Hyperexcitability of sensory neurons in Fragile X mouse model

Sensory hypersensitivity and somatosensory deficits represent the core symptoms of Fragile X syndrome (FXS). These alterations are believed to arise from changes in cortical sensory processing, while potential deficits in the function of peripheral sensory neurons residing in dorsal root ganglia remain unexplored. We found that peripheral sensory neurons exhibit pronounced hyperexcitability i

Dynamics of BMP and Hes1/Hairy1 signaling in the dorsal neural tube underlies the transition from neural crest to definitive roof plate

caBMPR1A/caAlk3 stimulates ectopic pSMAD activity. (A–A”) Electroporation of control GFP (PBI-GFP) or caBMPR1a-GFP-PBI (B–B”) followed by pSMAD immunostaining. Note in A–A” that the pSMAD signal is restricted to the dorsal NT even if the transfection attains half of the NT length. In contrast, caBMPR1a/Alk3 induces ectopic pSMAD activity in transfected cells throughout the electroporated domain (B–B”). Bar = 50 μM. (JPG 516 kb

Analysis of neuronal injury transcriptional response identifies CTCF and YY1 as co-operating factors regulating axon regeneration

Injured sensory neurons activate a transcriptional program necessary for robust axon regeneration and eventual target reinnervation. Understanding the transcriptional regulators that govern this axon regenerative response may guide therapeutic strategies to promote axon regeneration in the injured nervous system. Here, we used cultured dorsal root ganglia neurons to identify pro-regenerative transcription factors. Using RNA sequencing, we first characterized this neuronal culture and determined that embryonic day 13.5 DRG (eDRG) neurons cultured for 7 days are similar to e15.5 DRG neuron

Endothelial ether lipids link the vasculature to blood pressure, behavior, and neurodegeneration

Vascular disease contributes to neurodegeneration, which is associated with decreased blood pressure in older humans. Plasmalogens, ether phospholipids produced by peroxisomes, are decreased in Alzheimer's disease, Parkinson's disease, and other neurodegenerative disorders. However, the mechanistic links between ether phospholipids, blood pressure, and neurodegeneration are not fully understood. Here, we show that endothelium-derived ether phospholipids affect blood pressure, behavior, and neurodegeneration in mice. In young adult mice, inducible endothelial-specific disruption of PexRAP, a peroxisomal enzyme required for ether lipid synthesis, unexpectedly decreased circulating plasmalogens. PexRAP endothelial knockout (PEKO) mice responded normally to hindlimb ischemia but had lower blood pressure and increased plasma renin activity. In PEKO as compared with control mice, tyrosine hydroxylase was decreased in the locus coeruleus, which maintains blood pressure and arousal. PEKO mice moved less, slept more, and had impaired attention to and recall of environmental events as well as mild spatial memory deficits. In PEKO hippocampus, gliosis was increased, and a plasmalogen associated with memory was decreased. Despite lower blood pressure, PEKO mice had generally normal homotopic functional connectivity by optical neuroimaging of the cerebral cortex. Decreased glycogen synthase kinase-3 phosphorylation, a marker of neurodegeneration, was detected in PEKO cerebral cortex. In a co-culture system, PexRAP knockdown in brain endothelial cells decreased glycogen synthase kinase-3 phosphorylation in co-cultured astrocytes that was rescued by incubation with the ether lipid alkylglycerol. Taken together, our findings suggest that endothelium-derived ether lipids mediate several biological processes and may also confer neuroprotection in mice

Direct visualization of colloid transport over natural heterogeneous and artificial smooth rock surfaces

