Biology subjects

Kay, D.

Publications and source records attributed to Kay, D..

3 recordsLinked to original sources

bioRxiv2025

APOE4 homozygotes have less sleep fragmentation in late adulthood

Background and ObjectivesAPOE4, a genetic risk factor for Alzheimers Disease (AD), is associated with reduced functional connectivity of brain regions that regulate sleep, which may predispose persons to AD via altering sleep architecture. However, little is known about differences in sleep architecture by APOE genotype. MethodsThis cross-sectional study examined the association between APOE genotype and sleep architecture among middle-aged and older adults, using polysomnography (Sleep Heart Health Study, N=3,132). APOE genotype included: APOE4 heterozygotes, APOE4 homozygotes, APOE2 carriers, and APOE3 homozygotes. Macro sleep architecture was quantified using the percentage of time spent in rapid eye movement sleep (%REM), N1 (N1%), N2 (%N2), N3 (%N3), and arousal index. Micro sleep architecture was quantified as odds ratio product (ORP; a continuous measure of sleep depth) for overall sleep and each sleep stage, and spindle characteristics (power, density, and frequency). Linear regression was used, adjusting for covariates. ResultsThe mean age was 67, 53 percent were female, 24% were APOE4 heterozygotes, 2% were APOE4 homozygotes, 14% were APOE2 carriers, and 60% were APOE3 homozygotes. Macro sleep architecture did not vary across genotypes. Compared with APOE3 homozygotes, APOE4 homozygotes exhibited fewer arousals with age ({beta}=-0.33 per hour/year, p=0.04), resulting in significantly fewer arousals at age 70+. ORP decreased in a dose-response pattern with the number of APOE4 alleles during overall sleep and across all sleep stages (ORPAPOE3/3=0.94, ORPAPOE3/4=0.91, ORPAPOE4/4=0.87), and these group difference widened with each year of age. Finally, there was a trend for lower spindle density and power in APOE4 homozygotes relative to APOE3 homozygotes (ps=0.06). ConclusionsArousal threshold increased in a dose-response manner with each APOE4 allele, as evidenced by the findings on ORP. The differences in ORP between APOE3 homozygotes and APOE4 carriers widened further with age, paralleling age-related declines in arousal index among APOE4 homozygotes. Despite these indications of elevated arousal thresholds that might suggest less sleep fragmentation in APOE4 carriers, APOE4 homozygotes exhibited poorer sleep micro architecture, including trends toward reduced sleep spindle activity. Taken together, reduced arousability in APOE4 carriers may reflect abnormalities in cortical activation that blunt arousal rather than an indicator of healthier sleep.

physiology↗

bioRxiv2021

Circadian clock function does not require the histone methyltransferase MLL3

AO_SCPLOWBSTRACTC_SCPLOWThe circadian clock controls the physiological function of tissues through the regulation of thousands of genes in a cell-type specific manner. The core cellular circadian clock is a transcription-translation negative feedback loop, which can recruit epigenetic regulators to facilitate temporal control of gene expression. Histone methyltransferase, mixed lineage leukemia gene 3 (MLL3) was reported to be required for maintenance of circadian oscillations in cultured cells. Here, we test the role of MLL3 in circadian organisation in whole animals. Using mice expressing catalytically inactive MLL3, we show that MLL3 methyltransferase activity is in fact not required for circadian oscillations in vitro in a range of tissues, nor for maintenance of circadian behavioural rhythms in vivo. In contrast to a previous report, loss of MLL3-dependent methylation did not affect global levels of H3K4 methylation in liver, indicating substantial compensation from other methyltransferases. Further, we found little evidence of genomic repositioning of H3K4me3 marks. We did, however, observe repositioning of H3K4me1 from intronic regions to intergenic regions and gene promoters, however there were no changes in H3K4me1 mark abundance around core circadian clock genes. Output functions of the circadian clock, such as control of inflammation, were largely intact in MLL3-methyltransferase deficient mice, although some gene specific changes were observed, with sexually dimorphic loss of circadian regulation of specific cytokines. Taken together, these observations call for a major reassessment of the inter-relationship between the circadian clock and MLL3-directed histone methylation, and a deeper examination of other epigenetic mechanisms which may facilitate circadian clock function. SO_SCPLOWIGNIFICANCEC_SCPLOWO_SCPCAP C_SCPCAPO_SCPLOWSTATEMENTC_SCPLOWA highly cited paper published in PNAS previously reported an essential role for the histone methyltransferase MLL3 in maintaining circadian oscillations in cultured cells. We tested the role of MLL3 in vivo and in primary tissues showing that MLL3 in fact plays no role in organising the core circadian clock, and has no functional impact on whole animal circadian behaviour. However, in further analysis, we newly discover a role for MLL3 in conferring circadian control to components of the inflammatory response, doing so in a sexually dimorphic manner. As the MLL family of histone methyltransferases are being targeted by pharmaceuticals for cancer, it is important to understand how methyltransferases may be driving circadian rhythms in gene expression.

molecular biology↗

bioRxiv2017

Geospatial statistics of high field functional MRI reveal topographical clustering for binocular stereo depth in early visual cortex

Significance statementFunctional topography is present throughout the cerebral cortex, often in the form of columns or clusters of neurons with similar functional properties within identified cortical regions. Most of the evidence for these structures comes from work with non-human species. Using high-field strength magnetic resonance imaging in living human cortex, the search for this structure is frustrated by the presence of a background of local spatial correlations in the signal across the cortical surface. This structured background, which we term neural dust, is a form of noise that imposes a fundamental limit on the detection of clustering and topography. We apply a novel analysis approach that quantifies the background of spatial correlations, so that we achieve reliable identification of high-signal clusters of activation in the human cortex at a scale previously only visible with invasive optical imaging in animals. We searched specifically in visual cortex for correlates of binocular stereoscopic depth. We show both that signals for stereoscopic depth are clustered into specific zones within the cortex and that these signals occur within spatially extended cortical domains, which have similar preferences for the stereoscopic depth. The revealed structures are reliably identified in all subjects tested and in repeated testing of individual subjects. Our methods provide an objective approach for defining the size and locations of clusters of activation within functional images of neural activity.\n\nAbstractA characteristic principle of the organization of cerebral neocortex is the presence of clusters or columns of neurons with similar functional properties. Animals with forward-facing eyes exploit slight differences between the images in the two eyes to determine binocular depth using stereopsis. Evidence for an organized structure in human visual cortex for the representation of stereoscopic depth has proved elusive. Using 7-tesla functional MRI, with gradient-echo echo-planar imaging at 0.75 mm isotropic resolution and a novel analytical approach based on geospatial mapping methods, we find that clustered responses for disparity-defined depth can be clearly segregated from a background of spatially correlated signals in all subjects tested. High-signal clusters are associated with cortical domains as large as 12-15mm across the cortical surface, in which nearby points in the cortical map tend to respond to the same stereoscopic depth. These domains are found predominantly within visual cortical area V3A.

neuroscience↗