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Neuroscience Sep 2022Synaptic vesicle glycoprotein 2A (SV2A) is a transmembrane protein that binds levetiracetam and is involved in neurotransmission via an unknown mechanism....
Synaptic vesicle glycoprotein 2A (SV2A) is a transmembrane protein that binds levetiracetam and is involved in neurotransmission via an unknown mechanism. SV2A-immunoreactivity is reduced in animal models of epilepsy, and in postmortem hippocampi from patients with temporal lobe epilepsy. It is not known if other regions outside the hippocampus are affected in epilepsy, and whether SV2A expression is permanently reduced or regulated over time. In this study, we induced a generalized status epilepticus (SE) by systemic administration of lithium-pilocarpine to adult female rats. The brains from all animals experiencing SE were collected at different time points after the treatment. The radiotracer, [C]-UCB-J, binds to SV2A with high affinity, and has been used for in vivo imaging as an a-proxy marker for synaptic density. Here we determined the level of tritiated UCB-J binding by semiquantitative autoradiography in the cerebral cortex, hippocampus, thalamus, and hypothalamus, and in cortical subregions. A prominent and highly significant reduction in SV2A binding capacity was observed over the first days after SE in the cerebral cortex and the hippocampus, but not in the thalamus and hypothalamus. The magnitude in reduction was larger and occurred earlier in the hippocampus and the piriform cortex, than in other cortical subregions. Interestingly, in all areas examined, the binding capacity returned to control levels 12 weeks after the SE comparable to the chronic epileptic phase. These data indicate that lithium-pilocarpine-induced epileptogenesis involves both loss and gain of synapses in the in a time-dependent manner.
Topics: Animals; Brain; Epilepsy; Female; Hippocampus; Lithium; Membrane Glycoproteins; Nerve Tissue Proteins; Pilocarpine; Rats; Status Epilepticus
PubMed: 35878719
DOI: 10.1016/j.neuroscience.2022.07.020 -
Brain Structure & Function Mar 2023The nonapeptide system modulates numerous social behaviors through oxytocin and vasopressin activation of the oxytocin receptor (OXTR) and vasopressin receptor (AVPR1A)...
The nonapeptide system modulates numerous social behaviors through oxytocin and vasopressin activation of the oxytocin receptor (OXTR) and vasopressin receptor (AVPR1A) in the brain. OXTRs and AVPR1As are widely distributed throughout the brain and binding densities exhibit substantial variation within and across species. Although OXTR and AVPR1A binding distributions have been mapped for several rodents, this system has yet to be characterized in the spiny mouse (Acomys cahirinus). Here we conducted receptor autoradiography and in situ hybridization to map distributions of OXTR and AVPR1A binding and Oxtr and Avpr1a mRNA expression throughout the basal forebrain and midbrain of male and female spiny mice. We found that nonapeptide receptor mRNA is diffuse throughout the forebrain and midbrain and does not always align with OXTR and AVPR1A binding. Analyses of sex differences in brain regions involved in social behavior and reward revealed that males exhibit higher OXTR binding densities in the lateral septum, bed nucleus of the stria terminalis, and anterior hypothalamus. However, no association with gonadal sex was observed for AVPR1A binding. Hierarchical clustering analysis further revealed that co-expression patterns of OXTR and AVPR1A binding across brain regions involved in social behavior and reward differ between males and females. These findings provide mapping distributions and sex differences in nonapeptide receptors in spiny mice. Spiny mice are an excellent organism for studying grouping behaviors such as cooperation and prosociality, and the nonapeptide receptor mapping here can inform the study of nonapeptide-mediated behavior in a highly social, large group-living rodent.
