Oxygen Level-Dependent (BOLD) functional Magnetic Resonance Imaging (fMRI) allows for non-invasive, indirect recordings of neural activity across the whole brain in both humans and animals. However, the relationship between the local neural population activity and the vascular activity is not completely understood. To investigate this relationship, we present a novel MRI compatible single-photon microscope capable of measuring cellular resolution Ca2+ activity of genetically defined neurons during whole-brain BOLD fMRI in awake behaving mice. Using this combined imaging approach, we found a difference in activity patterns between cells which was dependent on their location with respect to the vasculature. Notably, neurons near the vasculature showed pronounced negative activity during contralateral whisker movements at 3 Hz. In a second proof of concept experiment, we demonstrate the potential of recording both local neural activities, like those in the barrel field (SSp-bfd), and BOLD fMRI readings from interlinked brain regions. In sum, the presented technological advancement paves the way for studies examining the interplay between local brain circuits and overarching brain functions. In addition, the new approach enhances our understanding of the vascular BOLD fMRI signal, providing insights into the determinants of local neurovascular functions and the brains organizational framework across various scales.

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bioRxiv2022

Locus Coeruleus firing patterns selectively modulate brain activity and dynamics

Noradrenaline (NA) release from the brainstem nucleus locus coeruleus (LC) changes activity and connectivity in neuronal networks across the brain, thus modulating multiple behavioural states. NA release is mediated by both tonic and burst-like neuronal LC activity. However, it remains unknown whether the functional changes in downstream projection areas depend on these firing patterns. Using optogenetics, pupillometry, photometry, and functional MRI in mice, we show that tonic and burst LC firing patterns elicit brain responses that are specific to the activation frequency and temporal pattern. Tonic activation of the LC evokes nonlinear responses in prefrontal, limbic, and cerebellar regions, in line with the proposed inverted-U relationship between LC activity and behaviour. We further demonstrate that LC activity enhances network integration and acts as a facilitator of brain state transitions, hence increasing brain flexibility. Together, these findings reveal how the LC-NA system achieves a nuanced regulation of global circuit operations.

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bioRxiv2022

Neuromodulation of striatal D1 cells shapes BOLD fluctuations in anatomically connected thalamic and cortical regions

Understanding how the brains 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, are shaped by chemogenetically exciting or inhibiting D1 medium spiny neurons (MSNs) of the right dorsomedial striatum (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, the strongest changes in local dynamics were observed in unimodal regions, i.e., regions that process information from a single sensory modality, while changes in the local dynamics weakened along a putative cortical hierarchical gradient towards transmodal regions. In contrast, a decrease in functional connectivity was observed only for cortico-striatal connections after D1 excitation. Our results provide a comprehensive understanding of how targeted cellular-level manipulations affect local BOLD dynamics at the macroscale, including the role of a circuits structural characteristics and hierarchical cortical level in shaping those dynamics. These findings contribute to ongoing attempts to understand the influence of structure-function relationships in shaping inter-regional communication at subcortical and cortical levels.

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bioRxiv2021

Extracting dynamical understanding from neural-mass models of mouse cortex

New brain atlases with high spatial resolution and whole-brain coverage have rapidly advanced our knowledge of the brains neural architecture, including the systematic variation of excitatory and inhibitory cell densities across the mammalian cortex. But understanding how the brains microscale physiology shapes brain dynamics at the macroscale has remained a challenge. While physiologically based mathematical models of brain dynamics are well placed to bridge this explanatory gap, their complexity can form a barrier to providing clear mechanistic interpretation of the dynamics they generate. In this work we develop a neural-mass model of the mouse cortex and show how bifurcation diagrams, which capture local dynamical responses to inputs and their variation across brain regions, can be used to understand the resulting whole-brain dynamics. We show that strong fits to resting-state functional magnetic resonance imaging (fMRI) data can be found in surprisingly simple dynamical regimes--including where all brain regions are confined to a stable fixed point--in which regions are able to respond strongly to variations in their inputs, consistent with direct structural connections providing a strong constraint on functional connectivity in the anesthetized mouse. We also use bifurcation diagrams to show how perturbations to local excitatory and inhibitory coupling strengths across the cortex, constrained by cell-density data, provide spatially dependent constraints on resulting cortical activity, and support a greater diversity of coincident dynamical regimes. Our work illustrates methods for visualizing and interpreting model performance in terms of underlying dynamical mechanisms, an approach that is crucial for building explanatory and physiologically grounded models of the dynamical principles that underpin large-scale brain activity.

