Biology subjects

Paolicelli, R. C.

Publications and source records attributed to Paolicelli, R. C..

8 recordsLinked to original sources

bioRxiv2025

MICROGLIAL EXTRACELLULAR VESICLES MEDIATE C1Q DEPOSITION AT THE PRE-SYNAPSE AND PROMOTE SYNAPTIC PRUNING

C1q is released by microglia, localizes on weak synapses and acts as a tag for microglial synaptic pruning. However, how C1q tags synapses during the pruning period remains to be fully elucidated. Here, we report that C1q is delivered by microglia to pre-synaptic sites that externalize phosphatidylserine through extracellular vesicles. Using approaches to increase or reduce vesicles production in microglia, by C9orf72 knock out or pharmacological inhibition respectively, we provided mechanistic evidence linking extracellular vesicle release to pre-synaptic remodelling in neuron-microglia cultures. In C9orf72 knockout mice, we confirmed larger production of microglial extracellular vesicles, and showed augmented C1q presynaptic deposition associated with enhanced engulfment by microglia in the early postnatal hippocampus. Finally, we provide evidence that microglia physiologically release more vesicles during the period of postnatal circuit refinement. These findings implicate abnormal release of microglial extracellular vesicles in both neurodevelopmental and age-related disorders characterized by dysregulated microglia-mediated synaptic pruning.

neuroscience↗

bioRxiv2025

Sound-Enhanced Sleep Depth Reduces Traumatic Brain Injury Damage and Sequelae and Supports Microglial Response

Traumatic brain injury significantly reduces the quality of life for millions of survivors worldwide, with no established treatments currently available. High slow-wave activity (SWA) sleep immediately after rodent TBI improves posttraumatic outcomes. However, pharmacological SWA-enhancing strategies are hindered by severe specificity and scalability issues that prevent it from effectively reaching clinical implementation. Alternatively, closed-loop auditory stimulation (CLAS) of sleep slow waves offers specific SWA enhancement with high translational potential. Our present results demonstrate that up-phase-targeted CLAS (upCLAS)-mediated SWA enhancement reduced diffuse axonal injury, decreased demyelination, and preserved cognitive ability in TBI rats. The alleviated posttraumatic phenotype was associated with increased microglia response, likely mediating CLAS neuroprotective effect in the acute injury phase. Auditory-enhanced SWA may thus constitute a novel noninvasive neuroprotective therapy preventing TBI sequelae via boosted cellular response to tissue damage.

neuroscience↗

bioRxiv2024

Early-life scarcity adversity biases behavioral development toward a bipolar-like phenotype in mice heterozygous for CNTNAP2

The etiological complexity of psychiatric disorders arises from the dynamic interplay between genetic and environmental vulnerabilities. Among the environmental components, early-life adversities (ELA) are a major risk-factors for developing a psychiatric disorder. Yet, the mechanistic interaction between ELA and genetic vulnerability contributing to psychopathology is poorly understood. To fill this gap, we took advantage of the ideally controlled conditions of a pre-clinical approach. In this study we raised a mouse model with genetic predisposition to multiple psychiatric disorders (autism spectrum, schizophrenia, bipolar disorder), the Cntnap2+/- mouse, with limited bedding and nesting (LBN), a well-established paradigm to induce early-life stress in rodents. These mice were compared to LBN-raised Cntnap2+/+ littermates, as well as parallel groups of Cntnap2+/+ and Cntnap2+/- raised in standard conditions. Using a battery for behavioral phenotyping we show that ELA shapes non-overlapping phenotypic landscapes based on genetic predisposition. Specifically, we found that LBN-raised Cntnap2+/- mice develop a perseverative risk-taking behavior in the elevated plus maze and that this behavior is highly predictive of their success in the social interaction, assessed with the 3-chamber test. This finding suggests that the intrusion of anxiety into the social behavioral domain contributes to extreme gain- or loss-of function in social interaction, resembling a bipolar-like phenotype. Finally, we show that LBN promotes synaptic hypertrophy in the basolateral nucleus of the amygdala, but only in Cntnap2+/- raised in LBN this condition was found in combination with microglia abnormalities. We conclude that the interplay between ELA and Cntnap2 haploinsufficiency exacerbates bipolar-like behaviors in mice, and that this may be consequence of deficient synaptic homeostasis in the basolateral amygdala.

neuroscience↗

bioRxiv2022

Analyses of circRNA expression throughout circadian rhythm reveal a strong link between Cdr1as and light-induced phase shifts in the SCN

Cdr1as is a conserved circular RNA (circRNA) enriched in the CNS and important for maintaining brain homeostasis. The loss of Cdr1as results in aberrant synaptic transmission and deregulation of stress response and circadian clock genes. However, it is not known whether the expression of Cdr1as or circRNAs, in general, follows a circadian pattern in different tissues. Here, using newly generated and public RNA-Seq data, we monitor circRNA expression throughout circadian rhythm in various mouse brain regions. We demonstrate that Cdr1as, despite its stable character, has a highly dynamic expression during the circadian cycle in the mouse suprachiasmatic nucleus (SCN). Cdr1as is one of the highest expressed RNAs in a cluster associated with light-induced synaptic transmission and phase shift in the SCN. Further, we identified that another brain enriched circRNA, mbl, is also substantially deregulated upon light induction in the fly head. Our study highlights the potential impact of abundant and conserved circRNAs on maintaining a healthy circadian cycle across species.

