NICO NeuroWebinar & Seminar

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Event date: from 28/06/2024 to 28/06/2024
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NeuroWebinar & Seminar

1 appointment per week, on Friday at 2.00 pm

**Hybrid seminar : both in presence (max 25 people in Seminar room) and on webex

Friday 28/6/2024
Massimo Hilliard, Queensland Brain Institute, Australia
to be communicated

Host: C. Pritz

2024

Wednesday 5/6/2024 h. 12.00 am -  Hybrid seminar
  Elisa Galliano , University of Cambridge, UK
Neuronal heterogeneity and plasticity in the olfactory bulb 
Dopaminergic neurons in the olfactory bulb regulate early sensory processing by adjusting synaptic gain and exhibiting remarkable plasticity. Recent findings highlight their diverse responses to sensory deprivation, with some altering structure and excitability while others rely on synaptic changes. This plasticity is more pronounced than that displayed by excitatory neurons, suggesting rapid adaptation for sensory processing. Our lab's current work aims to understand how these responses contribute to generating appropriate neuronal outputs at both network and behavioural levels.
Host: Silvia De Marchis 

Friday 31/5/2024 h. 2.00 pm -  Hybrid seminar
  Michèle Studer , Institute of Biology Valrose, iBV; Univ. Côte d’Azur (UCA)
In vitro and in vivo modelling of an emerging neurodevelopmental disorder
My team is interested in understanding the relationships between impaired cortical development, malformations, and consequent symptoms in neurodevelopmental disorders, as well as the genes implicated in these processes. BBSOAS (Boonstra-Bosch-Schaff Optic Atrophy Syndrome) is a recently described monogenic neurodevelopmental disorder caused by the haploinsufficiency of the NR2F1 gene, a transcriptional regulator playing a key role during brain development. Intellectual disability, autistic traits, and visual impairments are the most common symptoms affecting BBSOAS patients although with heterogenous levels of severity.
By employing a multidisciplinary approach including disease animal models, 3D organoids, genetic manipulation, -omics approaches as well as structural bioinformatics, we are starting to understand the impact of the different mutations on protein stability and cell function and contribute to unraveling the genotype/phenotype correlation of the disease.
Host: Silvia De Marchis 

Friday 10/5/2024 h. 2.00 pm -  Webinar
  Jeroen Pasterkamp , Utrecht University Medical Centre and Utrecht University
Modelling neurodegenerative disorders in a dish
The goal of our work is directed towards understanding how neural circuits form during development and why they change or degenerate during disease. For this research, we use a combination of molecular cell biological approaches (e.g. scRNAseq, CRISPR), (3D) microscopy, mouse genetics and iPSC-based modelling in combination with microfluidics. Here I will focus on our work that attempts to dissect the molecular mechanisms underlying neurodegenerative diseases, in particular amyotrophic lateral sclerosis (ALS). ALS is a fatal neurodegenerative disorder with a lifetime risk of 1:400, affecting upper and lower motor neurons. Loss of motor nerves leads to weakness of skeletal muscles, ultimately resulting in death 3-5 years after diagnosis. Treatment options for ALS are limited and the development of new therapeutic strategies requires further insight into the pathogenic mechanisms underlying ALS.
In addition to employing ALS animal models, we have invested in setting up a wide array of advanced  in vitro  systems generated from human induced pluripotent stem cells (iPSCs) in combination with sensitive readouts. These models range from individual cell types, such as motor neurons or skeletal muscle cells, to combinations of cell types in microfluidic devices and even engineered 3D tissues (organoids). We have developed several neural organoid protocols for analyzing 3D neural tissue and specific cell-cell interactions. Importantly, these models show established pathological hallmarks of ALS as well as pathogenic changes and can therefore be used to further dissect disease mechanisms and to identify therapeutic targets.
Host: Roberta Schellino

