Structural and Functional Neuroplasticity Following Bilateral Vestibular Loss: A Longitudinal [18F]-UCB-H/[18F]-FDG Dual Tracer Rat Study

Abstract Neuronal lesions trigger mechanisms of structural and functional neuroplasticity, which can support recovery. However, the temporal and spatial appearance of structure-function changes and their interrelation remain unclear. The current study aimed to directly compare serial whole-brain in vivo measurements of functional plasticity (by [18F]-FDG-PET) and structural synaptic plasticity (by [18F]-UCB-H-PET) before and after bilateral labyrinthectomy in rats and investigate the effect of locomotor training. Complex structure-function changes were found after bilateral labyrinthectomy: in brainstem-cerebellar circuits, regional cerebral glucose metabolism (rCGM) decreased early, followed by reduced synaptic density. In the thalamus, increased [18F]-UCB-H binding preceded a higher rCGM uptake. In frontal-basal ganglia loops, an increase in synaptic density was paralleled by a decrease in rCGM. In the group with locomotor training, thalamic rCGM and [18F]-UCB-H binding increased following bilateral labyrinthectomy compared to the no training group. Rats with training had relatively fewer body rotations. In conclusion, combined [18F]-FDG/[18F]-UCB-H dual tracer imaging reveals that adaptive neuroplasticity after bilateral vestibular loss is not a uniform process but is composed of complex spatial and temporal patterns of structure-function coupling in networks for vestibular, multisensory, and motor control, which can be modulated by early physical training.

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SAC3B is a target of CML19, the centrin 2 of Arabidopsis thaliana

Biochemical Journal ◽

10.1042/bcj20190674 ◽

2020 ◽

Vol 477 (1) ◽

pp. 173-189 ◽

Cited By ~ 1

Author(s):

Marco Pedretti ◽

Carolina Conter ◽

Paola Dominici ◽

Alessandra Astegno

Keyword(s):

Excision Repair ◽

Complex Structure ◽

Binding Motif ◽

C Terminus ◽

Repair Protein ◽

Nucleotide Excision ◽

Ef Hand ◽

Molecular Determinants ◽

Structure In Solution

Arabidopsis centrin 2, also known as calmodulin-like protein 19 (CML19), is a member of the EF-hand superfamily of calcium (Ca2+)-binding proteins. In addition to the notion that CML19 interacts with the nucleotide excision repair protein RAD4, CML19 was suggested to be a component of the transcription export complex 2 (TREX-2) by interacting with SAC3B. However, the molecular determinants of this interaction have remained largely unknown. Herein, we identified a CML19-binding site within the C-terminus of SAC3B and characterized the binding properties of the corresponding 26-residue peptide (SAC3Bp), which exhibits the hydrophobic triad centrin-binding motif in a reversed orientation (I8W4W1). Using a combination of spectroscopic and calorimetric experiments, we shed light on the SAC3Bp–CML19 complex structure in solution. We demonstrated that the peptide interacts not only with Ca2+-saturated CML19, but also with apo-CML19 to form a protein–peptide complex with a 1 : 1 stoichiometry. Both interactions involve hydrophobic and electrostatic contributions and include the burial of Trp residues of SAC3Bp. However, the peptide likely assumes different conformations upon binding to apo-CML19 or Ca2+-CML19. Importantly, the peptide dramatically increases the affinity for Ca2+ of CML19, especially of the C-lobe, suggesting that in vivo the protein would be Ca2+-saturated and bound to SAC3B even at resting Ca2+-levels. Our results, providing direct evidence that Arabidopsis SAC3B is a CML19 target and proposing that CML19 can bind to SAC3B through its C-lobe independent of a Ca2+ stimulus, support a functional role for these proteins in TREX-2 complex and mRNA export.

