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Alcohol acts as an addictive substance that may lead to alcohol use disorder. In humans, magnetic resonance imaging showed diverse structural and functional brain alterations associated with this complex pathology. Single magnetic resonance imaging modalities are used mostly but are insufficient to portray and understand the broad neuroadaptations to alcohol. Here, we combined structural and functional magnetic resonance imaging and connectome mapping in mice to establish brain-wide fingerprints of alcohol effects with translatable potential.Mice underwent a chronic intermittent alcohol drinking protocol for 6 weeks before being imaged under medetomidine anesthesia. We performed open-ended multivariate analysis of structural data and functional connectivity mapping on the same subjects.Structural analysis showed alcohol effects for the prefrontal cortex/anterior insula, hippocampus, and somatosensory cortex. Integration with microglia histology revealed distinct alcohol signatures, suggestive of advanced (prefrontal cortex/anterior insula, somatosensory cortex) and early (hippocampus) inflammation. Functional analysis showed major alterations of insula, ventral tegmental area, and retrosplenial cortex connectivity, impacting communication patterns for salience (insula), reward (ventral tegmental area), and default mode (retrosplenial cortex) networks. The insula appeared as a most sensitive brain center across structural and functional analyses.This study demonstrates alcohol effects in mice, which possibly underlie lower top-down control and impaired hedonic balance documented at the behavioral level, and aligns with neuroimaging findings in humans despite the potential limitation induced by medetomidine sedation. This study paves the way to identify further biomarkers and to probe neurobiological mechanisms of alcohol effects using genetic and pharmacological manipulations in mouse models of alcohol drinking and dependence.

La mesure de l’activité et de la connectivité cérébrale est désormais rendue possible par l’IRM fonctionnelle (IRMf) dont les principes sont résumés dans ce chapitre. Par contraste BOLD, basé sur des mécanismes neurovasculaires, ou par diffusion, reflétant les changements induits au niveau même du neuropile, l’IRMf permet une exploration des processus cognitifs. Elle met ainsi en évidence les régions cérébrales liées à une tâche mais également l’activité synchrone des réseaux cérébraux au repos, aussi appelé connectivité.

In Alzheimer’s disease, the tauopathy is known as a major mechanism responsible for the development of cognitive deficits. Early biomarkers of such affectations for diagnosis/stratification are crucial in Alzheimer’s disease research, and brain connectome studies increasingly show their potential establishing pathology fingerprints at the network level. In this context, we conducted an in vivo multimodal MRI study on young Thy-Tau22 transgenic mice expressing tauopathy, performing resting state functional MRI and structural brain imaging to identify early connectome signatures of the pathology, relating with histological and behavioural investigations. In the prodromal phase of tauopathy, before the emergence of cognitive impairments, Thy-Tau22 mice displayed selective modifications of brain functional connectivity involving three main centres: hippocampus (HIP), amygdala (AMG) and the isocortical areas, notably the somatosensory (SS) cortex. Each of these regions showed differential histopathological profiles. Disrupted ventral HIP-AMG functional pathway and altered dynamic functional connectivity were consistent with high pathological tau deposition and astrogliosis in both hippocampus and amygdala, and significant microglial reactivity in amygdalar nuclei. These patterns were concurrent with widespread functional hyperconnectivity of memory-related circuits of dorsal hippocampus—encompassing dorsal HIP-SS communication—in the absence of significant cortical histopathological markers. These findings suggest the coexistence of two intermingled mechanisms of response at the functional connectome level in the early phases of pathology: a maladaptive and a likely compensatory response. Captured in the connectivity patterns, such first responses to pathology could further be used in translational investigations as a lead towards an early biomarker of tauopathy as well as new targets for future treatments.

Mapping brain structural and functional connectivity (FC) became an essential approach in neuroscience as network properties can underlie behavioral phenotypes. In mouse models, revealing strain-related patterns of brain wiring is crucial, since these animals are used to answer questions related to neurological or neuropsychiatric disorders. C57BL/6 and BALB/cJ strains are two of the primary "genetic backgrounds" for modeling brain disease and testing therapeutic approaches. However, extensive literature describes basal differences in the behavioral, neuroanatomical and neurochemical profiles of the two strains, which raises questions on whether the observed effects are pathology specific or depend on the genetic background of each strain. Here, we performed a systematic comparative exploration of brain structure and function of C57BL/6 and BALB/cJ mice using Magnetic Resonance Imaging (MRI). We combined deformation-based morphometry (DBM), diffusion MRI and high-resolution fiber mapping (hrFM) along with resting-state functional MRI (rs-fMRI) and demonstrated brain-wide differences in the morphology and "connectome" features of the two strains. Essential inter-strain differences were depicted regarding the size and the fiber density (FD) within frontal cortices, along cortico-striatal, thalamic and midbrain pathways as well as genu and splenium of corpus callosum. Structural dissimilarities were accompanied by specific FC patterns, emphasizing strain differences in frontal and basal forebrain functional networks as well as hubness characteristics. Rs-fMRI data further indicated differences of reward-aversion circuitry and default mode network (DMN) patterns. The inter-hemispherical FC showed flexibility and strain-specific adjustment of their patterns in agreement with the structural characteristics.