Friday 3/5/2024 h. 2.00 pm -  Hybrid seminar
  Dustin J. Penn and Sarah M. Zala  - Konrad Lorenz Institute of Ethology, University of Veterinary Medicine, Vienna - Austria
Courtship vocalisations of wild house mice are highly dynamic and influence copulatory success
We analysed the courtship vocalisations of wild house mice (F1wild-caught  Mus musculus musculus)  emitted during different stages of courtship and mating, and we tested whether their calls predict male copulatory success. We recorded their behaviour and vocalisations over 40 h and analysed 40 - 50 min of recordings per pair. Of the ca. 53 000 vocalisations, 87% were ultrasonic (USVs), which we classified into 11 different syllable types, and 10% were partly audible broadband (BBVs) vocalisations; often called 'squeaks'. We found that the mice emitted a distinctive vocal repertoire and composition during each phase of courtship, and that their calls became increasingly complex over stages of courtship, especially once males began female mounting. During copulatory behaviour, USVs and BBVs (probably emitted by males and females respectively) became closely timed and uttered in tight synchrony, much like duetting birds. Approximately 40% of males copulated with ejaculation during the study and we found several differences between the vocalisations of the pairs that successfully copulated versus non-copulating pairs. USV emission increased during male sexual behaviours, and especially among the mice that successfully copulated. Our results show that the courtship vocalisations of wild house mice are much more complex and dynamic than has been assumed and they provide the first evidence for vocalisations that influence copulatory success. 
Host: Serena Bovetti

Friday 19/4/2024 h. 2.00 pm -  Hybrid seminar
  Pierre J. Magistretti , MD, PhD - Vice President for Research
Division of Biological and Environmental Sciences and Engineering, KAUST, Thuwal, Saudi Arabia
Neuron-glia metabolic coupling: role in neuronal plasticity and neuropsychiatric disorders

A tight metabolic coupling between astrocytes and neurons is a key feature of brain energy metabolism  (Magistretti and Allaman, Neuron, 2015). Over the years we have described two basic mechanisms of neurometabolic coupling. First the glycogenolytic effect of VIP and of noradrenaline indicating a regulation of brain homeostasis by neurotransmitters acting on astrocytes, as glycogen is exclusively localized in these cells. Second, the glutamate-stimulated aerobic glycolysis in astrocytes. Both the VIP-and noradrenaline-induced glycogenolysis and the glutamate-stimulated aerobic glycolysis result in the release of lactate from astrocytes as an energy substrate for neurons (Magistretti and Allaman, Neuron, 2015; Magistretti and Allaman, Nat Neurosci Rev, 2018).
We have subsequently shown that lactate is necessary not only as an energy substrate but also as a signaling molecule for long-term memory consolidation, for maintenance of LTP and for dendritic spine dynamics (Suzuki et al, Cell, 2011; Vezzoli et al, Cerebral Cortex, 2019). At the molecular level we have found that L-lactate stimulates the expression of synaptic plasticity-related genes such as  Arc Zif268  and BDNF through a mechanism involving NMDA receptor activity and its downstream signaling cascade Erk1/2 (Yang et al, PNAS, 2014). A transcriptome analysis in cortical neurons has shown that the expression of a total of 20 genes is modulated by L-Lactate; of these, 16 involved in plasticity and neuroprotection are upregulated and 4 involved in cell death are down regulated (Margineanu et al. Front in Mol Neurosci, 2018). This set of results reveal a novel action of L-lactate as a signaling molecule in addition to its role as an energy substrate (Magistretti and Allaman, Nat Neurosci Rev, 2018).
These actions of L-Lactate are also relevant for animal models of neuropsychiatric disorders. Indeed we have shown that peripheral administration of lactate exerts antidepressant-like effects in three animal models of depression (Carrard et al, Mol.Psy., 2016 and 2021). Finally, we have shown that the transfer of L-Lactate from astrocytes to neurons plays a key role in an appetitive memory task involving the basolateral amygdala such as cocaine place preference in mice (Boury-Jamot et al. Mol Psy, 2016).
Recently, using electrophysiology, two-photon imaging, cognitive tasks, and mathematical modeling, we have shown that both glucose  and lactate are involved in engram formation, with lactate  supporting long-term synaptic plasticity evoked  by  high-stimulation  load  activity  patterns  and  high attentional load in cognitive tasks while glucose is sufficient for less demanding neural computation  and  learning  tasks (Dembritskaya et al, PNAS, 2022).
In view of the critical role of astrocytes in the regulation of brain energy metabolism that we have explored over the past four decades, and of the evidence that dysregulation of astrocyte-mediated metabolic pathways is involved in brain hypometabolism, we are now focusing on pharmacologically targeting astrocytes to address the therapeutic needs in neuropsychiatric disorders characterized by hypometabolism. We have gathered recent evidence in preclinical animal models of genetic diseases such as for example Glucose Transporter 1 Deficiency Syndrome (GluT1DS or De Vivo disease) and neurodegenerative diseases such as Alzheimer’s disease  that targeting astrocytes to overcome brain hypometabolism opens promising therapeutic avenues (Beard et al 2022, Front in Physiol).

