Biology subjects

Gozzi, A.

Publications and source records attributed to Gozzi, A..

At least 37 records · Page 2Linked to original sources

bioRxiv2022

Sex-biasing influence of autism-associated Ube3a gene overdosage at connectomic, behavioral and transcriptomic levels

Many neurodevelopmental conditions, including autism, affect males more than females. Genomic mechanisms enhancing risk in males may contribute to this sex-bias. The ubiquitin protein ligase E3A gene (Ube3a) exerts pleiotropic effects on cellular homeostasis via control of protein turnover and by acting as transcriptional coactivator with steroid hormone receptors. Overdosage of Ube3a via duplication or triplication of chromosomal region 15q11-13 causes 1-2% of autistic cases. Here, we test the hypothesis that increased dosage of Ube3a may influence autism-relevant phenotypes in a sex-biased manner. We report robust sex-biasing effects on brain connectomics and repetitive behaviors in mice with extra copies of Ube3a. These effects were associated with a profound transcriptional dysregulation of several known autism-associated genes (e.g., FMR1, SCN2A, PTEN, MEF2C, SHANK3, TSC2) as well as differentially-expressed genes identified in human 15q duplication and in autistic patients. Notably, increased Ube3a dosage also affects multiple sex-relevant mechanisms, including genes on the X chromosome, genes influenced by sex steroid hormones, downstream targets of the androgen and estrogen receptors, or genes that are sex-differentially regulated by transcription factors. These results suggest that Ube3a overdosage can critically contribute to sex-bias in neurodevelopmental conditions via influence on sex-differential mechanisms.

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bioRxiv2022

The evolution of information transmission in mammalian brain networks

Brain communication, defined as information transmission through white-matter connections, is at the foundation of the brains computational capacities that subtend almost all aspects of behavior: from sensory perception shared across mammalian species, to complex cognitive functions in humans. How did communication strategies in macroscale brain networks adapted across evolution to accomplish increasingly complex functions? By applying a graph- and information-theory approach to assess information-related pathways in mouse, macaque and human brains, we show a brain communication gap between selective information transmission in non-human mammals, where brain regions share information through single polysynaptic pathways, and parallel information transmission in humans, where regions share information through multiple parallel pathways. In humans, parallel transmission acts as a major connector between unimodal and transmodal systems. The layout of information-related pathways is unique to individuals across different mammalian species, pointing at the individual-level specificity of information routing architecture. Our work provides evidence that different communication patterns are tied to the evolution of mammalian brain networks.

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bioRxiv2022

A model of the mouse cortex with attractor dynamics explains the structure and emergence of rsfMRI co-activation patterns

Resting state fMRI activity in mammals exhibits rich dynamics on a fast, frame-by-frame timescale of seconds, including the robust emergence of recurring fMRI co-activation patterns (CAPs). To understand how such dynamics emerges from the underlying anatomical cortico-cortical connectivity, we developed a whole-cortex model of resting-state fMRI activity in the mouse. Our model implemented neural input-output nonlinearities and excitatory-inhibitory interactions within cortical regions, as well as directed anatomical connectivity between regions inferred from the Allen mouse brain atlas. We found that, even if the model parameters were fitted to explain static properties of fMRI activity on the timescale of minutes, the model generated rich frame-by-frame attractor dynamics, with multiple stationary and oscillatory attractors. Guided by these theoretical predictions, we found that empirical mouse fMRI time series exhibited analogous signatures of attractor dynamics, and that model attractors recapitulated the topographical organization of empirical fMRI CAPs. The model established key relationships between attractor dynamics, CAPs and features of the directed cortico-cortical intra- and inter-hemispheric anatomical connectivity. Specifically, we found that neglecting fiber directionality severely affected the number of models attractors and their ability to explain CAPs. Furthermore, modifying inter-hemispheric anatomical connectivity strength by decreasing or increasing it from the value of real mouse anatomical data, resulted in fewer attractors generated by cortico-cortical interactions and reduced non-homotopic features of the attractors generated by the model, which were important for better predicting empirical CAPs. These results offer novel theoretical insight into the dynamic organization of resting state fMRI in the mouse brain and suggest that the frame-wise BOLD activity captured by CAPs reflects an emerging property of cortical dynamics resulting from directed cortico-cortical interactions. Author summaryWhole-brain activity at rest transitions on a timescale of seconds between stereotyped co-activation patterns (CAPs), each with a distinct spatial profile of co-activation across different brain regions. CAPs have been robustly reported across datasets and mammalian species, including humans and mice. However, the significance and origin of these patterns remain unknown. Here we studied the origin of CAPs using a computational model of the whole cortex based on real-world directed measurements of mouse cortical anatomical connectivity. We found that we could explain the formation and topography of CAPs in terms of attractors (that is, states the network tends to converge to) that reflect the information in the anatomical connections between cortical regions. Attractors and CAPs are significantly influenced by the directionality of connectivity (available in mice but not in humans) and the strength of inter-hemispheric coupling. Together, our findings provide a novel possible explanation of the mechanisms of CAP generation which relates to cortico-cortical connectivity, and suggest that CAPs are at least in part an emergent property of cortico-cortical interactions which can be generated also in absence of the action of arousing modulatory nuclei.

