Biology subjects

Peters, J.

Publications and source records attributed to Peters, J..

At least 73 records · Page 4Linked to original sources

bioRxiv2021

Online self-evaluation of fMRI-based neurofeedback performance

This study explores the subjective evaluation of supplementary motor area (SMA) regulation performance in a real-time functional magnetic resonance imaging neurofeedback (fMRI-NF) task. In fMRI-NF, people learn how to self-regulate their brain activity by performing mental actions to achieve a certain target level of blood-oxygen-level-dependent (BOLD) activation. This setup offers the possibility to study performance monitoring in the absence of somatosensory feedback. Here, we studied two types of self-evaluation expressed before receiving neurofeedback: performance predictions and perceived confidence in the prediction judgement. We hypothesized that throughout learning, participants would (1) improve the precision of their performance predictions about the actual changes in their BOLD response, and (2) that reported confidence would progressively increase with improved metacognitive precision. Participants completed three sessions of SMA regulation in a 7T fMRI scanner, performing a drawing motor imagery task. During each trial, they modulated their mental drawing strategy to achieve one of two different levels of target fMRI signal change. They then reported a performance prediction and their confidence in the prediction before receiving delayed BOLD-activation feedback. Results show that participants performance predictions improved with learning throughout the three sessions, and that these improvements were not driven exclusively by their knowledge of previous performance. Confidence reports on the other hand showed no change throughout training and did not differentiate between the better and worse predictions. In addition to shedding light on mechanisms of internal monitoring during neurofeedback training, these results also point to a dissociation between self-evaluation of performance and corresponding reported confidence in the presence of feedback.

neuroscience↗

bioRxiv2021

Chemogenetic Inhibition of Corticostriatal Circuits Reduces Cued Reinstatement of Methamphetamine Seeking

Methamphetamine (meth) causes enduring changes within the medial prefrontal cortex (mPFC) and the nucleus accumbens (NA). Projections from the mPFC to the NA have a distinct dorsal-ventral distribution, with the prelimbic (PL) mPFC projecting to the NAcore, and the infralimbic (IL) mPFC projecting to the NAshell. Inhibition of these circuits has opposing effects on cocaine relapse. Inhibition of PL-NAcore reduces cued reinstatement of cocaine seeking and IL-NAshell inhibition reinstates cocaine seeking. Meth, however, exhibits a different profile, as pharmacological inhibition of either the PL or IL decrease cued reinstatement of meth-seeking. The potentially opposing roles of the PL-NAcore and IL-NAshell projections remain to be explored in the context of cued meth seeking. Here we used an intersectional viral vector approach that employs a retrograde delivery of Cre from the NA and Cre-dependent expression of DREADD in the mPFC, in both male and female rats to inhibit or activate these parallel pathways. Inhibition of the PL-NAcore circuit reduced cued reinstatement of meth seeking under short and long-access meth self-administration and after withdrawal with and without extinction. Inhibition of the IL-NAshell also decreased meth cued reinstatement. Activation of the parallel circuits was without an effect. These studies show that inhibition of the PL-NAcore or the IL-NAshell circuits can inhibit reinstated meth seeking. Thus, the neural circuitry mediating cued reinstatement of meth seeking is similar to cocaine in the dorsal, but not ventral, mPFC-NA circuit.

neuroscience↗

bioRxiv2021

Trial-wise exposure to visual appetitive cues increases physiological arousal but not temporal discounting.

Humans and many animals devalue future rewards as a function of time (temporal discounting). Increased discounting has been linked to various psychiatric conditions, including substance-use-disorders, behavioral addictions and obesity. Despite its high intra-individual stability, temporal discounting is partly under contextual control. One prominent manipulation that has been linked to increases in discounting is the exposure to highly arousing appetitive cues. However, results from trial-wise cue exposure studies appear highly mixed, and changes in physiological arousal were not adequately controlled. Here we tested the effects of appetitive (erotic), aversive and neutral visual cues on temporal discounting in thirty-five healthy male participants. The contribution of single-trial physiological arousal was assessed using comprehensive monitoring of autonomic activity (pupil size, heart rate, electrodermal activity). Physiological arousal was elevated following aversive and in particular erotic cues. In contrast to our pre-registered hypothesis, if anything, we observed decreased temporal discounting following erotic cue exposure. Aversive cues tended to increase decision noise. Computational modeling revealed that trial-wise arousal only accounted for minor variance over and above aversive and erotic condition effects, arguing against a general effect of physiological arousal on temporal discounting.

