Publications by authors named "Alessandro Gozzi"

79 Publications

Differences in subcortico-cortical interactions identified from connectome and microcircuit models in autism.

Nat Commun 2021 04 13;12(1):2225. Epub 2021 Apr 13.

McConnell Brain Imaging Centre, Montreal Neurological Institute and Hospital, McGill University, Montreal, QC, Canada.

The pathophysiology of autism has been suggested to involve a combination of both macroscale connectome miswiring and microcircuit anomalies. Here, we combine connectome-wide manifold learning with biophysical simulation models to understand associations between global network perturbations and microcircuit dysfunctions in autism. We studied neuroimaging and phenotypic data in 47 individuals with autism and 37 typically developing controls obtained from the Autism Brain Imaging Data Exchange initiative. Our analysis establishes significant differences in structural connectome organization in individuals with autism relative to controls, with strong between-group effects in low-level somatosensory regions and moderate effects in high-level association cortices. Computational models reveal that the degree of macroscale anomalies is related to atypical increases of recurrent excitation/inhibition, as well as subcortical inputs into cortical microcircuits, especially in sensory and motor areas. Transcriptomic association analysis based on postmortem datasets identifies genes expressed in cortical and thalamic areas from childhood to young adulthood. Finally, supervised machine learning finds that the macroscale perturbations are associated with symptom severity scores on the Autism Diagnostic Observation Schedule. Together, our analyses suggest that atypical subcortico-cortical interactions are associated with both microcircuit and macroscale connectome differences in autism.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-021-21732-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044226PMC
April 2021

Network structure of the mouse brain connectome with voxel resolution.

Sci Adv 2020 Dec 18;6(51). Epub 2020 Dec 18.

Functional Neuroimaging Laboratory, Center for Neuroscience and Cognitive Systems @ UniTn, Istituto Italiano di Tecnologia, Rovereto, Italy.

Fine-grained descriptions of brain connectivity are required to understand how neural information is processed and relayed across spatial scales. Previous investigations of the mouse brain connectome have used discrete anatomical parcellations, limiting spatial resolution and potentially concealing network attributes critical to connectome organization. Here, we provide a voxel-level description of the network and hierarchical structure of the directed mouse connectome, unconstrained by regional partitioning. We report a number of previously unappreciated organizational principles in the mammalian brain, including a directional segregation of hub regions into neural sink and sources, and a strategic wiring of neuromodulatory nuclei as connector hubs and critical orchestrators of network communication. We also find that the mouse cortical connectome is hierarchically organized along two superimposed cortical gradients reflecting unimodal-transmodal functional processing and a modality-specific sensorimotor axis, recapitulating a phylogenetically conserved feature of higher mammals. These findings advance our understanding of the foundational wiring principles of the mammalian connectome.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/sciadv.abb7187DOI Listing
December 2020

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

Neuropsychopharmacology 2021 05 20;46(6):1194-1206. Epub 2020 Dec 20.

Eli Lilly and Company, Indianapolis, IN, 46285, USA.

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 Alzheimer's 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 the M1/M4-preferring muscarinic 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41386-020-00916-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8115158PMC
May 2021

Regional, Layer, and Cell-Type-Specific Connectivity of the Mouse Default Mode Network.

Neuron 2021 02 7;109(3):545-559.e8. Epub 2020 Dec 7.

Allen Institute for Brain Science, Seattle, WA 98109, USA. Electronic address:

The evolutionarily conserved default mode network (DMN) is a distributed set of brain regions coactivated during resting states that is vulnerable to brain disorders. How disease affects the DMN is unknown, but detailed anatomical descriptions could provide clues. Mice offer an opportunity to investigate structural connectivity of the DMN across spatial scales with cell-type resolution. We co-registered maps from functional magnetic resonance imaging and axonal tracing experiments into the 3D Allen mouse brain reference atlas. We find that the mouse DMN consists of preferentially interconnected cortical regions. As a population, DMN layer 2/3 (L2/3) neurons project almost exclusively to other DMN regions, whereas L5 neurons project in and out of the DMN. In the retrosplenial cortex, a core DMN region, we identify two L5 projection types differentiated by in- or out-DMN targets, laminar position, and gene expression. These results provide a multi-scale description of the anatomical correlates of the mouse DMN.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neuron.2020.11.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8150331PMC
February 2021

Dysfunctional d-aspartate metabolism in BTBR mouse model of idiopathic autism.

Biochim Biophys Acta Proteins Proteom 2020 12 25;1868(12):140531. Epub 2020 Aug 25.

Translational Neuroscience Unit, IRCCS "Casa Sollievo della Sofferenza", San Giovanni Rotondo, Italy; CEINGE Biotecnologie Avanzate, Naples, Italy; Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania "Luigi Vanvitelli", Caserta, Italy. Electronic address:

Background: Autism spectrum disorders (ASD) comprise a heterogeneous group of neurodevelopmental conditions characterized by impairment in social interaction, deviance in communication, and repetitive behaviors. Dysfunctional ionotropic NMDA and AMPA receptors, and metabotropic glutamate receptor 5 activity at excitatory synapses has been recently linked to multiple forms of ASD. Despite emerging evidence showing that d-aspartate and d-serine are important neuromodulators of glutamatergic transmission, no systematic investigation on the occurrence of these D-amino acids in preclinical ASD models has been carried out.