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bioRxiv2022

Functional MRI reveals memories of mother in newborn chicks

Filial imprinting has been used as a powerful ethological paradigm to investigate the neurobiology of early learning that affects lifelong behaviours. When a visually naive chick is exposed to one of a wide range of conspicuous objects, it may learn its characteristics and subsequently recognises and selectively approaches this stimulus (usually the mother hen and siblings). While the initial phases of memory acquisition have been unravelled, the long-term storage and retrieval components of imprinting memories are still unknown. Here, we used functional MRI in awake newly hatched chicks to identify the long-term storage of imprinting memories in a wide network comprising the hippocampal formation, the medial striatum, the arcopallium, and the prefrontal-like nidopallium caudolaterale. These results provide the first example of non-invasive imaging of the brain in a newborn vertebrate.

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bioRxiv2021

Unique spatiotemporal fMRI dynamics in the awake mouse brain

Human imaging studies have shown that spontaneous brain activity exhibits stereotypic spatiotemporal reorganization in awake, conscious conditions with respect to minimally conscious states. However, whether and how this phenomenon can be generalized to lower mammalian species, remains unclear. Leveraging a robust protocol for resting-state fMRI (rsfMRI) mapping in non-anesthetized, head-fixed mice, we investigated functional network topography and dynamic structure of spontaneous brain activity in wakeful animals. We found that rsfMRI networks in the awake state, while anatomically comparable to those observed under anesthesia, are topologically configured to maximize interregional communication, departing from the underlying community structure of the mouse axonal connectome. We further report that rsfMRI activity in wakeful animals exhibits unique spatiotemporal dynamics characterized by a state-dependent, dominant occurrence of coactivation patterns encompassing a prominent participation of arousal-related forebrain nuclei, and functional anti-coordination between visual-auditory and polymodal cortical areas. We finally show that rsfMRI dynamics in awake mice exhibits a stereotypical temporal structure, in which state-dominant coactivation patterns are configured as network attractors. These findings suggest that spontaneous brain activity in awake mice is critically shaped by state-specific involvement of basal forebrain arousal systems, and document that its dynamic structure recapitulates distinctive, evolutionarily-relevant principles that are predictive of conscious states in higher mammalian species.

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bioRxiv2021

Microglia complement signaling promotes neuronal elimination and normal brain functional connectivity

Complement signaling is thought to serve as an opsonization signal to promote the phagocytosis of synapses by microglia. However, while its role in synaptic remodeling has been demonstrated in the retino-thalamic system, it remains unclear whether complement signaling mediates synaptic pruning in the brain more generally. Here we show that mice lacking the complement 3 receptor (C3r), the major microglia complement receptor, fail to show a deficit in either synaptic pruning or axon elimination in the developing mouse cortex. Instead, mice lacking C3r show a deficit in the perinatal elimination of neurons, both in the retina as well as in the cortex, a deficit that is associated with increased cortical thickness and enhanced functional connectivity in these regions in adulthood. These data demonstrate a preferential role for complement in promoting neuronal elimination in the developing brain and argue for a reconsideration of the role of complement in synaptic pruning.

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bioRxiv2021

Somatosensory processing deficits and altered cortico-hippocampal connectivity in Shank3b-/- mice