Topics: Animals; Female; Male; Receptors, Oxytocin; RNA, Messenger; Basal Forebrain; Mesencephalon; Oxytocin; Receptors, Vasopressin; Vasopressins; Social Behavior; Murinae
PubMed: 36271259
DOI: 10.1007/s00429-022-02581-z -
Cortex; a Journal Devoted To the Study... Aug 2022The inferior frontal sulcus is conceptualized as the landmark delineating ventro-from dorsolateral prefrontal cortex. Functional imaging studies report activations... (Meta-Analysis)
Meta-Analysis
The inferior frontal sulcus is conceptualized as the landmark delineating ventro-from dorsolateral prefrontal cortex. Functional imaging studies report activations within the sulcus during tasks addressing cognitive control and verbal working memory, while their microstructural correlates are not well defined. Existing microstructural maps, e.g., Brodmann's map, do not distinguish separate areas within the sulcus. We identified six new areas in the inferior frontal sulcus and its junction to the precentral sulcus, ifs1-4, ifj1-ifj2, by combined cytoarchitectonic analysis and receptor autoradiography. A hierarchical cluster analysis of receptor densities of these and neighbouring prefrontal areas revealed that they form a distinct cluster within the prefrontal cortex. Major interhemispheric differences were found in both cyto- and receptorarchitecture. The function of cytoarchitectonically identified areas was explored by comparing probabilistic maps of the areas in stereotaxic space with their functions and co-activation patterns as analysed by means of a coordinate-based meta-analysis. We found a bilateral involvement in working memory, as well as a lateralization of different language-related processes to the left hemisphere, and of music processing and attention to the right-hemispheric areas. Particularly ifj2 might act as a functional hub between the networks. The cytoarchitectonic maps and receptor densities provide a powerful tool to further elucidate the function of these areas. The maps are available through the Human Brain Atlas of the Human Brain Project and serve in combination with the information on the cyto- and receptor architecture of the areas as a resource for brain models and simulations.
Topics: Brain; Brain Mapping; Frontal Lobe; Humans; Magnetic Resonance Imaging; Memory, Short-Term; Prefrontal Cortex
PubMed: 35568575
DOI: 10.1016/j.cortex.2022.03.019 -
Theranostics 2020Selective modulation of metabotropic glutamate receptor 2 (mGlu) represents a novel therapeutic approach for treating brain disorders, including schizophrenia,...
Selective modulation of metabotropic glutamate receptor 2 (mGlu) represents a novel therapeutic approach for treating brain disorders, including schizophrenia, depression, Parkinson's disease (PD), Alzheimer's disease (AD), drug abuse and addiction. Imaging mGlu using positron emission tomography (PET) would allow for quantification under physiological and pathological conditions and facilitate drug discovery by enabling target engagement studies. In this paper, we aimed to develop a novel specific radioligand derived from negative allosteric modulators (NAMs) for PET imaging of mGlu. A focused small molecule library of mGlu NAMs with tetrahydro naphthyridine scaffold was synthesized for pharmacology and physicochemical evaluation. GIRK dose-response assays and CNS panel binding selectivity assays were performed to study the affinity and selectivity of mGlu NAMs, among which compounds and were selected as PET ligand candidates. Autoradiography in SD rat brain sections was used to confirm the binding specificity and selectivity of [C] and [C] towards mGlu. binding specificity was then studied by PET imaging. Whole body biodistribution study and radiometabolite analysis were conducted to demonstrate the pharmacokinetic properties of [C] as most promising PET mGlu PET ligand. mGlu NAMs were synthesized in 14%-20% yields in five steps. NAMs and were selected to be the most promising ligands due to their high affinity in GIRK dose-response assays. [C] and [C] displayed similar heterogeneous distribution by autoradiography, consistent with mGlu expression in the brain. While PET imaging study showed good brain permeability for both tracers, compound [C] demonstrated superior binding specificity compared to [C]. Further radiometabolite analysis of [C] showed excellent stability in the brain. Compound exhibited high affinity and excellent subtype selectivity, which was then evaluated by autoradiography and PET imaging study after labeling with carbon-11. Ligand [C], which we named [C]MG2-1904, demonstrated high brain uptake and excellent / specific binding towards mGlu with high metabolic stability in the brain. As proof-of-concept, our preliminary work demonstrated a successful example of visualizing mGlu derived from NAMs, which represents a promising chemotype for further development and optimization aimed for clinical translation.
Topics: Allosteric Regulation; Animals; Autoradiography; Brain; Carbon Radioisotopes; Ligands; Male; Models, Animal; Naphthyridines; Positron-Emission Tomography; Radioligand Assay; Radiopharmaceuticals; Rats; Receptors, Metabotropic Glutamate; Tissue Distribution
PubMed: 33042277
DOI: 10.7150/thno.42587 -
Journal of Nuclear Medicine : Official... Jun 2022Synaptic dysfunction is a primary mechanism underlying Huntington disease (HD) progression. This study investigated changes in synaptic vesicle glycoprotein 2A (SV2A)...