International audience; PurposeTo determine optimal constrained tissue parameters and off-resonance sequence parameters for single-point macromolecular proton fraction (SP-MPF) mapping based on a comprehensive quantitative magnetization transfer (qMT) protocol in healthy and demyelinated living mice at 7T.MethodsUsing 3D spoiled gradient echo-based sequences, a comprehensive qMT protocol is performed by sampling the Z-spectrum of mice brains, in vivo. Provided additional T1, urn:x-wiley:07403194:media:mrm28397:mrm28397-math-0001 and B0 maps allow for the estimation of qMT tissue parameters, among which three will be constrained, namely the longitudinal and transverse relaxation characteristics of the free pool (R1,fT2,f), the cross-relaxation rate (R) and the bound pool transverse relaxation time (T2,r). Different sets of constrained parameters are investigated to reduce the bias between the SP-MPF and its reference based on the comprehensive protocol.ResultsBased on a whole-brain histogram analysis about the constrained parameters, the optimal experimental parameters that minimize the global bias between reference and SP-MPF maps consist of a 600° and 6 kHz off-resonance irradiation pulse. Following a Bland-Altman analysis over regions of interest, optimal constrained parameters were R1,fT2,f = 0.0129, R = 26.5 s−1, and T2,r = 9.1 µs, yielding an overall MPF bias of 10−4 (limits of agreement [−0.0068;0.0070]) and a relative variation of 0.64% ± 5.95% between the reference and the optimal single-point method across all mice.ConclusionThe necessity of estimating animal model- and field-dependent constrained parameters was demonstrated. The single-point MPF method can be reliably applied at 7T, as part of routine preclinical in vivo imaging protocol in mice.

Contains fulltext : 219632.pdf (Publisher’s version ) (Open Access) 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.

Connectomics of brain disorders seeks to reveal how altered brain function emerges from the architecture of cerebral networks; however the causal impact of targeted cellular damage on the whole brain functional and structural connectivity remains unknown. In the central nervous system, demyelination is typically the consequence of an insult targeted at the oligodendrocytes, the cells forming and maintaining the myelin. This triggered perturbation generates cascades of pathological events that most likely alter the brain connectome. Here we induced oligodendrocyte death and subsequent demyelinating pathology via cuprizone treatment in mice and combining mouse brain resting state functional Magnetic Resonance Imaging and diffusion tractography we established functional and structural pathology-to-network signatures. We demonstrated that demyelinated brain fundamentally reorganizes its intrinsic functional connectivity paralleled by widespread damage of the structural scaffolding. We evidenced default mode-like network as core target of demyelination-induced connectivity modulations and hippocampus as the area with strongest connectional perturbations.

Mapping the structural and functional brain connectivity fingerprints became an essential approach in neurology and experimental neuroscience because network properties can underlie behavioral phenotypes. In mouse models, revealing strain related patterns of brain wiring have a tremendous importance, since these animals are used to answer questions related to neurological or neuropsychiatric disorders. C57BL/6 and BALB/cJ inbred strains are primary “genetic backgrounds” for brain disease modelling and for testing therapeutic approaches. Nevertheless, extensive literature describes basal differences in the behavioral, neuroanatomical and neurochemical profiles of the two strains, which raises the question whether the observed effects are pathology specific or depend on the genetic background. Here we performed a systematic comparative exploration of brain structure and function of C57BL/6 and BALB/cJ mice via Magnetic Resonance Imaging (MRI). We combined voxel-based morphometry (VBM), diffusion MRI and high resolution fiber mapping (hrFM) and resting state functional MRI (rs-fMRI) and depicted brain-wide dissimilarities in the morphology and “connectome” features in the two strains. Particularly C57BL/6 animals show bigger and denser frontal cortical areas, cortico-striatal tracts and thalamic and midbrain pathways, and higher density of fibers in the genu and splenium of the corpus callosum. These features are fairly reflected in the functional connectograms that emphasize differences in “hubness”, frontal cortical and basal forbrain connectivity. We demonstrate strongly divergent reward-aversion circuitry patterns and some variations of the default mode network features. Inter-hemispherical functional connectivity showed flexibility and adjustment regarding the structural patterns in a strain specific manner. We further provide high-resolution tractograms illustrating also inter-individual variability across inter-hemispherical callosal pathways in the BALB/cJ strain.

