Biology subjects

Thiele, A.

Publications and source records attributed to Thiele, A..

18 recordsLinked to original sources

bioRxiv2026

Working memory limitations and dopamine modulation in probabilistic reasoning

Difficult decisions require gathering evidence over extended periods, placing demands on working memory. Yet, how working memory limitations affect decision-making remains largely unknown. We trained two macaque monkeys to perform a probabilistic reasoning task that involved extended sequential evidence sampling, requiring reliance on working memory. Monkeys made choices informed by a stream of briefly presented cues, each providing probabilistic evidence about which choice would be rewarded. In both animals, choices were significantly affected by working memory decay, primacy, recency, and priming. Despite individual differences in working memory limitations, both monkeys adopted sampling strategies that made their behavior nearly optimal. To test how dopamine affects working memory constraints on evidence accumulation, we systemically applied dopamine D1 receptor agonist and antagonist drugs midway during selected sessions. Activation of D1 receptors reduced priming. Blockade of D1 receptors reduced working memory decay and the subjective evidence weights assigned to individual cues. Our results reveal that complex decisions are constrained by working memory limitations and identify dopamine as a key modulator of this process, with potential implications for cognitive disorders and their treatment.

neuroscience↗

bioRxiv2026

Kidney disease reprograms microbiome-host signaling to promote heart failure

BackgroundHeart failure is prevalent in chronic kidney disease (CKD) and linked to chronic inflammation. CKD-typical gut microbiome dysbiosis may stimulate inflammation, as bacterial aromatic metabolites are highly abundant and engage transcriptional programs through the aryl hydrocarbon receptor (AhR). Whether this axis drives cardiac remodeling and is therapeutically targetable remains unknown. MethodsWe used the subtotal nephrectomy model (STNx) and microbiome depletion by oral antibiotics. We investigated cardiac and renal function, AhR activity, metabolite profiles, and immunophenotypes by flow cytometry and transcriptomics. Candidate metabolite indoxyl sulfate (IxS) was tested in experimental HFpEF. In vivo and in vitro AhR inhibition (AhRi) was performed using a clinically tested compound. Mechanistic studies were performed in primary human and murine cardiac fibroblasts and T cells, as well as translational validation using UK Biobank data. ResultsMicrobiome depletion lowered bacterial metabolites and attenuated cardiac fibrosis and diastolic dysfunction in STNx, identifying AhR-driven expansion of interleukin-17A (IL-17A)-producing T helper cells (TH17) as key effector. Plasma IL-17A was stage-dependently elevated in CKD patients, particularly in HFpEF, and associated with all-cause mortality. Bacterial metabolite IxS promoted TH17 polarization and exacerbated cardiac dysfunction in HFpEF. AhRi using a small molecule inhibitor reduced TH17 abundance and attenuated cardiac fibrosis in STNx. Mechanistically, AhR and IL-17A signaling synergistically induced a conserved pro-fibrotic phenotype in human and murine cardiac fibroblasts, and AhR inhibition blocked ECM production in response to CKD patient serum. ConclusionA microbiome-AhR-IL-17A axis drives CKD-associated cardiac fibrosis. AhRi prevents remodeling, highlighting a potential therapeutic avenue to prevent cardiorenal multimorbidity.

