rudyvdbrink/CitationDatabase huggingface dataset:
Calcium-channel number critically influences synaptic strength and plasticity at the active zone.
Nature neuroscience, 2012

How synaptic-vesicle release is controlled at the basic release structure, the active zone, is poorly understood. By performing cell-attached current and capacitance recordings predominantly at single active zones in rat calyces, we found that single active zones contained 5-218 (mean, 42) calcium channels and 1-10 (mean, 5) readily releasable vesicles (RRVs) and released 0-5 vesicles during a 2-ms depolarization. Large variation in the number of calcium channels caused wide variation in release strength (measured during a 2-ms depolarization) by regulating the RRV release probability (P(RRV)) and the RRV number. Consequently, an action potential opened ∼1-35 (mean, ∼7) channels, resulting in different release probabilities at different active zones. As the number of calcium-channels determined P(RRV), it critically influenced whether subsequent release would be facilitated or depressed. Regulating calcium channel density at active zones may thus be a major mechanism to yield synapses with different release properties and plasticity. These findings may explain large differences reported at synapses regarding release strength (release of 0, 1 or multiple vesicles), P(RRV), short-term plasticity, calcium transients and the requisite calcium-channel number for triggering release.
Imaging the effects of age on proactive control in healthy adults.
Brain imaging and behavior, 2019

Previous research has reported reduced efficiency in reactive inhibition, along with reduced brain activations, in older adults. The current study investigated age-related behavioral and neural changes in proactive inhibition, and whether age may influence the relationship between proactive and reactive inhibition. One-hundred-and-forty-nine adults (18 to 72 years) underwent fMRI while performing a stop signal task (SST). Proactive inhibition was defined by the sequential effect, the correlation between the estimated probability of stop signal - p(Stop) - and go trial reaction time (goRT). P(Stop) was estimated trial by trial with a Bayesian belief model; reactive inhibition was defined by the stop signal reaction time (SSRT). Behaviorally the magnitude of sequential effect was not correlated with age, replicating earlier reports of spared proactive control in older adults. Age was associated with greater activations to p(Stop) in the lateral prefrontal cortex (PFC), paracentral lobule, superior parietal lobule, and cerebellum, and activations to goRT in the inferior occipital gyrus (IOG). Granger Causality analysis demonstrated that the PFC Granger caused IOG, with the PFC-IOG connectivity significantly correlated with p(Stop) in older but not younger adults. These findings suggest that the PFC and IOG activations and PFC-IOG connectivity may compensate for proactive control during aging. In contrast, while the activations of the ventromedial prefrontal cortex and caudate head to p(Stop) were negatively correlated with SSRT, relating proactive to reactive control, these activities did not vary with age. These findings highlighted distinct neural processes underlying proactive inhibition and limited neural plasticity to support cognitive control in the aging brain.
Menthol shares general anesthetic activity and sites of action on the GABA(A) receptor with the intravenous agent, propofol.
European journal of pharmacology, 2008

Menthol and related compounds were investigated for modulation of recombinant human gamma-aminobutyric acid type A (GABA(A), alpha(1)beta(2)gamma(2s)) receptor currents expressed in Xenopus oocytes. Sub-maximal (EC(20)) GABA currents were typically enhanced by co-applications of 3-300 microM (+)-menthol (e.g. by approximately 2-fold at 50 microM) > isopulegol > isomenthol> alpha-terpineol >> cyclohexanol. We studied menthol's actions on GABA(A) receptors compared to sedatives (benzodiazepines) and intravenous anesthetics (barbiturates, steroids, etomidate and propofol). Flumazenil (a benzodiazepine antagonist) did not inhibit menthol enhancements while currents directly activated by 50 microM propofol were significantly inhibited (by 26+/-3%) by 50 microM (+)-menthol. GABA(A) receptors containing beta(2) subunits with either a point mutation in a methionine residue to a tryptophan at the 286 position (in transmembrane domain 3, TM-3) or a tyrosine to a tryptophan at the 444 position (TM-4) are insensitive to modulation by propofol. Enhancements of GABA EC(20) currents by menthol were equally abolished in GABA(A) alpha(1)beta(2)(M286W)gamma(2s) and alpha(1)beta(2)(Y444W)gamma(2s) receptors while positive modulations by benzodiazepines, barbiturates and steroids were unaffected. Menthol may therefore exert its actions on GABA(A) receptors via sites distinct from benzodiazepines, steroids and barbiturates, and via sites important for modulation by propofol. Finally, using an in vivo tadpole assay, addition of (+)-menthol resulted in a loss of righting reflex with an EC(50) of 23.5+/-4.7 microM (approximately10-fold less potent anesthesia than propofol). Thus, menthol and analogs share general anesthetic action with propofol, possibly via action at similar sites on the GABA(A) receptor.
Structural and Functional Brain Abnormalities in Attention-Deficit/Hyperactivity Disorder and Obsessive-Compulsive Disorder: A Comparative Meta-analysis.
JAMA psychiatry, 2016