neuroscience↗

bioRxiv2021

Gambling environment exposure increases temporal discounting but improves model-based control in regular slot-machine gamblers.

Gambling disorder is a behavioral addiction that negatively impacts personal finances, work, relationships and mental health. In this pre-registered study (https://osf.io/5ptz9/?view_only=62956a2afcd1495984db4be18c54b50a) we investigated the impact of real-life gambling environments on two computational markers of addiction, temporal discounting and model-based reinforcement learning. Gambling disorder is associated with increased temporal discounting and reduced model-based learning. Regular gamblers (n = 30, DSM-5 score range 3-9) performed both tasks in a neutral (cafe) and a gambling-related environment (slot-machine venue) in counterbalanced order. Data were modeled using drift diffusion models for temporal discounting and reinforcement learning via hierarchical Bayesian estimation. Replicating previous findings, gamblers discounted rewards more steeply in the gambling-related context. This effect was positively correlated with gambling related cognitive distortions (pre-registered analysis). In contrast to our pre-registered hypothesis, model-based reinforcement learning was improved in the gambling context. Here we show that temporal discounting and model-based reinforcement learning are modulated in opposite ways by real-life gambling cue exposure. Results challenge aspects of habit theories of addiction, and reveal that laboratory-based computational markers of psychopathology are under substantial contextual control.

neuroscience↗

bioRxiv2021

Human alveolar lining fluid from the elderly promotes Mycobacterium tuberculosis growth in alveolar epithelial cells and bacterial translocation into the cytosol

The elderly population is at significant risk of developing respiratory diseases, including tuberculosis (TB) caused by the airborne Mycobacterium tuberculosis (M.tb). Once M.tb reaches the alveolar space, it contacts alveolar lining fluid (ALF) which dictates host cell interactions. We previously determined that age-associated dysfunctionality in human ALF soluble innate components lead to accelerated M.tb growth within human alveolar macrophages. Here we determined the impact of human ALF on M.tb infection of alveolar epithelial cells (ATs), another critical cellular determinant of infection. We observed that E-ALF-exposed M.tb had significantly increased intracellular growth in ATs compared to adult ALF (A-ALF)-exposed bacteria. Despite this, there were no alterations in AT inflammatory mediators or cell activation. However, exposure to E-ALF altered endosomal trafficking of M.tb, driving bacterial translocation to both endosomal and cytosolic compartments in ATs. Our results indicate that exposure of M.tb to E-ALF promotes translocation of bacteria into the AT cytosol as a potential favorable niche for rapid bacterial growth and at the same time dampens ATs immune responses. Thus, our findings highlight the influence of the elderly lung mucosa on M.tb infection of ATs, an unexplored contributing factor to the elderly populations increased susceptibility of developing active TB disease.

immunology↗

bioRxiv2021

Testing hypotheses of marsupial brain size variation using phylogenetic multiple imputations and a Bayesian comparative framework

Considerable controversy exists about which hypotheses and variables best explain mammalian brain size variation. We use a new, high-coverage dataset of marsupial brain and body sizes, and the first phylogenetically imputed full datasets of 16 predictor variables, to model the prevalent hypotheses explaining brain size evolution using phylogenetically corrected Bayesian generalised linear mixed-effects modelling. Despite this comprehensive analysis, litter size emerges as the only significant predictor. Marsupials differ from the more frequently studied placentals in displaying much lower diversity of reproductive traits, which are known to interact extensively with many behavioural and ecological predictors of brain size. Our results therefore suggest that studies of relative brain size evolution in placental mammals may require targeted co-analysis or adjustment of reproductive parameters like litter size, weaning age, or gestation length. This supports suggestions that significant associations between behavioural or ecological variables with relative brain size may be due to a confounding influence of the extensive reproductive diversity of placental mammals.

evolutionary biology↗

bioRxiv2020

Human hippocampal neurons track moments in a sequence of events.