immunology↗

bioRxiv2025

Interleukin-17A Mediates Cardiorenal Injury In Oxalate Nephropathy

AimsCardiovascular disease (CVD) is the leading cause of mortality in chronic kidney disease (CKD). While CKD is known to give rise to systemic inflammation, its inciting factors remain poorly defined. Oxalate, long implicated in rare genetic kidney disorders, accumulates with decreased kidney function and has emerged as a driver of inflammation and independent risk factor for CVD. Here, we investigate the immunological mechanisms linking oxalate nephropathy to systemic inflammation, cardiac damage and kidney injury. Methods and ResultsOxalate nephropathy was induced in C57Bl6/N mice via an oxalate-enriched diet. Oxalate induced systemic immune activation, renal fibrosis, and cardiac remodeling, including pulmonary congestion with systolic and diastolic dysfunction. Flow cytometry analysis identified interleukin (IL)-17A as a dominant inflammatory effector, with expansion of Th17 and Th17-like Treg in the kidney, intestine, and spleen. Bulk mRNA sequencing confirmed these findings. Confirming the oxalate-IL-17A relationship, plasma IL-17A was elevated in patients with primary hyperoxaluria. Gut microbiome analysis by 16S amplicon sequencing showed only mild oxalate-induced alterations in mice. However, soluble oxalate directly enhanced Th17 polarization and disrupted mitochondrial respiration in vitro. In vivo, antibody-mediated (clone: 17F3) IL-17A blockade decreased cardiac fibrosis, reduced neutrophil infiltration, and partially restored cardiac function in oxalate-fed mice. ConclusionsOur study identifies oxalate as a systemic immunometabolic stressor and IL-17A as a central mediator of oxalate-induced cardiorenal injury. These findings establish the oxalate-IL-17A axis as a mechanistic link between CKD and CVD and suggest IL-17A inhibition as a potential therapeutic strategy to reduce cardiovascular damage in CKD. Translational PerspectiveThis study advances our understanding of targetable mediators of the cardiovascular risk in chronic kidney disease (CKD). We identify the organic anion oxalate, beyond its traditional role in crystal-induced kidney damage, as a systemic immunometabolic stressor. We demonstrate that oxalate induces IL-17A-mediated inflammation and thereby contributes to maladaptive cardiac remodeling. Therapeutic blockade of IL-17A protects against oxalate-induced cardiorenal injury, highlighting the oxalate-IL-17A axis as a relevant and druggable link between CKD and cardiovascular disease.

immunology↗

bioRxiv2025

Effect of fluid control on the affective state of laboratory macaques

Fluid control protocols are widely used in neuroscience to motivate laboratory macaques to engage with behavioural tasks. Despite strong evidence that the physiology of the animals is not compromised by such protocols, fluid control remains controversial due to its potential impact on the psychological well-being of the animals. To address this concern, we investigated the effect of fluid control on the affective state of 23 socially-housed adult macaques (10 females) engaged in neuroscience experiments. The protocol involved up to five consecutive days of fluid control per week, followed by a minimum of two days with unrestricted fluid access. The affective state of the animals was primarily assessed by quantifying the frequency of pharmacologically-validated behavioural indicators of high-arousal negative affect (self-scratching, body shaking, self-grooming). The analysis was subsequently extended to validated behavioural indicators of low-arousal negative affect (Inactive not alert) and other behaviours suspected of indicate high-arousal negative affect but lacking proper validation (pacing, yawning). In total, 700 hours of video footage spanning up to seven years of intermittent fluid control per animal were analysed. Despite this extensive dataset, the study found no significant impact of fluid control on average, or any evidence of habituation or sensitization over the years on any of the affective state indicators. Additional results indicate that these null results are not due to a lack of sensitivity, supporting the view that fluid control, as implemented in this study, does not have an adverse impact on the psychological well-being of laboratory macaques. We argue that macaque welfare will be best served by focusing future refinement on other procedures.

animal behavior and cognition↗

bioRxiv2025

Population coupling of V1 and V4 neurons and its relation to local cortical state fluctuations and attention in macaque monkey

