rudyvdbrink/CitationDatabase huggingface dataset:
Metabotropic glutamate receptor 5 activation inhibits microglial associated inflammation and neurotoxicity.
Glia, 2009

The Group I metabotropic glutamate receptor 5 (mGluR5) can modulate addiction, pain, and neuronal cell death. Expression of some mGluRs, such as Group II and III mGluRs, has been reported in microglia and may affect their activation. However, the expression and role of mGluR5 in microglia is unclear. Using immunocytochemistry and Western blot, we demonstrate that mGluR5 protein is expressed in primary microglial cultures. Activation of mGluR5 using the selective agonist (RS)-2-chloro-5-hydroxyphenylglycine (CHPG) significantly reduces microglial activation in response to lipopolysaccharide, as indicated by a reduction in nitric oxide, reactive oxygen species, and TNFalpha production. Microglial induced neurotoxicity is also markedly reduced by CHPG treatment. The anti-inflammatory effects of CHPG are not observed in microglial cultures from mGluR5 knockout mice and are blocked by selective mGluR5 antagonists, suggesting that these actions are mediated by the mGluR5 receptor. Anti-inflammatory actions of mGluR5 activation are attenuated by phospholipase C and protein kinase C inhibitors, as well as by calcium chelators, suggesting that the mGluR5 activation in microglia involves the G(alphaq)-protein signal transduction pathway. These data indicate that microglial mGluR5 may represent a novel target for modulating neuroinflammation, an important component of both acute and chronic neurodegenerative disorders.
Mechanisms underlying desynchronization of cholinergic-evoked thalamic network activity.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2014

Synchronous neuronal activity in the thalamocortical system is critical for a number of behaviorally relevant computations, but hypersynchrony can limit information coding and lead to epileptiform responses. In the somatosensory thalamus, afferent inputs are transformed by networks of reciprocally connected thalamocortical neurons in the ventrobasal nucleus (VB) and GABAergic neurons in the thalamic reticular nucleus (TRN). These networks can generate oscillatory activity, and studies in vivo and in vitro have suggested that thalamic oscillations are often accompanied by synchronous neuronal activity, in part mediated by widespread divergence and convergence of both reticulothalamic and thalamoreticular pathways, as well as by electrical synapses interconnecting TRN neurons. However, the functional organization of thalamic circuits and its role in shaping input-evoked activity patterns remain poorly understood. Here we show that optogenetic activation of cholinergic synaptic afferents evokes near-synchronous firing in mouse TRN neurons that is rapidly desynchronized in thalamic networks. We identify several mechanisms responsible for desynchronization: (1) shared inhibitory inputs in local VB neurons leading to asynchronous and imprecise rebound bursting; (2) TRN-mediated lateral inhibition that further desynchronizes firing in the VB; and (3) powerful yet sparse thalamoreticular connectivity that mediates re-excitation of the TRN but preserves asynchronous firing. Our findings reveal how distinct local circuit features interact to desynchronize thalamic network activity.
Building a pipeline to solicit expert knowledge from the community to aid gene summary curation.
Database : the journal of biological databases and curation, 2020

Brief summaries describing the function of each gene's product(s) are of great value to the research community, especially when interpreting genome-wide studies that reveal changes to hundreds of genes. However, manually writing such summaries, even for a single species, is a daunting task; for example, the Drosophila melanogaster genome contains almost 14 000 protein-coding genes. One solution is to use computational methods to generate summaries, but this often fails to capture the key functions or express them eloquently. Here, we describe how we solicited help from the research community to generate manually written summaries of D. melanogaster gene function. Based on the data within the FlyBase database, we developed a computational pipeline to identify researchers who have worked extensively on each gene. We e-mailed these researchers to ask them to draft a brief summary of the main function(s) of the gene's product, which we edited for consistency to produce a 'gene snapshot'. This approach yielded 1800 gene snapshot submissions within a 3-month period. We discuss the general utility of this strategy for other databases that capture data from the research literature. Database URL: https://flybase.org/.
Neurological Soft Signs and Brain Network Abnormalities in Schizophrenia.
Schizophrenia bulletin, 2020

