Kilpatrick, C. | Search bioRxiv

bioRxiv2026

Hierarchical Transcriptomic and Epigenetic Recovery and Remodeling in the Developing Hippocampus Following Early-life Environmental Insults: An Iron Deficiency Rat Model

BackgroundsEarly-life environmental insults cause persistent neurodevelopmental abnormalities accompanied by transcriptional and epigenetic dysregulation despite removal of the original insult or postnatal intervention. However, transcriptomic and epigenomic responses to developmental insults and subsequent treatment during active neurodevelopment remain insufficiently characterized. Developmental iron deficiency (ID) provides a unique model for investigating this question because iron is an essential cofactor for TET DNA dioxygenases and developmental ID causes persistent behavioral and molecular alterations despite iron repletion. ResultsWe integrated the hippocampal transcriptome, DNA methylome (5mC), and hydroxymethylome (5hmC) in male rats at postnatal day 15 following developmental ID and postnatal iron treatment, using Oxford Nanopore sequencing for native DNA modification profiling. Developmental ID induced substantial transcriptional and epigenetic alterations associated with synaptic function, neurodevelopment, and neuroinflammation. Postnatal iron treatment induced a hierarchical response across molecular layers: while transcriptomic alterations largely normalized, 5mC showed only partial recovery, and 5hmC showed extensive de novo modifications. Recovered, persistent, and newly emerged epigenetic marks were associated with increasingly specialized biological functions, from broad neurodevelopmental processes to specific pathways. Furthermore, while 5mC enrichment was associated with transcriptionally suppressed pathways, 5hmC enrichment showed weaker coupling with concurrent transcriptomic activity, suggesting epigenetic poising rather than immediate transcriptional output. MergeOmics integration identified key driver genes showing post-treatment epigenetic regulation despite transcriptional recovery. ConclusionsMolecular recovery following developmental ID extends beyond transcriptomic normalization, involving persistent and extensive epigenetic remodeling. This study provides a framework for understanding molecular responses following early-life environmental insults and highlights the importance of delineating persistent regulatory reprogramming.

genomics↗

bioRxiv2022

Dissociating Attentional Capture from Action Cancellation in the Stop Signal Task

Inhibiting ongoing responses when environmental demands change is a critical component of human motor control. Experimentally, the stop signal task (SST) represents the gold standard response inhibition paradigm. However, an emerging body of evidence suggests that the SST conflates two dissociable sources of inhibition, namely an involuntarily pause associated with attentional capture and the (subsequent) voluntary cancellation of action. The extent to which these processes also occur in other response tasks is unknown. 24 younger (20-35 years) and 23 older (60-85 years) adults completed a series of tasks involving rapid unimanual or bimanual responses to a visual stimulus. A subset of trials required cancellation of one component of an initial bimanual response (i.e., selective stop task; stop left response, continue with right response) or enacting an additional response (e.g., press left button as well as right button). Critically, both tasks involved some infrequent stimuli which bore no behavioural imperative (i.e., they had to be ignored). EMG recordings of voluntary responses during the stopping tasks revealed bimanual covert responses (i.e., muscle activation which was suppressed before a button press ensued), consistent with a pause process, following both stop and ignore stimuli, before the required response was subsequently enacted. Critically, we also observed the behavioural consequences of a similar involuntary pause in trials where action cancellation was not part of the response set (i.e., when the additional stimulus required additional action or ignoring, but not inhibition). The findings shed new light on the mechanisms of inhibition and their generalisability to other task contexts.

neuroscience↗