Patients with attention-deficit/hyperactivity disorder (ADHD) and obsessive-compulsive disorder (OCD) share impaired inhibitory control. However, it is unknown whether impairments are mediated by shared or disorder-specific neurostructural and neurofunctional abnormalities.
Using synchronized eye and motion tracking to determine high-precision eye-movement patterns during object-interaction tasks.
Journal of vision, 2018

This study explores the role that vision plays in sequential object interactions. We used a head-mounted eye tracker and upper-limb motion capture to quantify visual behavior while participants performed two standardized functional tasks. By simultaneously recording eye and motion tracking, we precisely segmented participants' visual data using the movement data, yielding a consistent and highly functionally resolved data set of real-world object-interaction tasks. Our results show that participants spend nearly the full duration of a trial fixating on objects relevant to the task, little time fixating on their own hand when reaching toward an object, and slightly more time-although still very little-fixating on the object in their hand when transporting it. A consistent spatial and temporal pattern of fixations was found across participants. In brief, participants fixate an object to be picked up at least half a second before their hand arrives at the object and stay fixated on the object until they begin to transport it, at which point they shift their fixation directly to the drop-off location of the object, where they stay fixated until the object is successfully released. This pattern provides additional evidence of a common system for the integration of vision and object interaction in humans, and is consistent with theoretical frameworks hypothesizing the distribution of attention to future action targets as part of eye and hand-movement preparation. Our results thus aid the understanding of visual attention allocation during planning of object interactions both inside and outside the field of view.
Cumulative activation of voltage-dependent KVS-1 potassium channels.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2008

In this study, we reveal the existence of a novel use-dependent phenomenon in potassium channels, which we refer to as cumulative activation (CA). CA consists of an increase in current amplitude in response to repetitive depolarizing step pulses to the same potential. CA persists for up to 20 s and is similar to a phenomenon called "voltage-dependent facilitation" observed in some calcium channels. The KVS-1 K+ channel, which exhibits CA, is a rapidly activating and inactivating voltage-dependent potassium channel expressed in chemosensory and other neurons of Caenorhabditis elegans. It is unusual in being most closely related to the Shab (Kv2) family of potassium channels, which typically behave like delayed rectifier K+ channels in other species. The magnitude of CA depends on the frequency, voltage, and duration of the depolarizing step pulse. CA also radically changes the activation and inactivation kinetics of the channel, suggesting that the channel may undergo a physical modification in a use-dependent manner; thus, a model that closely simulates the behavior of the channel postulates the existence of two populations of channels, unmodified and modified. Use-dependent changes in the behavior of potassium channels, such as CA observed in KVS-1, could be involved in functional mechanisms of cellular plasticity such as synaptic depression that represent the cellular basis of learning and memory.
Assessment of dosimetric and positioning accuracy of a magnetic resonance imaging-only solution for external beam radiotherapy of pelvic anatomy.
Physics and imaging in radiation oncology, 2019