Methods: Through HPLC and qPCR analyses we investigated d-aspartate and d-serine metabolism in the brain and serum of four ASD mouse models. These include BTBR mice, an idiopathic model of ASD, and Cntnap2, Shank3, and 16p11.2 mice, three established genetic mouse lines recapitulating high confidence ASD-associated mutations.

Results: Biochemical and gene expression mapping in Cntnap2, Shank3, and 16p11.2 failed to find gross cerebral and serum alterations in d-aspartate and d-serine metabolism. Conversely, we found a striking and stereoselective increased d-aspartate content in the prefrontal cortex, hippocampus and serum of inbred BTBR mice. Consistent with biochemical assessments, in the same brain areas we also found a robust reduction in mRNA levels of d-aspartate oxidase, encoding the enzyme responsible for d-aspartate catabolism.

Conclusions: Our results demonstrated the presence of disrupted d-aspartate metabolism in a widely used animal model of idiopathic ASD.

General Significance: Overall, this work calls for a deeper investigation of D-amino acids in the etiopathology of ASD and related developmental disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.bbapap.2020.140531DOI Listing
December 2020

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

Elife 2020 08 4;9. Epub 2020 Aug 4.

Laboratory for Autism and Neurodevelopmental Disorders, Center for Neuroscience and Cognitive Systems @UniTn, Istituto Italiano di Tecnologia, Rovereto, Italy.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7554/eLife.55684DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7402681PMC
August 2020

Biological history of an Italian prehistoric community and the population of the central Italy during the 1 millennium BCE.

Homo 2020 Aug;71(3):219-244

SABAP-RM-MET - Italian Ministry of Culture MIBACT, Via Cavalletti 2, Rome, 00169, Italy.

Understanding the population of Central Italy during the 1 millennium BCE is a crucial topic in the biological history of the Mediterranean basin. This period saw the emergence of the Etruscan and Roman cultures which had a significant impact on the bio-cultural history of the region. In this study, we analyse a prehistoric population from Caracupa (Iron Age, Latium, Central Italy). The results suggest an overall good level of health for the population. Despite this, some musculoskeletal changes related to biomechanical stressors were observed, probably as the result of strenuous physical activity. The results of a Simple Matching analysis of intragroup distance distributions suggest potential model of kinship structures and lineages. This may be due to the relative geographic isolation of the Caracupa population. Furthermore, in order to investigate the wider population of Central Italy during the 1 millennium BCE, we have constructed a population pattern using genetic and phenotypic skeletal and dental traits. The comparison between Central Italy and more isolated populations indicated a divergence between the Western and Eastern sides of Central Italy. However, we do not exclude a probable common genetic for all Central Italian populations during the 1 millennium BCE.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1127/homo/2020/1247DOI Listing
August 2020

Toward Neurosubtypes in Autism.

Biol Psychiatry 2020 07 22;88(1):111-128. Epub 2020 Apr 22.

Autism Center, Child Mind Institute, New York. Electronic address:

There is a consensus that substantial heterogeneity underlies the neurobiology of autism spectrum disorder (ASD). As such, it has become increasingly clear that a dissection of variation at the molecular, cellular, and brain network domains is a prerequisite for identifying biomarkers. Neuroimaging has been widely used to characterize atypical brain patterns in ASD, although findings have varied across studies. This is due, at least in part, to a failure to account for neurobiological heterogeneity. Here, we summarize emerging data-driven efforts to delineate more homogeneous ASD subgroups at the level of brain structure and function-that is, neurosubtyping. We break this pursuit into key methodological steps: the selection of diagnostic samples, neuroimaging features, algorithms, and validation approaches. Although preliminary and methodologically diverse, current studies generally agree that at least 2 to 4 distinct ASD neurosubtypes may exist. Their identification improved symptom prediction and diagnostic label accuracy above and beyond group average comparisons. Yet, this nascent literature has shed light onto challenges and gaps. These include 1) the need for wider and more deeply transdiagnostic samples collected while minimizing artifacts (e.g., head motion), 2) quantitative and unbiased methods for feature selection and multimodal fusion, 3) greater emphasis on algorithms' ability to capture hybrid dimensional and categorical models of ASD, and 4) systematic independent replications and validations that integrate different units of analyses across multiple scales. Solutions aimed to address these challenges and gaps are discussed for future avenues leading toward a comprehensive understanding of the mechanisms underlying ASD heterogeneity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.biopsych.2020.03.022DOI Listing
July 2020

Animal Functional Magnetic Resonance Imaging: Trends and Path Toward Standardization.

Front Neuroinform 2019 22;13:78. Epub 2020 Jan 22.

Singapore Bioimaging Consortium, Agency for Science, Technology and Research, Singapore, Singapore.

Animal whole-brain functional magnetic resonance imaging (fMRI) provides a non-invasive window into brain activity. A collection of associated methods aims to replicate observations made in humans and to identify the mechanisms underlying the distributed neuronal activity in the healthy and disordered brain. Animal fMRI studies have developed rapidly over the past years, fueled by the development of resting-state fMRI connectivity and genetically encoded neuromodulatory tools. Yet, comparisons between sites remain hampered by lack of standardization. Recently, we highlighted that mouse resting-state functional connectivity converges across centers, although large discrepancies in sensitivity and specificity remained. Here, we explore past and present trends within the animal fMRI community and highlight critical aspects in study design, data acquisition, and post-processing operations, that may affect the results and influence the comparability between studies. We also suggest practices aimed to promote the adoption of standards within the community and improve between-lab reproducibility. The implementation of standardized animal neuroimaging protocols will facilitate animal population imaging efforts as well as meta-analysis and replication studies, the gold standards in evidence-based science.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fninf.2019.00078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6987455PMC
January 2020

Acute and Repeated Intranasal Oxytocin Differentially Modulate Brain-wide Functional Connectivity.

