Biology subjects

Gozzi, A.

Publications and source records attributed to Gozzi, A..

6 recordsLinked to original sources

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.

neuroscience↗

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.

neuroscience↗

bioRxiv2018

Multi-Link Analysis: Brain Network Comparison via Sparse Connectivity Analysis

The analysis of the brain from a connectivity perspective is unveiling novel insights into brain structure and function. Discovery is, however, hindered by the lack of prior knowledge used to make hypotheses. On the other hand, exploratory data analysis is made complex by the high dimensionality of data. Indeed, in order to assess the effect of pathological states on brain networks, neuroscientists are often required to evaluate experimental effects in case-control studies, with hundreds of thousand connections.\n\nIn this paper, we propose an approach to identify the multivariate relationships in brain connections that characterise two distinct groups, hence permitting the investigators to immediately discover sub-networks that contain information about the differences between experimental groups. In particular, we are interested in data discovery related to connectomics, where the connections that characterize differences between two groups of subjects are found. Nevertheless, those connections not necessarily maximize accuracy in classification since this does not guarantee reliable interpretation of specific differences between groups. In practice, our method exploits recent machine learning techniques employing sparsity to deal with weighted networks describing the whole-brain macro connectivity. We evaluated our technique on functional and structural connectomes from human and mice brain data. In our experiments, we automatically identified disease-relevant connections in datasets with supervised and unsupervised anatomy-driven parcellation approaches, and by using high-dimensional datasets.

neuroscience↗

bioRxiv2017

Distinctive Behavioural Anomalies, Structural Brain Phenotypes And Cortical Hyper-Connectivity In Chd8-Deficient Mice

Truncating CHD8 mutations are amongst the highest confidence risk factors for autism spectrum disorders (ASD) identified to date. To investigate how reduced Chd8 gene dosage may disrupt brain development and predispose individuals to ASD, we generated a Chd8 heterozygous mouse model. In line with clinical observations, we found that Chd8 heterozygous mice displayed subtle brain hyperplasia and hypertelorism, coupled with increased postnatal brain weight. Chd8 heterozygous mice displayed anomalous behaviours, but autism-like social deficits, repetitive and restricted behaviours were not present. Only minor gene expression changes were observed in the embryonic neocortex at E12.5, with more pronounced gene expression changes in postnatal cortex at P5. Differentially expressed genes showed highly significant enrichment for known autism candidates. Amongst the down-regulated transcripts, genes involved in cell adhesion and axon guidance were particularly prominent, implicating impaired connectivity as a potential mechanism underlying the ASD phenotype. To probe this further, we performed resting state functional fMRI and found increased synchronised activity in cortico-hippocampal and auditory-parietal networks, hinting at impaired sensory processing. Together, these data show that Chd8 heterozygous mice recapitulate key clinical features found in patients with CHD8 mutations and show a unique combination of behavioural phenotypes, which may be underpinned by a distinctive disruption of brain connectivity and sensory processing.

neuroscience↗

bioRxiv2017

Brainwide Mapping Of Endogenous Serotonergic Transmission Via Chemogenetic-fMRI

Serotonergic transmission affects behaviours and neuro-physiological functions via the orchestrated recruitment of distributed neural systems. It is however unclear whether serotonins modulatory effect entails a global regulation of brainwide neural activity, or is relayed and encoded by a set of primary functional substrates. Here we combine DREADD-based chemogenetics and mouse fMRI, an approach we term \"chemo-fMRI\", to causally probe the brainwide substrates modulated by phasic serotonergic activity. We describe the generation of a conditional knock-in mouse line that, crossed with serotonin-specific Cre-recombinase mice, allowed us to remotely stimulate serotonergic neurons during fMRI scans. We show that chemogenetic stimulation of the serotonin system does not affect global brain activity, but results in region-specific activation of a set of primary target regions encompassing parieto-cortical, hippocampal, and midbrain structures, as well as ventro-striatal components of the mesolimbic reward systems. Many of the activated regions also exhibit increased c-Fos immunostaining upon chemogenetic stimulation in freely-behaving mice, corroborating a neural origin for the observed functional signals. These results identify a set of regional substrates that act as primary functional targets of endogenous serotonergic stimulation, and establish causation between phasic activation of serotonergic neurons and regional fMRI signals. They further highlight a functional cross-talk between serotonin and mesolimbic dopamine systems hence providing a novel framework for understanding serotonin dependent functions and interpreting data obtained from human fMRI studies of serotonin modulating agents.

neuroscience↗

bioRxiv2017

Serotonin Buffers Hippocampal Neuroplasticity And Emotional Behavior

Adaptation to environmental insults is an evolutionary mechanism essential for survival. The hippocampus participates in controlling adaptive responses to stress and emotional state through the modulation of neuroplasticity events, which are dysregulated in stress-related neuropsychiatric disorders. The neurotransmitter serotonin (5-HT) has been proposed as a pivotal player in hippocampal neuroplasticity in both normal and neuropsychiatric conditions though its role remains still poorly understood. Here, we investigated the impact of 5-HT deficiency on hippocampal activity combining RNA-seq, in vivo neuroimaging, neuroanatomical, biochemical and behavioral experiments on 5-HT depleted mice. We unveil that serotonin is required for appropriate activation of neuroplasticity adaptive mechanisms to environmental insults. Bidirectional deregulation of these programs in serotonin depleted mice is associated with opposite behavioral traits that model core symptoms of bipolar disorder. These findings delineate a previously unreported buffering role of 5-HT in instructing hippocampal activity and emotional responses to environmental demands.

neuroscience↗