Biology subjects

Grandjean, J.

Publications and source records attributed to Grandjean, J..

25 records · Page 2Linked to original sources

bioRxiv2020

Disrupted structural connectivity in ArcAβ mouse model of Aβ amyloidosis

Although amyloid beta (A{beta}) deposition is one of the major causes of white matter (WM) alterations in Alzheimers disease (AD), little is known about the underlying basis of WM damage and its association with global structural connectivity and network topology. We aimed to dissect the contributions of WM microstructure to structural connectivity and network properties in the ArcA{beta} mice model of A{beta} amyloidosis. We acquired diffusion-weighted images (DWI) of wild type (WT) and ArcA{beta} transgenic (TG) mice using a 9.4 T MRI scanner. Fixel-based analysis (FBA) was performed to measure fiber tract-specific properties. We also performed three complementary experiments; to identify the global differences in structural connectivity, to compute network properties and to measure cellular basis of white matter alterations. Transgenic mice displayed disrupted structural connectivity centered to the entorhinal cortex (EC) and a lower fiber density and fiber bundle cross-section. In addition, there was a reduced network efficiency and degree centrality in weighted structural connectivity in the transgenic mice. To further examine the underlying neuronal basis of connectivity and network deficits, we performed histology experiments. We found no alteration in myelination and an increased level of neurofilament light (NFL) in the brain regions with disrupted connectivity in the TG mice. Furthermore, TG mice had a reduced number of perineuronal nets (PNN) in the EC. The observed FDC reductions may indicate a decrease in axonal diameter or axon count which would explain the basis of connectivity deficits and reduced network efficiency in TG mice. The increase in NFL suggests a breakdown of axonal integrity, which would reduce WM fiber health. Considering the pivotal role of the EC in AD, A{beta} deposition may primarily increase NFL release, damaging PNN in the entorhinal pathway, resulting in disrupted structural connectivity.

neuroscience↗

bioRxiv2020

Local and global dichotomic dysfunction in resting and evoked functional connectivity precedes tauopathy

Functional network activity alterations are one of the earliest hallmarks of Alzheimers disease (AD), detected prior to amyloidosis and tauopathy. Better understanding the neuronal underpinnings of such network alterations could offer mechanistic insight into AD progression. Here, we examined a mouse model (early-tauopathy 3xTgAD mice) recapitulating this early AD stage. We found resting functional connectivity loss within ventral networks, including the entorhinal cortex, aligning with the spatial distribution of tauopathy reported in humans. Unexpectedly, in contrast to decreased connectivity at rest, 3xTgAD mice show enhanced fMRI signal within several projection areas following optogenetic activation of the entorhinal cortex. We corroborate this finding by demonstrating neuronal facilitation within ventral networks and synaptic hyperexcitability in projection targets. 3xTgAD mice thus reveal a dichotomic hypo-connected resting/hyper-responsive active phenotype. The strong homotopy between the areas affected supports the translatability of this pathophysiological model to tau-related deficits in humans.

neuroscience↗

bioRxiv2020

Conjugates of neuroprotective chaperone L-PGDS provide MRI contrast for detection of amyloid β-rich regions in live Alzheimer's Disease mouse model brain

Endogenous brain proteins can recognize the toxic oligomers of amyloid-{beta} (A{beta}) peptides implicated in Alzheimers disease (AD) and interact with them to prevent their aggregation. Lipocalin-type Prostaglandin D Synthase (L-PGDS) is a major A{beta}-chaperone protein in the human cerebrospinal fluid. Here we demonstrate that L-PGDS detects amyloids in diseased mouse brain. Conjugation of L-PGDS with magnetic nanoparticles enhanced the contrast for magnetic resonance imaging. We conjugated the L-PGDS protein with ferritin nanocages to detect amyloids in the AD mouse model brain. We show here that the conjugates administered through intraventricular injections co-localize with amyloids in the mouse brain. These conjugates can target the brain regions through non-invasive intranasal administration, as shown in healthy mice. These conjugates can inhibit the aggregation of amyloids in vitro and show potential neuroprotective function by breaking down the mature amyloid fibrils.

biochemistry↗

bioRxiv2020

Gradients of functional connectivity in the mouse cortex reflect neocortical evolution