Neuroscience 2020 10 7;445:83-94. Epub 2020 Jan 7.

Functional Neuroimaging Laboratory, Center for Neuroscience and Cognitive Systems @UniTn, Istituto Italiano di Tecnologia, Corso Bettini 31, 38068 Rovereto (TN), Italy. Electronic address:

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neuroscience.2019.12.036DOI Listing
October 2020

Common functional networks in the mouse brain revealed by multi-centre resting-state fMRI analysis.

Neuroimage 2020 01 12;205:116278. Epub 2019 Oct 12.

Douglas Mental Health University Institute, McGill University, Montreal, Quebec, Canada; Department of Psychiatry, McGill University, Montreal, Quebec, Canada; Department of Biological and Biomedical Engineering, McGill University, Montreal, Quebec, Canada.

Preclinical applications of resting-state functional magnetic resonance imaging (rsfMRI) offer the possibility to non-invasively probe whole-brain network dynamics and to investigate the determinants of altered network signatures observed in human studies. Mouse rsfMRI has been increasingly adopted by numerous laboratories worldwide. Here we describe a multi-centre comparison of 17 mouse rsfMRI datasets via a common image processing and analysis pipeline. Despite prominent cross-laboratory differences in equipment and imaging procedures, we report the reproducible identification of several large-scale resting-state networks (RSN), including a mouse default-mode network, in the majority of datasets. A combination of factors was associated with enhanced reproducibility in functional connectivity parameter estimation, including animal handling procedures and equipment performance. RSN spatial specificity was enhanced in datasets acquired at higher field strength, with cryoprobes, in ventilated animals, and under medetomidine-isoflurane combination sedation. Our work describes a set of representative RSNs in the mouse brain and highlights key experimental parameters that can critically guide the design and analysis of future rodent rsfMRI investigations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neuroimage.2019.116278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7116112PMC
January 2020

Infraslow State Fluctuations Govern Spontaneous fMRI Network Dynamics.

Curr Biol 2019 07 11;29(14):2295-2306.e5. Epub 2019 Jul 11.

Functional Neuroimaging Laboratory, Istituto Italiano di Tecnologia, Center for Neuroscience and Cognitive Systems @ UniTn, 38068 Rovereto (TN), Italy. Electronic address:

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 used a framewise 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. Importantly, we document that the identified fMRI states exhibit contrasting patterns of functional activity and coupled infraslow network dynamics, with each network state occurring at specific phases of global fMRI signal fluctuations. Finally, we show that autism-associated genetic alterations entail the engagement of atypical functional states and altered infraslow network dynamics. Our results reveal a novel set of fundamental principles guiding the spatiotemporal organization of resting-state fMRI activity and its disruption in brain disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.cub.2019.06.017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6657681PMC
July 2019

Deletion of Autism Risk Gene Shank3 Disrupts Prefrontal Connectivity.

J Neurosci 2019 07 6;39(27):5299-5310. Epub 2019 May 6.

Functional Neuroimaging Laboratory, Center for Neuroscience and Cognitive Systems, Istituto Italiano di Tecnologia, 38068 Rovereto, Italy,

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 adult male mice, here we show that loss of () results in disrupted local and long-range prefrontal and frontostriatal functional connectivity. We document that prefrontal hypoconnectivity 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. Mutations in the synaptic scaffolding protein SHANK3 are commonly associated with autism, intellectual, and language deficits. Previous research has linked SHANK3 deficiency to basal ganglia dysfunction, motor stereotypies, and social deficits. However, the neural mechanism whereby gene mutations affects cortical functional connectivity and higher-order socio-communicative functions remain unclear. Here we show that loss of SHANK3 in mice results in largely disrupted functional connectivity and abnormal gray matter anatomy in prefrontal areas. We also show that prefrontal connectivity disruption is tightly linked to socio-communicative deficits. Our findings suggest that SHANK3 is a critical orchestrator of frontocortical function, and that disrupted connectivity of prefrontal areas may underpin socio-communicative impairments observed in SHANK3 mutation carriers.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1523/JNEUROSCI.2529-18.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6607754PMC
July 2019

MultiLink Analysis: Brain Network Comparison via Sparse Connectivity Analysis.

Sci Rep 2019 01 11;9(1):65. Epub 2019 Jan 11.

Pattern Analysis and Computer Vision, Istituto Italiano di Tecnologia, Genova, Italy.

The analysis of the brain from a connectivity perspective is revealing novel insights into brain structure and function. Discovery is, however, hindered by the lack of prior knowledge used to make hypotheses. Additionally, exploratory data analysis is made complex by the high dimensionality of data. Indeed, 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 thousands of connections. In this paper, we propose an approach to identify the multivariate relationships in brain connections that characterize two distinct groups, hence permitting the investigators to immediately discover the subnetworks 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 do not necessarily maximize the 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 murine 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-018-37300-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6329758PMC
January 2019

Aberrant Somatosensory Processing and Connectivity in Mice Lacking .

