Biology subjects

Siegel, J.

Publications and source records attributed to Siegel, J..

8 recordsLinked to original sources

bioRxiv2026

α-tACS Modulates Reward-Dependent Pupil Responses and Corticostriatal Connectivity

IntroductionNoninvasive brain stimulation can help clarify the neural basis of reward processing and potentially inform treatments for disorders involving reward dysfunction. However, widely used methods such as transcranial magnetic and electrical stimulation cannot directly stimulate deep-brain regions like the striatum. Here, we tested whether stimulating the ventrolateral prefrontal cortex (VLPFC)--a cortical region strongly connected to the striatum-- could indirectly influence reward-related neural and physiological responses. MethodsIn a within-subjects design, participants performed a card-guessing task involving monetary rewards for correct guesses and punishments for incorrect guesses. During the task, participants underwent functional magnetic resonance imaging (fMRI) and pupillometry while receiving concurrent 10 Hz transcranial alternating current stimulation (-tACS). Stimulation targeted either the VLPFC or a control region (temporoparietal junction). We measured pupil dilation, brain activation (BOLD signal), and functional connectivity between the ventral striatum and dorsal anterior cingulate cortex (VS-dACC). ResultsVLPFC stimulation increased pupil size during reward and punishment outcomes, indicating greater physiological arousal. At the neural level, -tACS enhanced VLPFC activation during reward and suppressed its responses during punishment. Stimulation also changed VS- dACC connectivity in a context-dependent manner. Importantly, stimulation-driven increases in pupil size during reward correlated positively with stimulation-induced changes in VS-dACC connectivity. Exploratory moderated mediation analyses suggested that stimulation influenced the degree to which striatal responses mediated the relationship between task outcomes and pupil size changes. ConclusionsTargeting VLPFC with -tACS modulates local cortical activity and corticostriatal networks during reward processing, providing a promising noninvasive approach to influence reward circuitry. HighlightsO_LI-tACS over VLPFC increases pupil responses to reward and punishment. C_LIO_LIStimulation alters reward-related VLPFC activity without enhancing striatal BOLD. C_LIO_LI-tACS modulates ventral striatum-dACC connectivity in a task-dependent manner. C_LIO_LIConnectivity changes predict pupil dilation, linking brain and autonomic responses. C_LI

neuroscience↗

bioRxiv2025

Design to Data for mutants of β-glucosidase B from Paenibacillus polymyxa: L336M, L336A, L336S, L336H, D35E, D35W

Recent groundbreaking advances in protein structure prediction have significantly propelled the fields of protein design and engineering. However, improving computational enzyme modeling remains a key area of interest, with exciting opportunities to enhance predictive capabilities. Existing algorithms face a crucial hurdle - predicting enzyme stability and function with accuracy. To address this limitation, large sets of experimental data that capture enzyme structure-function are needed to guide the training and testing of next-gen tools. The Design 2 Data (D2D) program aims to build such a data set by engaging students from around the world to contribute standardized experimental data of enzyme variants. The flagship enzyme dataset of D2D, {beta}-glucosidase B (BglB), currently contains over 1300 records. The data consists of kinetic (kcat, KM, and kcat/KM), and thermal stability measures to expand the range of data available to train new computational algorithms. This paper explores six new single point mutants produced as part of this larger project and investigates variations in functional outcomes across the mutated sites. These data taken together with the larger and growing mutant library aim to deepen our understanding of the relationship between structure and function in BglB.

biochemistry↗

bioRxiv2025

Brainstem pathology in human narcolepsy: Neurodegeneration in the locus coeruleus in narcoleptic humans, but not in genetically narcoleptic mice or dogs