Neurological soft signs (NSS) are often found in patients with schizophrenia. A wealth of neuroimaging studies have reported that NSS are related to disturbed cortical-subcortical-cerebellar circuitry in schizophrenia. However, the association between NSS and brain network abnormalities in patients with schizophrenia remains unclear. In this study, the graph theoretical approach was used to analyze brain network characteristics based on structural magnetic resonance imaging (MRI) data. NSS were assessed using the Heidelberg scale. We found that there was no significant difference in global network properties between individuals with high and low levels of NSS. Regional network analysis showed that NSS were associated with betweenness centrality involving the inferior orbital frontal cortex, the middle temporal cortex, the hippocampus, the supramarginal cortex, the amygdala, and the cerebellum. Global network analysis also demonstrated that NSS were associated with the distribution of network hubs involving the superior medial frontal cortex, the superior and middle temporal cortices, the postcentral cortex, the amygdala, and the cerebellum. Our findings suggest that NSS are associated with alterations in topological attributes of brain networks corresponding to the cortical-subcortical-cerebellum circuit in patients with schizophrenia, which may provide a new perspective for elucidating the neural basis of NSS in schizophrenia.
Age-Dependent Hippocampal Proteomics in the APP/PS1 Alzheimer Mouse Model: A Comparative Analysis with Classical SWATH/DIA and directDIA Approaches.
Cells, 2021

Alzheimer's disease (AD) is the most common neurodegenerative disorder in the human population, for which there is currently no cure. The cause of AD is unknown; however, the toxic effects of amyloid-β (Aβ) are believed to play a role in its onset. To investigate this, we examined changes in global protein levels in a hippocampal synaptosome fraction of the Amyloid Precursor Protein swe/Presenelin 1 dE9 (APP/PS1) mouse model of AD at 6 and 12 months of age (moa). Data independent acquisition (DIA), or Sequential Window Acquisition of all THeoretical fragment-ion (SWATH), was used for a quantitative label-free proteomics analysis. We first assessed the usefulness of a recently improved directDIA workflow as an alternative to conventional DIA data analysis using a project-specific spectral library. Subsequently, we applied directDIA to the 6- and 12-moa APP/PS1 datasets and applied the Mass Spectrometry Downstream Analysis Pipeline (MS-DAP) for differential expression analysis and candidate discovery. We observed most regulation at 12-moa, in particular of proteins involved in Aβ homeostasis and microglial-dependent processes, like synaptic pruning and the immune response, such as APOE, CLU and C1QA-C. All proteomics data are available via ProteomeXchange with identifier PXD025777.
Longitudinal epigenetic predictors of amygdala:hippocampus volume ratio.
Journal of child psychology and psychiatry, and allied disciplines, 2017

The ratio between amygdala:hippocampal (AH) volume has been associated with multiple psychiatric problems, including anxiety and aggression. Yet, little is known about its biological underpinnings. Here, we used a methylome-wide approach to test (a) whether DNA methylation in early life (birth, age 7) prospectively associates with total AH volume ratio in early adulthood, and (b) whether significant DNA methylation markers are influenced by prenatal risk factors.
Priority setting at the clinical level: the case of nusinersen and the Norwegian national expert group.
BMC medical ethics, 2021

Nusinersen is one of an increasing number of new, expensive orphan drugs to receive authorization. These drugs strain public healthcare budgets and challenge principles for resource allocation. Nusinersen was introduced in the Norwegian public healthcare system in 2018. A national expert group consisting of physicians was formed to oversee the introduction and continuation of treatment in light of specific start and stop criteria.
Finding prefrontal cortex in the rat.
Brain research, 2016