Synaptic dysfunction is a primary mechanism underlying Huntington disease (HD) progression. This study investigated changes in synaptic vesicle glycoprotein 2A (SV2A) density by means of C-UCB-J small-animal PET imaging in the central nervous system of mice with HD. Dynamic C-UCB-J small-animal PET imaging was performed at clinically relevant disease stages (at 3, 7, 10, and 16 mo) in the heterozygous knock-in Q175DN mouse model of HD and wild-type littermates (16-18 mice per genotype and time point). Cerebral C-UCB-J analyses were performed to assess genotypic differences during presymptomatic (3 mo) and symptomatic (7-16 mo) disease stages. C-UCB-J binding in the spinal cord was quantified at 16 mo. H-UCB-J autoradiography and SV2A immunofluorescence were performed postmortem in mouse and human brain tissues. C-UCB-J binding was lower in symptomatic heterozygous mice than in wild-type littermates in parallel with disease progression (7 and 10 mo: < 0.01; 16 mo: < 0.0001). Specific C-UCB-J binding was detectable in the spinal cord, with symptomatic heterozygous mice displaying a significant reduction ( < 0.0001). H-UCB-J autoradiography and SV2A immunofluorescence corroborated the in vivo measurements demonstrating lower SV2A in heterozygous mice ( < 0.05). Finally, preliminary analysis of SV2A in the human brain postmortem suggested lower SV2A in HD gene carriers than in controls without dementia. C-UCB-J PET detected SV2A deficits during symptomatic disease in heterozygous mice in both the brain and the spinal cord and therefore may be suitable as a novel marker of synaptic integrity widely distributed in the central nervous system. On clinical application, C-UCB-J PET imaging may have promise for SV2A measurement in patients with HD during disease progression and after disease-modifying therapeutic strategies.
Topics: Animals; Brain; Disease Progression; Humans; Huntington Disease; Membrane Glycoproteins; Mice; Nerve Tissue Proteins; Positron-Emission Tomography; Pyridines; Synaptic Vesicles
PubMed: 34531262
DOI: 10.2967/jnumed.121.262709 -
Brain Research Sep 2023Physical exercise benefits Parkinson's disease (PD) patients but the mechanism is unclear. Cannabinoid receptor type 1 (CB1R) is known to be reduced in PD patients and...
Physical exercise benefits Parkinson's disease (PD) patients but the mechanism is unclear. Cannabinoid receptor type 1 (CB1R) is known to be reduced in PD patients and animal models. We test the hypothesis that binding of the CB1R inverse agonist, [H]SR141716A, is normalized by treadmill exercise in the toxin-induced 6-hydroxydopamine (6-OHDA) model of PD. Male rats had unilateral striatal injections of 6-OHDA or saline. After 15 days, half were submitted to treadmill exercise and half remained sedentary. [H]SR141716A autoradiography was performed in postmortem tissue from striatum, substantia nigra (SN) and hippocampus. There was a 41% decrease of [H]SR141716A specific binding in the ipsilateral SN of 6-OHDA-injected sedentary animals which was attenuated to 15% by exercise, when compared to saline-injected animals. No striatal differences were observed. A 30% bilateral hippocampal increase was observed in both healthy and 6-OHDA exercised groups. In addition, a positive correlation between nigral [H]SR141716A binding and nociceptive threshold was observed in PD-exercised animals (p = 0.0008), suggesting a beneficial effect of exercise in the pain associated with the model. Chronic exercise can reduce the detrimental effects of PD on nigral [H]SR141716A binding, similar to the reported reduction after dopamine replacement therapy, so should be considered as an adjunct therapy for PD.
Topics: Rats; Male; Animals; Parkinson Disease; Oxidopamine; Rats, Wistar; Drug Inverse Agonism; Rimonabant; Substantia Nigra; Corpus Striatum; Hippocampus; Receptors, Cannabinoid; Disease Models, Animal
PubMed: 37268248
DOI: 10.1016/j.brainres.2023.148436 -
Biomedicines Mar 2022The 18 kDa translocator protein (TSPO) is increasingly recognized as an interesting target for the imaging of glioblastoma (GBM). Here, we investigated TSPO PET imaging...