The clinical feasibility of synthetic computed tomography (sCT) images derived from magnetic resonance imaging (MRI) images for external beam radiation therapy (EBRT) planning have been studied and adopted into clinical use recently. This paper evaluates the dosimetric and positioning performance of a sCT approach for different pelvic cancers.
Small effects of neck torsion on healthy human voluntary eye movements.
European journal of applied physiology, 2013

Although several lines of research suggest that the head and eye movement systems interact, previous studies have reported that applying static neck torsion does not affect smooth pursuit eye movements in healthy controls. This might be due to several methodological issues. Here we systematically investigated the effect of static neck torsion on smooth pursuit and saccadic eye movement behavior in healthy subjects.
Reaction time correlations during eye-hand coordination: behavior and modeling.
The Journal of neuroscience : the official journal of the Society for Neuroscience, 2011

During coordinated eye-hand movements, saccade reaction times (SRTs) and reach reaction times (RRTs) are correlated in humans and monkeys. Reaction times (RTs) measure the degree of movement preparation and can correlate with movement speed and accuracy. However, RTs can also reflect effector nonspecific influences, such as motivation and arousal. We use a combination of behavioral psychophysics and computational modeling to identify plausible mechanisms for correlations in SRTs and RRTs. To disambiguate nonspecific mechanisms from mechanisms specific to movement coordination, we introduce a dual-task paradigm in which a reach and a saccade are cued with a stimulus onset asynchrony (SOA). We then develop several variants of integrate-to-threshold models of RT, which postulate that responses are initiated when the neural activity encoding effector-specific movement preparation reaches a threshold. The integrator models formalize hypotheses about RT correlations and make predictions for how each RT should vary with SOA. To test these hypotheses, we trained three monkeys to perform the eye-hand SOA task and analyzed their SRTs and RRTs. In all three subjects, RT correlations decreased with increasing SOA duration. Additionally, mean SRT decreased with decreasing SOA, revealing facilitation of saccades with simultaneous reaches, as predicted by the model. These results are not consistent with the predictions of the models with common modulation or common input but are compatible with the predictions of a model with mutual excitation between two effector-specific integrators. We propose that RT correlations are not simply attributable to motivation and arousal and are a signature of coordination.
Implication of NOTCH1 gene in susceptibility to anxiety and depression among sexual abuse victims.
Translational psychiatry, 2016

Sexual abuse contributes to the development of multiple forms of psychopathology, including anxiety and depression, but the extent to which genetics contributes to these disorders among sexual abuse victims remains unclear. In this translational study, we first examined gene expression in the brains of rodents exposed to different early-life conditions (long, brief or no maternal separation). Hypothesizing that genes revealing changes in expression may have relevance for psychiatric symptoms later in life, we examined possible association of those genes with symptoms of anxiety and depression in a human sample of sexual abuse victims. Changes in rodent brain gene expression were evaluated by means of correspondence and significance analyses of microarrays by comparing brains of rodents exposed to different early-life conditions. Tag single-nucleotide polymorphisms (SNPs) of resulting candidate genes were genotyped and tested for their association with symptoms of anxiety and depression (Hospital Anxiety and Depression Scale) in a sample of 361 sexual abuse victims, using multinomial logistic regression. False discovery rate was applied to account for multiple testing in the genetic association study, with q-value of 0.05 accepted as significant. We identified four genes showing differential expression among animals subjected to different early-life conditions as well as having potential relevance to neural development or disorders: Notch1, Gabrr1, Plk5 and Zfp644. In the human sample, significant associations were observed for two NOTCH1 tag SNPs: rs11145770 (OR=2.21, q=0.043) and rs3013302 (OR=2.15, q=0.043). Our overall findings provide preliminary evidence that NOTCH1 may be implicated in the susceptibility to anxiety and depression among sexual abuse victims. The study also underscores the potential importance of animal models for future studies on the health consequences of early-life stress and the mechanisms underlying increased risk for psychiatric disorders.
Sonic hedgehog expressing and responding cells generate neuronal diversity in the medial amygdala.
Neural development, 2010