Neurons couple to various degrees to the activity level of the local neighboring population whereby strongly coupled choristers and weakly coupled soloists have been identified as two extremes of a continuous spectrum. At the same time neuronal populations undergo coordinated ON and OFF cortical state activity fluctuations, which are locally modulated by attention. The population coupling of soloists and choristers suggests that soloists should show limited alignment with cortical state fluctuations, while choristers should exhibit profound alignment. To test this, we recorded neurons across cortical layers in macaque areas V1 and V4, while animals performed a feature based spatial attention task. As expected, we found a wide range of population coupling strength of neurons. In line with our prediction, coupling of choristers to cortical state changes (ON-OFF transitions) was generally stronger than that of soloists. The strength of population coupling of neurons was similar during spontaneous and stimulus driven activity. Allocation of attention to the receptive field reduced the population coupling strength. Attentional modulation of neurons was positively correlated with population coupling strength. While neurons on average retained their coupling strengths across conditions, some neurons change coupling strength condition dependent, thereby potentially enhancing the coding abilities of cortical circuits.

neuroscience↗

bioRxiv2024

Brain Charts for the Rhesus Macaque Lifespan

Recent efforts to chart human brain growth across the lifespan using large-scale MRI data have provided reference standards for human brain development. However, similar models for nonhuman primate (NHP) growth are lacking. The rhesus macaque, a widely used NHP in translational neuroscience due to its similarities in brain anatomy, phylogenetics, cognitive, and social behaviors to humans, serves as an ideal NHP model. This study aimed to create normative growth charts for brain structure across the macaque lifespan, enhancing our understanding of neurodevelopment and aging, and facilitating cross-species translational research. Leveraging data from the PRIMatE Data Exchange (PRIME-DE) and other sources, we aggregated 1,522 MRI scans from 1,024 rhesus macaques. We mapped non-linear developmental trajectories for global and regional brain structural changes in volume, cortical thickness, and surface area over the lifespan. Our findings provided normative charts with centile scores for macaque brain structures and revealed key developmental milestones from prenatal stages to aging, highlighting both species-specific and comparable brain maturation patterns between macaques and humans. The charts offer a valuable resource for future NHP studies, particularly those with small sample sizes. Furthermore, the interactive open resource (https://interspeciesmap.childmind.org) supports cross-species comparisons to advance translational neuroscience research.

neuroscience↗

bioRxiv2024

Effect of muscarinic blockade on the speed of attention shifting and learning

The study aimed to investigate to what extent blockade of muscarinic receptors affects the speed of endogenous versus exogenous attentional shift times, and how it affects learning induced improvements of attention shift times. Subjects viewed an array of 10 moving clocks and reported the time a clock indicated when cued. Target clocks were indicated by peripheral or central cues, including conditions of pre-cuing. This allowed assessing shift times when attention was pre-allocated, when peripheral cues triggered exogenous attention shifts, and when central cues triggered endogenous attention shifts. In study 1, each subject participated in 2 sessions (scopolamine/placebo), whereby the order of drug intake was counterbalanced across subjects, and subjects were blinded to conditions. Scopolamine/placebo was administered before a psychophysical experiment was conducted. In study 2, the effect of muscarinic blockade on learning induced improvements of attention shift times was investigated. Here scopolamine/placebo was administered immediately after the first (of two) psychophysical sessions, whereby a given subject either received scopolamine or placebo pills. Confirming previous results, we show that pre-cuing resulted in the fastest shift times, followed by exogenous cuing, with endogenous attentional shifts being slowest. Scopolamine application increased attentional shift times across all 3 conditions compared to placebo, but in a dose dependent manner. Additionally, blockade of muscarinic receptors immediately after the first session reduced learning dependent improvement of attention shift times. These results demonstrate that muscarinic receptors play an important role in attention shifting, and they contribute to learning of attention shifting.

neuroscience↗

bioRxiv2024

Effect of alcohol on the speed of shifting endogenous and exogenous attention

The study aimed to investigate to what extent acute moderate doses of alcohol affect the speed of endogenous versus exogenous attentional shift times. Subjects viewed an array of 10 moving clocks and reported the time a clock indicated when cued. Target clocks were indicated by peripheral or central cues, including conditions of pre-cuing. This allowed assessing shift times when attention was pre-allocated, when peripheral cues triggered exogenous attention shifts, and when central cues triggered endogenous attention shifts. Each subject participated in 2 sessions (alcohol/placebo), whereby the order of drug intake was counterbalanced across subjects, and subjects were blinded to conditions. Confirming previous results, we show that pre-cuing resulted in the fastest shift times, followed by exogenous cuing, with endogenous attentional shifts being slowest. Alcohol increased attentional shift times across all 3 conditions compared to placebo. Thus, the detrimental effects of alcohol on attentional shift times did not depend on the type of attention probed.

