rudyvdbrink/CitationDatabase huggingface dataset:
Chronic intermittent ethanol exposure and withdrawal leads to adaptations in nucleus accumbens core postsynaptic density proteome and dendritic spines.
Addiction biology, 2016

Alcohol use disorder is a chronic relapsing brain disease characterized by the loss of ability to control alcohol (ethanol) intake despite knowledge of detrimental health or personal consequences. Clinical and pre-clinical models provide strong evidence for chronic ethanol-associated alterations in glutamatergic signaling and impaired synaptic plasticity in the nucleus accumbens (NAc). However, the neural mechanisms that contribute to aberrant glutamatergic signaling in ethanol-dependent individuals in this critical brain structure remain unknown. Using an unbiased proteomic approach, we investigated the effects of chronic intermittent ethanol (CIE) exposure on neuroadaptations in postsynaptic density (PSD)-enriched proteins in the NAc of ethanol-dependent mice. Compared with controls, CIE exposure significantly changed expression levels of 50 proteins in the PSD-enriched fraction. Systems biology and functional annotation analyses demonstrated that the dysregulated proteins are expressed at tetrapartite synapses and critically regulate cellular morphology. To confirm this latter finding, the density and morphology of dendritic spines were examined in the NAc core of ethanol-dependent mice. We found that CIE exposure and withdrawal differentially altered dendrite diameter and dendritic spine density and morphology. Through the use of quantitative proteomics and functional annotation, these series of experiments demonstrate that ethanol dependence produces neuroadaptations in proteins that modify dendritic spine morphology. In addition, these studies identified novel PSD-related proteins that contribute to the neurobiological mechanisms of ethanol dependence that drive maladaptive structural plasticity of NAc neurons.
Differential roles of microglia and monocytes in the inflamed central nervous system.
The Journal of experimental medicine, 2014

In the human disorder multiple sclerosis (MS) and in the model experimental autoimmune encephalomyelitis (EAE), macrophages predominate in demyelinated areas and their numbers correlate to tissue damage. Macrophages may be derived from infiltrating monocytes or resident microglia, yet are indistinguishable by light microscopy and surface phenotype. It is axiomatic that T cell-mediated macrophage activation is critical for inflammatory demyelination in EAE, yet the precise details by which tissue injury takes place remain poorly understood. In the present study, we addressed the cellular basis of autoimmune demyelination by discriminating microglial versus monocyte origins of effector macrophages. Using serial block-face scanning electron microscopy (SBF-SEM), we show that monocyte-derived macrophages associate with nodes of Ranvier and initiate demyelination, whereas microglia appear to clear debris. Gene expression profiles confirm that monocyte-derived macrophages are highly phagocytic and inflammatory, whereas those arising from microglia demonstrate an unexpected signature of globally suppressed cellular metabolism at disease onset. Distinguishing tissue-resident macrophages from infiltrating monocytes will point toward new strategies to treat disease and promote repair in diverse inflammatory pathologies in varied organs.
Organotypic Cultures from the Adult CNS: A Novel Model to Study Demyelination and Remyelination Ex Vivo.
Cellular and molecular neurobiology, 2018

Experimental models of multiple sclerosis (MS) have significantly advanced our understanding of pathophysiology and therapeutic interventions. Although in vivo rodent models are considered to most closely represent the complex cellular and molecular disease states of the human central nervous system (CNS), these can be costly to maintain and require long timelines. Organotypic slice cultures maintain the cytotypic organization observed in the intact CNS, yet provide many of the experimental advantages of in vitro cell culture models. Cerebellar organotypic cultures have proven useful for studying myelination and remyelination, but this model has only been established using early postnatal tissue. This young brain tissue allows for neuro development ex vivo to mimic the 'mature' CNS; however, there are many differences between postnatal and adult organotypic cultures. This may be particularly relevant to MS, as a major barrier to myelin regeneration is age. This paper describes a modified protocol to study demyelination and remyelination in adult cerebellar tissue, which has been used to demonstrate neuroprotection with omega-3 fatty acids. Thus, adult cerebellar organotypic cultures provide a novel ex vivo platform for screening potential therapies in myelin degeneration and repair.
Multiple sclerosis in Iceland from 1900 to 2000: A total population study.
Multiple sclerosis and related disorders, 2014