An indispensable feature of episodic memory is our ability to temporally piece together different elements of an experience into a coherent memory. Hippocampal "time cells" - neurons that represent temporal information - may play a critical role in this process. While these cells have been repeatedly found in rodents, it is still unclear to what extent similar temporal selectivity exists in the human hippocampus. Here we show that temporal context modulates the firing activity of human hippocampal neurons during structured temporal experiences. We recorded neuronal activity in the human brain while patients learned predictable sequences of pictures. We report that human time cells fire at successive moments in this task. Furthermore, time cells also signaled inherently changing temporal contexts during empty 10-second gap periods between trials, while participants waited for the task to resume. Finally, population activity allowed for decoding temporal epoch identity, both during sequence learning and during the gap periods. These findings suggest that human hippocampal neurons could play an essential role in temporally organizing distinct moments of an experience in episodic memory. Significance StatementEpisodic memory refers to our ability to remember the "what, where, and when" of a past experience. Representing time is an important component of this form of memory. Here, we show that neurons in the human hippocampus represent temporal information. This temporal signature was observed both when participants were actively engaged in a memory task, as well as during 10s-long gaps when they were asked to wait before performing the task. Furthermore, the activity of the population of hippocampal cells allowed for decoding one temporal epoch from another. These results suggest a robust representation of time in the human hippocampus.

neuroscience↗

bioRxiv2020

Chronic deep brain stimulation of the human nucleus accumbens region disrupts the stability of inter-temporal preferences.

When choosing between rewards that differ in temporal proximity (inter-temporal choice), human preferences are typically stable, constituting a clinically-relevant transdiagnostic trait. Here we show in patients undergoing deep brain stimulation (DBS) of the anterior limb of the internal capsule / nucleus accumbens region for treatment-resistant obsessivecompulsive disorder (OCD), that long-term chronic (but not phasic) DBS disrupts inter-temporal preferences. Hierarchical Bayesian modeling accounting for temporal discounting behavior across multiple time points allowed us to assess both short-term and long-term reliability of inter-temporal choice. In controls, temporal discounting was highly reliable, both long-term (6 months) and short-term (1 week). In contrast, in patients undergoing DBS, short-term reliability was high, but long-term reliability (6 months) was severely disrupted. Control analyses confirmed that this effect was not due to range restriction, the presence of OCD symptoms or group differences in choice stochasticity. Model-agnostic between- and within-subject analyses confirmed this effect. These findings provide initial evidence for long-term modulation of cognitive function via DBS and highlight a potential contribution of the human nucleus accumbens region to inter-temporal preference stability over time. Significance StatementChoosing between rewards that differ in temporal proximity is in part a stable trait with relevance for many mental disorders, and depends on prefrontal regions and regions of the dopamine system. Here we show that chronic deep brain stimulation (DBS) of the human anterior limb of the internal capsule / nucleus accumbens region for treatment-resistant obsessive compulsive disorder disrupts the stability of inter-temporal preferences. These findings show that chronic stimulation of one of the brains central motivational hubs can disrupt preferences thought to depend on this circuit.

neuroscience↗

bioRxiv2020

The mixed genetic origin of the first farmers of Europe

The precise genetic origins of the first Neolithic farming populations, as well as the processes and the timing of their differentiation, remain largely unknown. Based on demogenomic modeling of high-quality ancient genomes, we show that the early farmers of Anatolia and Europe emerged from a multiphase mixing of a Near Eastern population with a strongly bottlenecked Western hunter-gatherer population after the Last Glacial Maximum. Moreover, the population branch leading to the first farmers of Europe and Anatolia is characterized by a 2,500-year period of extreme genetic drift during its westward range expansion. Based on these findings, we derive a spatially explicit model of the population history of Southwest Asia and Europe during the late Pleistocene and early Holocene. One-Sentence SummaryEarly European farmers emerged from multiple post LGM mixtures and experienced extreme drift during their westward expansion.