neuroscience↗

bioRxiv2023

Noise reduction as a unified mechanism of perceptual learning in humans, macaques, and convolutional neural networks

Visual perceptual learning (VPL), defined as long-term improvement in a visual task, is considered a crucial tool for elucidating underlying visual and brain plasticity. However, the identification of a unified theory of VPL has long been controversial. Multiple existing models have proposed diverse mechanisms, including improved signal-to-noise ratio, changes in tuning curves, and reduction of noise correlations, as major contributors to improved neural representations associated with VPL. However, each model only accounts for specific aspects of the empirical findings, and there exists no theory that can comprehensively explain all empirical results. Here, we argue that all neural changes at single units can be conceptualized as geometric transformations of population response manifolds in a high-dimensional neural space. This approach enables conflicting major models of VPL to be quantitatively tested and compared within a unified computational theory. Following this approach, we found that changes in tuning curves and noise correlations, as emphasized by previous models, make no significant contributions to improved population representations by visual training. Instead, we identified neural manifold shrinkage due to reduced trial-by-trial neural response variability, a previously unexplored factor, as the primary mechanism underlying improved population representations. Furthermore, we showed that manifold shrinkage successfully accounts for learning effects across various domains, including artificial neural responses in deep neural networks trained on typical VPL tasks, multivariate BOLD signals in humans, and multi-unit activities in monkeys. These converging results suggest that our neural geometry theory offers a quantitative and comprehensive approach to explain a wide range of empirical results and to reconcile previously conflicting models of VPL.

neuroscience↗

bioRxiv2022

Distinct feedforward and feedback pathways for cell-type specific attention effects in macaque V4.

Spatial attention selectively enhances neural responses to visual stimuli. There are two long-standing hypotheses about how top-down feedback enhances sensory responses in areas like V4: First, by amplifying V1-to-V4 feedforward communication via 30-80Hz gamma-coherence. Second, via top-down feedback to V4 supra- and infra-granular layers. To test these hypotheses, we recorded distinct cell-types across macaque V1 and V4 layers. Attention increased both V1-V4 gamma-coherence and V4 spike-rates, yet with distinct laminar and cell-type profiles. Surprisingly, V1 gamma did not engage V4 excitatory neurons, but only Layer-4 fast-spiking interneurons. Similar observations were made in mouse visual-cortex, where feedforward gamma-influences preferentially recruit optogenetically-tagged PV+ and narrowwaveform SSt+ interneurons. By contrast, attention enhanced V4 spike-rates in both excitatory neurons and fast-spiking interneurons, with the strongest and earliest modulation in Layer-2/3, consistent with a feedback influence. These findings reveal distinct feedforward and feedback pathways for the attentional modulation of inter-areal coherence and spike rates, respectively.

neuroscience↗

bioRxiv2022

Sharp wave ripples in macaque V1 and V4 are modulated by top-down visual attention

Sharp-wave ripples (SWRs) are highly synchronous neuronal activity events. They have been predominantly observed in the hippocampus during offline states such as pause in exploration, slow-wave sleep and quiescent wakefulness. SWRs have been linked to memory consolidation, spatial navigation, and spatial decision-making. Recently, SWRs have been reported during visual search, a form of remote spatial exploration, in macaque hippocampus. However, the association between SWRs and multiple forms of awake conscious and goal-directed behavior is unknown. We report that ripple activity occurs in macaque visual areas V1 and V4 during focused spatial attention. The frequency of ripples is modulated by characteristics of the stimuli, by spatial attention directed toward a receptive field, and by the size of the attentional focus. Critically, the monkeys reaction times in detecting behaviorally relevant stimulus changes was affected on trials with SWRs. These results show that ripple activity is not limited to hippocampal activity during offline states, rather they occur in the neocortex during active attentive states and vigilance behaviors.