International audienceColloid transport in fractured rock formations is an important process impacting the fate of pollutants in the subsurface. Despite intensive and outstanding research on their transport phenomena, the impact of small-scale surface heterogeneity on colloid behavior at the fracture scale remains difficult to assess. In particular, there is relatively little direct experimental evidence on the impact of natural fracture surface heterogeneity on colloid transport. To investigate this, we developed an experimental setup allowing the direct visualization of fluorescent colloid transport in a flow cell containing a natural chalk rock sample while simultaneously monitoring effluent colloid concentrations. We used samples containing both a natural fracture surface and an artificially made smooth surface from the same chalk core. We characterized the roughness and chemical composition of both surface types and numerically calculated each surface's velocity field. From the experiments, we obtained direct images of colloid transport over the surfaces, from which we calculated their dispersion coefficients and quantified the residual deposition of colloids on the rock surface. We also measured the colloid breakthrough curves by collecting eluent samples from the flow cell outlet. The natural fracture surface exhibited larger physical and chemical heterogeneity than the smooth, artificially generated surface. The aperture variability across the natural surface led to preferential flow and colloid transport which was qualitatively apparent in the fluorescent images. The colloid transport patterns matched the calculated velocity fields well, directly linking the surface topography and aperture variation to colloid transport. Compared to the artificially made surface, the natural surface also showed higher dispersion coefficients, which corresponded to the colloids' earlier breakthrough from the flow cell. While we found differences between the elemental composition of the natural and artificially smooth surfaces, we could not observe their impact on the colloids' surface attachment and retention. The main novelty in this work is the coupling of direct colloid transport imaging, breakthrough curve measurements, and colloid surface deposition analyses, in a flow cell containing a natural carbonate rock sample. Our experimental setup can be used to further investigate the link between surface heterogeneity, both chemical and physical, and colloid transport and deposition in natural rock fractures

Disrupted association of sensory neurons with enveloping satellite glial cells in Fragile X mouse model

Among most prevalent deficits in individuals with Fragile X syndrome (FXS) is hypersensitivity to sensory stimuli and somatosensory alterations. Whether dysfunction in peripheral sensory system contributes to these deficits remains poorly understood. Satellite glial cells (SGCs), which envelop sensory neuron soma, play critical roles in regulating neuronal function and excitability. The potential contributions of SGCs to sensory deficits in FXS remain unexplored. Here we found major structural defects in sensory neuron-SGC association in the dorsal root ganglia (DRG), manifested by aberrant covering of the neuron and gaps between SGCs and the neuron along their contact surface. Single-cell RNAseq analyses demonstrated transcriptional changes in both neurons and SGCs, indicative of defects in neuronal maturation and altered SGC vesicular secretion. We validated these changes using fluorescence microscopy, qPCR, and high-resolution transmission electron microscopy (TEM) in combination with computational analyses using deep learning networks. These results revealed a disrupted neuron-glia association at the structural and functional levels. Given the well-established role for SGCs in regulating sensory neuron function, altered neuron-glia association may contribute to sensory deficits in FXS

Profiling sensory neuron microenvironment after peripheral and central axon injury reveals key pathways for neural repair

Sensory neurons with cell bodies in dorsal root ganglia (DRG) represent a useful model to study axon regeneration. Whereas regeneration and functional recovery occurs after peripheral nerve injury, spinal cord injury or dorsal root injury is not followed by regenerative outcomes. Regeneration of sensory axons in peripheral nerves is not entirely cell autonomous. Whether the DRG microenvironment influences the different regenerative capacities after injury to peripheral or central axons remains largely unknown. To answer this question, we performed a single-cell transcriptional profiling of mouse DRG in response to peripheral (sciatic nerve crush) and central axon injuries (dorsal root crush and spinal cord injury). Each cell type responded differently to the three types of injuries. All injuries increased the proportion of a cell type that shares features of both immune cells and glial cells. A distinct subset of satellite glial cells (SGC) appeared specifically in response to peripheral nerve injury. Activation of the PPARα signaling pathway in SGC, which promotes axon regeneration after peripheral nerve injury, failed to occur after central axon injuries. Treatment with the FDA-approved PPARα agonist fenofibrate increased axon regeneration after dorsal root injury. This study provides a map of the distinct DRG microenvironment responses to peripheral and central injuries at the single-cell level and highlights that manipulating non-neuronal cells could lead to avenues to promote functional recovery after CNS injuries or disease