Abnormal tactile response is considered an integral feature of Autism Spectrum Disorders (ASDs), and hypo-responsiveness to tactile stimuli is often associated with the severity of ASDs core symptoms. Patients with Phelan-McDermid syndrome (PMS), caused by mutations in the SHANK3 gene, show ASD-like symptoms associated with aberrant tactile responses. However, the neural underpinnings of these somatosensory abnormalities are still poorly understood. Here we investigated, in Shank3b-/- adult mice, the neural substrates of whisker-guided behaviors, a key component of rodents interaction with the surrounding environment. To this aim, we assessed whisker-dependent behaviors in Shank3b-/- adult mice and age-matched controls, using the textured novel object recognition (tNORT) and whisker nuisance (WN) test. Shank3b-/- mice showed deficits in whisker-dependent texture discrimination in tNORT and behavioral hypo-responsiveness to repetitive whisker stimulation in WN. Notably, sensory hypo-responsiveness was accompanied by a significantly reduced activation of the primary somatosensory cortex (S1) and hippocampus, as measured by c-fos mRNA in situ hybridization, a proxy of neuronal activity following whisker stimulation. Moreover, resting-state fMRI showed a significantly reduced S1-hippocampal connectivity in Shank3b mutant mice. Together, these findings suggest that impaired crosstalk between hippocampus and S1 might underlie Shank3b-/- hypo-reactivity to whisker-dependent cues, highlighting a potentially generalizable form of dysfunctional somatosensory processing in ASD. Significance StatementPatients with Phelan-McDermid syndrome, a syndromic form of ASD caused by mutation of the SHANK3 gene, often show aberrant responses to touch. However, the neural basis of atypical sensory responses in ASD remains undetermined. Here we used Shank3 deficient mice to investigate the neural substrates of behavioral responses to repetitive stimulation of the whiskers, a highly developed sensory organ in mice. We found that mice lacking the Shank3 gene are hypo-responsive to repetitive whisker stimulation. This trait was associated with reduced engagement and connectivity between the primary somatosensory cortex and hippocampus. These results suggest that dysfunctional cortico-hippocampal coupling may underlie somatosensory processing deficits in SHANK3 mutation carriers and related syndromic forms of ASD.

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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

A cross-species link between mTOR-related synaptic pathology and functional hyperconnectivityin autism

Postmortem studies have revealed increased density of excitatory synapses in the brains of individuals with autism, with a putative link to aberrant mTOR-dependent synaptic pruning. Autism is also characterized by atypical macroscale functional connectivity as measured with resting-state fMRI (rsfMRI). These observations raise the question of whether excess of synapses cause aberrant functional connectivity in autism. Using rsfMRI, electrophysiology and in silico modelling in Tsc2 haploinsufficient mice, we show that mTOR-dependent increased spine density is associated with autism-like stereotypies and cortico-striatal hyperconnectivity. These deficits are completely rescued by pharmacological inhibition of mTOR. Notably, we further demonstrate that children with idiopathic autism exhibit analogous cortical-striatal hyperconnectivity, and document that this connectivity fingerprint is enriched for autism-dysregulated genes interacting with mTOR or TSC2. Finally, we show that the identified transcriptomic signature is predominantly expressed in a subset of children with autism, thereby defining a segregable autism subtype. Our findings causally link mTOR-related synaptic pathology to large-scale network aberrations, revealing a unifying multi-scale framework that mechanistically reconciles developmental synaptopathy and functional hyperconnectivity in autism. SignificanceAberrant brain functional connectivity is a hallmark of autism, but the neural basis of this phenomenon remains unclear. We show that a mouse line recapitulating mTOR-dependent synaptic pruning deficits observed in postmortem autistic brains exhibits widespread functional hyperconnectivity. Importantly, pharmacological normalization of mTOR signalling completely rescues synaptic, behavioral and functional connectivity deficits. We also show that a similar connectivity fingerprint can be isolated in human fMRI scans of people with autism, where it is linked to over-expression of mTOR-related genes. Our results reveal a unifying multi-scale translational framework that mechanistically links aberrations in synaptic pruning with functional hyperconnectivity in autism.

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bioRxiv2020

Cortical silencing results in paradoxical fMRI overconnectivity

fMRI-based measurements of functional connectivity are commonly interpreted as an index of anatomical coupling and direct interareal communication. However, causal testing of this hypothesis has been lacking. Here we combine neural silencing, resting-state fMRI and in vivo electrophysiology to causally probe how inactivation of a cortical region affects brain-wide functional coupling. We find that chronic silencing of the prefrontal cortex (PFC) via overexpression of a potassium channel paradoxically increases rsfMRI connectivity between the silenced area and its thalamo-cortical terminals. Acute chemogenetic silencing of the PFC reproduces analogous patterns of overconnectivity, an effect associated with over-synchronous fMRI coupling between polymodal thalamic regions and widespread cortical districts. Notably, multielectrode recordings revealed that chemogenetic inactivation of the PFC attenuates gamma activity and increases delta power in the silenced area, resulting in robustly increased delta band coherence between functionally overconnected regions. The observation of enhanced rsfMRI coupling between chemogenetically silenced areas challenges prevailing interpretations of functional connectivity as a monotonic index of direct axonal communication, and points at a critical contribution of slow rhythm generators to the establishment of brain-wide functional coupling.