systems biology↗

bioRxiv2021

All-polymeric transient neural probe for prolonged in-vivo electrophysiological recordings

Transient bioelectronics has grown fast, opening possibilities never thought before. In medicine, transient implantable devices are interesting because they could eliminate the risks related to surgical retrieval and reduce the chronic foreign body reaction. However, despite recent progress in this area, the short functional lifetime of devices due to short-lived transient metals, which is typically a few days or weeks, still limits the potential of transient medical devices. We report that a switch from transient metals to an entirely polymer-based approach allows for a slower degradation process and a longer lifetime of the transient probe, thus opening new possibilities for transient medical devices. As a proof-of-concept, we fabricated all-polymeric transient neural probes that can monitor brain activity in mice for a few months rather than a few days or weeks. Also, we extensively evaluated the foreign body reaction around the implant during the probes degradation. This kind of devices might pave the way for several applications in neuroprosthetics.

bioengineering↗

bioRxiv2020

Nutrient signaling pathways regulate amyloid clearance and synaptic loss in Alzheimer's disease

Extra-cellular accumulation of Amyloid-{beta} (A{beta}) plaques is causatively associated with Alzheimers disease (AD). However, mechanisms that mediate the pre-pathological state of amyloid plaque formation remain elusive. Here, using paired RNAi and kinase inhibitor screens, we discovered that AKT-mediated insulin/nutrient signaling suppresses lysosomal clearance of A{beta} and promotes amyloid formation. This mechanism is cell-autonomous and functions in multiple systems, including iPSC-derived human neurons and in vivo. Nutrient signaling regulates amyloid formation via distinct lysosomal functional mechanisms, while enhanced amino acid signaling promotes amyloid formation by transcriptionally suppressing lysosome biogenesis, and high intracellular cholesterol levels suppress lysosomal clearance of amyloid by increasing the number of non-functional lysosomes. The nutrient signaling pathway, present in both neurons and microglia, regulates lysosomal clearance of amyloid and microglia mediated synapse loss, both in vitro and in vivo. Clinically, older hyperlipidemic patients showed less synapse loss through microglia and performed better in cognitive tests. Thus, our results reveal a bi-partite cellular quality control system regulated by the insulinnutrient signaling that in neurons regulates A{beta} peptide clearance and in microglia regulates synaptic loss, both processes causally associated with AD. Our results also caution against reducing amyloid through such processes as this might also result in synapse loss.

neuroscience↗

bioRxiv2020

Enzymatic dissociation induces transcriptional and proteotype bias in brain cell populations

Different cell isolation techniques exist for transcriptomic and proteotype profiling of brain cells. Here, we provide a systematic investigation of the influence of different cell isolation protocols on transcriptional and proteotype profiles in mouse brain tissue by taking into account single-cell transcriptomics of brain cells, proteotypes of microglia and astrocytes, and flow cytometric analysis of microglia. We show that standard enzymatic digestion of brain tissue at 37{degrees}C induces profound and consistent alterations in the transcriptome and proteotype of neuronal and glial cells, as compared to an optimized mechanical dissociation protocol at 4{degrees}C. These findings emphasize the risk of introducing technical biases and biological artefacts when implementing enzymatic digestion-based isolation methods for brain cell analyses.

neuroscience↗

bioRxiv2020

Blocking gephyrin phosphorylation or microglia BDNF signaling prevents synapse loss and reduces infarct volume after ischemia

Microglia interact with neurons to facilitate synapse plasticity; however, signal transducers between microglia and neuron remain unknown. Here, using in vitro organotypic hippocampal slice cultures and transient MCAO in genetically-engineered mice in vivo, we report that at 24 h post-ischemia microglia release BDNF to downregulate glutamatergic and GABAergic synapses within the peri-infarct area. Analysis of the CA1 hippocampal formation in vitro shows that proBDNF and mBDNF downregulate glutamatergic dendritic spines and gephyrin scaffold stability through p75NTR and TrkB receptors respectively. Post-MCAO, we report that in the peri- infarct area and in the corresponding contralateral hemisphere similar neuroplasticity occur through microglia activation and gephyrin phosphorylation at Ser268, Ser270 in vivo. Targeted deletion of the Bdnf gene in microglia or GphnS268A/S270A (phospho-null) point-mutations protect against ischemic brain damage, neuroinflamation and synapse downregulation normally seen post-MCAO. Collectively, we report that gephyrin phosphorylation and microglia derived BDNF faciliate synapse plasticity after transient ischemia.

neuroscience↗