While the contribution of Mu Opioid Receptors (MORs) to hedonic aspects of reward processing is well-established, the notion that these receptors may also regulate motivation to gain a reward, and possibly other related cognitive dimensions, has been less investigated. The prefrontal cortex (PFC) is a critical site for these processes. Our previous functional magnetic resonance imaging study found alterations of functional connectivity (FC) in reward/aversion networks in MOR knockout mice. Here we pursued voxelwise seed-based FC analyses using the same dataset with a focus on the PFC. We observed significant reduction of PFC FC in mutant mice, predominantly with the nucleus accumbens, supporting the notion of altered reward-driven top-down controls. We tested motivation for palatable food in a classical operant self-administration paradigm, and found delayed performance for mutant mice. We then evaluated motivational and cognitive abilities of MOR knockout mice in TouchScreen-based behavioral tests. Learning was delayed and stimulus/reward association was impaired, suggesting lower hedonic reward value and reduced motivation. Perseverative responses were decreased, while discriminatory behavior and attention were unchanged, indicative of increased inhibitory controls with otherwise intact cognitive performance. Together, our data suggest that MORs contribute to enhance reward-seeking and facilitate perseverative behaviors. The possibility that MOR blockade could reduce maladaptive compulsivity deserves further investigation in addiction and self-control disorder research.

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.

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.

Growing evidence supports the implication of DYRK1A in the development of cognitive deficits seen in Down syndrome (DS) and Alzheimer's disease (AD). We here demonstrate that pharmacological inhibition of brain DYRK1A is able to correct recognition memory deficits in three DS mouse models with increasing genetic complexity [Tg(Dyrk1a), Ts65Dn, Dp1Yey], all expressing an extra copy of Dyrk1a. Overexpressed DYRK1A accumulates in the cytoplasm and at the synapse. Treatment of the three DS models with the pharmacological DYRK1A inhibitor leucettine L41 leads to normalization of DYRK1A activity and corrects the novel object cognitive impairment observed in these models. Brain functional magnetic resonance imaging reveals that this cognitive improvement is paralleled by functional connectivity remodelling of core brain areas involved in learning/memory processes. The impact of Dyrk1a trisomy and L41 treatment on brain phosphoproteins was investigated by a quantitative phosphoproteomics method, revealing the implication of synaptic (synapsin 1) and cytoskeletal components involved in synaptic response and axonal organization. These results encourage the development of DYRK1A inhibitors as drug candidates to treat cognitive deficits associated with DS and AD., Summary: Normalization of DYRK1A kinase activity can be achieved in three different mouse models of Down syndrome with pharmacological inhibitors of DYRK1A, leading to correction of recognition memory deficits.

Mouse models are widely used to understand genetic bases of behavior. Traditional testing typically requires multiple experimental settings, captures only snapshots of behavior, and involves human intervention. The recent development of automated home cage monitoring offers an alternative method to study mouse behavior in their familiar and social environment, and over weeks. Here we used the IntelliCage system to test this approach for mouse phenotyping, and studied mice lacking the Gpr88 that have been extensively studied using standard testing. We monitored mouse behavior over 22 days in 4 different phases. In the free adaptation phase, Gpr88−/− mice showed delayed habituation to the home cage, and increased frequency of same corner returns behavior in their alternation pattern. In the following nose-poke adaptation phase, non-habituation continued, however mutant mice acquired nose-poke conditioning similarly to controls. In the place learning and reversal phase, Gpr88−/− mice developed preference for the water/sucrose corner with some delay, but did not differ from controls for reversal. Finally, in a fixed schedule-drinking phase, control animals showed higher activity during the hour preceding water accessibility, and reduced activity after access to water was terminated. Mutant mice did not show this behavior, revealing lack of anticipatory behavior. Our data therefore confirm hyperactivity, non-habituation and altered exploratory behaviors that were reported previously. Learning deficits described in other settings were barely detectable, and a novel phenotype was discovered. Home cage monitoring therefore extends previous findings and reveals yet another facet of GPR88 function that deserves further investigation.

