Lina Qu

Sleep disturbance is a prevalent public health concern associated with cognitive deficits and emotional dysregulation, yet the mechanisms underlying SD-induced hypothalamic dysfunction remain incompletely understood. Here, we found that two weeks of SD induced marked hypothalamic neuroinflammation, accompanied by increased expression of the pro-inflammatory cytokines IL-1β, IL-6, and TNF-α, as well as the chemokine Ccl2, together with reduced neuronal markers, including decreased Nissl-body and NeuN⁺ cells. Single-nucleus RNA sequencing (snRNA-seq) suggested that inhibitory neurons exhibited prominent transcriptional responses to SD, including enrichment of inflammatory pathways such as TNF and IL-17 signaling and transcriptional programs associated with neuronal dysfunction. Furthermore, SD was also associated with microglial activation and a phenotypic shift toward a disease-associated state, exhibiting enhanced antigen-presenting and pro-inflammatory capacity. Notably, intercellular communication analysis identified the neural cell adhesion molecule 1 (NCAM1)/fibroblast growth factor receptor 1 (FGFR1) signaling axis as a key mediator of crosstalk between microglia and other cell types. In BV2 cells, recombinant NCAM1 attenuated lipopolysaccharide-induced inflammatory responses in an Fgfr1-dependent manner. Consistently, PVN-targeted Fgfr1 knockdown in vivo exacerbated SD-associated microglial activation, neuroinflammation, and neuronal injury. Collectively, our findings elucidate a critical protective role for the NCAM1/FGFR1 axis in mitigating SD-induced hypothalamic neuroinflammation and neuronal injury. This highlights this pathway as a candidate mechanism for further therapeutic investigation in sleep-related neurological dysfunction.

Age-related decline in learning and memory functions poses significant challenges in an aging society, with epigenetic dysregulation emerging as a key contributor to cognitive deterioration. As the most prevalent internal RNA modification, N6-methyladenosine (m6A) dynamically orchestrates neural transcriptome plasticity through its “writers,” “erasers,” and “readers,” yet its role in aging-associated cognitive impairment remains underexplored. This study employs an integrated epitranscriptomic approach to investigate m6A-mediated regulation in hippocampal aging processes. Through comparative m6A-mRNA epitranscriptomic microarray analysis of senescence-accelerated mouse prone 8 (SAMP8) and senescence-resistant SAMR1 hippocampi, we identified neural cell adhesion molecule 1 (NCAM1) as a key m6A-regulated effector whose decreased expression correlates with accelerated cognitive deterioration. Mechanistically, we revealed that Methyltransferase-like 3 (METTL3)-mediated m6A modification governs Ncam1 mRNA stability through insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) reader protein-dependent mechanisms, forming a regulatory axis that modulates cyclic AMP response element-binding protein (CREB) signaling pathway activity. Remarkably, targeting of this METTL3/IGF2BP1/NCAM1 axis significantly attenuated cognitive deficits in aged SAMP8 mice. Our findings establish an m6A methylation-dependent paradigm for NCAM1-mediated cognitive preservation during aging, uncovering a novel epitranscriptomic layer in age-related neurodegeneration.

Prolonged microgravity exposure disrupts cerebral hemodynamic homeostasis, yet longitudinal cerebral blood flow (CBF) adaptation remains poorly understood. This study investigated CBF changes under 90 days head-down bed rest (HDBR) in 36 healthy adults using pseudo-continuous arterial spin labeling (pCASL) MRI. Analyses included region-of-interest (global/regional CBF) and voxel-based whole-brain assessments, alongside physiological correlations. Results demonstrated stable global CBF after HDBR but revealed distinct microcirculatory redistribution: the vertebrobasilar (VB) territory exhibited significant perfusion increases, while voxel-based analysis identified elevated CBF in the left fusiform gyrus and reduced perfusion in the right superior frontal gyrus, middle cingulate gyrus, and Heschl’s gyrus. Physiological correlations indicated negative associations between VB-CBF and diastolic blood pressure (DBP)/mean arterial pressure (MAP), with pre-HDBR heart rate as a key modulator of VB perfusion changes. A potential relationship between age and altered CBF has been found in the right superior frontal gyrus in young adults. These findings suggest that although global CBF stabilizes during simulated microgravity, posterior circulation-dominated microvascular redistribution occurs, tightly coupled with cardiovascular dynamics, offering critical insights for optimizing countermeasures in spaceflight and terrestrial cerebrovascular diseases.

Space exploration presents tremendous health challenges. Here, we report time series of multi-omic and phenotypic profiles of seventeen astronauts from six China Manned Space missions with continuous spaceflight durations ranging from 13 to 180 days. We revealed a key role of DNA methylation regulation in reshaping gene expression patterns to adapt to the space environment. Notably, long-duration spaceflight showed more alterations in epigenetic modifications correlated with alternative splicing and protein acetylation. During recovery, an "overrange rebound" phenomenon was observed, furthermore, a mathematical model was established to describe this implying important phenomenon. Moreover, we revealed the correlations between molecular alterations and phenotypic changes such as coagulation activation and bone intensity loss. Additionally, we performed ground-based simulation experiments to estimate the impacts of individual stressors in the space environment on DNA methylation. In summary, our study highlights the importance and complexity of epigenetic regulation in adaptation to and recovery from the space environment.