The prefrontal cortex of the rat. I. Cortical projection of the mediodorsal nucleus. II. Efferent connections The cortical projection field of the mediodorsal nucleus of the thalamus (MD) was identified in the rat using the Fink-Heimer silver technique for tracing degenerating fibers. Small stereotaxic lesions confined to MD were followed by terminal degeneration in the dorsal bank of the rhinal sulcus (sulcal cortex) and the medial wall of the hemisphere anterior and dorsal to the genu of the corpus callosum (medial cortex). No degenerating fibers were traced to the convexity of the hemisphere. The cortical formation receiving a projection from MD is of a relatively undifferentiated type which had been previously classified as juxtallocortex. A study of the efferent fiber connections of the rat׳s MD-projection cortex demonstrated some similarities to those of monkey prefrontal cortex. A substantial projection to the pretectal area and deep layers of the superior colliculus originates in medial cortex, a connection previously reported for caudal prefrontal (area 8) cortex in the monkey. Sulcal cortex projects to basal olfactory structures and lateral hypothalamus, as does orbital frontal cortex in the monkey. The rat׳s MD-projection cortex differs from that in the monkey in that it lacks a granular layer and appears to have no prominent direct associations with temporal and juxtahippocampal areas. Furthermore, retrograde degeneration does not appear in the rat thalamus after damage to MD-projection areas, suggesting that the striatum or thalamus receives a proportionally larger share of the MD-projection in this animal than it does in the monkey. Comparative behavioral investigations are in progress to investigate functional differences between granular prefrontal cortex in the primate and the relatively primitive MD-projection cortex in the rat. © 1969. This article is part of a Special Issue entitled SI:50th Anniversary Issue.
Network dysfunction in Alzheimer's disease: refining the disconnection hypothesis.
Brain connectivity, 2014

Much effort in recent years has focused on understanding the effects of Alzheimer's disease (AD) on neural function. This effort has resulted in an enormous number of papers describing different facets of the functional derangement seen in AD. A particularly important tool for these investigations has been resting-state functional connectivity. Attempts to comprehensively synthesize resting-state functional connectivity results have focused on the potential utility of functional connectivity as a biomarker for disease risk, disease staging, or prognosis. While these are all appropriate uses of this technique, the purpose of this review is to examine how functional connectivity disruptions inform our understanding of AD pathophysiology. Here, we examine the rationale and methodological considerations behind functional connectivity studies and then provide a critical review of the existing literature. In conclusion, we propose a hypothesis regarding the development and spread of functional connectivity deficits seen in AD.
The danger-associated molecular pattern HMGB1 mediates the neuroinflammatory effects of methamphetamine.
Brain, behavior, and immunity, 2016

Methamphetamine (METH) induces neuroinflammatory effects, which may contribute to the neurotoxicity of METH. However, the mechanism by which METH induces neuroinflammation has yet to be clarified. A considerable body of evidence suggests that METH induces cellular damage and distress, particularly in dopaminergic neurons. Damaged neurons release danger-associated molecular patterns (DAMPs) such as high mobility group box-1 (HMGB1), which induces pro-inflammatory effects. Therefore, we explored the notion here that METH induces neuroinflammation indirectly through the release of HMGB1 from damaged neurons. Adult male Sprague-Dawley rats were injected IP with METH (10mg/kg) or vehicle (0.9% saline). Neuroinflammatory effects of METH were measured in nucleus accumbens (NAcc), ventral tegmental area (VTA) and prefrontal cortex (PFC) at 2h, 4h and 6h after injection. To assess whether METH directly induces pro-inflammatory effects in microglia, whole brain or striatal microglia were isolated using a Percoll density gradient and exposed to METH (0, 0.1, 1, 10, 100, or 1000μM) for 24h and pro-inflammatory cytokines measured. The effect of METH on HMGB1 and IL-1β in striatal tissue was then measured. To determine the role of HMGB1 in the neuroinflammatory effects of METH, animals were injected intra-cisterna magna with the HMGB1 antagonist box A (10μg) or vehicle (sterile water). 24h post-injection, animals were injected IP with METH (10mg/kg) or vehicle (0.9% saline) and 4h later neuroinflammatory effects measured in NAcc, VTA, and PFC. METH induced robust pro-inflammatory effects in NAcc, VTA, and PFC as a function of time and pro-inflammatory analyte measured. In particular, METH induced profound effects on IL-1β in NAcc (2h) and PFC (2h and 4h). Exposure of microglia to METH in vitro failed to induce a pro-inflammatory response, but rather induced significant cell death as well as a decrease in IL-1β. METH treatment increased HMGB1 in parallel with IL-1β in striatum. Pre-treatment with the HMGB1 antagonist box A blocked the neuroinflammatory effects (IL-1β) of METH in NAcc, VTA and PFC. The present results suggest that HMGB1 mediates, in part, the neuroinflammatory effects of METH and thus may alert CNS innate immune cells to the toxic effects of METH.
Modulation of recognition memory performance by light requires both melanopsin and classical photoreceptors.
Proceedings. Biological sciences, 2016