neuroscience↗

bioRxiv2021

Attentional modulation of intrinsic timescales in visual cortex and spatial networks

Intrinsic timescales characterize dynamics of endogenous fluctuations in neural activity. Variation of intrinsic timescales across the neocortex reflects functional specialization of cortical areas, but less is known about how intrinsic timescales change during cognitive tasks. We measured intrinsic timescales of local spiking activity within columns of area V4 while monkeys performed spatial attention tasks. The ongoing spiking activity unfolded across at least two distinct timescales, fast and slow. The slow timescale increased when monkeys attended to the receptive fields location and correlated with reaction times. By evaluating predictions of several network models, we found that spatiotemporal correlations in V4 activity were best explained by the model in which multiple timescales arise from recurrent interactions shaped by spatially arranged connectivity, and attentional modulation of timescales results from an increase in the efficacy of recurrent interactions. Our results suggest that multiple timescales arise from the spatial connectivity in the visual cortex and flexibly change with the cognitive state due to dynamic effective interactions between neurons.

neuroscience↗

bioRxiv2020

Directed information exchange between cortical layers in macaque V1 and V4 and its modulation by selective attention

Achieving behavioral goals requires integration of sensory and cognitive information, across cortical laminae and cortical regions. How this computation is performed remains unknown. Using local field potential recordings and spectrally resolved conditional Granger causality (cGC) analysis, we mapped visual information flow, and its attentional modulation, between cortical layers within and between macaque areas V1 and V4. Stimulus induced inter-laminar information flow within V1 dominated upwardly, channeling information towards supragranular cortico-cortical output layers. Within V4, information flow dominated from granular to supragranular layers, but interactions between supragranular and infragranular layers dominated downwardly. Low-frequency across-area communication was stronger from V4 to V1, with little layer specificity. Gamma-band communication was stronger in the feedforward V1 to V4 direction. Attention to the receptive field of V1 decreased communication between all V1 layers, except for granular to supragranular layers interactions. Communication within V4, and from V1 to V4, increased with attention across all frequencies. While communication from V4 to V1 was stronger in lower frequency bands (4-25 Hz), attention modulated cGCs from V4 to V1 across all investigated frequencies. Our data show that top down cognitive processes result in reduced communication within cortical areas, increased feedforward communication across all frequency bands and increased gamma band feedback communication.

neuroscience↗

bioRxiv2020

Dopamine influences attentional rate modulation in Macaque posterior parietal cortex

Cognitive neuroscience has made great strides in understanding the neural substrates of attention, but our understanding of its neuropharmacology remains incomplete. Although dopamine has historically been studied in relation to frontal functioning, emerging evidence suggests important dopaminergic influences in parietal cortex. We recorded single- and multi-unit activity whilst iontophoretically administering dopaminergic agonists and antagonists while rhesus macaques performed a spatial attention task. Out of 88 units, 50 revealed activity modulation by drug administration. Dopamine inhibited firing rates according to an inverted-U shaped dose-response curve and increased gain variability. Dopamine modulated attention-related rate changes and Fano Factors in broad and narrow-spiking units, respectively. D1 receptor antagonists diminished firing rates according to a monotonic function and interacted with attention modulating gain variability in broad-spiking units. Finally, both drugs decreased the pupil light reflex. These data show that dopamine shapes neuronal responses and modulates attentional processing in parietal cortex.

