Biology subjects

Mather, M.

Publications and source records attributed to Mather, M..

24 records · Page 2Linked to original sources

bioRxiv2021

Intrinsic and extrinsic regulation of human fetal bone marrow haematopoiesis and perturbations in Down syndrome

Throughout postnatal life, haematopoiesis in the bone marrow (BM) maintains blood and immune cell production. Haematopoiesis first emerges in human BM at 12 post conception weeks while fetal liver (FL) haematopoiesis is still expanding. Yet, almost nothing is known about how fetal BM evolves to meet the highly specialised needs of the fetus and newborn infant. Here, we detail the development of fetal BM including stroma using single cell RNA-sequencing. We find that the full blood and immune cell repertoire is established in fetal BM in a short time window of 6-7 weeks early in the second trimester. Fetal BM promotes rapid and extensive diversification of myeloid cells, with granulocytes, eosinophils and dendritic cell (DC) subsets emerging for the first time. B-lymphocyte expansion occurs, in contrast with erythroid predominance in FL at the same gestational age. We identify transcriptional and functional differences that underlie tissue-specific identity and cellular diversification in fetal BM and FL. Finally, we reveal selective disruption of B-lymphocyte, erythroid and myeloid development due to cell intrinsic differentiation bias as well as extrinsic regulation through an altered microenvironment in the fetal BM from constitutional chromosome anomaly Down syndrome during this crucial developmental time window.

developmental biology↗

bioRxiv2021

Fear in the mind's eye: Mental imagery can generate and regulate acquired differential fear conditioned reactivity

Mental imagery is an important tool in the cognitive control of emotion. The present study tests the prediction that visual imagery can generate and regulate differential fear conditioning via the activation and prioritization of stimulus representations in early visual cortices. We combined differential fear conditioning with manipulations of viewing and imagining basic visual stimuli in humans. We discovered that mental imagery of a fear-conditioned stimulus compared to imagery of a safe conditioned stimulus generated a significantly greater conditioned response as measured by self-reported fear, the skin conductance response, and right anterior insula activity (experiment 1). Moreover, mental imagery effectively down- and up-regulated the fear conditioned responses (experiment 2). Multivariate classification using the functional magnetic resonance imaging data from retinotopically defined early visual regions revealed significant decoding of the imagined stimuli in V2 and V3 (experiment 1) but significantly reduced decoding in these regions during imagery-based regulation (experiment 2). Together, the present findings indicate that mental imagery can generate and regulate a differential fear conditioned response via mechanisms of the depictive theory of imagery and the biased-competition theory of attention. These findings also highlight the potential importance of mental imagery in the manifestation and treatment of psychological illnesses.

neuroscience↗

bioRxiv2020

Locus coeruleus MRI contrast is associated with cortical thickness in older adults

There is growing evidence that neuronal integrity of the noradrenergic locus coeruleus (LC) is important for later-life cognition. Less understood is how LC integrity relates to brain correlates of cognition, such as brain structure. Here, we examined the relationship between cortical thickness and a measure reflecting LC integrity in older (n = 229) and younger adults (n = 67). Using a magnetic resonance imaging sequence which yields high signal intensity in the LC, we assessed the contrast between signal intensity of the LC and that of neighboring pontine reference tissue. The Freesurfer software suite was used to quantify cortical thickness. LC contrast was positively related to cortical thickness in older adults, and this association was prominent in parietal, frontal, and occipital regions. Brain regions where LC contrast was related to cortical thickness include portions of the frontoparietal network which have been implicated in noradrenergically modulated cognitive functions. These findings provide novel evidence for a link between LC structure and cortical brain structure in later adulthood.

neuroscience↗

bioRxiv2019

Isometric exercise facilitates attention to salient events in women via the noradrenergic system

The locus coeruleus (LC) plays a critical role in regulating attention via the release of norepinephrine (NE), with levels of tonic LC activity constraining the intensity of phasic LC responses. However, the effects of manipulating tonic LC-NE activity on phasic activity have yet to be demonstrated in humans. In the current fMRI study, we used isometric handgrip to modulate tonic LC-NE activity in the time period immediately afterwards. During this post-handgrip time, an oddball detection task was used to probe how changes in tonic arousal influenced functional coordination between the LC and a right frontoparietal network that supports attentional selectivity. As expected, the frontoparietal network responded more to infrequent target and novel sounds than to frequent sounds. Across participants, greater LC-frontoparietal functional connectivity, pupil dilation, and faster oddball detection were all positively associated with LC MRI contrast from a neuromelanin-sensitive structural scan. Thus, LC structural integrity was related to LC functional dynamics and attentional performance during the oddball task. We also found that handgrip led to larger phasic pupil responses to oddball sounds, faster oddball detection speed, and greater frontoparietal network activation, suggesting that something that induces strong LC activity benefits attentional performance for at least the next few minutes. In addition, older women showed a similar benefit of handgrip on frontoparietal network activation as younger women, despite showing lower frontoparietal network activation overall. Together these findings suggest that a simple exercise may improve selective attention in healthy aging, at least for several minutes afterwards.\n\nHighlightsO_LIWe examined how handgrip affects arousal-attention dynamics during an oddball task\nC_LIO_LISalient stimuli enhanced pupil dilation and were detected faster post-handgrip\nC_LIO_LIA decrease in tonic pupil size after handgrip suggests norepinephrine depletion\nC_LIO_LIMRI-assessed LC integrity was related to oddball detection and pupil dilation\nC_LIO_LILC integrity also associated with LC-frontoparietal network functional connectivity\nC_LI

neuroscience↗

bioRxiv2019

Decoding the development of the blood and immune systems during human fetal liver haematopoiesis

Definitive haematopoiesis in the fetal liver supports self-renewal and differentiation of haematopoietic stem cells/multipotent progenitors (HSC/MPPs), yet remains poorly defined in humans. Using single cell transcriptome profiling of ~133,000 fetal liver and ~65,000 fetal skin and kidney cells, we identify the repertoire of blood and immune cells in first and early second trimesters of development. From this data, we infer differentiation trajectories from HSC/MPPs, and evaluate the impact of tissue microenvironment on blood and immune cell development. We predict coupling of mast cell differentiation with erythro-megakaryopoiesis and identify physiological erythropoiesis in fetal skin. We demonstrate a shift in fetal liver haematopoietic composition during gestation away from being erythroid-predominant, accompanied by a parallel change in HSC/MPP differentiation potential, which we functionally validate. Our integrated map of fetal liver haematopoiesis provides a blueprint for the study of paediatric blood and immune disorders, and a valuable reference for understanding and harnessing the therapeutic potential of HSC/MPPs.

developmental biology↗

bioRxiv2018

Locus coeruleus integrity preserves memory performance across the adult life span

For decades, research into memory decline in human cognitive aging has focused on neocortical regions, the hippocampus, and dopaminergic neuromodulation. Recent findings indicate that the locus coeruleus (LC) and noradrenergic neuromodulation may also play an important role in shaping memory development in later life. However, technical challenges in quantifying LC integrity have hindered the study of LC-cognition associations in humans. Using high-resolution neuromelanin-sensitive magnetic resonance imaging, we found that individual differences in learning and memory were positively associated with LC integrity across a variety of memory tasks in younger (n = 66), and older adults (n = 228). Moreover, we observed functionally relevant age differences confined to rostral LC. Older adults with a more youth-like rostral LC also showed higher memory performance. These findings link non-invasive, in vivo indices of LC integrity to memory in aging and highlight the role of the LC norepinephrine system in the decline of cognition.

neuroscience↗