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Faculty Opinions recommendation of Effectiveness of head-mounted vibrotactile stimulation in subjects with bilateral vestibular loss: a phase 1 clinical trial.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1164123.624796 ◽

2009 ◽

Author(s):

Joseph Furman ◽

Maha Tayseer Mohammad

Keyword(s):

Clinical Trial ◽

Phase 1 ◽

Vibrotactile Stimulation ◽

Vestibular Loss ◽

Phase 1 Clinical Trial ◽

Bilateral Vestibular Loss

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Structure, Function and Cerebral Asymmetry: In Vivo Morphometry of the Planum Temporale

Neuroscience & Biobehavioral Reviews ◽

10.1016/0149-7634(95)00071-2 ◽

1996 ◽

Vol 20 (4) ◽

pp. 587-591 ◽

Cited By ~ 134

Author(s):

HELMUTH STEINMETZ

Keyword(s):

Structure Function ◽

Planum Temporale ◽

Cerebral Asymmetry

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Mouse models to study von Willebrand factor structure-function relationships in vivo

Hämostaseologie ◽

10.1055/s-0037-1616933 ◽

2009 ◽

Vol 29 (01) ◽

pp. 17-20 ◽

Cited By ~ 2

Author(s):

I. Marx ◽

I. Badirou ◽

R. Pendu ◽

O. Christophe ◽

C. V. Denis

Keyword(s):

Structure Function ◽

Transient Expression ◽

Von Willebrand Factor ◽

Large Size ◽

Mouse Hepatocytes ◽

Function Relationship ◽

Von Willebrand ◽

Willebrand Factor

SummaryVon Willebrand factor (VWF) structure-function relationship has been studied only through in vitro approaches. The VWF-deficient mouse model has been extremely useful to examine the in vivo function of VWF but does not allow a more subtle analysis of the relative importance of its different domains. However, considering the large size of VWF and its capacity to interact with various ligands in order to support platelet adhesion and aggregation, the necessity to evaluate independently these interactions appeared increasingly crucial. A recently developed technique, known as hydrodynamic injection, which allows transient expression of a transgene by mouse hepatocytes, proved very useful in this regard. Indeed, transient expression of various VWF mutants in VWF-deficient mice contributed to improve our knowledge about the role of VWF interaction with subendothelial collagens and with platelets receptors in VWF roles in haemostasis and thrombosis. These findings can provide new leads in the development of anti-thrombotic therapies.

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Improved synthesis of SV2A targeting radiotracer [11C]UCB-J

EJNMMI Radiopharmacy and Chemistry ◽

10.1186/s41181-019-0080-5 ◽

2019 ◽

Vol 4 (1) ◽

Cited By ~ 2

Author(s):

Johanna Rokka ◽

Eva Schlein ◽

Jonas Eriksson

Keyword(s):

Methyl Iodide ◽

Water Solution ◽

Synthesis Method ◽

Radiochemical Yield ◽

Preparative Hplc ◽

Step Method ◽

Synaptic Density ◽

Excellent Starting Point ◽

Starting Point

Abstract Introduction [11C]UCB-J is a tracer developed for PET (positron emission tomography) that has high affinity towards synaptic vesicle glycoprotein 2A (SV2A), a protein believed to participate in the regulation of neurotransmitter release in neurons and endocrine cells. The localisation of SV2A in the synaptic terminals makes it a viable target for in vivo imaging of synaptic density in the brain. Several SV2A targeting compounds have been evaluated as PET tracers, including [11C]UCB-J, with the aim to facilitate studies of synaptic density in neurological diseases. The original two-step synthesis method failed in our hands to produce sufficient amounts of [11C]UCB-J, but served as an excellent starting point for further optimizations towards a high yielding and simplified one-step method. [11C]Methyl iodide was trapped in a clear THF-water solution containing the trifluoroborate substituted precursor, potassium carbonate and palladium complex. The resulting reaction mixture was heated at 70 °C for 4 min to produce [11C]UCB-J. Results After semi-preparative HPLC purification and reformulation in 10% ethanol/phosphate buffered saline, the product was obtained in 39 ± 5% radiochemical yield based on [11C]methyl iodide, corresponding to 1.8 ± 0.5 GBq at EOS. The radiochemical purity was > 99% and the molar activity was 390 ± 180 GBq/μmol at EOS. The product solution contained < 2 ppb palladium. Conclusions A robust and high yielding production method has been developed for [11C]UCB-J, suitable for both preclinical and clinical PET applications.