Acute light exposure exerts various effects on physiology and behaviour. Although the effects of light on brain network activity in humans are well demonstrated, the effects of light on cognitive performance are inconclusive, with the size, as well as direction, of the effect depending on the nature of the task. Similarly, in nocturnal rodents, bright light can either facilitate or disrupt performance depending on the type of task employed. Crucially, it is unclear whether the effects of light on behavioural performance are mediated via the classical image-forming rods and cones or the melanopsin-expressing photosensitive retinal ganglion cells. Here, we investigate the modulatory effects of light on memory performance in mice using the spontaneous object recognition task. Importantly, we examine which photoreceptors are required to mediate the effects of light on memory performance. By using a cross-over design, we show that object recognition memory is disrupted when the test phase is conducted under a bright light (350 lux), regardless of the light level in the sample phase (10 or 350 lux), demonstrating that exposure to a bright light at the time of test, rather than at the time of encoding, impairs performance. Strikingly, the modulatory effect of light on memory performance is completely abolished in both melanopsin-deficient and rodless-coneless mice. Our findings provide direct evidence that melanopsin-driven and rod/cone-driven photoresponses are integrated in order to mediate the effect of light on memory performance.
Transcranial approach to pituitary adenomas invading the cavernous sinus: A modification of the classical technique to be used in a low-technology environment.
Surgical neurology international, 2010

Pituitary adenomas invading the cavernous sinus represent a therapeutic challenge. Those tumors have been traditionally treated with incomplete surgical removal, observation and/ or adjunctive medical therapy, and radiotherapy. In relatively recent years, some authors have suggested a main direct surgical approach to cavernous sinus (CS) with the aim of complete removal of the adenoma, either by a modified trans-sphenoidal route, using or not an endoscopy-assisted approach, or by a transcranial direct approach. The latter has the advantage of allowing direct exposure of the lesion with a view of the surgical field unhindered by important neurovascular structures.
Dystroglycan is a scaffold for extracellular axon guidance decisions.
eLife, 2019

Axon guidance requires interactions between extracellular signaling molecules and transmembrane receptors, but how appropriate context-dependent decisions are coordinated outside the cell remains unclear. Here we show that the transmembrane glycoprotein Dystroglycan interacts with a changing set of environmental cues that regulate the trajectories of extending axons throughout the mammalian brain and spinal cord. Dystroglycan operates primarily as an extracellular scaffold during axon guidance, as it functions non-cell autonomously and does not require signaling through its intracellular domain. We identify the transmembrane receptor Celsr3/Adgrc3 as a binding partner for Dystroglycan, and show that this interaction is critical for specific axon guidance events in vivo. These findings establish Dystroglycan as a multifunctional scaffold that coordinates extracellular matrix proteins, secreted cues, and transmembrane receptors to regulate axon guidance.
Learning to make external sensory stimulus predictions using internal correlations in populations of neurons.
Proceedings of the National Academy of Sciences of the United States of America, 2018

