Biology subjects

Eed, A.

Publications and source records attributed to Eed, A..

3 recordsLinked to original sources

bioRxiv2025

Aberrant recursive splicing in a human disease locus

Recursive splice sites are rare motifs postulated to facilitate splicing across massive introns and shape isoform diversity, especially for long, brain-expressed genes. The necessity of this unique mechanism remains unsubstantiated, as does the role of recursive splicing (RS) in human disease. From analyses of rare copy number variants (CNVs) from almost one million individuals, we previously identified large, heterozygous deletions eliminating an RS site (RS1) in the first intron of CADM2 that conferred substantial risk for attention deficit hyperactivity disorder (ADHD) and other neurobehavioral traits. CADM2 encodes a neuronally expressed cell adhesion molecule that has repeatedly been associated with ADHD and numerous similar traits. To explore the molecular impact of RS ablation in CADM2, we used CRISPR to model patient deletions and to target a smaller region ([~]500 base pairs) containing RS1 in both human induced neurons (iNs) and rats. Transcriptome analyses in unedited iNs provided a catalog of CADM2 transcripts, including novel transcripts that retained RS exons. Intriguingly, ablating RS1 altered the gradient of RNA abundance across the first intron of CADM2, decreased the level of CADM2 expression, and impacted transcript usage. Decreased CADM2 expression was reflected in reduced exon usage downstream of the RS1 site and global alteration to genes involved in neuronal processes including synapse and axon development. Given the scale of our analyses and the widespread association of CADM2 with neurobehavioral traits, we sought to validate these findings using in vivo models and found that rodent models harboring Cadm2 RS1 deletions exhibited significant changes in relevant behaviors and functional brain connectivity. In summary, our analyses demonstrate a functional role for RS as a noncoding regulatory mechanism in a gene associated with a spectrum of neuropsychiatric and behavioral traits. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/666599v1_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@171156borg.highwire.dtl.DTLVardef@13553baorg.highwire.dtl.DTLVardef@bee7forg.highwire.dtl.DTLVardef@156f19e_HPS_FORMAT_FIGEXP M_FIG Graphical Abstract C_FIG

genomics↗

bioRxiv2025

A non-invasive approach to awake mouse fMRI compatible with multi-modal techniques

Mouse functional magnetic resonance imaging (fMRI) studies contribute significantly to basic fundamental and translational neuroscience research. Performing fMRI in awake mice could facilitate complex tasks in the magnet and improve translational validity by avoiding anesthesia-related neural and neurovascular changes. Existing surgical approaches provide excellent motion control but are not desirable for all experiments aiming to scan awake mice. These include studies with transgenic mouse lines that are vulnerable to anesthesia or mice in longitudinal studies involving cognition. To address these needs, we propose a non-invasive restraint to scan mice in the awake state. The restraint was designed to be compatible with brain stimulation and recording approaches often combined with fMRI. It was evaluated on the basis of motion, fMRI data quality, and animal stress levels, and compared to a conventional headpost restraint. We found the proposed approach was effective at restraining mice across a broad range of weights without the need for any anesthesia for setup. The non-invasive restraint led to higher data attrition after censoring high motion volumes, but by acquiring roughly 25% more data we could obtain comparable network spatial specificity to the headpost approach. Our results demonstrate a simple open-source head restraint that can be used for awake mouse fMRI for certain cohorts, and we establish suitable acclimation and scanning protocols for use with this restraint.

neuroscience↗

bioRxiv2024

Stimulus-modulated approach to steady-state: A new paradigm for event-related fMRI.

Functional MRI (fMRI) studies discard the initial volumes acquired during the approach of the magnetization to its steady-state value. Here, we leverage the higher temporal signal-to-noise ratio (tSNR) of these initial volumes to increase the sensitivity of event-related fMRI experiments. To do this, we introduce Acquisition Free Periods (AFPs) that allow for the full recovery of the magnetization, followed by task or baseline acquisition blocks (AB) of fMRI volumes. An appropriately placed stimulus in the AFP produces a Blood Oxygenation-Level-Dependent (BOLD) response that peaks during the initial high tSNR phase of the AB, yielding up to a [~]50% reduction in the number of trials needed to achieve a given statistical threshold relative to conventional fMRI. The silent AFP can be exploited for the presentation of auditory stimuli or uncontaminated electrophysiological recording and its variable duration allows aperiodic stimulus or response-locked signal averaging as well as gating to physiology or motion.

physiology↗