J Neurosci 2019 02 28;39(8):1525-1538. Epub 2018 Dec 28.

Center for Mind/Brain Sciences (CIMeC), University of Trento, 38068 Rovereto, Italy,

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 (fragile X mental retardation protein 1). 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 knock-out () adult mice, which show a lower expression of and anatomical defects common to knock-outs. MRI-based resting-state functional connectivity in adult mice revealed significantly reduced synchronization in somatosensory-auditory/associative cortices and dorsal thalamus, suggesting the presence of aberrant somatosensory processing in these mutants. Accordingly, when tested in the whisker nuisance test, but not WT mice of both sexes showed fear behavior in response to repeated whisker stimulation. 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, and WT mice spent a comparable time in whisker-guided exploration, indicating that whisker-mediated behaviors are otherwise preserved in mutants. Therefore, fearful responses to somatosensory stimuli in 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. Overreactivity to tactile stimuli is a common symptom in autism spectrum disorder (ASD) patients. Recent studies performed in mice bearing ASD-related mutations confirmed these findings. Here, we evaluated the behavioral response to whisker stimulation in mice lacking the ASD-related gene ( mice). Compared with WT controls, mice showed reduced functional connectivity in the somatosensory cortex, which was paralleled by fear behavior, reduced activation of somatosensory cortex, and increased activation of the basolateral amygdala in response to repeated whisker stimulation. These results suggest that impaired somatosensory signal processing is a common feature in mice harboring ASD-related mutations.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1523/JNEUROSCI.0612-18.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6381254PMC
February 2019

Serotonin depletion causes valproate-responsive manic-like condition and increased hippocampal neuroplasticity that are reversed by stress.

Sci Rep 2018 08 7;8(1):11847. Epub 2018 Aug 7.

Department of Biology, Unit of Cell and Developmental Biology, University of Pisa, 56127, Pisa, Italy.

Abnormal hippocampal neural plasticity has been implicated in behavioural abnormalities and complex neuropsychiatric conditions, including bipolar disorder (BD). However, the determinants of this neural alteration remain unknown. This work tests the hypothesis that the neurotransmitter serotonin (5-HT) is a key determinant of hippocampal neuroplasticity, and its absence leads to maladaptive behaviour relevant for BD. Depletion of brain 5-HT in Tph2 mutant mice resulted in reduced behavioural despair, reduced anxiety, marked aggression and lower habituation in novel environments, reminiscent of bipolar-associated manic behaviour. Treatment with valproate produced a substantial improvement of the mania-like behavioural phenotypes displayed by Tph2 mutants. Brain-wide fMRI mapping in mutants revealed functional hippocampal hyperactivity in which we also observed dramatically increased neuroplasticity. Importantly, remarkable correspondence between the transcriptomic profile of the Tph2 mutant hippocampus and neurons from bipolar disorder patients was observed. Chronic stress reversed the emotional phenotype and the hippocampal transcriptional landscape of Tph2 mutants. These changes were associated with inappropriate activation of transcriptional adaptive response to stress as assessed by gene set enrichment analyses in the hippocampus of Tph2 mutant mice. These findings delineate 5-HT as a critical determinant in BD associated maladaptive emotional responses and aberrant hippocampal neuroplasticity, and support the use of Tph2-/- mice as a new research tool for mechanistic and therapeutic research in bipolar disorder.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41598-018-30291-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6081464PMC
August 2018

Pharmacological Inhibition of ERK Signaling Rescues Pathophysiology and Behavioral Phenotype Associated with 16p11.2 Chromosomal Deletion in Mice.

J Neurosci 2018 07 22;38(30):6640-6652. Epub 2018 Jun 22.

Department of Neurosciences, Case Western Reserve University, Cleveland, Ohio 44106-4928,

The human microdeletion is one of the most common gene copy number variations linked to autism, but the pathophysiology associated with this chromosomal abnormality is largely unknown. The 593 kb deletion contains the ERK1 gene and other genes that converge onto the ERK/MAP kinase pathway. Perturbations in ERK signaling are linked to a group of related neurodevelopmental disorders hallmarked by intellectual disability, including autism. We report that mice harboring the deletion exhibit a paradoxical elevation of ERK activity, cortical cytoarchitecture abnormalities and behavioral deficits. Importantly, we show that treatment with a novel ERK pathway inhibitor during a critical period of brain development rescues the molecular, anatomical and behavioral deficits in the deletion mice. The ERK inhibitor treatment administered to adult mice ameliorates a subset of these behavioral deficits. Our findings provide evidence for potential targeted therapeutic intervention in deletion carriers. The ERK/MAPK pathway is genetically linked to autism spectrum disorders and other syndromes typified by intellectual disability. We provide direct evidence connecting the ERK/MAP kinases to the developmental abnormalities in neurogenesis and cortical cytoarchitecture associated with the chromosomal deletion. Most importantly, we demonstrate that treatment with a novel ERK-specific inhibitor during development rescues aberrant cortical cytoarchitecture and restores normal levels of cell-cycle regulators during cortical neurogenesis. These treatments partially reverse the behavioral deficits observed in the mouse model, including hyperactivity, memory as well as olfaction, and maternal behavior. We also report a rescue of a subset of these deficits upon treatment of adult mice. These data provide a strong rationale for therapeutic approaches to this disorder.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1523/JNEUROSCI.0515-17.2018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6705960PMC
July 2018

Autism-associated 16p11.2 microdeletion impairs prefrontal functional connectivity in mouse and human.