Original Article Ophthalmic changes are associated with visual cortex functional network reorganization after 90-day head-down tilt bed rest Linkun Cai, Ke Lv, Haijun Niu, Pengling Ren, Hongmei Li, Yuan Xie, Yawen Liu, Kai Li, Tingting Zhang, Xia Ma, Yingdi Fu, Zi Xu, Yaqi Shao, Liang Lu, Penggang Qiao, Han Lv, Wei Zheng, Chengjia Yang, Ningli Wang, Linjie Wang, Dehong Luo, Lina Qu, Yinghui Li, Zhenchang Wang

Background: Abnormal alterations in cerebral blood flow (CBF) have been implicated in cognitive decline and neurodegeneration. Maintaining adequate CBF in astronauts during long-duration microgravity is therefore crucial for the success of manned spaceflight. However, the quantitative assessment of CBF during space missions remains challenging. Methods: Thirty-six participants underwent a 90-d −6° head-down tilt bed rest (HDTBR) protocol, a well-established ground-based analog of microgravity. Multimodal imaging data, including internal carotid artery Doppler ultrasound and brain magnetic resonance imaging, were collected during HDTBR. Multiple machine learning (ML) algorithms were developed to investigate carotid–CBF mapping relationship and establish CBF change prediction models. Results: After 90-d HDTBR, significant regional CBF decreases were observed, primarily in the right Heschl’s gyrus, right middle cingulate gyrus, and right superior frontal gyrus. The optimal ML model CatBoost showed robust predictive performance for CBF in these regions (right Heschl’s gyrus: AUC = 0.88, accuracy = 0.84; right middle cingulate gyrus: AUC = 0.92, accuracy = 0.83; right superior frontal gyrus: AUC = 0.82, accuracy = 0.72). To enhance accessibility and practical utility, the prediction model was implemented as an interactive web application for in-orbit deployment. Conclusion: This study demonstrates the feasibility of constructing ML-driven CBF prediction models under microgravity based on multimodal imaging. The developed prediction models show promise as early warning tools for brain health of astronauts in spaceflight.

Background: Long-term fasting demonstrates greater therapeutic potential and broader application prospects in extreme environments than intermittent fasting. Method: This pilot study of 10-day complete fasting (CF), with a small sample size of 13 volunteers, aimed to investigate the time-series impacts on gut microbiome, serum metabolome, and their interrelationships with biochemical indices. Results: The results show CF significantly affected gut microbiota diversity, composition, and interspecies interactions, characterized by an expansion of the Proteobacteria phylum (about six-fold) and a decrease in Bacteroidetes (about 50%) and Firmicutes (about 34%) populations. Notably, certain bacteria taxa exhibited complex interactions and strong correlations with serum metabolites implicated in energy and amino acid metabolism, with a particular focus on fatty acylcarnitines and tryptophan derivatives. A key focus of our study was the effect of Ruthenibacterium lactatiformans, which was highly increased during CF and exhibited a strong correlation with fat metabolic indicators. This bacterium was found to mitigate high-fat diet-induced obesity, glucose intolerance, dyslipidemia, and intestinal barrier dysfunction in animal experiments. These effects suggest its potential as a probiotic candidate for the amelioration of dyslipidemia and for mediating the benefits of fasting on fat metabolism. Conclusions: Our pilot study suggests that alterations in gut microbiota during CF contribute to the shift of energy metabolic substrate and the establishment of a novel homeostatic state during prolonged fasting.

Long-term spaceflight is known to induce disruptions in circadian rhythms, which are driven by a central pacemaker located in the suprachiasmatic nucleus (SCN) of the hypothalamus, but the underlying molecular mechanisms remain unclear. Here, we developed a rat model that simulated microgravity and isolation environments through tail suspension and isolation (TSI). We found that the TSI environment imposed circadian disruptions to the core body temperature, heart rate, and locomotor-activity rhythms of rats, especially in the amplitude of these rhythms. In TSI model rats’ SCNs, the core circadian gene NR1D1 showed higher protein but not mRNA levels along with decreased BMAL1 levels, which indicated that NR1D1 could be regulated through post-translational regulation. The autophagosome marker LC3 could directly bind to NR1D1 via the LC3-interacting region (LIR) motifs and induce the degradation of NR1D1 in a mitophagy-dependent manner. Defects in mitophagy led to the reversal of NR1D1 degradation, thereby suppressing the expression of BMAL1. Mitophagy deficiency and subsequent mitochondrial dysfunction were observed in the SCN of TSI models. Urolithin A (UA), a mitophagy activator, demonstrated an ability to enhance the amplitude of core body temperature, heart rate, and locomotor-activity rhythms by prompting mitophagy induction to degrade NR1D1. Cumulatively, our results demonstrate that mitophagy exerts circadian control by regulating NR1D1 degradation, revealing mitophagy as a potential target for long-term spaceflight as well as diseases with SCN circadian disruption.