The epidemiology of multiple sclerosis (MS) in Iceland in1900-2000 is presented. The incidence increased significantly from 2.58×10(5) in 1950 to 5.06×10(5) in 2000 (from 2.71 to 7.03×10(5) for women and from 2.55 to 3.10×10(5) for men) with a yearly increase by a factor of 1.0816 per year for women and 1.01207 per year for men (Poisson regression analysis). Prevalence standardized to the European standard population rose from 29.9×10(5) in 1950 to 131.7×10(5) in 2000. The standardized prevalence was constantly higher amongst women (42.8-181.6×10(5) vs. 16.7-81.5×10(5) for men) with a female to male ratio of 2.6 in 1950 and in 2000. Mean age at onset for all patients increased from 27.8 years in 1950 to 30.7 years in 2000 (from 27.0 to 30.1 years for women and from 28.6 to 32.2 years for men). Children and adolescents (<18 years) were 9.6% of all, of whom 60% were diagnosed after 1970. Mean age of onset for children and adolescents was 14.7 years (9-17 years, 95% CI 4.2 years). The rise in incidence and prevalence can have multiple explanations, including diagnosis of milder forms of MS, increased awareness of MS in the older population, better diagnostic measures and longer survival but the authors find it likely that there has been a true rise in the MS incidence.
Assessment of Neurocognitive Impairment and Speech Functioning Before Head and Neck Cancer Treatment.
JAMA otolaryngology-- head & neck surgery, 2019

Head and neck cancer (HNC) and its treatment may negatively alter neurocognitive and speech functioning. However, the prevalence of neurocognitive impairment among patients with HNC before treatment is poorly studied, and the association between neurocognitive and speech functioning is unknown, which hampers good interpretability of the effect of HNC treatment on neurocognitive and speech function.
Between destiny and disease: genetics and molecular pathways of human central nervous system aging.
Progress in neurobiology, 2011

Aging of the human brain is associated with "normal" functional, structural, and molecular changes that underlie alterations in cognition, memory, mood and motor function, amongst other processes. Normal aging also imposes a robust constraint on the onset of many neurological diseases, ranging from late onset neurodegenerative diseases, such as Alzheimer's (AD) and Parkinson's diseases (PD), to early onset psychiatric disorders, such as bipolar disorder (BPD) and schizophrenia (SCZ). The molecular mechanisms and genetic underpinnings of age-related changes in the brain are understudied, and, while they share some overlap with peripheral mechanisms of aging, many are unique to the largely non-mitotic brain. Hence, understanding mechanisms of brain aging and identifying associated modulators may have profound consequences for the prevention and treatment of age-related impairments and diseases. Here we review current knowledge on age-related functional and structural changes, their molecular and genetic underpinnings, and discuss how these pathways may contribute to the vulnerability to develop age-related neurological diseases. We highlight recent findings from human post-mortem brain microarray studies, which we hypothesize, point to a potential genetically controlled transcriptional program underlying molecular changes and age-gating of neurological diseases. Finally, we discuss the implications of this model for understanding basic mechanisms of brain aging and for the future investigation of therapeutic approaches.
Glycoreplica peptides to investigate molecular mechanisms of immune-mediated physiological versus pathological conditions.
Archives of biochemistry and biophysics, 2019