To compensate for sensory processing delays, the visual system must make predictions to ensure timely and appropriate behaviors. Recent work has found predictive information about the stimulus in neural populations early in vision processing, starting in the retina. However, to utilize this information, cells downstream must be able to read out the predictive information from the spiking activity of retinal ganglion cells. Here we investigate whether a downstream cell could learn efficient encoding of predictive information in its inputs from the correlations in the inputs themselves, in the absence of other instructive signals. We simulate learning driven by spiking activity recorded in salamander retina. We model a downstream cell as a binary neuron receiving a small group of weighted inputs and quantify the predictive information between activity in the binary neuron and future input. Input weights change according to spike timing-dependent learning rules during a training period. We characterize the readouts learned under spike timing-dependent synaptic update rules, finding that although the fixed points of learning dynamics are not associated with absolute optimal readouts they convey nearly all of the information conveyed by the optimal readout. Moreover, we find that learned perceptrons transmit position and velocity information of a moving-bar stimulus nearly as efficiently as optimal perceptrons. We conclude that predictive information is, in principle, readable from the perspective of downstream neurons in the absence of other inputs. This suggests an important role for feedforward prediction in sensory encoding.
Neurosilence: profound suppression of neural activity following intracerebral administration of the protein synthesis inhibitor anisomycin.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2012

Early in their formation, memories are thought to be labile, requiring a process called consolidation to give them near-permanent stability. Evidence for consolidation as an active and biologically separate mnemonic process has been established through posttraining manipulations of the brain that promote or disrupt subsequent retrieval. Consolidation is thought to be ultimately mediated via protein synthesis since translational inhibitors such as anisomycin disrupt subsequent memory when administered in a critical time window just following initial learning. However, when applied intracerebrally, they may induce additional neural disturbances. Here, we report that intrahippocampal microinfusions of anisomycin in urethane-anesthetized rats at dosages previously used in memory consolidation studies strongly suppressed (and in some cases abolished) spontaneous and evoked local field potentials (and associated extracellular current flow) as well as multiunit activity. These effects were not coupled to the production of pathological electrographic activity nor were they due to cell death. However, the amount of suppression was correlated with the degree of protein synthesis inhibition as measured by autoradiography and was also observed with cycloheximide, another translational inhibitor. Our results suggest that (1) the amnestic effects of protein synthesis inhibitors are confounded by neural silencing and that (2) intact protein synthesis is crucial for neural signaling itself.
The National ALS Registry: a recruitment tool for research.
Muscle & nerve, 2014

Subject recruitment is critical for understanding fatal diseases like ALS, however linking patients with researchers can be challenging. The U.S. population-based National ALS Registry allows recruitment of persons with ALS (PALS) for research opportunities.
Latent typologies of DSM-5 PTSD symptoms in U.S. military veterans.
Psychiatry research, 2019

Posttraumatic stress disorder (PTSD) is a heterogeneous condition that can be characterized by unique typologies of symptoms. To date, no study has examined predominant PTSD typologies using DSM-5 criteria. We used latent class analysis (LCA) to identify typologies of DSM-5 PTSD symptoms in 158 U.S. veterans who screened positive for this condition. A three-class solution provided the best fit to the data, described as Dysphoric (36.2%), High Symptom (34.0%) and Threat (29.8%). The Threat class had higher probabilities of intrusions and avoidance compared to the Dysphoric class; the Dysphoric class had higher probabilities of negative affect, anhedonia and externalizing behavior relative to Threat; the High Symptom class had high probabilities of all symptoms. Compared to the Threat class, the Dysphoric class was more likely to have a lifetime history of major depressive, alcohol and drug use disorders; the High Symptom class was more likely to have a lifetime history of alcohol, drug, and nicotine use disorder, current generalized anxiety, or to have attempted or currently contemplated suicide. The High Symptom class reported greater mental, physical and cognitive impairment and lower quality of life. These findings underscore the importance of a personalized approach to the assessment and treatment of DSM-5 PTSD.