Recent studies have demonstrated that orchestrated gene activity and expression support synchronous activity of brain networks. However, there is a paucity of information on the consequences of single gene function on overall brain functional organization and connectivity and how this translates at the behavioral level. In this study, we combined mouse mutagenesis with functional and structural magnetic resonance imaging (MRI) to determine whether targeted inactivation of a single gene would modify whole-brain connectivity in live animals. The targeted gene encodes GPR88 (G protein-coupled receptor 88), an orphan G protein-coupled receptor enriched in the striatum and previously linked to behavioral traits relevant to neuropsychiatric disorders. Connectivity analysis of Gpr88-deficient mice revealed extensive remodeling of intracortical and cortico-subcortical networks. Most prominent modifications were observed at the level of retrosplenial cortex connectivity, central to the default mode network (DMN) whose alteration is considered a hallmark of many psychiatric conditions. Next, somatosensory and motor cortical networks were most affected. These modifications directly relate to sensorimotor gating deficiency reported in mutant animals and also likely underlie their hyperactivity phenotype. Finally, we identified alterations within hippocampal and dorsal striatum functional connectivity, most relevant to a specific learning deficit that we previously reported in Gpr88-/- animals. In addition, amygdala connectivity with cortex and striatum was weakened, perhaps underlying the risk-taking behavior of these animals. This is the first evidence demonstrating that GPR88 activity shapes the mouse brain functional and structural connectome. The concordance between connectivity alterations and behavior deficits observed in Gpr88-deficient mice suggests a role for GPR88 in brain communication.

GPR88 is an orphan G-protein coupled receptor originally characterized as a striatal-enriched transcript and is a potential target for neuropsychiatric disorders. At present, gene knockout studies in the mouse have essentially focused on striatal-related functions and a comprehensive knowledge of GPR88 protein distribution and function in the brain is still lacking. Here, we first created Gpr88-Venus knock-in mice expressing a functional fluorescent receptor to fine-map GPR88 localization in the brain. The receptor protein was detected in neuronal soma, fibers and primary cilia depending on the brain region, and remarkably, whole-brain mapping revealed a yet unreported layer-4 cortical lamination pattern specifically in sensory processing areas. The unique GPR88 barrel pattern in L4 of the somatosensory cortex appeared three days after birth and persisted into adulthood, suggesting a potential function for GPR88 in sensory integration. We next examined Gpr88 knockout mice for cortical structure and behavioral responses in sensory tasks. Magnetic resonance imaging of live mice revealed abnormally high fractional anisotropy, predominant in somatosensory cortex and caudate putamen, indicating significant microstructural alterations in these GPR88-enriched areas. Further, behavioral analysis showed delayed responses in somatosensory-, visual- and olfactory-dependent tasks, demonstrating a role for GPR88 in the integration rather than perception of sensory stimuli. In conclusion, our data show for the first time a prominent role for GPR88 in multisensory processing. Because sensory integration is disrupted in many psychiatric diseases, our study definitely positions GPR88 as a target to treat mental disorders perhaps via activity on cortical sensory networks.