Host: Corrado Calì

Friday 5/4/2024 h. 2.00 pm -  Hybrid seminar
Deborah Chiabrando , Department of Molecular Biotechnology and Health Sciences, Molecular Biotechnology Center “Guido Tarone”, University of Torino
Dysregulation of FLVCR1-dependent mitochondrial calcium handling in neural stem cells causes congenital hydrocephalus.
Congenital hydrocephalus (CH), occurring in approximately 1/1000 live births, represents an important clinical challenge due to the limited knowledge of underlying molecular mechanisms. The discovery of novel CH-genes is thus essential to shed light on the intricate processes responsible for ventricular dilatation in CH. Here, we identify FLVCR1 (Feline Leukemia Virus Subgroup C Receptor 1) as a novel gene responsible for a severe form of CH in humans and mice.
Mechanistically, our data reveal that FLVCR1a interacts with the IP3R3-VDAC complex located on mitochondria-associated membranes (MAMs) that controls mitochondrial calcium handling. Loss of Flvcr1a in mouse neural stem cells (NSCs) affects mitochondrial calcium levels and energy metabolism, leading to defective cortical neurogenesis and brain ventricle enlargement. These data point to defective NSC calcium handling and metabolic activity as one of the pathogenetic mechanisms driving CH.
Host: Enrica Boda

Friday 22/3/2024 h. 2.00 pm -  Hybrid seminar
Silvia Diviccaro, Dipartimento di Scienze Farmacologiche e Biomolecolari - Università di Milano
GUT-MICROBIOTA-BRAIN AXIS: FOCUS ON GUT STEROIDS

Sex steroids, derived mainly from gonads, can shape gut microbiota composition. Therefore, it is not surprising that sexual dimorphic features dictated by sex steroids also concern microbes [1-3]. The gut microbiome as well as its metabolites actively participate in host homeostasis prominently in intestinal health and brain response via the gut-microbiota-brain axis (GMBA), a bidirectional communication that includes immune, endocrine, neural, and humoral routes. Thus, in GMBA, the involvement of steroid molecules is plausible and should be highlighted. Importantly, the total lack of microbiota in axenic experimental models drastically influences steroid levels both in plasma and in the brain, regardless of where the molecules are synthesized.
However, to take into consideration peripheral steroidogenic glands and the brain as exclusive steroidogenic centers is limited. The gastrointestinal tract has a strong ability to synthesize glucocorticoids in inflammatory conditions and, as demonstrated more recently, the synthesis of other steroids such as the first precursor (i.e., pregnenolone), estrogens (i.e., 17beta-estradiol), testosterone, progesterone, and their active metabolites, such as dihydrotestosterone and allopregnanolone. The pattern of intestinal steroid levels (i.e., gut steroids) is sexually dimorphic and is maintained after gonadectomy, suggesting a significant gut steroid pool locally acting by steroid receptors, such as GABA-A receptor.
Interestingly, intestinal steroidogenesis and gut steroid levels do not reflect the brain environment in some pathological conditions, suggesting that the gut and brain may be differently affected. In particular, in type 1 diabetes mellitus as well as after treatment with a steroidogenic inhibitor (i.e., finasteride), or a selective-serotonin reuptake inhibitor (i.e., paroxetine) gut steroid levels are affected in animal models. Of note, the steroid alterations were coupled with gut microbiota alterations, which were also observed in patients affected by these disorders, highlighting a putative dysfunction of GMBA. Bearing in mind that the gut and brain constantly send messages to each other and are influenced by microbiota will be also crucial to investigate how steroids influence these three different compartments in physiopathological conditions.