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bioRxiv2021

Multimodal Gradient Mapping of Rodent Hippocampus

The hippocampus plays a central role in supporting our coherent and enduring sense of self and our place in the world. Understanding its functional organisation is central to understanding this complex role. Previous studies suggest function varies along a long hippocampal axis, but there is disagreement about the presence of sharp discontinuities or gradual change along that axis. Other open questions relate to the underlying drivers of this variation and the conservation of organisational principles across species. Here, we delineate the primary organisational principles underlying patterns of hippocampal functional connectivity (FC) in the mouse using gradient analysis on resting state fMRI data. We further applied gradient analysis to mouse gene co-expression data to examine the relationship between variation in genomic anatomy and functional organisation. Two principal FC gradients along a hippocampal axis were revealed. The principal gradient exhibited a sharp discontinuity that divided the hippocampus into dorsal and ventral compartments. The second, more continuous, gradient followed the long axis of the ventral compartment. Dorsal regions were more strongly connected to areas involved in spatial navigation while ventral regions were more strongly connected to areas involved in emotion, recapitulating patterns seen in humans. In contrast, gene co-expression gradients showed a more segregated and discrete organisation. Our findings suggest that hippocampal functional organisation exhibits both sharp and gradual transitions and that hippocampal genomic anatomy exerts a subtle influence on this organisation.

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bioRxiv2021

Optogenetic Activation of Striatal D1/D2 Medium Spiny Neurons Differentially Engages Downstream Connected Areas Beyond the Basal Ganglia

The basal ganglia (BG) are a group of subcortical nuclei responsible for motor control, motor learning and executive function. Central to BG function are striatal medium spiny neurons (MSNs) expressing D1 and D2 dopamine receptors. D1 and D2 MSNs are typically considered functional antagonists that facilitate voluntary movements and inhibit competing motor patterns, respectively. While their opposite role is well documented for certain sensorimotor loops of the BG-thalamocortical network, it is unclear whether MSNs maintain a uniform functional role across the striatum and which influence they exert on brain areas outside the BG. Here, we addressed these questions by combining optogenetic activation of D1 and D2 MSNs in the mouse ventrolateral caudoputamen (vl CPu) with whole-brain functional MRI (fMRI) recordings. Neuronal excitation of either cell population in the vl CPu evoked distinct activity patterns in key regions of the BG-thalamocortical network including the pallidum, thalamus and motor cortex. Importantly, we report that striatal D1 and D2 MSN stimulation differentially engaged cerebellar and prefrontal regions. We characterised these long-range interactions by computational modelling of effective connectivity and confirmed that changes in D1 / D2 output drive functional relationships between regions within and beyond the BG. These results suggest a more complex functional organization of MSNs across the striatum than previously anticipated and provide evidence for the existence of an interconnected fronto - BG - cerebellar network modulated by striatal D1 and D2 MSNs. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=129 HEIGHT=200 SRC="FIGDIR/small/436576v1_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@a18349org.highwire.dtl.DTLVardef@1b256faorg.highwire.dtl.DTLVardef@16c454aorg.highwire.dtl.DTLVardef@1392b23_HPS_FORMAT_FIGEXP M_FIG C_FIG

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bioRxiv2020

Transient Maternal IL-6 boosts glutamatergic synapses and disrupts hippocampal connectivity in the offspring

Early prenatal inflammatory conditions are thought to represent a risk factor for different neurodevelopmental disorders, with long-term consequences on adult brain connectivity. Here we show that a transient IL-6 elevation, occurring at vulnerable stages of early neurodevelopment, directly impacts brain developmental trajectories through the aberrant enhancement of glutamatergic synapses and overall brain hyper-connectivity. The IL6-mediated boost of excitatory synapse density results from the neuron-autonomous, genomic effect of the transcription factor STAT3 and causally involves the activation of RGS4 gene as a candidate downstream target. The STAT3/RGS4 pathway is also activated in neonatal brains as a consequence of maternal immune activation protocols mimicking a viral infection during pregnancy. By demonstrating that prenatal IL-6 elevations result in aberrant synaptic and brain connectivity through the molecular players identified, we provide a mechanistic framework for the association between prenatal inflammatory events and brain neurodevelopmental disorders.

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bioRxiv2020

Brain mapping across 16 autism mouse models reveals a spectrum of functional connectivity subtypes

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 modelled 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.

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bioRxiv2020

Intrinsic excitation-inhibition imbalance affects medial prefrontal cortex differently in autistic men versus women

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.

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bioRxiv2019

Primate homologs of mouse cortico-striatal circuits

With the increasing necessity of animal models in biomedical research, there is a vital need to harmonise findings across species by establishing similarities and differences in rodent and primate neuroanatomy. Using a connectivity fingerprint matching approach, we compared cortico-striatal circuits across humans, non-human primates, and mice using resting state fMRI data in all species. Our results suggest that the connectivity patterns for both the nucleus accumbens and cortico-striatal motor circuits (posterior/lateral putamen) were conserved across species, making them reliable targets for cross-species comparisons. However, a large number of human and macaque striatal voxels were not matched to any mouse cortico-striatal circuit (mouse->human: 85% unassigned; mouse->macaque 69% unassigned; macaque->human; 31% unassigned). These unassigned voxels were largely localised to the caudate nucleus and anterior putamen, overlapping with executive function and social/language regions of the striatum, and connected to prefrontal-projecting cerebellar lobules and anterior prefrontal cortex, forming circuits that seem to be unique for non-human primates and humans. Our results demonstrate the potential of connectivity fingerprint matching to bridge the gap between rodent and primate neuroanatomy.

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