Brain 2018 07;141(7):2055-2065

Functional Neuroimaging Laboratory, Istituto Italiano di Tecnologia, Center for Neuroscience and Cognitive Systems @UniTn, Rovereto, Italy.

Human genetic studies are rapidly identifying variants that increase risk for neurodevelopmental disorders. However, it remains unclear how specific mutations impact brain function and contribute to neuropsychiatric risk. Chromosome 16p11.2 deletion is one of the most common copy number variations in autism and related neurodevelopmental disorders. Using resting state functional MRI data from the Simons Variation in Individuals Project (VIP) database, we show that 16p11.2 deletion carriers exhibit impaired prefrontal connectivity, resulting in weaker long-range functional coupling with temporal-parietal regions. These functional changes are associated with socio-cognitive impairments. We also document that a mouse with the same genetic deficiency exhibits similarly diminished prefrontal connectivity, together with thalamo-prefrontal miswiring and reduced long-range functional synchronization. These results reveal a mechanistic link between specific genetic risk for neurodevelopmental disorders and long-range functional coupling, and suggest that deletion in 16p11.2 may lead to impaired socio-cognitive function via dysregulation of prefrontal connectivity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/brain/awy111DOI Listing
July 2018

Serotonergic Signaling Controls Input-Specific Synaptic Plasticity at Striatal Circuits.

Neuron 2018 05 26;98(4):801-816.e7. Epub 2018 Apr 26.

Neuromodulation of Cortical and Subcortical Circuits Laboratory, Neuroscience and Brain Technologies Department, Istituto Italiano di Tecnologia, Genova, Italy. Electronic address:

Monoaminergic modulation of cortical and thalamic inputs to the dorsal striatum (DS) is crucial for reward-based learning and action control. While dopamine has been extensively investigated in this context, the synaptic effects of serotonin (5-HT) have been largely unexplored. Here, we investigated how serotonergic signaling affects associative plasticity at glutamatergic synapses on the striatal projection neurons of the direct pathway (dSPNs). Combining chemogenetic and optogenetic approaches reveals that impeding serotonergic signaling preferentially gates spike-timing-dependent long-term depression (t-LTD) at thalamostriatal synapses. This t-LTD requires dampened activity of the 5-HT4 receptor subtype, which we demonstrate controls dendritic Ca signals by regulating BK channel activity, and which preferentially localizes at the dendritic shaft. The synaptic effects of 5-HT signaling at thalamostriatal inputs provide insights into how changes in serotonergic levels associated with behavioral states or pathology affect striatal-dependent processes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.neuron.2018.04.008DOI Listing
May 2018

Altered Neocortical Gene Expression, Brain Overgrowth and Functional Over-Connectivity in Chd8 Haploinsufficient Mice.

Cereb Cortex 2018 06;28(6):2192-2206

Centre for Craniofacial and Regenerative Biology, King's College London, London SE1 9RT, UK.

Truncating CHD8 mutations are amongst the highest confidence risk factors for autism spectrum disorder (ASD) identified to date. Here, we report that Chd8 heterozygous mice display increased brain size, motor delay, hypertelorism, pronounced hypoactivity, and anomalous responses to social stimuli. Whereas gene expression in the neocortex is only mildly affected at midgestation, over 600 genes are differentially expressed in the early postnatal neocortex. Genes involved in cell adhesion and axon guidance are particularly prominent amongst the downregulated transcripts. Resting-state functional MRI identified increased synchronized activity in cortico-hippocampal and auditory-parietal networks in Chd8 heterozygous mutant mice, implicating altered connectivity as a potential mechanism underlying the behavioral phenotypes. Together, these data suggest that altered brain growth and diminished expression of important neurodevelopmental genes that regulate long-range brain wiring are followed by distinctive anomalies in functional brain connectivity in Chd8+/- mice. Human imaging studies have reported altered functional connectivity in ASD patients, with long-range under-connectivity seemingly more frequent. Our data suggest that CHD8 haploinsufficiency represents a specific subtype of ASD where neuropsychiatric symptoms are underpinned by long-range over-connectivity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/cercor/bhy058DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6018918PMC
June 2018

Brain-wide Mapping of Endogenous Serotonergic Transmission via Chemogenetic fMRI.

Cell Rep 2017 Oct;21(4):910-918

Functional Neuroimaging Laboratory, Center for Neuroscience and Cognitive Systems, Istituto Italiano di Tecnologia, 38068 Rovereto, Italy; Biology Department, University of Pisa, 56127 Pisa, Italy.