Host: Marilena Marraudino 

Friday 15/3/2024 h. 2.00 pm -  Webinar
Ferdinand Althammer , Heidelberg University Hospital, Institute for Human Genetics, Germany
Microglial Angiotensin II signaling in cardiovascular diseases

Heart failure (HF) is a widespread and debilitating condition impacting over 64 million individuals globally. Beyond compromised cardiovascular function and related systemic issues, HF patients commonly experience depression and significant cognitive decline. Despite the presence of neuroinflammation and brain hypoperfusion in both humans and rodents with HF, the specific neuronal substrates and mechanisms contributing to cognitive deficits remain elusive.
To address this knowledge gap, we employed a well-established HF rat model replicating clinical outcomes and employed a multidisciplinary approach spanning behavioral, electrophysiological, neuroanatomical, molecular, and systemic physiological analyses. Our investigations revealed neuroinflammation, hypoperfusion/hypoxia, and neuronal deficits in the hippocampus of HF rats, correlating with disease progression. Increased expression of Ang II receptor type 1a (AT1aRs) in hippocampal microglia preceded neuroinflammation onset. Blocking AT1Rs with the therapeutic drug Losartan efficiently reversed neuroinflammatory endpoints, improving cognitive performance in HF rats. Additionally, we demonstrated that circulating Ang II could access the hippocampal parenchyma in HF rats, potentially initiating the neuroinflammatory cascade.
This study identified the hippocampus as a crucial neuronal substrate, Ang II–driven neuroinflammation as a key mechanism, and AT1aRs as a potential neuroprotective therapeutic target for treating cognitive deficits in HF. The findings underscore the significance of understanding the interplay between microglia and local microvasculature, revealing an impact on blood-brain barrier integrity and cerebral blood flow regulation during HF. In our ischemic HF rat model, increased vessel-associated microglia (VAM) in HF rat hippocampi exhibited heightened Ang II AT1a receptor expression.
Acute Ang II administration induced microglia recruitment to the perivascular space, emphasizing the role of microglia-vascular interactions in HF-induced neuroinflammation. Administering an AT1aR blocker to HF rats prevented microglia recruitment to the perivascular space, normalizing levels to those in healthy rats. These results unveil novel therapeutic avenues targeting microglia-vascular interactions to mitigate neuroinflammation in cardiovascular diseases, providing valuable insights into the pathophysiology of this prevalent condition.

Host: Ilaria Bettocchi | 

Friday 1/3/2024 h. 2.00 pm -   Hybrid Sem inar
  Marco Terenzio , OIST - Okinawa Institute of Science and Technology, Japan
Regulation of RNP granule dynamics and axonal translation in sensory and motor neurons
Neurons are highly polarized cells with an elongated axon that extends far away from the cell body. In order to maintain neuronal homeostasis, neurons rely extensively on axonal transport of membranous organelles and other molecular complexes in addition to local translation of proteins. Axonal transport plays a central role in the establishment of neuronal polarity, axonal growth and stabilization and synapses formation, allowing for precise spatio-temporal activation and modulation of numerous molecular cascades. Anterograde and retrograde axonal transport are supported by various molecular motors, such as kinesins and dyneins, and a complex microtubule network. In this seminar I will discuss some aspects of retrograde signaling in neurons, ranging from injury signals to dynein-mediated axonal transport, which are critical for the survival of neurons. We will also discuss the storage and translation of mRNA granules in axons and strategies to promote axonal regeneration through the use of specialized substrates and the tools we have developed to investigate the mechanisms underlying axonal degeneration in Amyothrophic Lateral Sclerosis (ALS).
Host: Letizia Marvaldi

Friday 23/2/2024 h. 2.00 pm -   Hybrid Sem inar
  Helena L. A. Vieira , UCIBIO, Applied Molecular Biosciences Unit, Department of Chemistry, NOVA School of Science and Technology, Universidade Nova de Lisboa, Portugal
Carbon monoxide promotes mitochondrial homeostasis in brain cells:   Cell energy and fate control in stroke context 
Carbon monoxide (CO) is a gasotransmitter endogenously produced by the activity of heme oxygenase, which is a stress-response enzyme. Endogenous CO or low concentrations of exogenous CO have been described to present several cytoprotective functions: anti-apoptosis, anti-inflammatory, vasomodulation, maintenance of homeostasis, stimulation of preconditioning and modulation of cell differentiation.

