rudyvdbrink/CitationDatabase huggingface dataset:
Imaging of inflammation in the peripheral and central nervous system by magnetic resonance imaging.
Neuroscience, 2009

Inflammation plays a central role in the pathophysiology of numerous disorders of the nervous system, but is also pivotal for repair processes like peripheral nerve regeneration. In this review we summarize recent advances in cellular magnetic resonance imaging (MRI) while nuclear imaging methods to visualize neuroinflammation are covered by Wunder et al. [Wunder A, Klohs J, Dirnagl U (2009) Non-invasive imaging of central nervous system inflammation with nuclear and optical imaging. Neuroscience, in press]. Use of iron oxide-contrast agents allows assessment of inflammatory processes in living organisms. Upon systemic application, circulating small (SPIO) and ultrasmall particles of iron oxide (USPIO) are preferentially phagocytosed by monocytes before clearance within the reticuloendothelial system of the liver, spleen and lymph nodes. Upon acute migration into the diseased nervous system these iron oxide-laden macrophages become visible on MRI by the superparamagnetic effects of iron oxide resulting in a signal loss on T2-w and/or bright contrast on T1-w MRI. There is an ongoing controversy, however, to what extent SPIO/USPIO also diffuses passively into the brain after disruption of the blood-brain barrier pretending macrophage invasion. Other confounding factors include circulating SPIO/USPIO particles within the blood pool, local hemorrhages, and intrinsic iron oxide-loading of phagocytes. These uncertainties can be overcome by in vitro preloading of cells with iron oxide contrast agents and consecutive systemic application into animals. Iron oxide-contrast-enhanced MRI allowed in vivo visualization of cellular inflammation during wallerian degeneration, experimental autoimmune neuritis and encephalomyelitis, and stroke in rodents, but also in patients with multiple sclerosis and stroke. Importantly, cellular MRI provides additional information to gadolinium-DTPA-enhanced MRI since cellular infiltration and breakdown of the blood-brain barrier are not closely linked. Coupling of antibodies to iron oxide particles opens new avenues for molecular MRI and has been successfully used to visualize cell adhesion molecules guiding inflammation.
Serotonin 1A receptors and sexual behavior in female rats: a review.
Pharmacology, biochemistry, and behavior, 2014

This review focuses on the role of serotonin and especially 5-HT₁A receptors in female rat sexual behavior. In addition, the differences and/or similarities with male rats are discussed. Overall, in both males and females 5-HT₁A receptors do not appear to be involved in sexual behavior under normal circumstances, but become very important under conditions of elevated serotonin levels. 5-HT₁A receptor agonists facilitate sexual behavior in male rats, but inhibit female sexual activity. At first sight, this seems quite conflicting, but could be due to our definitions of different elements of sexual behavior. Three different phases can be distinguished in rats' sexual cycle, the introductory (precopulatory), the copulatory and the executive (ejaculatory) phases. Different mechanisms and brain regions are involved in these phases. If the appropriate phases of males and females are properly compared, the role of 5-HT₁A receptors in rats might be more similar than assumed thus far.
Heme Oxygenase 1 and 2 Common Genetic Variants and Risk for Essential Tremor.
Medicine, 2015

Several reports suggested a role of heme oxygenase genes 1 and 2 (HMOX1 and HMOX2) in modifying the risk to develop Parkinson disease (PD). Because essential tremor (ET) and PD share phenotypical and, probably, etiologic factors of the similarities, we analyzed whether such genes are related with the risk to develop ET. We analyzed the distribution of allelic and genotype frequencies of the HMOX1 rs2071746, HMOX1 rs2071747, HMOX2 rs2270363, and HMOX2 rs1051308 single nucleotide polymorphisms, as well as the presence of copy number variations of these genes in 202 subjects with familial ET and 747 healthy controls. Allelic frequencies of rs2071746T and rs1051308G were significantly lower in ET patients than in controls. None of the studied polymorphisms influenced the disease onset. The present study suggests a weak association between HMOX1 rs2071746 and HMOX2 rs1051308 polymorphisms and the risk to develop ET in the Spanish population.
Monoubiquitination of nuclear RelA negatively regulates NF-κB activity independent of proteasomal degradation.
Cellular and molecular life sciences : CMLS, 2012

