Biology subjects

Wolman, A.

Publications and source records attributed to Wolman, A..

4 recordsLinked to original sources

bioRxiv2025

How Intrinsic Neural Timescales Relate To Event-Related Activity - Key Role For Intracolumnar Connections

The relationship of the brains intrinsic neural timescales (INTs) during the resting state with event-related activity in response to external stimuli remains poorly understood. Here, we bridge this gap by combining computational modeling with magnetoencephalography (MEG) data to investigate the relation of intrinsic neuronal timescales (INT) with task-related activity, e.g., event-related fields (ERFs). Using the Jansen-Rit model, we first show that intracolumnar (and thus intra-regional) excitatory and inhibitory connections (rather than inter-regional feedback, feedforward and lateral connections between the columns of different regions) strongly influence both resting state INTs and task-related ERFs. Secondly, our results demonstrate a positive relationship between the magnitude of event-related fields (mERFs) and INTs, observed in both model simulations and empirical MEG data collected during an emotional face recognition task. Thirdly, modeling shows that the positive relationship of mERF and INT depends on intracolumnar connections through observing that the correlation between them disappears for fixed values of intracolumnar connections. Together, these findings highlight the importance of intracolumnar connections as a shared biological mechanism underlying both the resting-states INTs and the task-states event-related activity including their interplay.

neuroscience↗

bioRxiv2023

Intrinsic neural timescales attenuate information transfer along the uni-transmodal hierarchy

The brains intrinsic timescales are organized in a hierarchy with shorter timescales in sensory regions and longer ones in associative regions. This timescale hierarchy overlaps with the timing demands of sensory information. Our question was how does this timescale hierarchy affect information transfer. We used a model of the timescale hierarchy based on connected excitatory and inhibitory populations across the cortex. We found that a hierarchy of information transfer follows the hierarchy of timescales with higher information transfer in sensory areas while it is lower in associative regions. Probing the effect of changes in timescale hierarchy on information transfer, we changed various model parameters which all, through, the loss of hierarchy, induced increased information transfer. Finally, the steepness of the timescale hierarchy relates negatively to total information transfer. Human MEG data confirmed our results. In sum, we demonstrate a key role of the brains timescale hierarchy in mediating information transfer.

neuroscience↗

bioRxiv2020

An autoimmune disease risk variant has a trans master regulatory effect mediated by IRF1 under immune stimulation

Functional mechanisms remain unknown for most genetic loci associated to complex human traits and diseases. In this study, we first mapped trans-eQTLs in a data set of primary monocytes stimulated with LPS, and discovered that a risk variant for autoimmune disease, rs17622517 in an intron of C5ORF56, affects the expression of the transcription factor IRF1 20 kb away. The cis-regulatory effect on IRF1 is active under early immune stimulus, with a large number of trans-eQTL effects across the genome under late LPS response. Using CRISPRi silencing, we showed that the SNP locus indeed functions as an IRF1 enhancer with widespread transcriptional effects. Genome editing by CRISPR further indicated that rs17622517 is indeed a causal variant in this locus, and recapitulated the LPS-specific trans-eQTL signal. Our results suggest that this common genetic variant affects inter-individual response to immune stimuli via regulation of IRF1. For this autoimmune GWAS locus, our work provides evidence of the causal variant, demonstrates a condition-specific enhancer effect, identifies IRF1 as the likely causal gene in cis, and indicates that overactivation of the downstream immune-related pathway may be the cellular mechanism increasing disease risk. This work not only provides rare experimental validation of a master-regulatory trans-eQTL, but also demonstrates the power of eQTL mapping to build mechanistic hypotheses amenable for experimental follow-up using the CRISPR toolkit.

genomics↗

bioRxiv2017

Modified penetrance of coding variants by cis-regulatory variation shapes human traits

Coding variants represent many of the strongest associations between genotype and phenotype, however they exhibit inter-individual differences in effect, known as variable penetrance. In this work, we study how cis-regulatory variation modifies the penetrance of coding variants in their target gene. Using functional genomic and genetic data from GTEx, we observed that in the general population, purifying selection has depleted haplotype combinations that lead to higher penetrance of pathogenic coding variants. Conversely, in cancer and autism patients, we observed an enrichment of haplotype combinations that lead to higher penetrance of pathogenic coding variants in disease implicated genes, which provides direct evidence that regulatory haplotype configuration of causal coding variants affects disease risk. Finally, we experimentally demonstrated that a regulatory variant can modify the penetrance of a coding variant by introducing a Mendelian SNP using CRISPR/Cas9 on distinct expression haplotypes and using the transcriptome as a phenotypic readout. Our results demonstrate that joint effects of regulatory and coding variants are an important part of the genetic architecture of human traits, and contribute to modified penetrance of disease-causing variants.

genetics↗