The seminar will present and discuss how CO is cytoprotective in glial cells and how CO improves neuronal differentiation. In fact, COprevents oxidative stress-induced astrocytic cell death by improving oxidative metabolism [1] and mitochondrial quality control [2]. The anti-neuroinflammatory effect of CO is also dependent on microglial metabolism control regulated by neuroglobin [3]. Finally, neuronal differentiation is facilitated by CO modulation of metabolism: oxidative phosphorylation [4] and pentose phosphate pathway [5].

[1]  A.S. Almeida, C.S.F. Queiroga, M.F.Q. Sousa, P.M. Alves, H.L.A. Vieira, Carbon monoxide modulates apoptosis by reinforcing oxidative metabolism in astrocytes: Role of Bcl-2, J. Biol. Chem. 287 (2012) 10761–10770. doi:10.1074/jbc.M111.306738.
[2]  C. Figueiredo-Pereira, B. Villarejo-Zori, P.C. Cipriano, D. Tavares, I. Ramírez-Pardo, P. Boya, H.L.A. Vieira, Carbon Monoxide Stimulates Both Mitophagy And Mitochondrial Biogenesis to Mediate Protection Against Oxidative Stress in Astrocytes, Mol. Neurobiol. 60 (2023) 851–863. doi:10.1007/s12035-022-03108-7.
[3]  D. Dias-Pedroso, J.S. Ramalho, V.A. Sardão, J.G. Jones, C.C. Romão, P.J. Oliveira, H.L.A. Vieira, Carbon Monoxide-Neuroglobin Axis Targeting Metabolism Against Inflammation in BV-2 Microglial Cells, Mol. Neurobiol. 59 (2022) 916–931. doi:10.1007/s12035-021-02630-4.
[4]  A.S. Almeida, U. Sonnewald, P.M. Alves, H.L.A. Vieira, Carbon monoxide improves neuronal differentiation and yield by increasing the functioning and number of mitochondria, J. Neurochem. 138 (2016) 423–435. doi:10.1111/jnc.13653.
[5]  A.S. Almeida, N.L. Soares, C.O. Sequeira, S.A. Pereira, U. Sonnewald, H.L.A. Vieira, Improvement of neuronal differentiation by carbon monoxide: Role of pentose phosphate pathway, Redox Biol. 17 (2018) 338–347. doi:10.1016/j.redox.2018.05.004.

Host: Alessandro Vercelli 

Friday 16/2/2024 h. 2.00 pm -   Hybrid Sem inar
  Vasco Meneghini , San Raffaele Telethon Institute for Gene Therapy (SR-Tiget), IRCCS San Raffaele Scientific Institute, Milan, Italy
Targeting astrocytes with editing technologies to treat Alexander Disease

Alexander disease (AxD) is a rare, lethal leukodystrophy caused by gain-of-function mutations in the gene encoding for glial fibrillary acidic protein (GFAP), the main intermediate filament of astrocytes. Accumulation of GFAP aggregates in Rosenthal fibers leads to central nervous system (CNS)dysfunction with typical pathological traits such as astrogliosis, loss of myelin, seizures, and spasticity. No cure is currently available for this neurodegenerative disorder.
We developed a novel, single-dose gene editing strategy for the lifetime treatment of AxD. We selected a single guide RNA (gRNA) targeting the murineGfapgenein3T3 cells transduced with a lentiviral vector (LV) harboring the R76H-mutant GFAP protein fused to mCherry. FACS analysis of mCherry expression showed that the best gRNA candidate induced a robust knock-down ofGFAP-mCherry, while nogene editing at top off-target loci was evident. To optimize the in vivo brain-directed delivery of theGfap-targeting CRISPR system, pilot experiments defined the optimal injection protocol, AAV serotype and promoter, resulting in high astrocytic tropism and transduction rates of AxD-affected brain regions. Selected AAV carrying the Gfap-targetinggRNA and the Cas9 nuclease was administered by intracerebroventricular injections in neonatal AxD mice. AVV-mediated Cas9/sgRNAdelivery resulted in on-target editingin GFAP+ astrocytes, decreased astrogliosis and reduced accumulation of Rosenthal fibers - a hallmark of AxD pathology - in white matter regions. These data provide in vivo proof-of-concept of the efficacy of a CRISPR/Cas9 editing approach in ameliorating disease-associated phenotypes.
To expand on the potential of gene editing as a mutation-specific treatment for AxD, we are currently developing allele-specific gene therapies targeting the murine R76H mutation, homolog of the human mutation hotspot detected in AxD patients. Among them, we identified adenine base editors that efficiently correct the Gfap mutation in vitro and we are currently validating this approach in vivo. Overall, our study provides initial proof-of-concept data on the efficacy of a CRISPR/Cas9 editing approach in ameliorating disease-associated phenotypes. Our results pave the way for pre-clinical studies aimed at improving the editing tolls targeting the mutated Gfap allele in the CNS using AAV vectors or, prospectively, non-viral delivery systems.
Host: Martina Lorenzati