Our earlier study led to the conclusion that human narcolepsy with cataplexy was caused by the loss of forebrain hypocretin (orexin) neurons in the hypothalamus. We now report that humans having narcolepsy with cataplexy also have a 46% decrease in the number and an 18% increase in the size of brainstem neuromelanin-pigmented locus coeruleus (LC) neurons and increased microglial activity in LC. However, no such changes are observed in the LC of hypocretin peptide depleted narcoleptic mice, hypocretin neuron depleted orexin-tTA/TetO-DTA (orexin-DTA) narcoleptic mice or in narcoleptic dogs. Sodium oxybate, an effective treatment for narcolepsy, decreased the size of LC norepinephrine neurons and increased the number and size of LC microglial cells in mice. Our results indicate that the autoimmune process believed to cause human narcolepsy affects both forebrain Hcrt neurons and brainstem LC norepinephrine cells. Addressing both forebrain and brainstem pathologies may improve understanding of, and treatments for, human narcolepsy.

neuroscience↗

bioRxiv2023

Opiate anticipation,opiate induced anatomical changes in hypocretin (Hcrt, orexin) neurons and opiate induced microglial activation are blocked by the dual Hcrt receptor antagonist suvorexant, while opiate analgesia is maintained

We previously found that heroin addiction in humans is accompanied by an increase in the number of detected Hcrt neurons and a decrease in their soma size. We now show that the increased number of Hcrt cells visible after morphine treatment is likely the result of increased Hcrt production in neurons having sub-detection levels of the peptides. We find that morphine increases Hcrt projections to the ventral tegmental area (VTA), the level of tyrosine hydroxylase enzyme (TH) and the number of TH positive cells in VTA, with no changes in the adjacent substantia nigra. We find that the dual Hcrt receptor antagonist suvorexant prevents morphine-induced changes in the number and size of Hcrt neurons, microglial activation and morphine anticipatory behavior, but does not diminish morphine analgesia. These findings suggest that combined administration of opiates and suvorexant may be a less addictive way of administering opiates for pain relief in humans.

neuroscience↗

bioRxiv2021

Ensuring scientific reproducibility in bio-macromolecular modeling via extensive, automated benchmarks

Each year vast international resources are wasted on irreproducible research. The scientific community has been slow to adopt standard software engineering practices, despite the increases in high-dimensional data, complexities of workflows, and computational environments. Here we show how scientific software applications can be created in a reproducible manner when simple design goals for reproducibility are met. We describe the implementation of a test server framework and 40 scientific benchmarks, covering numerous applications in Rosetta bio-macromolecular modeling. High performance computing cluster integration allows these benchmarks to run continuously and automatically. Detailed protocol captures are useful for developers and users of Rosetta and other macromolecular modeling tools. The framework and design concepts presented here are valuable for developers and users of any type of scientific software and for the scientific community to create reproducible methods. Specific examples highlight the utility of this framework and the comprehensive documentation illustrates the ease of adding new tests in a matter of hours.

bioinformatics↗

bioRxiv2021

Furanoditerpenoid biosynthesis in the bioenergy crop switchgrass is catalyzed by an alternate metabolic pathway

Specialized diterpenoid metabolites are important mediators of stress resilience in monocot crops. A deeper understanding of how species-specific diterpenoid-metabolic pathways and functions contribute to plant chemical defenses can enable crop improvement strategies. Here, we report the genomics-enabled discovery of five cytochrome P450 monooxygenases (CYP71Z25-29) that form previously unknown furanoditerpenoids in the monocot bioenergy crop switchgrass (Panicum virgatum). Combinatorial pathway reconstruction showed that CYP71Z25-29 catalyze furan ring addition to diterpene alcohol intermediates derived from distinct class II diterpene synthases, thus bypassing the canonical role of class I diterpene synthases in plant diterpenoid metabolism. Transcriptional co-expression patterns and presence of select diterpenoids in droughted switchgrass roots support possible roles of CYP71Z25-29 in abiotic stress responses. Integrating molecular dynamics, structural analysis, and targeted mutagenesis, identified active site determinants controlling distinct CYP71Z25-29 catalytic specificities and, combined with broad substrate promiscuity for native and non-native diterpenoids, highlights the potential of these P450s for natural product engineering. Significance StatementDiterpenoids play important roles in stress resilience and chemically mediated interactions in many plant species, including major food and bioenergy crops. Enzymes of the cytochrome P450 monooxygenase family catalyze the various functional decorations of core diterpene scaffolds that determine the large diversity of biologically active diterpenoids. This study describes the identification and mechanistic analysis of an unusual group of cytochrome P450 monooxygenases, CYP71Z25-29, from the bioenergy crop switchgrass (Panicum virgatum). These enzymes catalyze the furan ring addition directly to class II diterpene synthase products, thus bypassing the conserved pairwise reaction of class II and class I diterpene synthases in labdane diterpenoid metabolism. Insight into the distinct substrate-specificity of CYP71Z25-29 offers opportunity for engineering of furanoditerpenoid bioproducts.

