A5055848943- Neuroscience and Neuropharmacology Research
- Health Systems, Economic Evaluations, Quality of Life
- Dementia and Cognitive Impairment Research
- Statistical Methods in Clinical Trials
- Genetic Neurodegenerative Diseases
- Ion channel regulation and function
- Photoreceptor and optogenetics research
- Alzheimer's disease research and treatments
- Memory and Neural Mechanisms
- Medical Imaging Techniques and Applications
- Neurogenesis and neuroplasticity mechanisms
- Biomedical Ethics and Regulation
- Biomedical Text Mining and Ontologies
- Machine Learning in Healthcare
- Ethics in Clinical Research
- Meta-analysis and systematic reviews
- Advanced Neuroimaging Techniques and Applications
- Protein Kinase Regulation and GTPase Signaling
- Epilepsy research and treatment
- Mitochondrial Function and Pathology
- Cerebrovascular and Carotid Artery Diseases
- Biotechnology and Related Fields
- Gene Regulatory Network Analysis
- Medicinal Plants and Neuroprotection
- Retinal Development and Disorders
Critical Path Institute
2020-2024
Boston University
2017-2020
University of Helsinki
2014-2015
Tufts University
2015
Scuola Internazionale Superiore di Studi Avanzati
2006-2013
Italian Institute of Technology
2012
Inserm
2012
Tecnologie Avanzate (Italy)
2010
University of California, Irvine
2007
The University of Tokyo
2006
GABA A receptors form Cl − permeable channels that mediate the majority of fast synaptic inhibition in brain. The K + /Cl cotransporter KCC2 is main mechanism by which neurons establish low intracellular levels, thought to enable GABAergic inhibitory control neuronal activity. However, widely used inhibitor furosemide nonselective with antiseizure efficacy slices and vivo , leading a conflicting scheme how influences synchronization. Here we selective VU0463271 [ N -cyclopropyl-...
Abstract INTRODUCTION Tau‐positron emission tomography (PET) outcome data of patients with Alzheimer's disease (AD) cannot currently be meaningfully compared or combined when different tracers are used due to differences in tracer properties, instrumentation, and methods analysis. METHODS Using head‐to‐head from five cohorts tau PET radiotracers designed target deposition AD, we tested a joint propagation model (JPM) harmonize quantification (units termed “CenTauR” [CTR]). JPM is statistical...
Summary Objective We investigated the role of chloride homeostasis in seizure progression and development pharmacoresistant status epilepticus ( SE ) by pharmacologically targeting Na‐K‐Cl cotransporter NKCC 1) with bumetanide. also ability bumetanide to restore efficacy diazepam following . Methods Kainic acid KA )–induced vivo 0‐Mg 2+ ‐induced seizure‐like events SLE s) vitro were monitored using electroencephalography EEG recordings freely moving adult male mice extracellular field...
Maternal immune activation (MIA) disrupts the central innate system during a critical neurodevelopmental period. Microglia are primary cells in brain although their direct influence on MIA phenotype is largely unknown. Here we show that alters microglial gene expression with upregulation of cellular protrusion/neuritogenic pathways, concurrently causing repetitive behavior, social deficits, and synaptic dysfunction to layer V intrinsically bursting pyramidal neurons prefrontal cortex mice....
Analysis of cellular signaling interactions is expected to pose an enormous informatics challenge, perhaps even larger than analyzing the genome. The complex networks arising from processes are traditionally represented as block diagrams. A key step in evolution toward a more quantitative understanding explicitly specify kinetics all chemical reaction steps pathway. Technical advances proteomics and high-throughput protein interaction assays promise flood such data. While annotations,...
At early developmental stages, correlated neuronal activity is thought to exert a critical control on functional and structural refinement of synaptic connections. In the hippocampus, between postnatal day 2 (P2) P6, network-driven giant depolarizing potentials (GDPs) are generated by synergistic action glutamate GABA, which excitatory. Here rising phase GDPs was used trigger Schaffer collateral stimulation in such way that synchronized network coincident with presynaptic activation afferent...
In the adult rat hippocampus, axons of granule cells in dentate gyrus, mossy fibers (MF), form excitatory glutamatergic synapses with CA3 principal cells. neonates, MF release into their targets mainly GABA, which at this developmental stage is depolarizing. Here we tested hypothesis that, immature MF–CA3 synapses, correlated presynaptic [single fiber-evoked GABA A -mediated postsynaptic potentials (GPSPs)] and activity (back propagating action potentials) may exert a critical control on...
A robust increase in the functional expression of neuronal K-Cl cotransporter KCC2 during CNS development is necessary for emergence hyperpolarizing ionotropic GABAergic transmission. BDNF-TrkB signaling has been implicated developmental up-regulation and, mature animals, fast activity-dependent down-regulation function following seizures and trauma. In contrast to decrease observed adult hippocampus trauma, neonate trigger a TrkB-dependent Cl(-) extrusion capacity associated with enhanced...