Termination and resolution of inflammation are tightly linked to the inactivation of one of its strongest inducers, NF-κB. While canonical post-stimulus inactivation is achieved by upregulation of inhibitory molecules that relocate NF-κB complexes to the cytoplasm, termination of the NF-κB response can also be accomplished directly in the nucleus by posttranslational modifications, e.g., ubiquitination of the RelA subunit. Here we reveal a functional role for RelA monoubiquitination in regulating NF-κB activity. By employing serine-to-alanine mutants, we found that hypo-phosphorylated nuclear RelA is monoubiquitinated on multiple lysine residues. Ubiquitination was reversed by IκBα expression and was reduced when nuclear translocation was inhibited. RelA monoubiquitination decreased NF-κB transcriptional activity despite prolonged nuclear presence and independently of RelA degradation, possibly through decreased CREB-binding protein (CBP) co-activator binding. Polyubiquitin-triggered proteasomal degradation has been proposed as a model for RelA inactivation. However, here we show that proteasomal inhibition, similar to RelA hypo-phosphorylation, resulted in nuclear translocation and monoubiquitination of RelA. These findings indicate a degradation-independent mechanism for regulating the activity of nuclear RelA by ubiquitination.
Neural mechanisms of social decision-making in the primate amygdala.
Proceedings of the National Academy of Sciences of the United States of America, 2015

Social decisions require evaluation of costs and benefits to oneself and others. Long associated with emotion and vigilance, the amygdala has recently been implicated in both decision-making and social behavior. The amygdala signals reward and punishment, as well as facial expressions and the gaze of others. Amygdala damage impairs social interactions, and the social neuropeptide oxytocin (OT) influences human social decisions, in part, by altering amygdala function. Here we show in monkeys playing a modified dictator game, in which one individual can donate or withhold rewards from another, that basolateral amygdala (BLA) neurons signaled social preferences both across trials and across days. BLA neurons mirrored the value of rewards delivered to self and others when monkeys were free to choose but not when the computer made choices for them. We also found that focal infusion of OT unilaterally into BLA weakly but significantly increased both the frequency of prosocial decisions and attention to recipients for context-specific prosocial decisions, endorsing the hypothesis that OT regulates social behavior, in part, via amygdala neuromodulation. Our findings demonstrate both neurophysiological and neuroendocrinological connections between primate amygdala and social decisions.
Treatment with an interleukin-1 receptor antagonist mitigates neuroinflammation and brain damage after polytrauma.
Brain, behavior, and immunity, 2017

Traumatic brain injury (TBI) and long bone fracture are common in polytrauma. This injury combination in mice results in elevated levels of the pro-inflammatory cytokine interleukin-1β (IL-1β) and exacerbated neuropathology when compared to isolated-TBI. Here we examined the effect of treatment with an IL-1 receptor antagonist (IL-1ra) in mice given a TBI and a concomitant tibial fracture (i.e., polytrauma). Adult male C57BL/6 mice were given sham-injuries or polytrauma and treated with saline-vehicle or IL-1ra (100mg/kg). Treatments were subcutaneously injected at 1, 6, and 24h, and then once daily for one week post-injury. 7-8 mice/group were euthanized at 48h post-injury. 12-16 mice/group underwent behavioral testing at 12weeks post-injury and MRI at 14weeks post-injury before being euthanized at 16weeks post-injury. At 48h post-injury, markers for activated microglia and astrocytes, as well as neutrophils and edema, were decreased in polytrauma mice treated with IL-1ra compared to polytrauma mice treated with vehicle. At 14weeks post-injury, MRI analysis demonstrated that IL-1ra treatment after polytrauma reduced volumetric loss in the injured cortex and mitigated track-weighted MRI markers for axonal injury. As IL-1ra (Anakinra) is approved for human use, it may represent a promising therapy in polytrauma cases involving TBI and fracture.
The inferior colliculus encodes the Franssen auditory spatial illusion.
The European journal of neuroscience, 2013