The 18 kDa translocator protein (TSPO) is increasingly recognized as an interesting target for the imaging of glioblastoma (GBM). Here, we investigated TSPO PET imaging and autoradiography in the frequently used GL261 glioblastoma mouse model and aimed to generate insights into the temporal evolution of TSPO radioligand uptake in glioblastoma in a preclinical setting. We performed a longitudinal [18F]GE-180 PET imaging study from day 4 to 14 post inoculation in the orthotopic syngeneic GL261 GBM mouse model (n = 21 GBM mice, n = 3 sham mice). Contrast-enhanced computed tomography (CT) was performed at the day of the final PET scan (±1 day). [18F]GE-180 autoradiography was performed on day 7, 11 and 14 (ex vivo: n = 13 GBM mice, n = 1 sham mouse; in vitro: n = 21 GBM mice; n = 2 sham mice). Brain sections were also used for hematoxylin and eosin (H&E) staining and TSPO immunohistochemistry. [18F]GE-180 uptake in PET was elevated at the site of inoculation in GBM mice as compared to sham mice at day 11 and later (at day 14, TBRmax +27% compared to sham mice, p = 0.001). In GBM mice, [18F]GE-180 uptake continuously increased over time, e.g., at day 11, mean TBRmax +16% compared to day 4, p = 0.011. [18F]GE-180 uptake as depicted by PET was in all mice co-localized with contrast-enhancement in CT and tissue-based findings. [18F]GE-180 ex vivo and in vitro autoradiography showed highly congruent tracer distribution (r = 0.99, n = 13, p < 0.001). In conclusion, [18F]GE-180 PET imaging facilitates non-invasive in vivo monitoring of TSPO expression in the GL261 GBM mouse model. [18F]GE-180 in vitro autoradiography is a convenient surrogate for ex vivo autoradiography, allowing for straightforward identification of suitable models and scan time-points on previously generated tissue sections.
PubMed: 35453488
DOI: 10.3390/biomedicines10040738 -
Frontiers in Neuroanatomy 2021The uptake, transmission and processing of sensory olfactory information is modulated by inhibitory and excitatory receptors in the olfactory system. Previous studies...
The uptake, transmission and processing of sensory olfactory information is modulated by inhibitory and excitatory receptors in the olfactory system. Previous studies have focused on the function of individual receptors in distinct brain areas, but the receptor architecture of the whole system remains unclear. Here, we analyzed the receptor profiles of the whole olfactory system of adult male mice. We examined the distribution patterns of glutamatergic (AMPA, kainate, mGlu, and NMDA), GABAergic (GABA, GABA, and GABA), dopaminergic (D) and noradrenergic (α and α) neurotransmitter receptors by quantitative receptor autoradiography combined with an analysis of the cyto- and myelo-architecture. We observed that each subarea of the olfactory system is characterized by individual densities of distinct neurotransmitter receptor types, leading to a region- and layer-specific receptor profile. Thereby, the investigated receptors in the respective areas and strata showed a heterogeneous expression. Generally, we detected high densities of mGluRs, GABARs and GABARs. Noradrenergic receptors revealed a highly heterogenic distribution, while the dopaminergic receptor D displayed low concentrations, except in the olfactory tubercle and the dorsal endopiriform nucleus. The similarities and dissimilarities of the area-specific multireceptor profiles were analyzed by a hierarchical cluster analysis. A three-cluster solution was found that divided the areas into the (1) olfactory relay stations (main and accessory olfactory bulb), (2) the olfactory cortex (anterior olfactory cortex, dorsal peduncular cortex, taenia tecta, piriform cortex, endopiriform nucleus, entorhinal cortex, orbitofrontal cortex) and the (3) olfactory tubercle, constituting its own cluster. The multimodal receptor-architectonic analysis of each component of the olfactory system provides new insights into its neurochemical organization and future possibilities for pharmaceutic targeting.
PubMed: 33967704
DOI: 10.3389/fnana.2021.632549 -
International Journal of Nanomedicine 2020Beyond clinical atherosclerosis imaging of vessel stenosis and plaque morphology, early detection of inflamed atherosclerotic lesions by molecular imaging could improve...
BACKGROUND
Beyond clinical atherosclerosis imaging of vessel stenosis and plaque morphology, early detection of inflamed atherosclerotic lesions by molecular imaging could improve risk assessment and clinical management in high-risk patients. To identify inflamed atherosclerotic lesions by molecular imaging in vivo, we studied the specificity of our radiotracer based on maleylated (Mal) human serum albumin (HSA), which targets key features of unstable atherosclerotic lesions.
MATERIALS AND METHODS
Mal-HSA was radiolabeled with a positron-emitting metal ion, zirconium-89 (Zr). The targeting potential of this probe was compared with unspecific Zr-HSA and F-FDG in an experimental model of atherosclerosis ( mice, n=22), and compared with wild-type (WT) mice (C57BL/6J, n=21) as controls.