plant biology↗

bioRxiv2019

Reward does not facilitate visual perceptual learning until sleep occurs

A growing body of evidence indicates that visual perceptual learning (VPL) is enhanced by reward provided during training. Another line of studies has shown that sleep following training also plays a role in facilitating VPL, an effect known as the offline performance gain of VPL. However, whether the effects of reward and sleep interact on VPL remains unclear. Here, we show that reward interacts with sleep to facilitate offline performance gains of VPL. First, we demonstrated a significantly larger offline performance gain over a 12-h interval including sleep in a reward group than that in a No-reward group. However, the offline performance gains over the 12-h interval without sleep were not significantly different with or without reward during training, indicating a crucial interaction between reward and sleep in VPL. Next, we tested whether neural activations during posttraining sleep were modulated after reward was provided during training. Reward provided during training enhanced REM sleep time, increased oscillatory activities for reward processing in the prefrontal region during REM sleep, and inhibited neural activation in the untrained region in early visual areas in NREM and REM sleep. The offline performance gains were significantly correlated with oscillatory activities of visual processing during NREM sleep and reward processing during REM sleep in the reward group but not in the No-reward group. These results suggest that reward provided during training becomes effective during sleep, with excited reward processing sending inhibitory signals to suppress noise in visual processing, resulting in larger offline performance gains over sleep.\n\nSignificance statementIndependent lines of research have shown that visual perceptual learning (VPL) is improved by reward or sleep. Here, we show that reward provided during training increased offline performance gains of VPL over sleep. Moreover, during posttraining sleep, reward was associated with longer REM sleep, increased activity in reward processing in the prefrontal region during REM sleep, and decreased activity in the untrained region of early visual areas during NREM and REM sleep. Offline performance gains were correlated with modulated oscillatory activity in reward processing during REM sleep and visual processing during NREM sleep. These results suggest that reward provided during training becomes effective on VPL through the interaction between reward and visual processing during sleep after training.

neuroscience↗

bioRxiv2017

Genetics of trans-regulatory variation in gene expression

Heritable variation in gene expression provides a critical bridge between differences in genome sequence and the biology of many traits, including common human diseases. However, the sources of most regulatory genetic variation remain unknown. Here, we used transcriptome profiling in 1,012 yeast segregants to map the genetic basis of variation in gene expression with high statistical power. We identified expression quantitative trait loci (eQTL) that together account for over 70% of the total genetic contribution to variation in mRNA levels, allowing us to examine the sources of regulatory variation comprehensively. We found that variation in the expression of a typical gene has a complex genetic architecture involving multiple eQTL. We also detected hundreds of eQTL pairs with significant non-additive interactions in an unbiased genome-wide scan. Although most genes were influenced by a local eQTL located close to the gene, most expression variation arose from distant, trans-acting eQTL located far from their target genes. Nearly all distant eQTL clustered at 102 \"hotspot\" locations, some of which influenced the expression of thousands of genes. Hotspot regions were enriched for transcription factor genes and altered expression of their target genes though both direct and indirect mechanisms. Many local eQTL had no detectable effects on the expression of other genes in trans. These results reveal the complexity of genetic influences on transcriptome variation in unprecedented depth and detail.

genetics↗