Understanding cortical organization is a fundamental goal of neuroscience that requires comparisons across species and modalities. Large-scale connectivity gradients have recently been introduced as a data-driven representation of the intrinsic organization of the cortex. We studied resting-state functional connectivity gradients in the mouse cortex and found robust spatial patterns across four data sets. The principal gradient of functional connectivity shows a striking overlap with an axis of neocortical evolution from two primordial origins. Additional gradients reflect sensory specialization and aspects of a sensory-to-transmodal hierarchy, and are associated with transcriptomic features. While some of these gradients strongly resemble observations in the human cortex, the overall pattern in the mouse cortex emphasizes the specialization of sensory areas over a global functional hierarchy. HighlightsO_LIThe principal gradient of functional connectivity in the mouse cortex recapitulates an axis of neocortical evolution from archicortex and paleocortex. C_LIO_LIAdditional gradients highlight sensory specialization and reflect aspects of a sensory-to-transmodal hierarchy. C_LIO_LIFunctional connectivity gradients partly align with gene expression patterns. C_LIO_LIMouse cortical gradients are stable across data sets. C_LI

neuroscience↗

bioRxiv2020

Motor training strengthens corticospinal suppression during movement preparation

Training can improve motor skills and modify neural activity at rest and during movement execution. Learning-related modulations may also concern motor preparation but the neural correlates and the potential behavioral relevance of such adjustments remain unclear. In humans, preparatory processes have been largely investigated using transcranial magnetic stimulation (TMS) with several studies reporting decreased corticospinal excitability (CSE) relative to a baseline measure; a phenomenon called preparatory suppression. Here, we investigated the effect of motor training on preparatory suppression of CSE in humans, as compared to modulatory changes at rest. We trained participants to initiate quick movements in an instructed-delay reaction time (RT) task and used TMS to investigate changes in CSE over the practice blocks. Training on the task speeded up RTs, with no repercussion on error rates. Training also increased baseline CSE at rest. Most interestingly, we found that motor activity during action preparation did not mirror the training-related rise in resting CSE. Rather, the degree of preparatory suppression from the rising baseline strengthened with practice. This training-related change in preparatory suppression predicted RT gains (but not the changes in baseline CSE): subjects showing a stronger expansion of preparatory suppression were also those exhibiting larger gains in RTs. Finally, such relationship between RTs and preparatory suppression was also evident at the single-trial level: RTs were generally faster in trials where preparatory suppression was deeper. These findings suggest that training induces changes in motor preparatory processes that are linked to an enhanced ability to initiate fast movements. New and NoteworthyAny movement is preceded by a period of preparation, which involves a broad suppression of the corticospinal pathway, a phenomenon called preparatory suppression. Here, we show that motor training strengthens preparatory suppression and that this strengthening is associated with an acceleration of movement initiation. Our findings yield an extension of former work, highlighting a key role of preparatory suppression in training-driven behavioral improvements.

neuroscience↗

bioRxiv2019

Psilocybin exerts distinct effects on resting state networks associated with serotonin and dopamine in mice

Hallucinogenic agents have been proposed as potent antidepressants; this includes the serotonin (5-HT) receptor 2A agonist psilocybin. In human subjects, psilocybin alters functional connectivity (FC) within the default-mode network (DMN), a constellation of inter-connected regions that is involved in self-reference and displays altered FC in depressive disorders. In this study we investigated the effects of psilocybin on FC in the analogue of the DMN in mouse, with a view to establishing an experimental animal model to investigate underlying mechanisms. Psilocybin effects were investigated in lightly-anaesthetized mice using resting-state fMRI. Dual-regression analysis identified reduced FC within the ventral striatum in psilocybin-relative to vehicle-treated mice. Refinement of the analysis using spatial references derived from both gene expression maps and viral tracer projection fields revealed two distinct effects of psilocybin: it increased FC between 5-HT-associated networks and elements of the murine DMN, thalamus, and midbrain; it decreased FC within dopamine (DA)-associated striatal networks. These results suggest that interaction between 5-HT- and DA-regulated neural networks contributes to the neural and therefore psychological effects of psilocybin. Furthermore, they highlight how information on molecular expression patterns and structural connectivity can assist in the interpretation of pharmaco-fMRI findings.

neuroscience↗

bioRxiv2019

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

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 world-wide. 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 murine 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. 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.

neuroscience↗