RESULTS
PET/MRI, gamma counter measurements, and autoradiography showed the accumulation of Zr-Mal-HSA in the atherosclerotic lesions of mice. The maximum standardized uptake values (SUV) for Zr-Mal-HSA at 16 and 20 weeks were 26% and 20% higher (<0.05) in mice than in control WT mice, whereas no difference in SUV was observed for F-FDG in the same animals. Zr-Mal-HSA uptake in the aorta, as evaluated by a gamma counter 48 h postinjection, was 32% higher (<0.01) for mice than in WT mice, and the aorta-to-blood ratio was 8-fold higher (<0.001) for Zr-Mal-HSA compared with unspecific Zr-HSA. HSA-based probes were mainly distributed to the liver, spleen, kidneys, bone, and lymph nodes. The phosphor imaging autoradiography (PI-ARG) results corroborated the PET and gamma counter measurements, showing higher accumulation of Zr-Mal-HSA in the aortas of mice than in WT mice (9.4±1.4 vs 0.8±0.3%; <0.001).
CONCLUSION
Zr radiolabeling of Mal-HSA probes resulted in detectable activity in atherosclerotic lesions in aortas of mice, as demonstrated by quantitative in vivo PET/MRI. Zr-Mal-HSA appears to be a promising diagnostic tool for the early identification of macrophage-rich areas of inflammation in atherosclerosis.
Topics: Animals; Aorta; Atherosclerosis; Autoradiography; Disease Models, Animal; Female; Fluorodeoxyglucose F18; Humans; Isotope Labeling; Macrophages; Magnetic Resonance Imaging; Maleates; Mice, Inbred C57BL; Mice, Knockout, ApoE; Molecular Imaging; Molecular Probes; Plaque, Atherosclerotic; Positron-Emission Tomography; Radioisotopes; Radiopharmaceuticals; Serum Albumin, Human; Tissue Distribution; Zirconium
PubMed: 32884268
DOI: 10.2147/IJN.S256395 -
Journal of Nuclear Medicine : Official... Nov 2021The gastrin-releasing peptide receptor (GRPr) is overexpressed in prostate cancer (PCa) cells, making it an excellent tool for targeted imaging. The Ga-labeled GRPr...
The gastrin-releasing peptide receptor (GRPr) is overexpressed in prostate cancer (PCa) cells, making it an excellent tool for targeted imaging. The Ga-labeled GRPr antagonist SB3 has shown excellent results in preclinical and clinical studies and was selected for further clinical investigation. The aims of this phase I study were to investigate Ga-SB3 PET/CT imaging of primary PCa tumors and assess safety. More aims included an investigation of biodistribution and dosimetry and a comparison with pathology and GRPr expression. Ten therapy-naïve, biopsy-confirmed PCa patients planned for prostatectomy were included. A 3-h extensive PET/CT imaging protocol was performed within 2 wk before prostatectomy. Prostate tissue was evaluated for tumor localization and Gleason score, and in vitro autoradiography was performed to determine GRPr expression. Available MRI scans performed within 3 mo before the study were matched. For dosimetry, residence times were estimated and effective dose to the body as well as absorbed doses to organs were calculated using the IDAC dose model, version 2.1. Administration of Ga-SB3 (187.4 ± 40.0 MBq, 40 ± 5 μg) was well tolerated; no significant changes in vital signs or laboratory results were observed. Ga-SB3 PET/CT showed lesions in 8 of 10 patients. Pathologic analysis revealed a total of 16 tumor lesions, of which PET/CT showed 14, resulting in a sensitivity of 88%. Ga-SB3 PET/CT imaging showed uptake in 2 large prostatic intraepithelial neoplasia foci, considered a precursor to PCa, resulting in an 88% specificity. Autoradiography of tumor lesions revealed heterogeneous GRPr expression and was negative in 4 patients. Both PET/CT-negative patients had a GRPr-negative tumor. In autoradiography-positive tumors, the level of GRPr expression showed a significant correlation to tracer uptake on PET/CT. Dosimetry calculations estimated the effective dose to be 0.0144 mSv/MBq, similar to other Ga-labeled radiopeptides. The highest absorbed dose was detected in the physiologic GRPr-expressing pancreas (0.198 mGy/MBq), followed by the bladder wall and kidneys. Ga-SB3 PET/CT is a safe imaging method and a promising tool for early PCa imaging.
Topics: Humans; Male; Middle Aged; Positron Emission Tomography Computed Tomography; Prostatic Neoplasms; Receptors, Bombesin; Tissue Distribution
PubMed: 33789933
DOI: 10.2967/jnumed.120.258814