Biology subjects

Reif, A.

Publications and source records attributed to Reif, A..

8 recordsLinked to original sources

bioRxiv2024

Impaired Visuospatial Working Memory but Preserved Attentional Control in Bipolar Disorder

BACKGROUNDPersistent deficits in working memory (WM) and attention have considerable clinical and functional impact in people with bipolar disorder (PBD). Understanding the neurocognitive underpinnings of these interacting cognitive constructs might facilitate the discovery of more effective pro-cognitive interventions. Therefore, we employed a paradigm designed for jointly studying attentional control and WM encoding. METHODSWe used a visuospatial change-detection task using four Gabor Patches with differing orientations in 63 euthymic PBD and 76 healthy controls (HCS), which investigated attentional competition during WM encoding. To manipulate bottom-up attention using stimulus salience, two Gabor patches flickered, which were designated as either targets or distractors. To manipulate top-down attention, the Gabor patches were preceded by either a predictive or a non-predictive cue for the target locations. RESULTSAcross all task conditions, PBD stored significantly less information in visual WM than HCS (significant effect of group). However, we observed no significant group by salience or group by cue interactions. This indicates that impaired WM was not caused by deficits in attentional control. CONCLUSIONSOur results imply that while WM is disturbed in PBD, attentional prioritization of salient targets and distractors as well as the utilization of external top-down cues were not compromised. Consequently, the control of attentional selection appears be intact. These findings provide important constraints for models of WM dysfunction in PBD by indicating that later stages of WM encoding are likely primarily impaired. We also demonstrate that selective attention is not among the main sources of cognitive impairment in PBD.

neuroscience↗

bioRxiv2023

Reduced discrimination between signals of danger and safety but not overgeneralization is linked to exposure to childhood adversity in healthy adults

Childhood adversity is a strong predictor of developing psychopathological conditions. Multiple theories on the mechanisms underlying this association have been suggested which, however, differ in the operationalization of exposure. Altered (threat) learning mechanisms represent central mechanisms by which environmental inputs shape emotional and cognitive processes and ultimately behavior. 1402 healthy participants underwent a fear conditioning paradigm (acquisition training, generalization), while acquiring skin conductance responses (SCRs) and ratings (arousal, valence, and contingency). Childhood adversity was operationalized as (1) dichotomization, and following (2) the specificity model, (3) the cumulative risk model, and (4) the dimensional model. Individuals exposed to childhood adversity showed blunted physiological reactivity in SCRs, but not ratings, and reduced CS+/CS-discrimination during both phases, mainly driven by attenuated CS + responding. The latter was evident across different operationalizations of exposure following the different theories. None of the theories tested showed clear explanatory superiority. Notably, a remarkably different pattern of increased responding to the CS-is reported in the literature for anxiety patients, suggesting that individuals exposed to childhood adversity may represent a specific sub-sample. We highlight that theories linking childhood adversity to (vulnerability to) psychopathology need refinement.

neuroscience↗

bioRxiv2021

Impaired and Intact Aspects of Attentional Competition and Prioritization during Visual Working Memory Encoding in Schizophrenia

BackgroundPeople with schizophrenia (PSZ) are impaired in attentional prioritization of non-salient but relevant stimuli over salient distractors during visual working memory (VWM) encoding. Conversely, guidance of top-down attention by external predictive cues is intact. Yet, it is unknown whether this preserved ability can help PSZ encode more information in the presence of salient distractors. MethodsWe employed a visuospatial change-detection task using four Gabor patches with differing orientations in 66 PSZ and 74 healthy controls (HCS). Two Gabor patches flickered which were designated either as targets or distractors and either a predictive or a non-predictive cue was displayed to manipulate top-down attention, resulting in four conditions. ResultsWe observed significant effects of group, salience and cue as well as significant interactions of salience by cue, group by salience and group by cue. Across all conditions, PSZ stored significantly less information in VWM than HCS. PSZ stored significantly less non-flickering than flickering information with a non-predictive cue. However, PSZ stored significantly more flickering and non-flickering information with a predictive cue. ConclusionsOur findings indicate that control of attentional selection is impaired in schizophrenia. We demonstrate that additional top-down information significantly improves performance in PSZ. The observed deficit in attentional control suggests a disturbance of GABAergic inhibition in early visual areas. Moreover, our findings are indicative of a mechanism for enhancing attentional control in PSZ, which could be utilized by pro-cognitive interventions. Thus, the current paradigm is suitable to reveal both preserved and compromised cognitive component processes in schizophrenia.