BACKGROUND: Mu opioid receptors (MORs) are central to pain control, drug reward, and addictive behaviors, but underlying circuit mechanisms have been poorly explored by genetic approaches. Here we investigate the contribution of MORs expressed in gamma-aminobutyric acidergic forebrain neurons to major biological effects of opiates, and also challenge the canonical disinhibition model of opiate reward. METHODS: We used Dlx5/6-mediated recombination to create conditional Oprm1 mice in gamma-aminobutyric acidergic forebrain neurons. We characterized the genetic deletion by histology, electrophysiology, and microdialysis; probed neuronal activation by c-Fos immunohistochemistry and resting-state functional magnetic resonance imaging; and investigated main behavioral responses to opiates, including motivation to obtain heroin and palatable food. RESULTS: Mutant mice showed MOR transcript deletion mainly in the striatum. In the ventral tegmental area, local MOR activity was intact, and reduced activity was only observed at the level of striatonigral afferents. Heroin-induced neuronal activation was modified at both sites, and whole-brain functional networks were altered in live animals. Morphine analgesia was not altered, and neither was physical dependence to chronic morphine. In contrast, locomotor effects of heroin were abolished, and heroin-induced catalepsy was increased. Place preference to heroin was not modified, but remarkably, motivation to obtain heroin and palatable food was enhanced in operant self-administration procedures. CONCLUSIONS: Our study reveals dissociable MOR functions across mesocorticolimbic networks. Thus, beyond a well-established role in reward processing, operating at the level of local ventral tegmental area neurons, MORs also moderate motivation for appetitive stimuli within forebrain circuits that drive motivated behaviors. This work was supported by the Centre National de la Recherche Scientifique (BLK), Institut National de la Santé et de la Recherche Médicale (BK), Université de Strasbourg (BLK), Medical Research Council/Economic and Social Research Council interdisciplinary studentship (to HLK), the British Pharmacological Society (IK), the European Commission (Genaddict Grant No. LSHMCT2004-005166 to BLK), the U.S. National Institutes of Health (National Institute of Drug Addiction, Grant No. 05010 to BLK and National Institute on Alcohol Abuse and Alcoholism, Grant No. 16658 to BLK), the Canada Fund for Innovation, and the Canada Research Chairs (to BLK). Electrophysiological experiments were funded by the Intramural Programs of National Institute on Alcohol Abuse and Alcoholism and National Institute of Neurological Disorders and Stroke (Grant No. ZIA-AA000421 to VAA) and Japan Society for Promotion of Science (to AMats). Self-administration studies were supported by the Intramural Programs of National Institute on Alcohol Abuse and Alcoholism and National Institute of Neurological Disorders and Stroke (Grant No. ZIA-AA000421 to RM), the Directorate-General for Research of the European Commission Framework Programme 7 (Grant No. HEALTH-2013-602891 to RM), the Spanish Redes Temáticas de Investigación Cooperativa en Salud-Instituto de Salud Carlos III (Grant No. RD12/0028/0023 to RM), the Spanish Ministerio de Economia y Competitividad (Grant No. SAF-2014-59648P to RM), the Plan Nacional Sobre Drogas (Grant No. PNSD-2013-5068 to RM), and the Catalan Government Agència de Gestió d'Ajuts Universitaris i de Recerca (Grant No. 2014-SGR-1547 to RM) and Institució Catalana de Recerca i Estudis Avançats-Acadèmia (Grant No. 2015 to RM). Part of the work was supported by German Research Foundation Excellence Cluster EXC-1086 BrainLinks-BrainTools (to JH).

OCT has been demonstrated as an efficient imaging modality in various biomedical and clinical applications. However, there is a missing link with respect to the source of contrast between OCT and other modern imaging modalities, no quantitative comparison has been demonstrated between them, yet. We evaluated, to our knowledge, for the first time in vivo OCT measurement of rat brain with our previously proposed forward imaging method by both qualitatively and quantitatively correlating OCT with the corresponding T1-weighted and T2-weighted magnetic resonance images, fiber density map (FDM), and two types of histology staining (cresyl violet and acetylcholinesterase AchE), respectively. Brain anatomical structures were identified and compared across OCT, MRI and histology imaging modalities. Noticeable resemblances corresponding to certain anatomical structures were found between OCT and other image profiles. Correlation was quantitatively assessed by estimating correlation coefficient (R) and mutual information (MI). Results show that the 1-D OCT measurements in regards to the intensity profile and estimated attenuation factor, do not have profound linear correlation with the other image modalities suggested from correlation coefficient estimation. However, findings in mutual information analysis demonstrate that there are markedly high MI values in OCT-MRI signals.

Significance Mice manipulated by targeted deletion of a specific brain gene show diverse pathological phenotypes, apparent, for example, in behavioral experiments. To explain observed findings, connectome genetics attempts to uncover how brain functional connectivity is affected by genetics. However the causal impact of a single gene on whole-brain networks is still unclear. Here the sole targeted deletion of the mu opioid receptor gene ( Oprm 1), the main target for morphine, induced widespread remodeling of brain functional connectome in mice. The strongest perturbations occurred within the so-called reward/aversion-circuitry, predominantly influencing the negative affect centers. We present a hypothesis-free analysis of combined structural and functional connectivity data obtained via MRI of the living mouse brain, and identify a specific Oprm 1 gene-to-network signature.

Until very recently, the study of neural architecture using fixed tissue has been a major scientific focus of neurologists and neuroanatomists. A non-invasive detailed insight into the brain's axonal connectivity in vivo has only become possible since the development of diffusion tensor magnetic resonance imaging (DT-MRI). This unique approach of analyzing axonal projections in the living brain was used in the present study to describe major white matter fiber tracts of the mouse brain and also to identify for the first time non-invasively the rich connectivity between the amygdala and different target regions. To overcome the difficulties associated with high spatially and temporally resolved DT-MRI measurements a 4-shot diffusion weighted spin echo (SE) echo planar imaging (EPI) protocol was adapted to mouse brain imaging at 9.4T. Diffusion tensor was calculated from data sets acquired by using 30 diffusion gradient directions while keeping the acquisition time at 91 min. Two fiber tracking algorithms were employed. A deterministic approach (fiber assignment by continuous tracking - FACT algorithm) allowed us to identify and generate the 3D representations of various neural pathways. A probabilistic approach was further used for the generation of probability maps of connectivity with which it was possible to investigate - in a statistical sense - all possible connecting pathways between selected seed points. We show here applications to determine the connection probability between regions belonging to the visual or limbic systems. This method does not require a priori knowledge about the projections' trajectories and is shown to be efficient even if the investigated pathway is long or three-dimensionally complex. Additionally, high resolution images of rotational invariant parameters of the diffusion tensor, such as fractional anisotropy, volume ratio or main eigenvalues allowed quantitative comparisons in-between regions of interest (ROIs) and showed significant differences between various white matter regions.

