Biology subjects

Muir, C.

Publications and source records attributed to Muir, C..

5 recordsLinked to original sources

bioRxiv2025

Differential Effects of Sex and Age on Daily and Infradian Rhythms of Mice Running Title: Sex and Age Differences in Mouse Rhythms

Intrinsic biological rhythms regulate key physiological and behavioural processes, yet the influence of sex and age on these rhythms is not fully understood. We comprehensively examined 24-hour (circadian) and >24-hour (infradian; 5-day and 10-day) rhythms in wheel-running and ingestive behaviours in single-housed young and middle-aged male and female mice. Circadian analysis revealed that middle-aged mice, particularly females, exhibited more precise daily rhythms and shifted a greater proportion of activity and feeding to the lights-on phase compared to young female mice. Middle-aged animals also ran for longer durations per day, suggesting age-related changes in activity regulation. Analysis of infradian rhythms further highlighted sex- and age-specific differences. Young female mice displayed robust 5-day rhythms in wheel-running activity, which were absent in middle-aged females. In contrast, few males (young or middle-aged) showed significant 5-day rhythms. Ten-day rhythms were most prominent in male mice, while females rarely expressed this periodicity. Physiologically, middle-aged mice lost more body weight in response to single housing, with middle-aged females being most affected. Interactions among behavioural rhythms in females also showed greater complexity, which increased with age. These findings reveal distinct sex- and age-dependent patterns in circadian and infradian rhythms as well as in physiological responses to isolation. Our work highlights the need to account for sex and age in chronobiological research, with broader implications for understanding vulnerability to age-related metabolic and behavioural disorders.

animal behavior and cognition↗

bioRxiv2024

Food-entrainment of circadian timekeeping in the dorsal vagal complex

The dorsal vagal complex (DVC) is a multi-component brainstem satiety centre which has gained attention as a key target of anti-obesity pharmacotherapies. Our recent studies revealed its circadian timekeeping properties, with molecular and electrophysiological 24h rhythms persisting independently of the primary hypothalamic clock. However, the factors entraining these brainstem oscillators, and the downstream transcriptional targets of the DVC molecular clock remain unclear. Here, using fluorescent in situ hybridisation, we demonstrate core clock gene expression in inhibitory and excitatory neuronal populations of the DVC, as well as in its output cholinergic vagal neurons. We further reveal that the molecular clock is associated with rhythmic expression of numerous neurotransmitter receptor genes in the DVC in vivo, with the phase of both clock and clock-controlled gene expression tightly regulated by meal timing. These findings uncover food-entrained circadian rhythms in the DVC and have important implications for clinical studies targeting brainstem satiety mechanisms.

neuroscience↗

bioRxiv2024

Convergent genetic adaptation in human tumors developed under systemic hypoxia and in populations living at high altitudes

EPAS1HIF2 is the primary gene implicated in systemic hypoxia adaptation. Conversely, aberrantly activated EPAS1HIF2 acts as a tumor driver against which anti-tumor therapeutics are proven effective. We elucidated connections between adaptation to systemic hypoxia in high-altitude populations, such as Tibetans and Sherpas, and human tumors. Similar to the accelerated adaptability observed in high-altitude populations via genetic introgression, tumors from patients with hypoxia since birth exhibited impaired DNA repair and increased mutation burden. As in high-altitude dwellers, EPAS1HIF2 genetic variants were positively selected within sympathetic tumors developed under hypoxia, with a consistently high frequency of 90%. Bulk and single-cell RNA sequencing followed by in vitro studies have shown that hypoxia and EPAS1HIF2 gain-of-function tumor mutations induce COX4i2 expression and impair mitochondrial respiration, indicating that decreased cellular oxygen consumption may confer a proliferative advantage in hypoxia. Analyzing medical data from a patient cohort with hypoxia since birth who developed/did not develop tumors revealed tissue-specific and time-dependent tumorigenic effects of systemic hypoxia, which is limited to oxygen-sensitive and responsive cells, particularly during the postnatal period. This study supports connections between the EPAS1HIF2 genetic adaptation in human tumors developed under systemic hypoxia to populations living in high altitudes. The genetic adaptations in populations to different stressors can be explored further to understand tumorigenesis and tumor evolution.

cancer biology↗

bioRxiv2021

The neural cell adhesion molecule NrCAM regulates development of hypothalamic tanycytes

Hypothalamic tanycytes are neural stem and progenitor cells, but little is known of how they are regulated. Here we provide evidence that the cell adhesion molecule, NrCAM, regulates tanycytes in the adult niche. NrCAM is strongly expressed in adult mouse tanycytes. Immunohistochemical and in situ hybridization analysis revealed that NrCAM loss of function leads to both a reduced number of tanycytes and reduced expression of tanycyte-specific cell markers, along with a small reduction in tyrosine hydroxylase-positive arcuate neurons. Similar analyses of NrCAM mutants at E16 identify few changes in gene expression or cell composition, indicating that NrCAM regulates tanycytes, rather than early embryonic hypothalamic development. Neurosphere and organotypic assays support the idea that NrCAM governs cellular homeostasis. Single-cell RNA sequencing (scRNA-Seq) shows that tanycyte-specific genes, including a number that are implicated in thyroid hormone metabolism, show reduced expression in the mutant mouse. However, the mild tanycyte depletion and loss of markers observed in NrCAM-deficient mice were associated with only a subtle metabolic phenotype.

neuroscience↗

bioRxiv2019

Is amphistomy an adaptation to high light? Optimality models of stomatal traits along light gradients

Stomata regulate the supply of CO2 for photosynthesis and the rate of water loss out of the leaf. The presence of stomata on both leaf surfaces, termed amphistomy, increases photosynthetic rate, is common in plants from high light habitats, and rare otherwise. In this study I use optimality models based on leaf energy budget and photosynthetic models to ask why amphistomy is common in high light habitats. I developed an R package leafoptimizer to solve for stomatal traits that optimally balance carbon gain with water loss in a given environment. The model predicts that amphistomy is common in high light because its marginal effect on carbon gain is greater than in the shade, but only if the costs of amphistomy are also lower under high light than in the shade. More generally, covariation between costs and benefits may explain why stomatal and other traits form discrete phenotypic clusters.

plant biology↗