The mammalian amygdala is composed of two primary functional subdivisions, classified according to whether the major output projection of each nucleus is excitatory or inhibitory. The posterior dorsal and ventral subdivisions of the medial amygdala, which primarily contain inhibitory output neurons, modulate specific aspects of innate socio-sexual and aggressive behaviors. However, the development of the neuronal diversity of this complex and important structure remains to be fully elucidated.
TDP-43 regulates early-phase insulin secretion via CaV1.2-mediated exocytosis in islets.
The Journal of clinical investigation, 2019

TAR DNA-binding protein 43 kDa (TDP-43), encoded by TARDBP, is an RNA-binding protein, the nuclear depletion of which is the histopathological hallmark of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder affecting both upper and lower motor neurons. Besides motor symptoms, patients with ALS often develop nonneuronal signs including glucose intolerance, but the underlying pathomechanism is still controversial, i.e., whether it is impaired insulin secretion and/or insulin resistance. Here, we showed that ALS subjects reduced early-phase insulin secretion and that the nuclear localization of TDP-43 was lost in the islets of autopsied ALS pancreas. Loss of TDP-43 inhibited exocytosis by downregulating CaV1.2 calcium channels, thereby reducing early-phase insulin secretion in a cultured β cell line (MIN6) and β cell-specific Tardbp knockout mice. Overexpression of CaV1.2 restored early-phase insulin secretion in Tardbp knocked-down MIN6 cells. Our findings suggest that TDP-43 regulates cellular exocytosis mediated by L-type voltage-dependent calcium channels and thus plays an important role in the early phase of insulin secretion by pancreatic islets. Thus, nuclear loss of TDP-43 is implicated in not only the selective loss of motor neurons but also in glucose intolerance due to impaired insulin secretion at an early stage of ALS.
The prevalence and correlates of self-harm in pregnant women with psychotic disorder and bipolar disorder.
Archives of women's mental health, 2016

Women with severe mental illness are at increased risk of suicide in the perinatal period, and these suicides are often preceded by self-harm, but little is known about self-harm and its correlates in this population. This study aimed to investigate the prevalence of suicidal ideation and self-harm, and its correlates, in women with psychotic disorders and bipolar disorder during pregnancy. Historical cohort study using de-identified secondary mental healthcare records linked with national maternity data. Women pregnant from 2007 to 2011, with ICD-10 diagnoses of schizophrenia and related disorders, bipolar disorder or other affective psychoses were identified. Data were extracted from structured fields, natural language processing applications and free text. Logistic regression was used to examine the correlates of self-harm in pregnancy. Of 420 women, 103 (24.5 %) had a record of suicidal ideation during the first index pregnancy, with self-harm recorded in 33 (7.9 %). Self-harm was independently associated with younger age (adjusted odds ratio (aOR) 0.91, 95 % CI 0.85-0.98), self-harm in the previous 2 years (aOR 2.55; 1.05-6.50) and smoking (aOR 3.64; 1.30-10.19). A higher prevalence of self-harm was observed in women with non-affective psychosis, those who discontinued or switched medication and in women on no medication at the start of pregnancy, but these findings were not statistically significant in multivariable analyses. Suicidal thoughts and self-harm occur in a significant proportion of pregnant women with severe mental illness, particularly younger women and those with a history of self-harm; these women need particularly close monitoring for suicidality.
FGF17, a gene involved in cerebellar development, is downregulated in a patient with Dandy-Walker malformation carrying a de novo 8p deletion.
Neurogenetics, 2011