neuroscience↗

bioRxiv2021

A new chemoenzymatic semisynthetic approach provides novel insight into the role of phosphorylation beyond exon1 of Huntingtin and reveals N-terminal fragment length-dependent distinct mechanisms of aggregation

Huntingtons disease is a neurodegenerative disorder caused by the expansion of a polyglutamine (poly Q) repeat (>36Q) in the N-terminal domain of the huntingtin protein (Htt), which renders the protein or fragments thereof more prone to aggregate and form inclusions. Although several Htt N-terminal fragments of different lengths have been identified within Htt inclusions, most studies on the mechanisms, sequence, and structural determinants of Htt aggregation have focused on the Htt exon1 (Httex1). Herein, we investigated the aggregation properties of mutant N-terminal Htt fragments of various lengths (Htt171, Htt140, and Htt104) in comparison to mutant Httex1. We also present a new chemoenzymatic semisynthetic strategy that enables site-specific phosphorylation of Htt beyond Httex1. These advances yielded novel insights into how PTMs and structured domains beyond Httex1 influence aggregation mechanisms, kinetics, and fibril morphology of longer N-terminal Htt fragments. We demonstrate that phosphorylation at T107 significantly slowed its aggregation, whereases phosphorylation at T107 and S116 accelerated the aggregation of Htt171, underscoring the importance of crosstalk between different PTMs. We demonstrate that mutant Htt171 proteins aggregate via a different mechanism and form oligomers and fibrillar aggregates with morphological properties that are distinct from that of mutant Httex1. These observations suggest that different N-terminal fragments could have distinct mechanisms of aggregation and that a single polyQ-targeting anti-aggregation strategy may not effectively inhibit the aggregation of all N-terminal Htt fragments. Finally, our results underscore the importance of further studies to investigate the aggregation mechanisms of Htt fragments and how the various fragments interact with each other and influence Htt toxicity, pathology formation, and disease progression. Table of content O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=136 SRC="FIGDIR/small/436743v1_ufig1.gif" ALT="Figure 1"> View larger version (60K): org.highwire.dtl.DTLVardef@113aebborg.highwire.dtl.DTLVardef@1349236org.highwire.dtl.DTLVardef@6b273borg.highwire.dtl.DTLVardef@dcad5f_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2021

Improved correspondence of fMRI visual field localizer data after macroanatomical alignment

Studying the visual system with fMRI often requires using localizer paradigms to define regions of interest (ROIs). However, the considerable interindividual variability of the cerebral cortex represents a crucial confound for group-level analyses. Cortex-based alignment (CBA) techniques reliably reduce interindividual macroanatomical variability. Yet, their utility has not been assessed for visual field localizer paradigms, which map specific parts of the visual field within retinotopically organized visual areas. We evaluated CBA for an attention-enhanced visual field localizer mapping homologous parts of each visual quadrant in 50 participants. We compared CBA with volume-based alignment and a surface-based analysis, which did not include macroanatomical alignment. CBA led to the strongest increase in the probability of activation overlap (up to 40 percent). On the group level, CBA led to the most consistent increase in ROI size while preserving vertical ROI symmetry. Overall, our results indicate, that in addition to the increased signal-to-noise ratio of a surface-based analysis macroanatomical alignment considerably improves statistical power. These findings confirm and extend the utility of CBA for the study of the visual system in the context of group analyses. CBA should be particularly relevant when studying neuropsychiatric disorders with abnormally increased interindividual macroanatomical variability.

neuroscience↗

bioRxiv2020

Site-specific phosphorylation of Huntingtin exon 1 recombinant proteins enabled by the discovery of novel kinases