Serotonin-producing neurons profusely innervate brain regions via long-range projections. However, it remains unclear whether and how endogenous serotonergic transmission specifically influences regional or global functional activity. We combined designed receptors exclusively activated by designed drugs (DREADD)-based chemogenetics and functional magnetic resonance imaging (fMRI), an approach we term "chemo-fMRI," to causally probe the brain-wide substrates modulated by endogenous serotonergic activity. We describe the generation of a conditional knockin mouse line that, crossed with serotonin-specific Cre-recombinase mice, allowed us to remotely stimulate serotonergic neurons during fMRI scans. We show that endogenous stimulation of serotonin-producing neurons does not affect global brain activity but results in region-specific activation of a set of primary target regions encompassing corticohippocampal and ventrostriatal areas. By contrast, pharmacological boosting of serotonin levels produced widespread fMRI deactivation, plausibly reflecting the mixed contribution of central and perivascular constrictive effects. Our results identify the primary functional targets of endogenous serotonergic stimulation and establish causation between activation of serotonergic neurons and regional fMRI signals.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.celrep.2017.09.087DOI Listing
October 2017

The Knockout of Synapsin II in Mice Impairs Social Behavior and Functional Connectivity Generating an ASD-like Phenotype.

Cereb Cortex 2017 10;27(10):5014-5023

Research Coordination and support Service, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy.

Autism spectrum disorders (ASD) and epilepsy are neurodevelopmental conditions that appear with high rate of co-occurrence, suggesting the possibility of a common genetic basis. Mutations in Synapsin (SYN) genes, particularly SYN1 and SYN2, have been recently associated with ASD and epilepsy in humans. Accordingly, mice lacking Syn1 or Syn2, but not Syn3, experience epileptic seizures and display autistic-like traits that precede the onset of seizures. Here, we analyzed social behavior and ultrasonic vocalizations emitted in 2 social contexts by SynI, SynII, or SynIII mutants and show that SynII mutants display the most severe ASD-like phenotype. We also show that the behavioral SynII phenotype correlates with a significant decrease in auditory and hippocampal functional connectivity as measured with resting state functional magnetic resonance imaging (rsfMRI). Taken together, our results reveal a permissive contribution of Syn2 to the expression of normal socio-communicative behavior, and suggest that Syn2-mediated synaptic dysfunction can lead to ASD-like behavior through dysregulation of cortical connectivity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/cercor/bhx207DOI Listing
October 2017

Repeated dexamphetamine treatment alters the dopaminergic system and increases the phMRI response to methylphenidate.

PLoS One 2017 27;12(2):e0172776. Epub 2017 Feb 27.

Department of Radiology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands.

Dexamphetamine (AMPH) is a psychostimulant drug that is used both recreationally and as medication for attention deficit hyperactivity disorder. Preclinical studies have demonstrated that repeated exposure to AMPH can induce damage to nerve terminals of dopamine (DA) neurons. We here assessed the underlying neurobiological changes in the DA system following repeated AMPH exposure and pre-treated rats with AMPH or saline (4 times 5 mg/kg s.c., 2 hours apart), followed by a 1-week washout period. We then used pharmacological MRI (phMRI) with a methylphenidate (MPH) challenge, as a sensitive and non-invasive in-vivo measure of DAergic function. We subsequently validated the DA-ergic changes post-mortem, using a.o. high-performance liquid chromatography (HPLC) and autoradiography. In the AMPH pre-treated group, we observed a significantly larger BOLD response to the MPH challenge, particularly in DA-ergic brain areas and their downstream projections. Subsequent autoradiography studies showed that AMPH pre-treatment significantly reduced DA transporter (DAT) density in the caudate-putamen (CPu) and nucleus accumbens, whereas HPLC analysis revealed increases in the DA metabolite homovanillic acid in the CPu. Our results suggest that AMPH pre-treatment alters DAergic responsivity, a change that can be detected with phMRI in rats. These phMRI changes likely reflect increased DA release together with reduced DAT binding. The ability to assess subtle synaptic changes using phMRI is promising for both preclinical studies of drug discovery, and for clinical studies where phMRI can be a useful tool to non-invasively investigate DA abnormalities, e.g. in neuropsychiatric disorders.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0172776PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5328278PMC
September 2017

Homozygous Loss of Autism-Risk Gene CNTNAP2 Results in Reduced Local and Long-Range Prefrontal Functional Connectivity.

Cereb Cortex 2018 04;28(4):1141-1153

Functional Neuroimaging Laboratory, Center for Neuroscience and Cognitive Systems @ UniTn, Istituto Italiano di Tecnologia, Rovereto 38068, Italy.

Functional connectivity aberrancies, as measured with resting-state functional magnetic resonance imaging (rsfMRI), have been consistently observed in the brain of autism spectrum disorders (ASD) patients. However, the genetic and neurobiological underpinnings of these findings remain unclear. Homozygous mutations in contactin associated protein-like 2 (CNTNAP2), a neurexin-related cell-adhesion protein, are strongly linked to autism and epilepsy. Here we used rsfMRI to show that homozygous mice lacking Cntnap2 exhibit reduced long-range and local functional connectivity in prefrontal and midline brain "connectivity hubs." Long-range rsfMRI connectivity impairments affected heteromodal cortical regions and were prominent between fronto-posterior components of the mouse default-mode network, an effect that was associated with reduced social investigation, a core "autism trait" in mice. Notably, viral tracing revealed reduced frequency of prefrontal-projecting neural clusters in the cingulate cortex of Cntnap2-/- mutants, suggesting a possible contribution of defective mesoscale axonal wiring to the observed functional impairments. Macroscale cortico-cortical white-matter organization appeared to be otherwise preserved in these animals. These findings reveal a key contribution of ASD-associated gene CNTNAP2 in modulating macroscale functional connectivity, and suggest that homozygous loss-of-function mutations in this gene may predispose to neurodevelopmental disorders and autism through a selective dysregulation of connectivity in integrative prefrontal areas.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/cercor/bhx022DOI Listing
April 2018

Differential Effects of Brain Disorders on Structural and Functional Connectivity.