Fibroblast growth factors (FGFs) are important signaling molecules which act during early vertebrate central nervous system development. FGF17, together with FGF8, is a key factor in the patterning of the mid-hindbrain region with a complex picture of spatiotemporal gene expression during the various stages of cerebellar development. Disruption or reduced expression of fgf17 in mice has been associated with cerebellar vermis abnormalities. We have identified a de novo 2.3-Mb deletion of chromosome 8p21.2-p21.3 in a girl with severe growth retardation, seizures, and classical Dandy-Walker malformation. Analysis of gene expression in blood lymphocytes and skin fibroblasts revealed markedly reduced levels of FGF17, which is located 1 Mb from the proximal deletion breakpoint. This is the first report of a human cerebellar malformation associated with transcriptional downregulation of the FGF17 gene.
Neuronal Expression of UBQLN2
Molecular neurobiology, 2019

Mutations in the gene encoding ubiquilin-2 (UBQLN2) are linked to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). UBQLN2 plays a central role in ubiquitin proteasome system (UPS) and UBQLN2 up-regulation exacerbates TDP-43 cytoplasmic aggregates. To analyze interaction between UBQLN2 and TDP-43 and to produce a relevant ALS animal model, we have generated a new transgenic mouse expressing UBQLN2
Periodicity, repression, and the molecular architecture of the mammalian circadian clock.
The European journal of neuroscience, 2020

Large molecular machines regulate daily cycles of transcriptional activity and help generate rhythmic behavior. In recent years, structural and biochemical analyses have elucidated a number of principles guiding the interactions of proteins that form the basis of circadian timing. In its simplest form, the circadian clock is composed of a transcription/translation feedback loop. However, this description elides a complicated process of activator recruitment, chromatin decompaction, recruitment of coactivators, expression of repressors, formation of a repressive complex, repression of the activators, and ultimately degradation of the repressors and reinitiation of the cycle. Understanding the core principles underlying the clock requires careful examination of molecular and even atomic level details of these processes. Here, we review major structural and biochemical findings in circadian biology and make the argument that shared protein interfaces within the clockwork are critical for both the generation of rhythmicity and timing of the clock.
Who goes to treatment? Predictors of treatment initiation among gambling help-line callers.
The American journal on addictions, 2013

Although the consequences of problem gambling can be severe, few ever seek treatment for this disorder. Problem gambling help-lines represent a crucial point of entry into the treatment system. Through brief telephone counseling, help-lines have the potential of enhancing callers' motivations to engage in longer-term treatment. We prospectively examined treatment initiation and its predictors among individuals calling a state help-line.
Transformation of odor representations in target areas of the olfactory bulb.
Nature neuroscience, 2009

The brain generates coherent perceptions of objects from elementary sensory inputs. To examine how higher-order representations of smells arise from the activation of discrete combinations of glomeruli, we analyzed transformations of activity patterns between the zebrafish olfactory bulb and two of its telencephalic targets, Vv and Dp. Vv is subpallial whereas Dp is the homolog of olfactory cortex. Both areas lack an obvious topographic organization but perform complementary computations. Responses to different odors and their mixtures indicate that Vv neurons pool convergent inputs, resulting in broadened tuning curves and overlapping odor representations. Neuronal circuits in Dp, in contrast, produce a mixture of excitatory and inhibitory synaptic inputs to each neuron that controls action potential firing in an odor-dependent manner. This mechanism can extract information about combinations of molecular features from ensembles of active and inactive mitral cells, suggesting that pattern processing in Dp establishes representations of odor objects.
The Divider Assay is a high-throughput pipeline for aggression analysis in Drosophila.
Communications biology, 2021

Aggression is a complex social behavior that remains poorly understood. Drosophila has become a powerful model system to study the underlying biology of aggression but lack of high throughput screening and analysis continues to be a barrier for comprehensive mutant and circuit discovery. Here we developed the Divider Assay, a simplified experimental procedure to make aggression analysis in Drosophila fast and accurate. In contrast to existing methods, we can analyze aggression over long time intervals and in complete darkness. While aggression is reduced in the dark, flies are capable of intense fighting without seeing their opponent. Twenty-four-hour behavioral analysis showed a peak in fighting during the middle of the day, a drastic drop at night, followed by re-engagement with a further increase in aggression in anticipation of the next day. Our pipeline is easy to implement and will facilitate high throughput screening for mechanistic dissection of aggression.