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bioRxiv2020

Regional, layer, and cell-class specific connectivity of the mouse default mode network

The evolutionarily conserved default mode network (DMN) is characterized by temporally correlated activity between brain regions during resting states. The DMN has emerged as a selectively vulnerable network in multiple disorders, so understanding its anatomical composition will provide fundamental insight into how its function is impacted by disease. Reproducible rodent analogs of the human DMN offer an opportunity to investigate the underlying brain regions and structural connectivity (SC) with high spatial and cell type resolution. Here, we performed systematic analyses using mouse resting state functional magnetic resonance imaging to identify the DMN and whole brain axonal tracing data, co-registered to the 3D Allen Mouse Common Coordinate Framework reference atlas. We identified the specific, predominantly cortical, brain regions comprising the mouse DMN and report preferential SC between these regions. Next, at the cell class level, we report that cortical layer (L) 2/3 neurons in DMN regions project almost exclusively to other DMN regions, whereas L5 neurons project to targets both in and out of the DMN. We then test the hypothesis that in- and out-DMN projection patterns originate from distinct L5 neuron sub-classes using an intersectional viral tracing strategy to label all the axons from neurons defined by a single target. In the ventral retrosplenial cortex, a core DMN region, we found two L5 projection types related to the DMN and mapped them to unique transcriptomically-defined cell types. Together, our results provide a multi-scale description of the anatomical correlates of the mouse DMN.

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bioRxiv2020

Connectome and microcircuit models implicate atypical subcortico-cortical interactions in autism pathophysiology

AO_SCPLOWBSTRACTC_SCPLOWBoth macroscale connectome miswiring and microcircuit anomalies have been suggested to play a role in the pathophysiology of autism. However, an overarching framework that consolidates these macro and microscale perspectives of the condition is lacking. Here, we combined connectome-wide manifold learning and biophysical simulation models to understand associations between global network perturbations and microcircuit dysfunctions in autism. Our analysis established that autism showed significant differences in structural connectome organization relative to neurotypical controls, with strong effects in low-level somatosensory regions and moderate effects in high-level association cortices. Computational models revealed that the degree of macroscale anomalies was related to atypical increases of subcortical inputs into cortical microcircuits, especially in sensory and motor areas. Transcriptomic decoding and developmental gene enrichment analyses provided biological context and pointed to genes expressed in cortical and thalamic areas during childhood and adolescence. Supervised machine learning showed the macroscale perturbations predicted socio-cognitive symptoms and repetitive behaviors. Our analyses provide convergent support that atypical subcortico-cortical interactions may contribute to both microcircuit and macroscale connectome anomalies in autism.

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bioRxiv2020

The M1/M4 agonist xanomeline modulates functional connectivity and NMDAR antagonist-induced changes in the mouse brain

Cholinergic drugs acting at M1/M4 muscarinic receptors hold promise for the treatment of symptoms associated with brain disorders characterized by cognitive impairment, mood disturbances or psychosis, such as Alzheimers disease or schizophrenia. However, the brain-wide functional substrates engaged by muscarinic agonists remain poorly understood. Here we used a combination of pharmacological fMRI (phMRI), resting-state fMRI (rsfMRI) and resting-state quantitative EEG (qEEG) to investigate the effects of a behaviorally-active dose of M1/M4 agonist xanomeline on brain functional activity in the rodent brain. We investigated both the effects of xanomeline per se and its modulatory effects on signals elicited by the NMDA-receptor antagonists phencyclidine (PCP) and ketamine. We found that xanomeline induces robust and widespread BOLD signal phMRI amplitude increases and decreased high frequency qEEG spectral activity. rsfMRI mapping in the mouse revealed that xanomeline robustly decreased neocortical and striatal connectivity but induces focal increases in functional connectivity within the nucleus accumbens and basal forebrain. Notably, xanomeline pre-administration robustly attenuated both the cortico-limbic phMRI response and the fronto-hippocampal hyper-connectivity induced by PCP, enhanced PCP-modulated functional connectivity locally within the nucleus accumbens and basal forebrain, and reversed the gamma and high frequency qEEG power increases induced by ketamine. Collectively, these results show that xanomeline robustly induces both cholinergic-like neocortical activation and desynchronization of functional networks in the mammalian brain. These effects could serve as a translatable biomarker for future clinical investigations of muscarinic agents, and bear mechanistic relevance for the putative therapeutic effect of these class of compounds in brain disorders.