Front Neurosci 2016 9;10:605. Epub 2017 Jan 9.

Istituto Italiano di Tecnologia, Center for Neuroscience and Cognitive Systems @UniTn Rovereto, Italy.

Different measures of brain connectivity can be defined based on neuroimaging read-outs, including structural and functional connectivity. Neurological and psychiatric conditions are often associated with abnormal connectivity, but comparing the effects of the disease on different types of connectivity remains a challenge. In this paper, we address the problem of quantifying the relative effects of brain disease on structural and functional connectivity at a group level. Within the framework of a graph representation of connectivity, we introduce a kernel two-sample test as an effective method to assess the difference between the patients and control group. Moreover, we propose a common representation space for structural and functional connectivity networks, and a novel test statistics to quantitatively assess differential effects of the disease on different types of connectivity. We apply this approach to a dataset from BTBR mice, a murine model of Agenesis of the Corpus Callosum (ACC), a congenital disorder characterized by the absence of the main bundle of fibers connecting the two hemispheres. We used normo-callosal mice (B6) as a comparator. The application of the proposed methods to this data-set shows that the two types of connectivity can be successfully used to discriminate between BTBR and B6, meaning that both types of connectivity are affected by ACC. However, our novel test statistics shows that structural connectivity is significantly more affected than functional connectivity, consistent with the idea that functional connectivity has a robust topology that can tolerate substantial alterations in its structural connectivity substrate.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fnins.2016.00605DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5221415PMC
January 2017

Intranasal Oxytocin and Vasopressin Modulate Divergent Brainwide Functional Substrates.

Neuropsychopharmacology 2017 Jun 20;42(7):1420-1434. Epub 2016 Dec 20.

Functional Neuroimaging Laboratory, Center for Neuroscience and Cognitive Systems @UniTn, Istituto Italiano di Tecnologia, Rovereto (TN), Italy.

The neuropeptides oxytocin (OXT) and vasopressin (AVP) have been identified as modulators of emotional social behaviors and associated with neuropsychiatric disorders characterized by social dysfunction. Experimental and therapeutic use of OXT and AVP via the intranasal route is the subject of extensive clinical research. However, the large-scale functional substrates directly engaged by these peptides and their functional dynamics remain elusive. By using cerebral blood volume (CBV) weighted fMRI in the mouse, we show that intranasal administration of OXT rapidly elicits the transient activation of cortical regions and a sustained activation of hippocampal and forebrain areas characterized by high oxytocin receptor density. By contrast, intranasal administration of AVP produced a robust and sustained deactivation in cortico-parietal, thalamic and mesolimbic regions. Importantly, intravenous administration of OXT and AVP did not recapitulate the patterns of modulation produced by intranasal dosing, supporting a central origin of the observed functional changes. In keeping with this notion, hippocampal local field potential recordings revealed multi-band power increases upon intranasal OXT administration. We also show that the selective OXT-derivative TGOT reproduced the pattern of activation elicited by OXT and that the deletion of OXT receptors does not affect AVP-mediated deactivation. Collectively, our data document divergent modulation of brainwide neural systems by intranasal administration of OXT and AVP, an effect that involves key substrates of social and emotional behavior. The observed divergence calls for a deeper investigation of the systems-level mechanisms by which exogenous OXT and AVP modulate brain function and exert their putative therapeutic effects.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/npp.2016.283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5436116PMC
June 2017

Can Mouse Imaging Studies Bring Order to Autism Connectivity Chaos?

Front Neurosci 2016 10;10:484. Epub 2016 Nov 10.

Functional Neuroimaging Laboratory, Center for Neuroscience and Cognitive Systems @ UniTn, Istituto Italiano di Tecnologia Rovereto, Italy.

Functional Magnetic Resonance Imaging (fMRI) has consistently highlighted impaired or aberrant functional connectivity across brain regions of autism spectrum disorder (ASD) patients. However, the manifestation and neural substrates of these alterations are highly heterogeneous and often conflicting. Moreover, their neurobiological underpinnings and etiopathological significance remain largely unknown. A deeper understanding of the complex pathophysiological cascade leading to aberrant connectivity in ASD can greatly benefit from the use of model organisms where individual pathophysiological or phenotypic components of ASD can be recreated and investigated via approaches that are either off limits or confounded by clinical heterogeneity. Despite some obvious limitations in reliably modeling the full phenotypic spectrum of a complex developmental disorder like ASD, mouse models have played a central role in advancing our basic mechanistic and molecular understanding of this syndrome. Recent progress in mouse brain connectivity mapping via resting-state fMRI (rsfMRI) offers the opportunity to generate and test mechanistic hypotheses about the elusive origin and significance of connectional aberrations observed in autism. Here we discuss recent progress toward this goal, and illustrate initial examples of how the approach can be employed to establish causal links between ASD-related mutations, developmental processes, and brain connectional architecture. As the spectrum of genetic and pathophysiological components of ASD modeled in the mouse is rapidly expanding, the use of rsfMRI can advance our mechanistic understanding of the origin and significance of the connectional alterations associated with autism, and their heterogeneous expression across patient cohorts.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fnins.2016.00484DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5102904PMC
November 2016

Hierarchical organization of functional connectivity in the mouse brain: a complex network approach.