Posttranslational modifications (PTMs) within the first 17 amino acids (Nt17) of exon1 of the Huntingtin protein (Httex1) play important roles in modulating its cellular properties and functions in health and disease. In particular, phosphorylation of threonine and serine residues (T3, S13, and/or S16) has been shown to inhibit Htt aggregation in vitro and inclusion formation in cellular and animal models of Huntingtons disease (HD). In this manuscript, we describe a new and simple methodology for producing milligram quantities of highly pure wild type or mutant Httex1 proteins that are site-specifically phosphorylated at T3 or at both S13 and S16. This advance was enabled by 1) the discovery and validation of novel kinases that efficiently phosphorylate Httex1 at S13 and S16 (TBK1), at T3 (GCK) or T3 and S13 (TNIK and HGK); and, 2) the development of an efficient methodology for producing recombinant native Httex1 proteins using a SUMO-fusion expression and purification strategy. As proof of concept, we demonstrate how this method can be applied to produce Httex1 proteins that are both site- specifically phosphorylated and fluorescently labeled or isotopically labeled. Together, these advances should increase access to these valuable tools and expand the range of methods and experimental approaches that can be used to elucidate the mechanisms by which phosphorylation influences Httex1 structure, aggregation, interactome and function(s) in health and disease.

biochemistry↗

bioRxiv2019

The Role of Gene Encoding Variation of DRD4 in the Relationship between Inattention and Seasonal Daylight

Daylight is the strongest synchronizer of human circadian rhythms. The circadian pathway hypothesis posits that synchrony between daylight and the circadian system relates to (in)attention. The dopamine neurotransmitter system is implicated in regulating the circadian system as well as in (attention)-deficit hyperactivity disorder [ADHD]. We studied the role of functional genetic variation in the gene encoding of dopamine-receptor-D4 (DRD4) in the relationship between inattention and seasonal daylight (changes). Gene-by-environment (GxE) mega-analyses were performed across eight studies including 3757 adult participants (with and without ADHD). We tested 1) the Spring-focus hypothesis, in which attention in 7R-carriers normalizes with increasing daylight levels preceding measurement, 2) the Summer-born ADHD hypothesis, in which 7R-carriers report more inattention when born in spring/summer than in autumn/winter, 3) the Winter-born ADHD hypothesis, opposing the second hypothesis. The Spring-focus hypothesis was upheld (1386 ADHD, 760 controls; d=-0.16 between periods); 7R-carriers reported even less inattention than 7R-non-carriers after winter solstice (d=0.27 between genotype-groups). Results were diagnosis-independent. Sensitivity analyses at individual study level confirmed the circannual patterns for 7R-carriers. Incorporating geographic changes into the independent measure, we also calculated changes in sunlight levels. This approach likewise showed that inattention correlated negatively with increasing light levels in 7R-carriers (r=-.135). Results emphasize peripheral effects of dopamine and the effects of (seasonal) daylight changes on cognition.

genetics↗

bioRxiv2019

Cross-disorder genetic analyses implicate dopaminergic signaling as a biological link between Attention-Deficit/Hyperactivity Disorder and obesity measures

Attention-Deficit/Hyperactivity Disorder (ADHD) and obesity are frequently comorbid, genetically correlated, and share brain substrates. The biological mechanisms driving this association are unclear, but candidate systems, like dopaminergic neurotransmission and circadian rhythm, have been suggested. Our aim was to identify the biological mechanisms underpinning the genetic link between ADHD and obesity measures and investigate associations of overlapping genes with brain volumes. We tested the association of dopaminergic and circadian rhythm gene sets with ADHD, body mass index (BMI), and obesity (using GWAS data of N=53,293, N=681,275, and N=98,697, respectively). We then conducted genome-wide ADHD-BMI and ADHD-obesity gene-based meta-analyses, followed by pathway enrichment analyses. Finally, we tested the association of ADHD-BMI overlapping genes with brain volumes (primary GWAS data N=10,720-10,928; replication data N=9,428). The dopaminergic gene set was associated with both ADHD (P=5.81x10-3) and BMI (P=1.63x10-5), the circadian rhythm was associated with BMI (P=1.28x10-3). The genome-wide approach also implicated the dopaminergic system, as the Dopamine-DARPP32 Feedback in cAMP Signaling pathway was enriched in both ADHD-BMI and ADHD-obesity results. The ADHD-BMI overlapping genes were associated with putamen volume (P=7.7x10-3; replication data P=3.9x10-2) - a brain region with volumetric reductions in ADHD and BMI and linked to inhibitory control. Our findings suggest that dopaminergic neurotransmission, partially through DARPP-32-dependent signaling and involving the putamen, is a key player underlying the genetic overlap between ADHD and obesity measures. Uncovering shared etiological factors underlying the frequently observed ADHD-obesity comorbidity may have important implications in terms of prevention and/or efficient treatment of these conditions.

genetics↗