Friday 9/2/2024 h. 2.00 pm -   Hybrid Sem inar
  Alessandro Usiello , Dept. Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania L. Vanvitelli
D-amino acids metabolism abnormalities in neurological and psychiatric disorders

D-aspartate (D-Asp) has a transient emergence in the mammalian brain. It is abundant in the embryonic phase and the first post-natal days before significantly decreasing thereafter. Interestingly, during prenatal phases, the intracellular localization of D-Asp seems to be developmentally regulated, according to the functional activity of neuroblasts. It has long been established that D-aspartate oxidase (DDO) is the enzyme responsible for D-Asp catabolism. Accordingly, the post-natal decrease of D-Asp content is associated with the concomitant, progressive increase in  Ddo  gene expression and DDO activity in the rodent brain. D-Asp is present at extracellular level, where it acts as an agonist at NMDA and mGlu5 receptors. In line with its pharmacological role, we found that adult mice with abnormally high cerebral D-Asp levels showed increased NMDA receptor-dependent functional and structural plasticity, and improved spatial memory.
Although these findings highlight the influence of non-physiologically high D-Asp levels on several cerebral processes at adulthood, it is so far unknown the significance of embryonic D-Asp in the mammalian brain and its involvement on brain functions and behaviors at adulthood. To clarify this issue, we have recently generated a novel knockin mouse model in which the expression of DDO is anticipated starting from the zygotic stage to enable the removal of the embryonic storage of cerebral D-Asp. To this aim, we targeted a  Ddo  cDNA cassette in the genomic  Rosa26  locus to allow the ectopic transcription of  Ddo  under the regulatory control of the constitutive  Rosa26  promoter. We found that knockin strategy resulted in a strong, allele-dependent increase of both  Ddo  expression and DDO enzymatic activity in heterozygous ( R26 Ddo/+ ) and homozygous ( R26 Ddo/Ddo Ddo  knockin brains, compared to wild-type controls ( R26 +/+ ). These molecular alterations resulted in a corresponding strong ontogenetic depletion of cerebral D-Asp, from embryonic to adult phase. However, deregulated  Ddo  gene expression did not affect the cerebral levels of L-Asp, the precursor of D-Asp biosynthesis, as well as the metabolism of D-serine and L-glutamate, the two main neuroactive molecules involved in NMDA receptor-dependent transmission. Surprisingly, despite the removal of embryonic cerebral D-Asp,  Ddo  knockin mice were viable, fertile and did not show any evident abnormalities at adulthood. Moreover, histological and immunohistochemical analysis revealed no gross differences in brain size or structural organization and no variations in neuronal density and distribution in adult  Ddo  knockin mice. Conversely, we found that early D-Asp depletion was associated with increased number of cortical parvalbumin-positive interneurons and improved cognitive abilities of adult  Ddo  knockin mice in spatial memory e recognition tasks. Overall, the molecular, morphological and behavioral characterization of  Ddo  knockin mice revealed unexpected phenotypes that deserve further investigations not only in adult but also in juvenile and embryonic phases of mouse brain development.