Sci Rep 2016 08 18;6:32060. Epub 2016 Aug 18.

Istituto dei Sistemi Complessi ISC-CNR, Università "Sapienza" di Roma, P.le A. Moro 5, 00185 Rome, Italy.

This paper represents a contribution to the study of the brain functional connectivity from the perspective of complex networks theory. More specifically, we apply graph theoretical analyses to provide evidence of the modular structure of the mouse brain and to shed light on its hierarchical organization. We propose a novel percolation analysis and we apply our approach to the analysis of a resting-state functional MRI data set from 41 mice. This approach reveals a robust hierarchical structure of modules persistent across different subjects. Importantly, we test this approach against a statistical benchmark (or null model) which constrains only the distributions of empirical correlations. Our results unambiguously show that the hierarchical character of the mouse brain modular structure is not trivially encoded into this lower-order constraint. Finally, we investigate the modular structure of the mouse brain by computing the Minimal Spanning Forest, a technique that identifies subnetworks characterized by the strongest internal correlations. This approach represents a faster alternative to other community detection methods and provides a means to rank modules on the basis of the strength of their internal edges.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/srep32060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4989195PMC
August 2016

Semi-automated registration-based anatomical labelling, voxel based morphometry and cortical thickness mapping of the mouse brain.

J Neurosci Methods 2016 07 11;267:62-73. Epub 2016 Apr 11.

Functional Neuroimaging Laboratory, Center for Neuroscience and Cognitive Systems, Istituto Italiano di Tecnologia, Rovereto (TN), Italy. Electronic address:

Background: Morphoanatomical MRI methods have recently begun to be applied in the mouse. However, substantial differences in the anatomical organisation of human and rodent brain prevent a straightforward extension of clinical neuroimaging tools to mouse brain imaging. As a result, the vast majority of the published approaches rely on tailored routines that address single morphoanatomical readouts and typically lack a sufficiently-detailed description of the complex workflow required to process images and quantify structural alterations.

New Method: Here we provide a detailed description of semi-automated registration-based procedures for voxel based morphometry, cortical thickness estimation and automated anatomical labelling of the mouse brain. The approach relies on the sequential use of advanced image processing tools offered by ANTs, a flexible open source toolkit freely available to the scientific community.

Results: To illustrate our procedures, we described their application to quantify morphological alterations in socially-impaired BTBR mice with respect to normosocial C57BL/6J controls, a comparison recently described by us and other research groups. We show that the approach can reliably detect both focal and large-scale grey matter alterations using complementary readouts.

Comparison With Existing Methods: No detailed operational workflows for mouse imaging are available for direct comparison with our methods. However, empirical assessment of the mapped inter-strain differences is in good agreement with the findings of other groups using analogous approaches.

Conclusion: The detailed operational workflows described here are expected to help the implementation of rodent morphoanatomical methods by non-expert users, and ultimately promote the use of these tools across the preclinical neuroimaging community.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.jneumeth.2016.04.007DOI Listing
July 2016

Effects of Omega-3 Fatty Acid Supplementation on Cognitive Functions and Neural Substrates: A Voxel-Based Morphometry Study in Aged Mice.

Front Aging Neurosci 2016 4;8:38. Epub 2016 Mar 4.

Functional Neuroimaging Laboratory, Istituto Italiano di Tecnologia Rovereto, Italy.

Human and experimental studies have revealed putative neuroprotective and pro-cognitive effects of omega-3 polyunsaturated fatty acids (n-3 PUFA) in aging, evidencing positive correlations between peripheral n-3 PUFA levels and regional grey matter (GM) volume, as well as negative correlations between dietary n-3 PUFA levels and cognitive deficits. We recently showed that n-3 PUFA supplemented aged mice exhibit better hippocampal-dependent mnesic functions, along with enhanced cellular plasticity and reduced neurodegeneration, thus supporting a role of n-3 PUFA supplementation in preventing cognitive decline during aging. To corroborate these initial results and develop new evidence on the effects of n-3 PUFA supplementation on brain substrates at macro-scale level, here we expanded behavioral analyses to the emotional domain (anxiety and coping skills), and carried out a fine-grained regional GM volumetric mapping by using high-resolution MRI-based voxel-based morphometry. The behavioral effects of 8 week n-3 PUFA supplementation were measured on cognitive (discriminative, spatial and social) and emotional (anxiety and coping) abilities of aged (19 month-old at the onset of study) C57B6/J mice. n-3 PUFA supplemented mice showed better mnesic performances as well as increased active coping skills. Importantly, these effects were associated with enlarged regional hippocampal, retrosplenial and prefrontal GM volumes, and with increased post mortem n-3 PUFA brain levels. These findings indicate that increased dietary n-3 PUFA intake in normal aging can improve fronto-hippocampal GM structure and function, an effect present also when the supplementation starts at late age. Our data are consistent with a protective role of n-3 PUFA supplementation in counteracting cognitive decline, emotional dysfunctions and brain atrophy.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fnagi.2016.00038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4777728PMC
March 2016