evolutionary biology↗

bioRxiv2020

Human-specific ARHGAP11B is necessary and sufficient for human-type basal progenitor levels in primate brain organoids

Based on studies in various animal models, including developing ferret neocortex (Kalebic et al., 2018), the human-specific gene ARHGAP11B has been implicated in human neocortex expansion. However, the extent of its contribution to this expansion during primate evolution is unknown. Here we addressed this issue by genetic manipulation of ARHGAP11B levels and function in chimpanzee and human cerebral organoids. Interference with ARHGAP11Bs function in human cerebral organoids caused a massive decrease, down to a chimpanzee level, in the proliferation and abundance of basal progenitors, the progenitors thought to have a key role in neocortex expansion. Conversely, ARHGAP11B expression in chimpanzee cerebral organoids resulted in a doubling of cycling basal progenitors. Taken together, our findings demonstrate that ARHGAP11B is necessary and sufficient to maintain the elevated basal progenitor levels that characterize the fetal human neocortex, suggesting that this human-specific gene was a major contributor to neocortex expansion during human evolution.

developmental biology↗

bioRxiv2020

A Virtual Reality setup for the combined assessment of behavioral and psychophysiological cue-reactivity in gambling disorder

In recent years the emergence of high-performance virtual reality (VR) technology has opened up new possibilities for the examination of context effects in psychological studies. The opportunity to create ecologically valid stimulation in a highly controlled lab environment is especially relevant for studies of psychiatric disorders, where it can be problematic to confront participants with certain stimuli in real life. However, before VR can be confidently applied widely it is important to establish that commonly used behavioral tasks generate reliable data within a VR surrounding. One field of research that could benefit greatly from VR-applications are studies assessing the reactivity to addiction related cues (cue-reactivity) in participants suffering from gambling disorder. Here we tested the reliability of a commonly used temporal discounting task in a novel VR set-up designed for the concurrent assessment of behavioral and psychophysiological cue-reactivity in gambling disorder. On two days, thirty-four healthy non-gambling participants explored two rich and navigable VR-environments (neutral: cafe vs. gambling-related: casino and sports-betting facility), while their electrodermal activity was measured using remote sensors. In addition, participants completed the temporal discounting task implemented in each VR environment. On a third day, participants performed the task in a standard lab testing context. We then used comprehensive computational modeling using both standard softmax and drift diffusion model (DDM) choice rules to assess the reliability of discounting model parameters assessed in VR. Test-retest reliability estimates were good to excellent for the discount rate log(k), whereas they were poor to moderate for additional DDM parameters. Differences in model parameters between standard lab testing and VR, reflecting reactivity to the different environments, were mostly numerically small and of inconclusive directionality. Finally, while exposure to VR generally increased tonic skin conductance, this effect was not modulated by the neutral vs. gambling-related VR-environment. Taken together this proof-of- concept study in non-gambling participants demonstrates that temporal discounting measures obtained in VR are reliable, suggesting that VR is a promising tool for applications in computational psychiatry, including studies on cue-reactivity in addiction.

neuroscience↗

bioRxiv2020

Characterization of gene repression by designed transcription activator-like effector dimer proteins

