Gumus-Akay, G. | bioRxiv Science

bioRxiv2025

Interval Timing Shows Selective Enhancement Under Psychosocial Stress: A Cortisol-Mediated Dissociation From Spatial Processing

Acute stress affects cognitive processes, including our perception of time, yet few studies have examined how HPA axis activation specifically modulates time perception. This study provides the first systematic examination of how psychosocial stress influences temporal versus spatial reproduction using the Trier Social Stress Test (TSST), investigating underlying epigenetic mechanisms. Forty-four healthy adults (21 men; mean age 21.96 {+/-} 3.03) completed temporal and spatial reproduction tasks before and after TSST, with salivary cortisol sampling and DNA methylation analysis of four dopamine-related genes (COMT, DRD2, SLC6A3, TH). The TSST successfully elevated cortisol and state anxiety, confirming effective HPA axis activation. Critically, stress selectively reduced temporal underestimation. Despite their shared neurocognitive mechanisms, spatial processing remained unchanged. This demonstrates that HPA-mediated stress enhances interval timing. Men demonstrated greater stress-induced improvement in temporal accuracy than women, while neither sex showed significant spatial changes, independent of cortisol reactivity differences. The results are discussed in the context of dopaminergic models of temporal processing. Exploratory epigenetic analyses revealed a DRD2 methylation x cortisol response interaction for temporal tasks, with higher methylation associated with greater stress-induced improvement among high cortisol responders. However, sensitivity analysis indicated these interactions were driven by participants with extreme methylation values, limiting generalizability of epigenetic results. These findings demonstrate that acute psychosocial stress selectively enhances temporal accuracy, potentially through cortisol-dopamine interactions in corticostriatal timing circuits. This work opens avenues for investigating stress-timing mechanisms and cortisol-dopamine interactions in timing circuits, and provides preliminary evidence for epigenetic moderation.

neuroscience↗

bioRxiv2019

Neuronal network dysfunction in a human model for Kleefstra syndrome mediated by enhanced NMDAR signaling

Epigenetic regulation of gene transcription plays a critical role in neural network development and in the etiology of Intellectual Disability (ID) and Autism Spectrum Disorder (ASD). However, little is known about the mechanisms by which epigenetic dysregulation leads to neural network defects. Kleefstra syndrome (KS), caused by mutation in the histone methyltransferase EHMT1, is a neurodevelopmental disorder with the clinical features of both ID and ASD. To study the impact of decreased EHMT1 function in human cells, we generated excitatory cortical neurons from induced pluripotent stem (iPS) cells derived from KS patients. In addition, we created an isogenic set by genetically editing healthy iPS cells. Characterization of the neurons at the single-cell and neuronal network level revealed consistent discriminative properties that distinguished EHMT1-mutant from wildtype neurons. Mutant neuronal networks exhibited network bursting with a reduced rate, longer duration, and increased temporal irregularity compared to control networks. We show that these changes were mediated by the upregulation of the NMDA receptor (NMDAR) subunit 1 and correlate with reduced deposition of the repressive H3K9me2 mark, the catalytic product of EHMT1, at the GRIN1 promoter. Furthermore, we show that EHMT1 deficiency in mice leads to similar neuronal network impairments and increased NMDAR function. Finally, we could rescue the KS patient-derived neuronal network phenotypes by pharmacological inhibition of NMDARs. Together, our results demonstrate a direct link between EHMT1 deficiency in human neurons and NMDAR hyperfunction, providing the basis for a more targeted therapeutic approach to treating KS.

neuroscience↗