Illusions are effective tools for the study of the neural mechanisms underlying perception because neural responses can be correlated to the physical properties of stimuli and the subject's perceptions. The Franssen illusion (FI) is an auditory spatial illusion evoked by presenting a transient, abrupt tone and a slowly rising, sustained tone of the same frequency simultaneously on opposite sides of the subject. Perception of the FI consists of hearing a single sound, the sustained tone, on the side that the transient was presented. Both subcortical and cortical mechanisms for the FI have been proposed, but, to date, there is no direct evidence for either. The data show that humans and rhesus monkeys perceive the FI similarly. Recordings were taken from single units of the inferior colliculus in the monkey while they indicated the perceived location of sound sources with their gaze. The results show that the transient component of the Franssen stimulus, with a shorter first spike latency and higher discharge rate than the sustained tone, encodes the perception of sound location. Furthermore, the persistent erroneous perception of the sustained stimulus location is due to continued excitation of the same neurons, first activated by the transient, by the sustained stimulus without location information. These results demonstrate for the first time, on a trial-by-trial basis, a correlation between perception of an auditory spatial illusion and a subcortical physiological substrate.
Non-invasive suppression of essential tremor via phase-locked disruption of its temporal coherence.
Nature communications, 2021

Aberrant neural oscillations hallmark numerous brain disorders. Here, we first report a method to track the phase of neural oscillations in real-time via endpoint-corrected Hilbert transform (ecHT) that mitigates the characteristic Gibbs distortion. We then used ecHT to show that the aberrant neural oscillation that hallmarks essential tremor (ET) syndrome, the most common adult movement disorder, can be transiently suppressed via transcranial electrical stimulation of the cerebellum phase-locked to the tremor. The tremor suppression is sustained shortly after the end of the stimulation and can be phenomenologically predicted. Finally, we use feature-based statistical-learning and neurophysiological-modelling to show that the suppression of ET is mechanistically attributed to a disruption of the temporal coherence of the aberrant oscillations in the olivocerebellar loop, thus establishing its causal role. The suppression of aberrant neural oscillation via phase-locked driven disruption of temporal coherence may in the future represent a powerful neuromodulatory strategy to treat brain disorders.
Brain mitochondrial metabolic dysfunction and glutamate level reduction in the pilocarpine model of temporal lobe epilepsy in mice.
Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism, 2013

Although certain metabolic characteristics such as interictal glucose hypometabolism are well established for temporal lobe epilepsy (TLE), its pathogenesis still remains unclear. Here, we performed a comprehensive study of brain metabolism in a mouse model of TLE, induced by pilocarpine-status epilepticus (SE). To investigate glucose metabolism, we injected mice 3.5-4 weeks after SE with [1,2-(13)C]glucose before microwave fixation of the head. Using (1)H and (13)C nuclear magnetic resonance spectroscopy, gas chromatography-mass spectrometry and high-pressure liquid chromatography, we quantified metabolites and (13)C labeling in extracts of cortex and hippocampal formation (HF). Hippocampal levels of glutamate, glutathione and alanine were decreased in pilocarpine-SE mice compared with controls. Moreover, the contents of N-acetyl aspartate, succinate and reduced nicotinamide adenine dinucleotide (phosphate) NAD(P)H were decreased in HF indicating impairment of mitochondrial function. In addition, the reduction in (13)C enrichment of hippocampal citrate and malate suggests decreased tricarboxylic acid (TCA) cycle turnover in this region. In cortex, we found reduced (13)C labeling of glutamate, glutamine and aspartate via the pyruvate carboxylation and pyruvate dehydrogenation pathways, suggesting slower turnover of these amino acids and/or the TCA cycle. In conclusion, mitochondrial metabolic dysfunction and altered amino-acid metabolism is found in both cortex and HF in this epilepsy model.
Circumvention of common labelling artefacts using secondary nanobodies.
Nanoscale, 2020