Many of the clinical manifestations of hyperthyroidism are due to the ability of thyroid hormones to alter myocardial contractility and cardiovascular hemodynamics, leading to cardiovascular impairment. In contrast, recent studies highlight also the potential beneficial effects of thyroid hormone administration for clinical or preclinical treatment of different diseases such as atherosclerosis, obesity and diabetes or as a new therapeutic approach in demyelinating disorders. In these contexts and in the view of developing thyroid hormone-based therapeutic strategies, it is, however, important to analyze undesirable secondary effects on the heart. Animal models of experimentally induced hyperthyroidism therefore represent important tools for investigating and monitoring changes of cardiac function. In our present study we use high-field cardiac MRI to monitor and follow-up longitudinally the effects of prolonged thyroid hormone (triiodothyronine) administration focusing on murine left ventricular function. Using a 9.4 T small horizontal bore animal scanner, cinematographic MRI was used to analyze changes in ejection fraction, wall thickening, systolic index and fractional shortening. Cardiac MRI investigations were performed after sustained cycles of triiodothyronine administration and treatment arrest in adolescent (8 week old) and adult (24 week old) female C57Bl/6 N mice. Triiodothyronine supplementation of 3 weeks led to an impairment of cardiac performance with a decline in ejection fraction, wall thickening, systolic index and fractional shortening in both age groups but with a higher extent in the group of adolescent mice. However, after a hormonal treatment cessation of 3 weeks, only young mice are able to partly restore cardiac performance in contrast to adult mice lacking this recovery potential and therefore indicating a presence of chronically developed heart pathology.

The ability to perform cell tracking using x-ray computed tomography combined with gold nanoparticles has been demonstrated recently on ex vivo samples using different malignant and nonmalignant cell lines. Here we proved the concept of the method for in vivo assessment in a small-animal model of malignant brain tumors. The limitations of the method due to radiation dose constraints were investigated using Monte Carlo simulations. Taking into consideration different x-ray entrance doses and the spatial resolution, the visibility of the cell clusters was evaluated. The results of the experiments conducted on mice implanted with F98 tumor cells confirmed the prediction of the Monte Carlo calculations. Small clusters of cells exogenously loaded with gold nanoparticles could be visualized using our in vivo method.This article discusses the use of CT-based detection of gold nanoparticle loaded cells of interest in small-animal models of malignant brain tumors, where small clusters of cells loaded with gold nanoparticles could be visualized.

Many of the clinical manifestations of hyperthyroidism are due to the ability of thyroid hormones to alter myocardial contractility and cardiovascular hemodynamics, leading to cardiovascular impairment. In contrast, recent studies highlight also the potential beneficial effects of thyroid hormone administration for clinical or preclinical treatment of different diseases such as atherosclerosis, obesity and diabetes or as a new therapeutic approach in demyelinating disorders. In these contexts and in the view of developing thyroid hormone-based therapeutic strategies, it is, however, important to analyze undesirable secondary effects on the heart. Animal models of experimentally induced hyperthyroidism therefore represent important tools for investigating and monitoring changes of cardiac function. In our present study we use high-field cardiac MRI to monitor and follow-up longitudinally the effects of prolonged thyroid hormone (triiodothyronine) administration focusing on murine left ventricular function. Using a 9.4 T small horizontal bore animal scanner, cinematographic MRI was used to analyze changes in ejection fraction, wall thickening, systolic index and fractional shortening. Cardiac MRI investigations were performed after sustained cycles of triiodothyronine administration and treatment arrest in adolescent (8 week old) and adult (24 week old) female C57Bl/6 N mice. Triiodothyronine supplementation of 3 weeks led to an impairment of cardiac performance with a decline in ejection fraction, wall thickening, systolic index and fractional shortening in both age groups but with a higher extent in the group of adolescent mice. However, after a hormonal treatment cessation of 3 weeks, only young mice are able to partly restore cardiac performance in contrast to adult mice lacking this recovery potential and therefore indicating a presence of chronically developed heart pathology.