Host: Alessandro Vercelli

Friday 2/2/2024 h. 2.00 pm - Webinar
  Ariel Di Nardo , CNRS Research Scientist and Co-director, Development & Neuropharmacology Team, CIRB, Collège de France
Anxiety-like behavior regulated by non-cell autonomous transcription factor activity
Our laboratory investigates the role of non-cell autonomous homeoprotein transcription factors in regulating cerebral cortex physiology. We discovered that OTX2 homeoprotein is expressed in the choroid plexus, secreted into cerebrospinal fluid, and transferred into parvalbumin (PV)-expressing interneurons in mice. OTX2 participates in PV cell maturation and regulates the timing of plasticity critical periods throughout the brain. These juvenile periods allow for remodeling of circuitry in response to the environmental and genetic contexts, and are associated with disease outcomes. Although our initial OTX2 studies were primarily focused on mouse visual system critical periods, we have also investigated higher order circuits involved in anxiety-like behavior shaped by early-life stress. Our recent findings revealed OTX2 target genes in cortical PV cells with epigenetic outcomes and showed that choroid plexus OTX2 affects animal behavior.
Host: Serena Stanga

Monday  22/1/2024 h. 2.00 pm - Hybrid Sem inar
  Elia Di Schiavi , Institute of Biosciences and BioResources, IBBR; Dept. Biology, Agriculture and Food Science, CNR Naples, Italy
Splicing regulation of Reticulon is involved in preventing neurodegeneration in a C. elegans model of SMA

An efficient splicing of mRNA is required in all cells, but neurons seem to be more vulnerable to splicing perturbations. In fact, numerous neurodegenerative diseases are caused by splicing defects, including Spinal Muscular Atrophy (SMA). However, why neurons are more affected to splicing alterations and which step of the RNA processing is impaired in this disease is still debated. SMA is caused by mutations in the Survival Motor Neuron (Smn) gene, which is involved in RNA metabolism and splicing. We have demonstrated that genes differentially expressed or spliced in induced pluripotent cell-derived motor neurons (iPS-MNs) from SMA patients are enriched in the RNA motif 7. This motif is specifically recognized by hnRNPQ, a spliceosomal component physically interacting with SMN. We demonstrated that hrpr-1, the hnRNPQ homolog in C. elegans, is involved in motoneurons (MNs) survival similarly to smn-1, the Smn homolog. We demonstrated that they genetically interact and exert a neuroprotective function specifically in MNs. Comparing hrpr-1 known targets in C. elegans and the alternatively spliced genes identified in SMA patients, we identified a new possible downstream target of the pathway: ret-1, the only homolog in C. elegans of Reticulon genes, a family of transmembrane proteins involved in vesicle recycling and formation, and in neurite outgrowth. We confirmed a possible involvement of ret-1 in SMA by observing alteration in its transcript levels in C. elegans, SMA mice and patients. Moreover, we demonstrated that ret-1 splicing pattern is altered when smn-1 is depleted and that hrpr-1 and smn-1 work together to guarantee the correct splicing of exon 5 of ret-1 gene. Thus, we identified for the first time a neuroprotective role of hrpr-1 and the involvement of ret-1 in neurodegeneration.

Piera Smeriglio ,   Center of Research in Myology, Sorbonne University, Paris, France
Deciphering key molecular players in skeletal muscle affected by SMA

Spinal Muscular Atrophy (SMA) is traditionally considered a disease of the motor neurons, however, increasingly the systemic role of the SMN protein is being underscored. In particular, the role of the muscle as both an axis of pathology and driver of overall disease, is being appreciated. After an initial characterization of the phenotypic and molecular features of the skeletal muscle tissue in a severe SMA mouse model, we sought to investigate the response of the muscle upon administration of the approved therapies. Therefore, we collected paravertebral muscle from SMA Type II patients (n=8) after treatment with Nusinersen and age matched controls (n=7) and performed RNA-sequencing. This analysis revealed a heterogeneous response of the skeletal muscle tissue to the therapy with most of the patients having a persistent DNA damage and P53 pathways activation despite the restoration of SMN levels. This study provides a molecular roadmap of the state of SMA muscle after treatment. Work is ongoing to determine that molecular reasons – be they genetic, epigenetic, or clinical for the heterogeneous response to Nusinersen injection, and to test drug candidates to improve mitochondrial function and decrease DNA damage in skeletal muscle.