GABA depolarizes immature neurons because of a high [Cl − ] i and orchestrates giant depolarizing potential (GDP) generation. Zilberter coworkers (Rheims et al., 2009; Holmgren 2010) showed recently that the ketone body metabolite dl -3-hydroxybutyrate ( -BHB) (4 m ), lactate or pyruvate (5 ) shifted actions to hyperpolarizing, suggesting effects are attributable inadequate energy supply when glucose is sole source. We now report that, in rat pups (postnatal days 4–7), plasma d -BHB,...
The cellular form of prion protein PrP(C) is highly expressed in the brain, where it can be converted into its abnormally folded isoform PrP(Sc) to cause neurodegenerative diseases. Its predominant synaptic localization suggests a crucial role signaling. Interestingly, developmentally regulated and high expression immature brain could instrumental regulating neurogenesis cell proliferation. Here, PrP(C)-deficient (Prnp(0/0)) mice were used assess whether involved plasticity processes...
Presynaptic kainate receptors regulate synaptic transmission in several brain areas but are not known to have this action at immature mossy fiber (MF) terminals, which during the first week of postnatal life release GABA, exerts into targeted cells a depolarizing and excitatory action. Here, we report that, life, endogenous activation GluK1 by glutamate present extracellular space severely depresses MF-mediated GABAergic currents [GABA A -mediated postsynaptic (GPSCs)]. Activation was...
Abstract The role of Arc in synaptic plasticity and memory consolidation has been investigated for many years with recent evidence that defects the expression or activity this immediate-early gene may also contribute to pathophysiology brain disorders including schizophrenia fragile X syndrome. These results bring forward concept reversing abnormalities could provide an avenue improve cognitive neurological impairments different disease contexts, but how achieve therapeutic objective...
Sustained contraction of cells depends on sustained Rho‐associated kinase (Rho‐kinase) activation. We developed a computational model the Rho‐kinase pathway to understand systems characteristics. Thrombin‐dependent in vivo transient responses Rho activation and Ca 2+ increase could be reproduced silico . Low high thrombin stimulation induced phosphorylation, respectively, myosin light chain (MLC) phosphatase targeting subunit 1 (MYPT1) The phosphorylation MLC MYPT1 , but their not. This...
Early in postnatal life, mossy fibres (MF), the axons of granule cells dentate gyrus, release GABA which is depolarizing and excitatory. Synaptic currents undergo spike-time dependent long-term depression (STD-LTD) regardless temporal order stimulation (pre versus post viceversa). Here we show that at P3 but not P21, STD-LTD, induced by negative pairing, mediated endocannabinoids mobilized from postsynaptic cell during spiking-induced membrane depolarization. By diffusing backward, activate...
Interest in drug development for rare diseases has expanded dramatically since the Orphan Drug Act was passed 1983, with 40% of new approvals 2019 targeting orphan indications. However, limited quantitative understanding natural history and disease progression hinders progress increases risks associated development. Use international data standards can assist harmonization enable exchange, integration into larger datasets, a history. The US Food Administration (FDA) requires use Clinical...
ABSTRACT Background Despite the monogenic autosomal dominant nature of Huntington’s disease (HD), current research paradigm is still based on overt clinical phenotypes and does not address pathobiology biomarkers that are evident decades before functional decline. A new framework needed to standardize enable interventional studies earlier in course HD. Methods The HD Regulatory Science Consortium (HD-RSC), a precompetitive Critical Path Institute initiative includes 37 member organizations,...
Abstract Background The primary objective of the Critical Path for Alzheimer’s Disease (CPAD) consortium, a pre‐competitive consortium Institute, is to promote, support, and manage data knowledge sharing from Alzheimer disease (AD) drug development stakeholders. Since 2019, CPAD has embarked on new initiative acquire fluid imaging biomarker‐rich sources novel tools quantify progression across AD continuum. Method Patient‐level contemporary Phase2/Phase3 clinical trials observational studies...
Huntington’s disease (HD) is a devastating neurodegenerative disorder that urgently needs disease-modifying therapeutics. To this end, collaboration to standardize clinical research practices in the field and drive progress addressing drug development challenges paramount. At meeting 2017 organized by CHDI Foundation Critical Path Institute, stakeholders across pharmaceutical industry, academia, regulatory agencies, patient advocacy groups discussed need for potential impact of consortium...
Abstract Background To help improve the Alzheimer’s disease (AD) therapeutics research and development process, Critical Path for Disease (CPAD) Consortium at Institute (C‐Path) provides a neutral framework drug industry, regulatory agencies, academia, patient advocacy organizations to collaborate. CPAD’s extensive track record of developing regulatory‐grade quantitative tools motivates sponsors share patient‐level data neuroimages from clinical trials. CPAD leverages these uses C‐Path’s...
Abstract Background Tau positron emission tomography (PET) is increasingly used in the clinical evaluation of patients and as an outcome measure Alzheimer’s disease (AD) trials. Due to differences tracer properties, instrumentation, methods analysis, however, tau‐PET data cannot currently be meaningfully compared or combined. Here, we tested i) feasibility adapting Centiloid method—an approach originally developed standardize amyloid PET—to harmonize quantification (CenTauRs); ii)...