Recent studies correlate chronic Toxoplasma gondii (T. gondii) infection with behavioral changes in rodents, besides the seropositivity in humans is reported to be associated with behavioral and neuropsychiatric diseases. In this study we investigated if the described behavioral changes in a murine model of chronic toxoplasmosis are associated with changes in synaptic plasticity and brain neuronal circuitry. In mice chronically infected with T. gondii, Magnetic Resonance Imaging (MRI) data analysis displayed the presence of heterogeneous lesions scattered throughout all brain areas. However, a higher density of lesions could be observed within specific regions such as the somatosensory cortex (SSC). Further histopathological examination of these brain areas indicated the presence of activated resident glia and recruited immune cells accompanied by limited alterations of neuronal viability. In vivo Diffusion Tensor MRI analysis of neuronal fiber density within the infected regions revealed connectivity abnormalities in the SSC. Altered fiber density was confirmed by morphological analysis of individual, pyramidal and granule neurons showing a reduction in dendritic arbor and spine density within the SSC, as well as in the hippocampus. Evaluation of synapse efficacy revealed diminished levels of two key synaptic proteins, PSD95 and Synaptophysin, within the same brain areas indicating deficits in functionality of the synaptic neurotransmission in infected mice. Our results demonstrate that persistent T. gondii infection in a murine model results in synaptic deficits within brain structures leading to disturbances in the morphology of noninfected neurons and modified brain connectivity, suggesting a potential explanation for the behavioral and neuropsychiatric alterations.

Understanding the intrinsic circuit-level functional organization of the brain has benefited tremendously from the advent of resting-state fMRI (rsfMRI). In humans, resting-state functional network has been consistently mapped and its alterations have been shown to correlate with symptomatology of various neurological or psychiatric disorders. To date, deciphering the mouse brain functional connectivity (MBFC) with rsfMRI remains a largely underexplored research area, despite the plethora of human brain disorders that can be modeled in this specie. To pave the way from pre-clinical to clinical investigations we characterized here the intrinsic architecture of mouse brain functional circuitry, based on rsfMRI data acquired at 7 T using the Cryoprobe technology. High-dimensional spatial group independent component analysis demonstrated fine-grained segregation of cortical and subcortical networks into functional clusters, overlapping with high specificity onto anatomical structures, down to single gray matter nuclei. These clusters, showing a high level of stability and reliability in their patterning, formed the input elements for computing the MBFC network using partial correlation and graph theory. Its topological architecture conserved the fundamental characteristics described for the human and rat brain, such as small-worldness and partitioning into functional modules. Our results additionally showed inter-modular interactions via “network hubs”. Each major functional system (motor, somatosensory, limbic, visual, autonomic) was found to have representative hubs that might play an important input/output role and form a functional core for information integration. Moreover, the rostro-dorsal hippocampus formed the highest number of relevant connections with other brain areas, highlighting its importance as core structure for MBFC.

A major challenge in neuroscience is to accurately decipher in vivo the entire brain circuitry (connectome) at a microscopic level. Currently, the only methodology providing a global noninvasive window into structural brain connectivity is diffusion tractography. The extent to which the reconstructed pathways reflect realistic neuronal networks depends, however, on data acquisition and postprocessing factors. Through a unique combination of approaches, we designed and evaluated herein a framework for reliable fiber tracking and mapping of the living mouse brain connectome. One important wiring scheme, connecting gray matter regions and passing fiber-crossing areas, was closely examined: the lemniscal thalamocortical (TC) pathway. We quantitatively validated the TC projections inferred from in vivo tractography with correlative histological axonal tracing in the same wild-type and reeler mutant mice. We demonstrated noninvasively that changes in patterning of the cortical sheet, such as highly disorganized cortical lamination in reeler, led to spectacular compensatory remodeling of the TC pathway.

Gold nanoparticles are excellent intracellular markers in X-ray imaging. Having shown previously the suitability of gold nanoparticles to detect small groups of cells with the synchrotron-based computed tomography (CT) technique bothex vivoandin vivo, it is now demonstrated that even single-cell resolution can be obtained in the brain at leastex vivo. Working in a small animal model of malignant brain tumour, the image quality obtained with different imaging modalities was compared. To generate the brain tumour, 1 × 105C6 glioma cells were loaded with gold nanoparticles and implanted in the right cerebral hemisphere of an adult rat. Raw data were acquired with absorption X-ray CT followed by a local tomography technique based on synchrotron X-ray absorption yielding single-cell resolution. The reconstructed synchrotron X-ray images were compared with images obtained by small animal magnetic resonance imaging. The presence of gold nanoparticles in the tumour tissue was verified in histological sections.