Host: Marina Boido 

Friday 19/1/2024  h. 9.00 am  - Webinar
  Makoto Sato , Department of Anatomy and Neuroscience, Graduate School of Medicine; Division of Child Development, United Graduate School of Child Development (UGSCD) - Osaka University, JAPAN
Cytoskeletons and cortical development: How does the neocortex develop to establish the prototype of neuronal circuits by neuronal migration and collateral formation?

To understand the complex neuronal circuits for higher functioning of the neocortex from a compositional perspective, I have studied cortical development, in particular cytoskeletal regulatory mechanisms underlying migration and collateral formation. Periventricular nodular heterotopia gave me the first hint to study cortical development focusing on the regulation of cytoskeletons. Periventricular heterotopia is a hereditary disease in which the brain has a second cortex (cluster of nerve cells) around the ventricle, a so-called double cortex, and one of its characteristics is intractable epilepsy.
The cause of the disease is believed to be a mutation in the actin-binding protein filamin A on the X chromosome, suggesting that filamin A is important for neurons to migrate out of the cortical ventricular zone to form the neocortex. We have identified and studied a novel molecule, FILIP (filamin A interacting protein), which promotes the degradation of filamin A. Very recently, it was reported that mutations in FILIP (FILIP1 in human) cause congenital arthrogryposis multiplex, intellectual disability, holoprosencephaly, and encephalocele in human (FILIP disease). In my talk, I will introduce a series of FILIP-related studies to and its regulatory factors, including some unpublished data.
It is generally believed that mutation of molecules involved in neuronal migration increases susceptibility to various neuropsychiatric diseases, but the relationship between these mutations has not been fully elucidated. Therefore, to examine changes in neural networks due to variations in neuronal arrangement, we first constructed a system to visualize single-cell level neural networks for individual cerebral cortical neurons. Sequential collateral formation to apparently predetermined targets is critical to establish the prototype of neuronal circuits. I will also present our latest results that underlie such collateral formation in my talk.
Host: Alessandro Vercelli 

Friday 12/1/2024 h. 2.00 pm -  Hybrid Sem inar
  Filippo Sean Giorgi , Dept. Translational Research and of New Surgical and Medical Technologies, University of Pisa
The central noradrenergic system and neurodegeneration occurring along the Alzheimer’s Disease continuum and ageing

Understanding Alzheimer’s Disease (AD) pathophysiology represents a major challenge of neuroscience research, and effective disease-modifying therapies are still far to be developed. In recent years, growing attention has been focused on the possible role of the noradrenergic nucleus Locus Coeruleus (LC) in AD pathogenesis and physiopathology. Experimental findings and human post-mortem data all converge in underscoring the impact of early LC degeneration in AD-related degenerative phenomena and AD natural history. A better shaping of the features and role of LC in AD might be crucial in detailing its role as a research biomarker, as well as a potential therapeutic target of AD.
In this seminar, an overview of the current research on the role of the LC in AD will be provided, including some pieces of data I have been collecting in recent years. In particular, we, in parallel with other groups, have been able to confirm in vivo in humans the significant involvement of LC in the AD continuum by profiting of advanced Magnetic Resonance Imaging (MRI) tools (LC-MRI) which have been developed ad-hoc.  Recently, we have also shown its involvement in the conversion from Mild Cognitive Impairment to dementia and the association between the degeneration of different parts of LC with the cortical metabolism of AD patients. Moreover, we explored the relationship between LC structural integrity and neuroinflammation, by assessing the association of LC-MRI with plasma interleukins in patients and healthy controls. Finally, I will illustrate and discuss experimental studies currently ongoing on the relationship between LC and normal ageing, and between LC degeneration and late-onset epilepsy; these might offer additional perspectives for dissecting the complex pathophysiology of AD and the role of LC.

Host: Alessandro Vercelli

Events & Meetings

28 june 2024

NICO NeuroWebinar & Seminar

1 appointment per week, on Friday at 2.00 pm