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In vivo synaptic density relates to glucose metabolism at rest in healthy subjects, but is strongly modulated by regional differences

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x20981502 ◽

2021 ◽

pp. 0271678X2098150

Author(s):

June van Aalst ◽

Jenny Ceccarini ◽

Stefan Sunaert ◽

Patrick Dupont ◽

Michel Koole ◽

...

Keyword(s):

Glucose Metabolism ◽

Medial Temporal Lobe ◽

Regional Differences ◽

Specific Binding ◽

Aerobic Glycolysis ◽

Glucose Consumption ◽

Brain Regions ◽

Synaptic Density ◽

Energy Demands

Preclinical and postmortem studies have suggested that regional synaptic density and glucose consumption (CMRGlc) are strongly related. However, the relation between synaptic density and cerebral glucose metabolism in the human brain has not directly been assessed in vivo. Using [11C]UCB-J binding to synaptic vesicle glycoprotein 2 A (SV2A) as indicator for synaptic density and [18F]FDG for measuring cerebral glucose consumption, we studied twenty healthy female subjects (age 29.6 ± 9.9 yrs) who underwent a single-day dual-tracer protocol (GE Signa PET-MR). Global measures of absolute and relative CMRGlc and specific binding of [11C]UCB-J were indeed highly significantly correlated ( r > 0.47, p < 0.001). However, regional differences in relative [18F]FDG and [11C]UCB-J uptake were observed, with up to 19% higher [11C]UCB-J uptake in the medial temporal lobe (MTL) and up to 17% higher glucose metabolism in frontal and motor-related areas and thalamus. This pattern has a considerable overlap with the brain regions showing different levels of aerobic glycolysis. Regionally varying energy demands of inhibitory and excitatory synapses at rest may also contribute to this difference. Being unaffected by astroglial and/or microglial energy demands, changes in synaptic density in the MTL may therefore be more sensitive to early detection of pathological conditions compared to changes in glucose metabolism.

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In vivo exploration of synaptic projections in frontotemporal dementia

Scientific Reports ◽

10.1038/s41598-021-95499-1 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Eric Salmon ◽

Mohamed Ali Bahri ◽

Alain Plenevaux ◽

Guillaume Becker ◽

Alain Seret ◽

...

Keyword(s):

Frontotemporal Dementia ◽

Input Function ◽

Parahippocampal Gyrus ◽

Exploratory Research ◽

Social Brain ◽

Synaptic Density ◽

Clinical Disorder ◽

Significant Difference ◽

The Right

AbstractThe purpose of this exploratory research is to provide data on synaptopathy in the behavioral variant of frontotemporal dementia (bvFTD). Twelve patients with probable bvFTD were compared to 12 control participants and 12 patients with Alzheimer’s disease (AD). Loss of synaptic projections was assessed with [18F]UCBH-PET. Total distribution volume was obtained with Logan method using carotid artery derived input function. Neuroimages were analyzed with SPM12. Verbal fluency, episodic memory and awareness of cognitive impairment were equally impaired in patients groups. Compared to controls, [18F]UCBH uptake tended to decrease in the right anterior parahippocampal gyrus of bvFTD patients. Loss of synaptic projections was observed in the right hippocampus of AD participants, but there was no significant difference in [18F]UCBH brain uptake between patients groups. Anosognosia for clinical disorder was correlated with synaptic density in the caudate nucleus and the anteromedial prefrontal cortex. This study suggests that synaptopathy in bvFTD targets the temporal social brain and self-referential processes.

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