Until very recently, the study of neural architecture using fixed tissue has been a major scientific focus of neurologists and neuroanatomists. A non-invasive detailed insight into the brain's axonal connectivity in vivo has only become possible since the development of diffusion tensor magnetic resonance imaging (DT-MRI). This unique approach of analyzing axonal projections in the living brain was used in the present study to describe major white matter fiber tracts of the mouse brain and also to identify for the first time non-invasively the rich connectivity between the amygdala and different target regions. To overcome the difficulties associated with high spatially and temporally resolved DT-MRI measurements a 4-shot diffusion weighted spin echo (SE) echo planar imaging (EPI) protocol was adapted to mouse brain imaging at 9.4T. Diffusion tensor was calculated from data sets acquired by using 30 diffusion gradient directions while keeping the acquisition time at 91 min. Two fiber tracking algorithms were employed. A deterministic approach (fiber assignment by continuous tracking - FACT algorithm) allowed us to identify and generate the 3D representations of various neural pathways. A probabilistic approach was further used for the generation of probability maps of connectivity with which it was possible to investigate - in a statistical sense - all possible connecting pathways between selected seed points. We show here applications to determine the connection probability between regions belonging to the visual or limbic systems. This method does not require a priori knowledge about the projections' trajectories and is shown to be efficient even if the investigated pathway is long or three-dimensionally complex. Additionally, high resolution images of rotational invariant parameters of the diffusion tensor, such as fractional anisotropy, volume ratio or main eigenvalues allowed quantitative comparisons in-between regions of interest (ROIs) and showed significant differences between various white matter regions.

With the increase in the availability of spatially structured complex data, i.e., 2D or 3D images that contain temporal information (fMRI, scintigraphy) or light spectrum information (hyperspectral imaging), novel techniques to estimate the presence, localisation and contribution of the signals sources are required. Such spatially structured data necessarily involve a trade-off between temporal/spectral resolution and spatial resolution. This compromise is generally in favour of the resolution of the signals that carry the information of interest. In the presence of several distinct sources in close proximity, the pixels/voxels present a strong mixture between the contribution of the different sources. Moreover, if the sources are spatially sparse, the unmixing problem becomes ill-posed and requires the introduction of regularisations to constrain the solution of the source separation problem. In this work, we are interested in data for which potentially approximate spatial location information of the sources is available (via another observation modality or knowledge provided by data experts). This work presents a generic dictionary learning method, where we incorporate localisation informationfor regularisation instead of the classic l1 sparsity constraint, to allow unmixing strictly under the regions of interest. In order to illustrate the performance of this approach, it is tested and compared to methods specifically developed in the literature for scintigraphy, astronomy, and fMRI. The results of this proposed generic method are comparable to the methods in the literature.; Avec l'augmentation de la disponibilité de données complexes spatialement structurées, c'est-à-dire des images 2D ou 3D contenant des informations temporelles (IRMf, scintigraphie) ou des informations spectrales (imagerie hyperspectrale), des nouvelles techniques pour estimer la présence, la localisation et la contribution des sources de ces signaux sont nécessaires. Les acquisitions de ces signaux spatialement structurés entraînent nécessairement un compromis entre la résolution temporelle/spectrale et la résolution spatiale. Cette dernière est généralement sacrifiée au profit de la résolution des signaux qui portent l'information d'intérêt. En présence de plusieurs sources distinctes proches, les pixels/voxels présentent un fort mélange entre la contribution des différentes sources. De plus, si les sources sont spatialement peu étendues, le démélange devient un problème très mal posé et nécessite l'introduction de régularisations pour contraindre la solution du problème de séparation de sources. Nous nous intéressons dans ce travail aux données pour lesquelles une information de localisation spatiale des sources, potentiellement approximative, est disponible (via une autre modalité d'observation ou des connaissances fournies par des experts des données). Ce travail présente ainsi une méthode générique de type apprentissage par dictionnaire, dans laquelle nous incorporons les informations de localisation dans la régularisation en place de la traditionnelle contrainte de parcimonie de type l1, pour permettre le démélange strictement sous les régions d'intérêt. Afin d'illustrer les performances de cette nouvelle approche, celle-ci est testée et comparée aux méthodes spécialisées, développées dans la littérature, en scintigraphie, astronomie, et IRMf. Les résultats obtenus avec la méthode générique proposée sont comparables à ceux de ces méthodes dans l’état de l’art.