A standard procedure to study cellular elements is via immunostaining followed by optical imaging. This methodology typically requires target-specific primary antibodies (1.Abs), which are revealed by secondary antibodies (2.Abs). Unfortunately, the antibody bivalency, polyclonality, and large size can result in a series of artifacts. Alternatively, small, monovalent probes, such as single-domain antibodies (nanobodies) have been suggested to minimize these limitations. The discovery and validation of nanobodies against specific targets are challenging, thus only a minimal amount of them are currently available. Here, we used STED, DNA-PAINT, and light-sheet microscopy, to demonstrate that secondary nanobodies (1) increase localization accuracy compared to 2.Abs; (2) allow direct pre-mixing with 1.Abs before staining, reducing experimental time, and enabling the use of multiple 1.Abs from the same species; (3) penetrate thick tissues more efficiently; and (4) avoid probe-induced clustering of target molecules observed with conventional 2.Abs in living or poorly fixed samples. Altogether, we show how secondary nanobodies are a valuable alternative to 2.Abs.
Rings of charge within the extracellular vestibule influence ion permeation of the 5-HT3A receptor.
The Journal of biological chemistry, 2011

The determinants of single channel conductance (γ) and ion selectivity within eukaryotic pentameric ligand-gated ion channels have traditionally been ascribed to amino acid residues within the second transmembrane domain and flanking sequences of their component subunits. However, recent evidence suggests that γ is additionally controlled by residues within the intracellular and extracellular domains. We examined the influence of two anionic residues (Asp(113) and Asp(127)) within the extracellular vestibule of a high conductance human mutant 5-hydroxytryptamine type-3A (5-HT(3)A) receptor (5-HT(3)A(QDA)) upon γ, modulation of the latter by extracellular Ca(2+), and the permeability of Ca(2+) with respect to Cs(+) (P(Ca)/P(Cs)). Mutations neutralizing (Asp → Asn), or reversing (Asp → Lys), charge at the 113 locus decreased inward γ by 46 and 58%, respectively, but outward currents were unaffected. The D127N mutation decreased inward γ by 82% and also suppressed outward currents, whereas the D127K mutation caused loss of observable single channel currents. The forgoing mutations, except for D127K, which could not be evaluated, ameliorated suppression of inwardly directed single channel currents by extracellular Ca(2+). The P(Ca)/P(Cs) of 3.8 previously reported for the 5-HT(3)A(QDA) construct was reduced to 0.13 and 0.06 by the D127N and D127K mutations, respectively, with lesser, but clearly significant, effects caused by the D113N (1.04) and D113K (0.60) substitutions. Charge selectivity between monovalent cations and anions (P(Na)/P(Cl)) was unaffected by any of the mutations examined. The data identify two key residues in the extracellular vestibule of the 5-HT(3)A receptor that markedly influence γ, P(Ca)/P(Cs), and additionally the suppression of γ by Ca(2+).
Delayed experience of volition in Gilles de la Tourette syndrome.
Journal of neurology, neurosurgery, and psychiatry, 2011

Gilles de la Tourette's syndrome (TS) is a neuropsychiatric movement disorder characterised by the presence of multiple tics. Tics have an unusual, intermediate status between voluntary and involuntary movements. This ambiguity might involve not just a disorder of movement generation but also an abnormality of voluntary experience. Here the experience of voluntary movements in adult patients with TS is investigated and compared with healthy controls. A group of adult TS patients and age matched control participants estimated the time of conscious intention to perform a simple keypress movement and movement onset. Patients with TS showed a delayed experience of intention relative to controls whereas estimates of the actual movement onset were similar for patients and controls. These data suggest an abnormal experience of volition in patients with TS. Delayed volition could either be an additional intrinsic feature of the syndrome or it could reflect a cognitive strategy to limit motor excitability, and thus tic generation, during voluntary action.
AIP mutations impair AhR signaling in pituitary adenoma patients fibroblasts and in GH3 cells.
Endocrine-related cancer, 2016

Germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene predispose humans to pituitary adenomas through unknown molecular mechanisms. The best-known interacting partner of AIP is the aryl hydrocarbon receptor (AhR), a transcription factor that mediates the effects of xenobiotics implicated in carcinogenesis. As 75% of AIP mutations disrupt the physical and/or functional interaction with AhR, we postulated that the tumorigenic potential of AIP mutations might result from altered AhR signaling. We evaluated the impact of AIP mutations on the AhR signaling pathway, first in fibroblasts from AIP-mutated patients with pituitary adenomas, by comparison with fibroblasts from healthy subjects, then in transfected pituitary GH3 cells. The AIP protein level in mutated fibroblasts was about half of that in cells from healthy subjects, but AhR expression was unaffected. Gene expression analyses showed significant modifications in the expression of the AhR target genes CYP1B1 and AHRR in AIP-mutated fibroblasts, both before and after stimulation with the endogenous AhR ligand kynurenine. Kynurenine increased Cyp1b1 expression to a greater extent in GH3 cells overexpressing wild type compared with cells expressing mutant AIP Knockdown of endogenous Aip in these cells attenuated Cyp1b1 induction by the AhR ligand. Both mutant AIP expression and knockdown of endogenous Aip affected the kynurenine-dependent GH secretion of GH3 cells. This study of human fibroblasts bearing endogenous heterozygous AIP mutations and transfected pituitary GH3 cells shows that AIP mutations affect the AIP protein level and alter AhR transcriptional activity in a gene- and tissue-dependent manner.
ALS/FTLD: experimental models and reality.
Acta neuropathologica, 2017

Amyotrophic lateral sclerosis is characterised by a loss of upper and lower motor neurons and characteristic muscle weakness and wasting, the most common form being sporadic disease with neuronal inclusions containing the tar DNA-binding protein 43 (TDP-43). Frontotemporal lobar degeneration is characterised by atrophy of the frontal and/or temporal lobes, the most common clinical form being the behavioural variant, in which neuronal inclusions containing either TDP-43 or 3-repeat tau are most prevalent. Although the genetic mutations associated with these diseases have allowed various experimental models to be developed, the initial genetic forms identified remain the most common models employed to date. It is now known that these first models faithfully recapitulate only some aspects of these diseases and do not represent the majority of cases or the most common overlapping pathologies. Newer models targeting the main molecular pathologies are still rare and in some instances, lack significant aspects of the molecular pathology. However, these diseases are complex and multigenic, indicating that experimental models may need to be targeted to different disease aspects. This would allow information to be gleaned from a variety of different yet relevant models, each of which has the capacity to capture a certain aspect of the disease, and together will enable a more complete understanding of these complex and multi-layered diseases.
Default network connectivity in medial temporal lobe amnesia.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2012

There is substantial overlap between the brain regions supporting episodic memory and the default network. However, in humans, the impact of bilateral medial temporal lobe (MTL) damage on a large-scale neural network such as the default mode network is unknown. To examine this issue, resting fMRI was performed with amnesic patients and control participants. Seed-based functional connectivity analyses revealed robust default network connectivity in amnesia in cortical default network regions such as medial prefrontal cortex, posterior medial cortex, and lateral parietal cortex, as well as evidence of connectivity to residual MTL tissue. Relative to control participants, decreased posterior cingulate cortex connectivity to MTL and increased connectivity to cortical default network regions including lateral parietal and medial prefrontal cortex were observed in amnesic patients. In contrast, somatomotor network connectivity was intact in amnesic patients, indicating that bilateral MTL lesions may selectively impact the default network. Changes in default network connectivity in amnesia were largely restricted to the MTL subsystem, providing preliminary support from MTL amnesic patients that the default network can be fractionated into functionally and structurally distinct components. To our knowledge, this is the first examination of the default network in amnesia.
Reduction of Severity of Recurrent Psychotic Episode by Sustained Treatment with Aripiprazole in a Schizophrenic Patient with Dopamine Supersensitivity: A Case Report.
Clinical psychopharmacology and neuroscience : the official scientific journal of the Korean College of Neuropsychopharmacology, 2017

Dopamine supersensitivity psychosis (DSP) is a type of acute exacerbation of recurrent psychosis caused by long-term treatment with antipsychotics in schizophrenic patients. Although DSP is exceedingly troublesome for clinicians, effective treatment has not yet been established. Based on clinical research and our animal study, we hypothesize that aripiprazole, an atypical antipsychotic, may reduce the exacerbation of recurrent psychotic episodes. We report the case of a 46-year-old female who suffered from schizophrenia with DSP. In this case, sustained treatment with a high dose of aripiprazole gradually reduced the　 severity of her recurrent psychotic episodes. In conclusion, sustained treatment with aripiprazole may reduce the exacerbation of recurrent psychotic episodes in schizophrenic patients with DSP, and may be an effective treatment of DSP.