Biology subjects

Doulazmi, M.

Publications and source records attributed to Doulazmi, M..

9 recordsLinked to original sources

bioRxiv2026

Age-related cerebellar genetic, neuronal and functional impairments are reversed by specific magnetic stimulation protocols

Age-related cognitive decline reflects progressive atrophic changes that advance through broad neural networks. There is no effective treatment. However, brain ageing is not homogenous, so treating the earliest-affected circuits may be successful in reversing and/or preventing ongoing neuronal atrophy and therefore cognitive decline. Repetitive transcranial magnetic stimulation (rTMS), a non-invasive technique that modulates cortical excitability, induces activity-dependent neuronal plasticity. Here we investigate short- and long-term effects of low intensity rTMS (LI-rTMS) on the cerebellum, which is adversely affected early during ageing. With age, cerebellar genes related to inflammation are strongly upregulated, whereas processes of synaptic-maintenance are reduced. Both abnormalities are rapidly corrected by LI-rTMS in a protocol-dependent manner. In parallel, LI-rTMS increases neuronal spine density and dendritic complexity, in association with improved spatial memory in both young adult and aged mice. These responses of the ageing cerebellum to low-intensity magnetic stimulation are extremely encouraging for treating age-related cognitive decline, but reinforce that appropriate stimulation parameters must be identified for effective treatment.

neuroscience↗

bioRxiv2025

GPR161 mechanosensitivity at the primary cilium drives neuronal saltatory migration

The saltatory migration of neurons is essential for brain formation. Whether mechanical stimuli regulate this process is unknown. Here we show that the primary cilium acts as a mechanical sensor through GPR161. Using an ex vivo neuronal migration model and microfluidic assays, we demonstrate that fluid shear stress induces migration via the mechanoreceptor GPR161 at the primary cilium, with its mechanosensitive Helix 8 being essential. We demonstrate that GPR161 activates a recently discovered cAMP/PKA signaling pathway leading to the phosphorylation of NDE1, a dynein complex regulator, and microtubule organization to regulate migration. These findings unveil a dynamic primary cilium-based pathway sensing mechanical stimulus to drive cyclic saltatory neuronal migration during brain development.

neuroscience↗

bioRxiv2023

Laminin γ1-dependent basement membranes are instrumental to ensure proper olfactory placode shape, position and boundary with the brain, as well as olfactory axon development

Despite recent progress, the complex roles played by the extracellular matrix in development and disease are still far from being fully understood. Here, we took advantage of the zebrafish sly mutation which affects Laminin {gamma}1, a major component of basement membranes, to explore its role in the development of the olfactory system. Following a detailed characterisation of Laminin distribution in the developing olfactory circuit, we analysed basement membrane integrity, olfactory placode and brain morphogenesis, and olfactory axon development in sly mutants, using a combination of immunochemistry, electron microscopy and quantitative live imaging of cell movements and axon behaviours. Our results point to an original and dual contribution of Laminin {gamma}1-dependent basement membranes in organising the border between the olfactory placode and the adjacent brain: they maintain placode shape and position in the face of major brain morphogenetic movements, they establish a robust physical barrier between the two tissues while at the same time allowing the local entry of the sensory axons into the brain and their navigation towards the olfactory bulb. This work thus identifies key roles of Laminin {gamma}1-dependent basement membranes in neuronal tissue morphogenesis and axon development in vivo.

developmental biology↗

bioRxiv2023

Cerebellar granular neuron progenitors exit their germinative niche via Barhl1 mediated silencing of T-Cell Factor transcriptional activity

SUMMARYT-Cell Factors (TCFs) are the main transcriptional effectors of Wnt/{beta}-catenin signaling. TCF responsiveness is a hallmark of self-renewal in mouse embryonic, and adult, neural stem cells (NSC). However, in vivo contribution(s) of TCF activities in long-lived NSCs are poorly understood. Granule neuron progenitors (GNP) in the upper rhombic lip (URL) are long-lived NSCs which express Atoh1 and generate cerebellar granule neurons. Using functional and transcriptomic approaches in amphibian, we demonstrate that TCFs are active in the URL, and are strictly necessary for the emergence and maintenance of the GNP germinative zone. We identify BarH-like 1 (Barhl1), a direct target of Atoh1, as a gate keeper for GNP exit from the URL, through silencing of TCF transcriptional activity. Our transcriptomic and in silico analysis identifies Barhl1/TCF URL target genes, and confirms our functional data. Our study provides in vivo evidence that inhibition of TCF repressive activity is necessary for maintenance of the URL, a long-lived neural germinative niche.