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bioRxiv2020

Network structure of the mouse brain connectome with voxel resolution

Fine-grained descriptions of brain connectivity are fundamental for understanding how neural information is processed and relayed across spatial scales. Prior investigations of the mouse brain connectome have employed discrete anatomical parcellations, limiting spatial resolution and potentially concealing network attributes critical to the organization of the mammalian connectome. Here we provide a voxel-level description of the network and hierarchical structure of the directed mouse connectome, unconstrained by regional partitioning. We show that integrative hub regions can be directionally segregated into neural sinks and sources, defining a hierarchical axis. We describe a set of structural communities that spatially reconstitute previously described fMRI networks of the mouse brain, and document that neuromodulatory nuclei are strategically wired as critical orchestrators of inter-modular and network communicability. Notably, like in primates, the directed mouse connectome is organized along two superimposed cortical gradients reflecting unimodal-transmodal functional processing and a modality-specific sensorimotor axis. These structural features can be related to patterns of intralaminar connectivity and to the spatial topography of dynamic fMRI brain states, respectively. Together, our results reveal a high-resolution structural scaffold linking mesoscale connectome topography to its macroscale functional organization, and create opportunities for identifying targets of interventions to modulate brain function in a physiologically-accessible species.

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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

Acute and repeated intranasal oxytocin differentially modulate brain-wide functional connectivity

Central release of the neuropeptide oxytocin (OXT) modulates neural substrates involved in socio-affective behavior. This property has prompted research into the use of intranasal OXT administration as an adjunctive therapy for brain conditions characterized by social impairment, such as autism spectrum disorders (ASD). However, the neural circuitry and brain-wide functional networks recruited by intranasal OXT administration remain elusive. Moreover, little is known of the neuroadaptive cascade triggered by long-term administration of this peptide at the network level. To address these questions, we applied fMRI-based circuit mapping in adult mice upon acute and repeated (seven-day) intranasal dosing of OXT. We report that acute and chronic OXT administration elicit comparable fMRI activity as assessed with cerebral blood volume mapping, but entail largely different patterns of brain-wide functional connectivity. Specifically, acute OXT administration focally boosted connectivity within key limbic components of the rodent social brain, whereas repeated dosing led to a prominent and widespread increase in functional connectivity, involving a strong coupling between the amygdala and extended cortical territories. Importantly, this connectional reconfiguration was accompanied by a paradoxical reduction in social interaction and communication in wild-type mice. Our results identify the network substrates engaged by exogenous OXT administration, and show that repeated OXT dosing leads to a substantial reconfiguration of brain-wide connectivity, entailing an aberrant functional coupling between cortico-limbic structures involved in socio-communicative and affective functions. Such divergent patterns of network connectivity might contribute to discrepant clinical findings involving acute or long-term OXT dosing in clinical populations.

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bioRxiv2018

Deletion of autism risk gene Shank3 disrupts prefrontal connectivity

Mutations in the synaptic scaffolding protein Shank3 are a major cause of autism, and are associated with prominent intellectual and language deficits. However, the neural mechanisms whereby SHANK3 deficiency affects higher order socio-communicative functions remain unclear. Using high-resolution functional and structural MRI in mice, here we show that loss of Shank3 (Shank3B-/-) results in disrupted local and long-range prefrontal functional connectivity, as well as fronto-striatal decoupling. We document that prefrontal hypo-connectivity is associated with reduced short-range cortical projections density, and reduced gray matter volume. Finally, we show that prefrontal disconnectivity is predictive of social communication deficits, as assessed with ultrasound vocalization recordings. Collectively, our results reveal a critical role of SHANK3 in the development of prefrontal anatomy and function, and suggest that SHANK3 deficiency may predispose to intellectual disability and socio-communicative impairments via dysregulation of higher-order cortical connectivity.

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bioRxiv2018

Oscillatory brain states govern spontaneous fMRI network dynamics

Spontaneous brain activity as assessed with resting-state fMRI exhibits rich spatiotemporal structure. However, the principles by which brain-wide patterns of spontaneous fMRI activity reconfigure and interact with each other, remain unclear. We devised a frame-wise clustering approach to map spatiotemporal dynamics of spontaneous fMRI activity with voxel resolution in the resting mouse brain. We show that brain-wide patterns of fMRI co-activation can be reliably mapped at the group and subject level, defining a restricted set of recurring brain states characterized by rich network structure. We document that these functional states are characterized by contrasting patterns of spontaneous fMRI activity and exhibit coupled oscillatory dynamics, with each state occurring at specific phases of global fMRI signal fluctuations. Finally, we show that autism-associated genetic alterations result in the engagement of non-canonical brain states and altered coupled oscillatory dynamics. Our approach reveals a new set of fundamental principles guiding the spatiotemporal organization of resting state fMRI activity, and its disruption in brain disorders.

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