Investigation of the role of saccharides and glycoconjugates in mechanisms of immune-mediated physiological and pathological conditions is a hot topic. In fact, in many autoimmune diseases cross-reactivity between sugar moieties exposed on exogenous pathogens and self-molecules has long been hinted. Several peptides have been reported as mimetics of glycans specifically interacting with sugar-binding antibodies. The seek for these glycoreplica peptides is instrumental in characterizing antigen mimicry pathways and their involvement in triggering autoimmunity. Therefore, peptides mimicking glycan-protein interactions are valuable molecular tools to overcome the difficulties of oligosaccharide preparations. The clinical impact of peptide-based probes for autoimmune diseases diagnosis and follow-up is emerging only recently as just the tip of the iceberg of an overlooked potential. Here we provide a brief overview of the relevance of the structural and functional aspects of peptide probes and their mimicry effect in autoimmunity mechanisms for promising applications in diagnostics and therapeutics.
Cocaine supersensitivity and enhanced motivation for reward in mice lacking dopamine D2 autoreceptors.
Nature neuroscience, 2011

Dopamine (DA) D2 receptors expressed in DA neurons (D2 autoreceptors) exert a negative feedback regulation that reduces DA neuron firing, DA synthesis and DA release. As D2 receptors are mostly expressed in postsynaptic neurons, pharmacological and genetic approaches have been unable to definitively address the in vivo contribution of D2 autoreceptors to DA-mediated behaviors. We found that midbrain DA neurons from mice deficient in D2 autoreceptors (Drd2(loxP/loxP); Dat(+/IRES-cre), referred to as autoDrd2KO mice) lacked DA-mediated somatodendritic synaptic responses and inhibition of DA release. AutoDrd2KO mice displayed elevated DA synthesis and release, hyperlocomotion and supersensitivity to the psychomotor effects of cocaine. The mice also exhibited increased place preference for cocaine and enhanced motivation for food reward. Our results highlight the importance of D2 autoreceptors in the regulation of DA neurotransmission and demonstrate that D2 autoreceptors are important for normal motor function, food-seeking behavior, and sensitivity to the locomotor and rewarding properties of cocaine.
Treatment of Bipolar Disorder in a Lifetime Perspective: Is Lithium Still the Best Choice?
Clinical drug investigation, 2017

Lithium preparations have been successfully used to treat bipolar disorder (BD), and remain the best established long-term treatment for the disorder. In fact, lithium is a cornerstone of treatment to minimize the risk of recurrences and improve inter-episodic symptomatology. We reviewed the available evidence for the use of lithium in the treatment of BD, including its efficacy, limitations, and potential benefits also in consideration of the different formulations available. We also overviewed salient comparative aspects regarding the long-term alternative use of anticonvulsants, antidepressants, and antipsychotics in BD patients. The available evidence indicates that BD patients should be treated primarily with lithium, combined in some cases with antipsychotics especially in acute treatments, and sometimes, because of intolerance or inefficacy of lithium, with anticonvulsants. The use of adjunctive antidepressants should be limited to episodes of breakthrough depression. Lithium should be offered to the majority of BD patients as initial treatment especially when suicide ideation or behavior is present with adequate information about its long-term benefits and its potential side effects. Many patients can tolerate lithium without concomitant use of antidepressants, which may worsen the course of the illness or antipsychotics, which may cause severe long-term side effects.
Characteristics of young people with long term conditions close to transfer to adult health services.
BMC health services research, 2015

For many young people with long term conditions (LTC), transferring from paediatric to adult health services can be difficult and outcomes are often reported to be poor. We report the characteristics and representativeness of three groups of young people with LTCs as they approach transfer to adult services: those with autism spectrum disorder with additional mental health problems (ASD); cerebral palsy (CP); or diabetes.
Metabolic syndrome is associated to an increased risk of low bone mineral density in free-living women with suspected osteoporosis.
Journal of endocrinological investigation, 2021

Osteoporosis (Op) and metabolic syndrome (MetS) are two common disorders showing common pathogenic patterns. This cross-sectional study was performed to evaluate if MetS and its constitutive elements are associated to an increased risk of low bone mineral density (BMD) in free-living women examined by Dual-energy X-ray absorptiometry (DXA) for suspected Op.
Application of transcranial magnetic stimulation for major depression: Coil design and neuroanatomical variability considerations.
European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology, 2021