developmental biology↗

bioRxiv2023

FMRP regulates postnatal neuronal migration via MAP1B

The Fragile X Syndrome (FXS) represents the most prevalent form of inherited intellectual disability and is the first monogenic cause of Autism Spectrum Disorder. FXS results from the absence of the RNA-binding protein FMRP (Fragile X Messenger Ribonucleoprotein). Neuronal migration is an essential step of brain development allowing displacement of neurons from their germinal niches to their final integration site. The precise role of FMRP in neuronal migration remains largely unexplored. Using live imaging of postnatal Rostral Migratory Stream (RMS) neurons in Fmr1-null mice, we observed that the absence of FMRP leads to delayed neuronal migration and altered trajectory, associated with defects of centrosomal movement. RNA-interference-induced knockdown of Fmr1 shows that these migratory defects are cell-autonomous. Notably, the primary FMRP mRNA target implicated in these migratory defects is MAP1B (Microtubule-Associated Protein 1B). Knocking-down MAP1B expression effectively rescued most of the observed migratory defects. Finally, we elucidate the molecular mechanisms at play by demonstrating that the absence of FMRP induces defects in the cage of microtubules surrounding the nucleus of migrating neurons, which is rescued by MAP1B knockdown. Our findings reveal a novel neurodevelopmental role for FMRP in collaboration with MAP1B, jointly orchestrating neuronal migration by influencing the microtubular cytoskeleton.

neuroscience↗

bioRxiv2021

Pax3 induces neural circuit repair through a developmental program of directed axon outgrowth.

Repairing damaged or dysfunctional human brain circuits remains an ongoing challenge for biomedical science. While surviving neuronal networks can be reorganised after lesion, for example by neurotrophins, these new connections are disorganised and rarely produce clinical improvement. Here we investigate how to promote axonal growth while retaining correct cellular targeting. We show that, in response to brain-derived neurotrophic factor (BDNF) in target-tissue, potential reinnervating neurons upregulate Pax3. Pax3 in turn increases polysialic acid-neural cell adhesion molecule (PSA-NCAM) on their axon terminals, facilitating their outgrowth and pathfinding, and resulting in correctly-targeted neural circuit repair in the mature nervous system. This is a novel role for Pax3, which we confirmed by showing its expression in afferent neurons is essential for spontaneous and BDNF-induced reinnervation in the developing and mature brains, respectively. Together these results suggest that Pax3 contributes to a repair program, in which axon growth is promoted and direction signaling maintained. These data advance our understanding for accurately rebuilding neural circuits: restricting growth-promotion to potential afferent neurons, as opposed to stimulating the whole circuit, allows axon growth without impairing its guidance.

neuroscience↗

bioRxiv2020

Loss of floor plate Netrin-1 impairs midline crossing of corticospinal axons and leads to mirror movements

In human, execution of unimanual movements requires lateralized activation of the primary motor cortex, which then transmits the motor command to the contralateral hand through the crossed corticospinal tract (CST). Mutations in NETRIN-1 alter motor control lateralization, leading to congenital mirror movements. To address the role of midline Netrin-1 on CST development and subsequent motor control, we analyzed the morphological and functional consequences of floor-plate Netrin-1 depletion in conditional knock-out mice (Shh::cre;Ntn1lox/lox mice). Here, we show that depletion of floor plate Netrin-1 critically disrupts midline crossing of the CST, whereas the other commissural systems are mostly preserved. The CST defect results in abnormal but functional ipsilateral projections, and is associated with abnormal symmetric movements. Therefore, our study reveals a new role for Netrin-1 in CST development. It also describes a unique mouse model recapitulating characteristics of human congenital mirror movements, through abnormal CST decussation.

neuroscience↗

bioRxiv2019

Primary cilium cAMP regulates cyclic saltatory neuronal migration at the centrosome

The primary cilium (PC) is a small centrosome-assembled organelle, protruding from the surface of most eukaryotic cells. It plays a key role in cell migration, but the underlying mechanisms are unknown. Here, we show that the PC regulates neuronal migration via cAMP production activating centrosomal Protein Kinase A (PKA). Biosensor live-imaging revealed a periodic cAMP hotspot at the centrosome of embryonic, postnatal and adult migrating neurons. Genetic ablation of the PC, or knock-down of ciliary Adenylate Cyclase 3, caused hotspot disappearance and migratory defects, with defective centrosome/nucleus coupling and altered nucleokinesis. Delocalization of PKA from the centrosome phenocopied the migratory defects. Our results show that the PC and centrosome form a single cAMP-signaling unit dynamically regulating migration, further highlighting the centrosome as a signaling hub. The primary cilium regulates neuronal migration via cyclic AMP production activating Protein Kinase A at the centrosome

neuroscience↗

bioRxiv2018

Neural circuit repair by low-intensity magnetic stimulation requires cryptochrome

Magnetic brain stimulation is a promising treatment in neurology and psychiatry, but clinical outcomes are variable. Unfortunately, mechanisms underlying magnetic stimulation effects are ill-defined, which impedes the development of stimulation protocols appropriate for different neurological conditions. Here we show, in vivo and ex vivo, that repetitive transcranial magnetic stimulation at low-intensity (LI-rTMS) induces axon outgrowth and synaptogenesis to repair a neural circuit. This repair depends on stimulation pattern, with complex patterns being particularly effective, and its mechanism requires the presence of cryptochrome (Cry), a putative magneto-receptor. Effective LI-rTMS patterns altered expression of Cry target genes known to promote neuronal repair. Because LI-rTMS generates electric fields too weak to depolarise neurons, these findings indicate that the magnetic field itself induces the repair. Our data open a new framework for magnetic stimulation - cryptochrome-mediated molecular and structural neuroplasticity. This information suggests new routes to treatments specific for each neurological disease.

neuroscience↗