Gene regulation by control of transcription initiation is a fundamental property of living cells. Much of our understanding of gene repression originated from studies of the E. coli lac operon switch, where DNA looping plays an essential role. To validate and generalize principles from lac for practical applications, we previously described artificial DNA looping driven by designed Transcription Activator-Like Effector Dimer (TALED) proteins. Because TALE monomers bind the idealized symmetrical lac operator sequence in two orientations, our prior studies detected repression due to multiple DNA loops. We now quantitatively characterize gene repression in living E. coli by a collection of individual TALED loops with systematic loop length variation. Fitting of a thermodynamic model allows unequivocal demonstration of looping and comparison of the engineered TALED repression system with the natural lac repressor system. Statement of SignificanceWe are designing and testing in living bacteria artificial DNA looping proteins engineered based on principles learned from studies of the E. coli lac repressor. The engineered proteins are based on artificial dimers of Transcription Activator-Like Effector (TALE) proteins that have programmable DNA binding specificities. The current work is the first to create unique DNA repression loops using this approach. Systematic study of repression as a function of loop size, with data fitting to a thermodynamic model, now allows this system to be compared in detail with lac repressor loops, and relevant biophysical parameters to be estimated. This approach has implications for the artificial regulation of gene expression.

biophysics↗

bioRxiv2020

Diffusion modeling reveals reinforcement learning impairments in gambling disorder that are linked to attenuated ventromedial prefrontal cortex value representations.

Gambling disorder is associated with deficits in feedback-based learning tasks, but the computational mechanisms underlying these learning impairments are still poorly understood. Here, we examined this question using a combination of computational modeling and functional resonance imaging (fMRI) in individuals that regular participate in gambling (n=23, seven fulfilled 1-3 DSM 5 criteria, sixteen fulfilled 4 or more) and matched controls (n=23). Participants performed a stationary reinforcement learning task with two pairs of stimuli (80% vs. 20% reinforcement rates per pair). As predicted, the gambling group made significantly fewer selections of the optimal stimulus, while overall response times (RTs) were not significantly different between groups. We then used comprehensive modeling using reinforcement learning drift diffusion models (RLDDMs) in combination with hierarchical Bayesian parameter estimation to shed light on the computational underpinnings of this performance impairment. In both groups, an RLDDM in which both non-decision time and response threshold (boundary separation) changed over the course of the experiment accounted for the data best. The model showed good parameter and model recovery, and posterior predictive checks revealed that in both groups, the model reproduced the evolution of both accuracy and RTs over time. The learning impairment in the gambling group was attributable to a more rapid reduction in boundary separation over time, and a reduced effect of value-differences on the drift rate, compared to controls. The gambling group also exhibted substantially shorter non-decision times. Imaging analyses replicated earlier effects of prediction error coding in the ventral striatum and value coding in the ventro-medial prefrontal cortex, but there was no credible evidence for group differences in these regions. Taken together, our findings highlight the computational mechanisms underlying reinforcement learning impairments in gambling disorder.

neuroscience↗

bioRxiv2020

Genomic evaluation of circulating proteins for drug target characterisation and precision medicine

Circulating proteins are vital in human health and disease and are frequently used as biomarkers for clinical decision-making or as targets for pharmacological intervention. By mapping and replicating protein quantitative trait loci (pQTL) for 90 cardiovascular proteins in over 30,000 individuals, we identified 467 pQTLs for 85 proteins. The pQTLs were used in combination with other sources of information to evaluate known drug targets, and suggest new target candidates or repositioning opportunities, underpinned by a) causality assessment using Mendelian randomization, b) pathway mapping using trans-pQTL gene assignments, and c) protein-centric polygenic risk scores enabling matching of plausible target mechanisms to sub-groups of individuals enabling precision medicine.

genetics↗

bioRxiv2020

Expression of a transcript encoding for cytosolic renin in the diseased human heart

Secretory renin promotes hypertrophy, apoptosis, necrosis and fibrosis through angiotensin generation. It has been claimed that local expression of renin contributes to the deleterious effects of the renin-angiotensin system in the heart. Besides the classic renin transcript (renin-a), encoding for secretory renin, a putative brain-specific (renin-b) and a putative lung-specific (renin-c) transcript may exist in human. In contrast to secretory renin, renin-b cannot be secreted, remains within the cytosol and is imported into mitochondria. In contradiction to renin-a, renin-b exerts cardioprotective effects in hearts and in cardiac cells of the rat under ischemia related conditions. To date, available data on cardiac renin expression remain inconsistent. Nobody has yet investigated which renin transcripts are expressed in the human heart. We systematically analyzed the levels of renin transcripts using specific and sensitive nested reverse-transcriptase polymerase chain reactions (RT-PCR) in human ventricular biopsies obtained from patients with heart diseases. In the 33 biopsies available, neither the expression of classic renin-a, nor of the alternative renin-c was detected. In contrast, the renin-b transcript, which was previously classified as brain-specific, was found in 11/33 ventricular biopsies. Our data exclude the expression of secretory renin and indicate that local expression of cytosolic renin but not of secretory renin can play a functional role in the human heart.