High-frequency repeated transcranial magnetic stimulation (rTMS) as a treatment for major depressive disorder (MDD) has received FDA clearance for both the figure-of-8 coil (figure-8 coil) and the H1 coil. The FDA-cleared MDD protocols for both coils include high frequency (10-18 Hz) stimulation targeting the dorsolateral prefrontal cortex (dlPFC) at an intensity that is 120% of the right-hand resting motor threshold. Despite these similar parameters, the two coils generate distinct electrical fields (e-fields) which result in differences in the cortical stimulation they produce. Due to the differences in coil designs, the H1 coil induces a stimulation e-field that is broader and deeper than the one induced by the figure-8 coil. In this paper we review theoretical and clinical implications of these differences between the two coils and compare evidence of their safety and efficacy in treating MDD. We present the design principles of the coils, the challenges of identifying, finding, and stimulating the optimal brain target of each individual (both from functional and connectivity perspectives), and the possible implication of stimulating outside that target. There is only one study that performed a direct comparison between clinical effectiveness of the two coils, using the standard FDA-approved protocols in MDD patients. This study indicated clinical superiority of the H1 coil but did not measure long-term effects. Post-marketing data suggest that both coils have a similar safety profile in clinical practice, whereas effect size comparisons of the two respective FDA pivotal trials suggests that the H1 coil may have an advantage in efficacy. We conclude that further head-to-head experiments are needed, especially ones that will compare long-term effects and usage of similar temporal stimulation parameters and similar number of pulses.
Electrophysiological correlates of hyperoxia during resting-state EEG in awake human subjects.
Psychophysiology, 2019

Recreational use of concentrated oxygen has increased. Claims have been made that hyperoxic breathing can help reduce fatigue, increase alertness, and improve attentional capacities; however, few systematic studies of these potential benefits exist. Here, we examined the effects of short-term (15 min) hyperoxia on resting states in awake human subjects by measuring spontaneous EEG activity between normoxic and hyperoxic situations, using a within-subject design for both eyes-opened and eyes-closed conditions. We also measured respiration rate, heart rate, and blood oxygen saturation levels to correlate basic physiological changes due to the hyperoxic challenge with any brain activity changes. Our results show that breathing short-term 100% oxygen led to increased blood oxygen saturation levels, decreased heart rate, and a slight, but nonsignificant, decrease in breathing rate. Changes of brain activity were apparent, including decreases in low-alpha (7-10 Hz), high-alpha (10-14 Hz), beta (14-30 Hz), and gamma (30-50 Hz) frequency ranges during eyes-opened hyperoxic conditions. During eyes-closed hyperoxia, increases in the delta (0.5-3.5 Hz) and theta (3.5-7 Hz) frequency range were apparent together with decreases in the beta range. Hyperoxia appeared to accentuate the decrease of low alpha and gamma ranges across the eyes-opened and eyes-closed conditions, suggesting that it modulated brain state itself. As decreased alpha during eyes-opened conditions has been associated with increased attentional processing and selective attention, and increased delta and theta during eyes-closed condition are typically associated with the initiation of sleep, our results suggest a state-specific and perhaps opposing influence of short-term hyperoxia.
Multiple functional therapeutic effects of the estrogen receptor β agonist indazole-Cl in a mouse model of multiple sclerosis.
Proceedings of the National Academy of Sciences of the United States of America, 2014