neuroscience↗

bioRxiv2020

Top-down coordination of local cortical state during selective attention

Spontaneous fluctuations in cortical excitability influence sensory processing and behavior. These fluctuations, long known to reflect global changes in cortical state, were recently found to be modulated locally within a retinotopic map during spatially selective attention. We found that periods of vigorous (On) and faint (Off) spiking activity, the signature of cortical state fluctuations, were coordinated across brain areas along the visual hierarchy and tightly coupled to their retinotopic alignment. During top-down attention, this interareal coordination was enhanced and progressed along the reverse cortical hierarchy. The extent of local state coordination between areas was predictive of behavioral performance. Our results show that cortical state dynamics are shared across brain regions, modulated by cognitive demands and relevant for behavior. One Sentence SummaryInterareal coordination of local cortical state is retinotopically precise and progresses in a reverse hierarchical manner during selective attention.

neuroscience↗

bioRxiv2018

Behavioural and neural signatures of perceptual evidence accumulation are modulated by pupil-linked arousal

The timing and accuracy of perceptual decision making is exquisitely sensitive to fluctuations in arousal. Although extensive research has highlighted the role of neural evidence accumulation in forming decisions, our understanding of how arousal impacts these processes remains limited. Here we isolated electrophysiological signatures of evidence accumulation alongside signals reflecting target selection, attentional engagement and motor output and examined their modulation as a function of both tonic and phasic arousal, indexed by baseline and task-evoked pupil diameter, respectively. For both pupillometric measures, the relationship with reaction time was best described by a second-order, U-shaped, polynomial. Additionally, the two pupil measures were predictive of a unique set of EEG signatures that together represent multiple information processing steps of perceptual decision-making, including evidence accumulation. Finally, we found that behavioural variability associated with fluctuations in both tonic and phasic arousal was largely mediated by variability in evidence accumulation.

neuroscience↗

bioRxiv2017

An open resource for nonhuman primate imaging

Non-human primate neuroimaging is a rapidly growing area of research that promises to transform and scale translational and cross-species comparative neuroscience.\n\nUnfortunately, the technological and methodological advances of the past two decades have outpaced the accrual of data, which is particularly challenging given the relatively few centers that have the necessary facilities and capabilities. The PRIMate Data Exchange (PRIME-DE) addresses this challenge by aggregating independently acquired non-human primate magnetic resonance imaging (MRI) datasets and openly sharing them via the International Neuroimaging Data-sharing Initiative (INDI). Here, we present the rationale, design and procedures for the PRIME-DE consortium, as well as the initial release, consisting of 13 independent data collections aggregated across 11 sites (total = 98 macaque monkeys). We also outline the unique pitfalls and challenges that should be considered in the analysis of the non-human primate MRI datasets, including providing automated quality assessment of the contributed datasets.

neuroscience↗

bioRxiv2017

Non-parametric test for connectivity detection in multivariate autoregressive networks and application to multiunit activity data

Directed connectivity inference has become a cornerstone in neuroscience following the recent progress in neuroimaging and elctrophysiological techniques to characterize anatomical and functional networks. This paper focuses on the detection of existing connections from the observed activity in networks of 50 to 150 nodes with linear feedback in discrete time. Through the variation of multiple network parameters, our numerical results indicate that directed connections - in the time domain - are more accurately estimated based on the coefficients obtained from multivariate autoregressive (MVAR) than Granger causality analysis, which is based on the error residuals of the same MVAR linear regression. Based on these findings, we propose a non-parametric significance test for connectivity detection, which achieves a good control of false positives (type 1 error) and is robust to various network topologies. When generating surrogate distributions, we compare the effects of circular shifts, random permutations and phase randomization of the observed time series, each breaking down covariances in a specific manner: the MVAR estimates from those shuffled covariances build a null-hypothesis distribution for each connection, from which the original connectivity estimate can be compared. We apply our method to multiunit activity data recorded from Utah electrode arrays in monkey and examine the detected interactions between 25 channels for a proof of concept. The results unravel a non-trivial underlying connectivity structure, which differentiates the effect of incoming and outgoing connections.

neuroscience↗