Biology subjects

Hitrec, T.

Publications and source records attributed to Hitrec, T..

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↗

bioRxiv2025

Synthetic torpor in the rat recapitulates key deatures of torpor and protects the heart from ischaemia-reperfusion injury

During times of environmental stress, many animals enter torpor: a reversible protective physiological state typically characterised by reductions in core temperature, heart rate and oxygen consumption. Species that naturally enter this hypothermic and hypometabolic state are tolerant of ischaemia-reperfusion injury. Consequently, there is a growing interest in utilizing aspects of torpor for clinical applications, such as protection from stroke or myocardial infarction. It is currently unknown, however, whether a torpor-like state is protective in animals that do not naturally enter torpor. Using viral vector-mediated chemogenetic activation of the medial preoptic area of the hypothalamus, we induced synthetic torpor in the rat, a species that does not naturally enter torpor. We demonstrate this state is cardioprotective in an ex vivo ischaemia-reperfusion injury model with an ~40% reduction in infarct size. Synthetic torpor-induced cardioprotection of the normothermic, isolated heart is not dependent on prior hypothermia in vivo. Phosphoproteomic analysis of cardiac tissue indicates the protective effects of synthetic torpor may be mediated by parallel activation of cell survival and stress tolerance pathways and inhibition of cell death pathways. These findings provide important insights into the mechanisms of organ protective effects of synthetic torpor states with implications for future clinical translation in humans.

neuroscience↗

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↗

bioRxiv2022

Synthetic torpor triggers a neuroprotective and regulated mechanism in the rat brain, leading to the reversibility of Tau protein hyperphosphorylation.

Hyperphosphorylated Tau protein (PPTau) is the hallmark of tauopathic neurodegeneration. During "synthetic torpor" (ST), a transient hypothermic state which can be induced in rats by the local pharmacological inhibition of the Raphe Pallidus, a reversible brain Tau hyperphosphorylation occurs. The aim of the present study was to elucidate the - as yet unknown - molecular mechanisms underlying this process, at both a cellular and systemic level. Different phosphorylated forms of Tau and the main cellular factors involved in Tau phospho-regulation were assessed by western blot in the parietal cortex and hippocampus of rats induced in ST, at either the hypothermic nadir or after the recovery of euthermia. Pro- and anti-apoptotic markers, as well as different systemic factors which are involved in natural torpor, were also assessed. Finally, the degree of microglia activation was determined through morphometry. Overall, the results show that ST triggers a regulated biochemical process which can counteract PPTau formation starting, unexpectedly even for a non-hibernator, from the hypothermic nadir. In particular, at the nadir, the glycogen synthase kinase-{beta} was largely inhibited in both regions, the antiapoptotic factor AKT was significantly activated in the hippocampus, and melatonin plasma levels were significantly increased, while a transient neuroinflammation was observed during the recovery period. Together, the present data suggest that ST can trigger a previously undescribed latent and regulated physiological process, that is able to cope with brain PPTau formation. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=113 SRC="FIGDIR/small/485745v3_ufig1.gif" ALT="Figure 1"> View larger version (56K): org.highwire.dtl.DTLVardef@12e4ccdorg.highwire.dtl.DTLVardef@b44201org.highwire.dtl.DTLVardef@598a7corg.highwire.dtl.DTLVardef@92df61_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗

bioRxiv2021

Neurons in the dorsomedial hypothalamus promote, prolong, and deepen torpor

Torpor is a naturally occurring, hypometabolic, hypothermic state engaged by a wide range of animals in response to imbalance between the supply and demand for nutrients. Recent work has identified some of the key neuronal populations involved in daily torpor induction in mice, in particular projections from the preoptic area of the hypothalamus (POA) to the dorsomedial hypothalamus (DMH). The DMH plays a role in thermoregulation, control of energy expenditure, and circadian rhythms, making it well positioned to contribute to the expression of torpor. We used activity dependent genetic TRAPing techniques to target DMH neurons that were active during natural torpor bouts in female mice. Chemogenetic reactivation of torpor-TRAPed DMH neurons in calorie-restricted mice promoted torpor, resulting in longer and deeper torpor bouts. Chemogenetic inhibition of torpor-TRAPed DMH neurons did not block torpor entry, suggesting a modulatory role for the DMH in the control of torpor. This work adds to the evidence that the POA and the DMH form part of a circuit within the mouse hypothalamus that controls entry into daily torpor. SignificanceDaily heterotherms such as mice employ torpor to cope with environments in which the supply of metabolic fuel is not sufficient for the maintenance of normothermia. Daily torpor involves reductions in body temperature, as well as active suppression of heart rate and metabolism. How the central nervous system controls this profound deviation from normal homeostasis is not known, but a projection from the preoptic area to the dorsomedial hypothalamus has recently been implicated. We demonstrate that the dorsomedial hypothalamus contains neurons that are active during torpor. Activity in these neurons promotes torpor entry and maintenance, but their activation alone does not appear to be sufficient for torpor entry.

neuroscience↗