Currently available immunomodulatory therapies do not stop the pathogenesis underlying multiple sclerosis (MS) and are only partially effective in preventing the onset of permanent disability in patients with MS. Identifying a drug that stimulates endogenous remyelination and/or minimizes axonal degeneration would reduce the rate and degree of disease progression. Here, the effects of the highly selective estrogen receptor (ER) β agonist indazole chloride (Ind-Cl) on functional remyelination in chronic experimental autoimmune encephalomyelitis (EAE) mice were investigated by assessing pathologic, functional, and behavioral consequences of both prophylactic and therapeutic (peak EAE) treatment with Ind-Cl. Peripheral cytokines from autoantigen-stimulated splenocytes were measured, and central nervous system infiltration by immune cells, axon health, and myelination were assessed by immunohistochemistry and electron microscopy. Therapeutic Ind-Cl improved clinical disease and rotorod performance and also decreased peripheral Th1 cytokines and reactive astrocytes, activated microglia, and T cells in brains of EAE mice. Increased callosal myelination and mature oligodendrocytes correlated with improved callosal conduction and refractoriness. Therapeutic Ind-Cl-induced remyelination was independent of its effects on the immune system, as Ind-Cl increased remyelination within the cuprizone diet-induced demyelinating model. We conclude that Ind-Cl is a refined pharmacologic agent capable of stimulating functionally relevant endogenous myelination, with important implications for progressive MS treatment.
Scribble1/AP2 complex coordinates NMDA receptor endocytic recycling.
Cell reports, 2014

The appropriate trafficking of glutamate receptors to synapses is crucial for basic synaptic function and synaptic plasticity. It is now accepted that NMDA receptors (NMDARs) internalize and are recycled at the plasma membrane but also exchange between synaptic and extrasynaptic pools; these NMDAR properties are also key to governing synaptic plasticity. Scribble1 is a large PDZ protein required for synaptogenesis and synaptic plasticity. Herein, we show that the level of Scribble1 is regulated in an activity-dependent manner and that Scribble1 controls the number of NMDARs at the plasma membrane. Notably, Scribble1 prevents GluN2A subunits from undergoing lysosomal trafficking and degradation by increasing their recycling to the plasma membrane following NMDAR activation. Finally, we show that a specific YxxR motif on Scribble1 controls these mechanisms through a direct interaction with AP2. Altogether, our findings define a molecular mechanism to control the levels of synaptic NMDARs via Scribble1 complex signaling.
The increased sensitivity of irregular peripheral canal and otolith vestibular afferents optimizes their encoding of natural stimuli.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2015

Efficient processing of incoming sensory input is essential for an organism's survival. A growing body of evidence suggests that sensory systems have developed coding strategies that are constrained by the statistics of the natural environment. Consequently, it is necessary to first characterize neural responses to natural stimuli to uncover the coding strategies used by a given sensory system. Here we report for the first time the statistics of vestibular rotational and translational stimuli experienced by rhesus monkeys during natural (e.g., walking, grooming) behaviors. We find that these stimuli can reach intensities as high as 1500 deg/s and 8 G. Recordings from afferents during naturalistic rotational and linear motion further revealed strongly nonlinear responses in the form of rectification and saturation, which could not be accurately predicted by traditional linear models of vestibular processing. Accordingly, we used linear-nonlinear cascade models and found that these could accurately predict responses to naturalistic stimuli. Finally, we tested whether the statistics of natural vestibular signals constrain the neural coding strategies used by peripheral afferents. We found that both irregular otolith and semicircular canal afferents, because of their higher sensitivities, were more optimized for processing natural vestibular stimuli as compared with their regular counterparts. Our results therefore provide the first evidence supporting the hypothesis that the neural coding strategies used by the vestibular system are matched to the statistics of natural stimuli.
Physiological evidence for impairment in autosomal dominant optic atrophy at the pre-ganglion level.
Graefe's archive for clinical and experimental ophthalmology = Albrecht von Graefes Archiv fur klinische und experimentelle Ophthalmologie, 2013

Functional studies in patients with autosomal dominant optic atrophy (ADOA) are usually confined to analysis of physiological and clinical impact at the ganglion cell (GG) and post GC levels. Here we aimed to investigate the impact of the disease at a pre-GC level and its correlation with GC/post-GC related measures.