physiology↗

bioRxiv2020

Effects of episodic future thinking on temporal discounting: a re-analysis of six data sets using hierarchical Bayesian parameter estimation and compilation of effect sizes

Temporal discounting refers to the tendency of humans and many animals to devalue rewards as a function of time. Steep discounting of value over time is associated with a range of psychiatric disorders, including substance use disorders and behavioral addictions, and therefore of potentially high clinical relevance. One cognitive factor that has repeatedly been shown to reduce temporal discounting in humans is episodic future thinking, the process of vividly imagining future outcomes, which has been linked to hippocampal mechanisms in a number of studies. However, the analytical approaches used to quantify the behavioral effects have varied between studies, which complicates a direct comparison of the obtained effect sizes. Here we re-analyzed temporal discounting data from previously published functional magnetic resonance imaging (fMRI) and behavioral studies (six data sets from five papers, n=204 participants in total) using an identical model structure and hierarchical Bayesian parameter estimation procedure. Analyses confirmed that engagement in episodic future thinking leads to robust and and consistent reductions in temporal discounting with on average medium effect sizes. In contrast, effects on choice consistency (decision noise) where small and with inconsistent directionality. We provide standardized and unstandardized effect size estimates for each data set and discuss clinical implications as well as issues of hierarchical Bayesian parameter estimation.

neuroscience↗

bioRxiv2020

Dissection of prostate tumour, stroma and immune transcription reveals a key contribution by the microenvironment to disease progression

Prostate cancer is caused by genomic aberrations in normal epithelial cells, however clinical translation of findings from analyses of cancer cells alone has been very limited. A deeper understanding of the tumour microenvironment is needed to identify the key drivers of disease progression and reveal novel therapeutic opportunities. In this study, the experimental enrichment of selected cell-types and the development of a Bayesian inference model for continuous differential transcript abundance permitted us to define the transcriptional landscape of the prostate cancer microenvironment along the disease progression axis. An important role of monocytes and macrophages in prostate cancer progression and disease recurrence was uncovered, supported by both transcriptional landscape findings and by differential tissue composition analyses. These findings were corroborated and validated by spatial analyses at the single-cell level using multiplex immunohistochemistry. This study advances our knowledge concerning the role of monocyte-derived recruitment in primary prostate cancer, and supports their key role in disease progression, patient survival and prostate microenvironment immune modulation.

cancer biology↗

bioRxiv2020

QUATERNIONIC ASSESSMENT OF EEG TRACES ON NERVOUS MULTIDIMENSIONAL HYPERSPHERES

The nervous activity of the brain takes place in higher-dimensional functional spaces. Indeed, recent claims advocate that the brain might be equipped with a phase space displaying four spatial dimensions plus time, instead of the classical three plus time. This suggests the possibility to investigate global visualization methods for exploiting four-dimensional maps of real experimental data sets. Here we asked whether, starting from the conventional neuro-data available in three dimensions plus time, it is feasible to find an operational procedure to describe the corresponding four-dimensional trajectories. In particular, we used quaternion orthographic projections for the assessment of electroencephalographic traces (EEG) from scalp locations. This approach makes it possible to map three-dimensional EEG traces to the surface of a four-dimensional hypersphere, which has an important advantage, since quaternionic networks make it feasible to enlighten temporally far apart nervous trajectories equipped with the same features, such as the same frequency or amplitude of electric oscillations. This leads to an incisive operational assessment of symmetries, dualities and matching descriptions hidden in the very structure of complex neuro-data signals.

neuroscience↗