Individuals recovering from post-traumatic stress disorder (PTSD) often relapse due to context-induced fear memory retrieval when exposed to the same context in which they first experienced the trauma. Previous studies showed that both the ventral hippocampus CA1 (vCA1) and the dorsal hippocampus CA1 (dCA1) were involved in context-induced retrieval of fear memories. However, the causal relationship and the neural circuits between vCA1 and dCA1 during this process remain unknown. The present results show that vCA1 is an upstream brain region of the activation of dCA1; neural circuits from the vCA1 to the dCA1 via the lateral entorhinal cortex (LEC) mediate context-induced retrieval of fear memory; downstream neural circuits of dCA1 involve projections to the basolateral amygdala (BLA) via the postrhinal cortex (POR). These results suggest that a long neural circuit spanning multiple brain regions is involved in context-induced retrieval of fear memory.
Sarcopenia, characterized by the progressive loss of skeletal muscle mass and function, is a major hallmark of aging. Post-translational modifications (PTMs) play essential roles in regulating protein activity and cellular homeostasis; however, how multiple PTMs are remodeled during skeletal muscle aging remains incompletely characterized. Here, we performed comprehensive multi-layered proteomic profiling of skeletal muscle from young (3-month-old) and aged (24-month-old) mice, systematically quantifying the global proteome together with five major PTMs: acetylation, phosphorylation, N-glycosylation, O-glycosylation, and ubiquitination. In total, we identified 5 337 proteins and mapped thousands of PTM sites, generating an integrated atlas of age-associated proteomic and PTM remodeling in skeletal muscle. Pathway enrichment analyses revealed distinct modification-specific patterns: acetylation and phosphorylation were predominantly associated with metabolic and mitochondrial-related pathways; N-glycosylation was enriched in immune- and secretory pathway-related processes; O-glycosylation was associated with muscle contraction-related pathways; and ubiquitination was preferentially linked to cytoskeletal organization in muscle cells. Correlation analyses further uncovered diverse association patterns among different PTMs across protein- and modification-level datasets. Phosphorylation and ubiquitination exhibited consistent positive associations, whereas acetylation and ubiquitination showed both inverse and concordant co-variation patterns across subsets of proteins. Phosphorylation and O-glycosylation displayed heterogeneous association patterns across different proteins, and acetylation and phosphorylation demonstrated positive correlations with distinct age-associated directional changes across protein subsets. Together, these results provide a comprehensive, multi-dimensional view of age-associated remodeling of the skeletal muscle proteome and multiple PTM layers, offering a valuable resource for understanding molecular alterations accompanying muscle aging and sarcopenia.
Oxygen levels in the ocean have decreased worldwide as a result of climate change and nutrient contamination, which has had a significant impact on marine ecosystems. Although deep-sea fish that reside in oxygen minimum zones (OMZs) demonstrate remarkable adaptations to hypoxia, the molecular mechanisms that underlie their resilience are still inadequately understood. The hypoxia-inducible factors (HIFs), regulated by the hypoxia signaling pathway, play a crucial role in maintaining cellular and systemic oxygen homeostasis in response to changes in oxygen supply. In this study, we investigated the HIFs pathway in three deep-sea fish species: Pseudoliparis swirei, Ilyophis sp., and Liparis tanakai. We found that Ilyophis sp. HIF-1α shows stronger transcriptional activity and upregulates hypoxia-response genes more efficiently than the other species. Mutational analysis revealed that the deletion mutation of the nuclear export signal (NES) in Ilyophis sp . HIF-1α may enhance its stability, while Plk3 may function as a negative regulator of deep-sea fish HIF-1α under hypoxic conditions. This study reveals divergent evolutionary strategies in hypoxia adaptation among deep-sea fishes, highlighting how structural and regulatory mechanisms enable survival in oxygen-deprived environments, and provides novel insights into the genetic mechanisms enabling survival in OMZs, advancing our understanding of marine hypoxia resilience and its implications for ecosystem dynamics under global deoxygenation.
The relationship between lineage output and transcriptional features of hematopoietic stem cells (HSCs) has been reported in adult bone marrow, yet it remains unclear in fetal liver, given their distinct developmental stage and microenvironment. Here, we systematically characterized the functions of E14.5 mouse fetal liver HSCs by lentiviral barcode labeling followed by transplantation, with subsequent single-cell RNA sequencing (scRNA-seq) and clonal analysis performed on donor-derived HSCs and their progeny in recipient bone marrow. We identified three HSC subtypes based on lineage bias, with myeloid-biased and balanced subtypes predominating. Importantly, within the same subtype, HSCs and their progeny share several transcriptional programs, and these programs show minimal overlap between subtypes. We term the retention of subtype-specific transcriptional features across lineages as "transcriptional persistence". Notably, this phenomenon was not observed in adult bone marrow. Alternatively, classification by progeny output activity revealed the presence of low-output and high-output subtypes within fetal liver HSCs. Although these two subtypes showed no significant difference in stemness features, they exhibited distinct transcriptional features and signaling activation states, which also differed from their counterparts in bone marrow, indicating that the biological characteristics of HSCs with different output activities vary by developmental stage. Of note, in both fetal liver and adult bone marrow, transcriptional persistence showed no obvious correlation with output activity, suggesting a specific coupling relationship between transcriptional persistence and lineage bias. Collectively, our study provides a clonal-resolution view of fetal liver HSC heterogeneity, enhancing our understanding of HSC diversity across different developmental stages.
TGF-β1, the core ligand of the transforming growth factor β (TGF-β) signaling pathway, is crucial for follicular development and female fertility. However, it remains unclear whether microRNAs (miRNAs), an important class of epigenetic regulators, mediate the anti-atretic effect of TGF-β1. Here, joint transcriptomic analysis demonstrated that miR-184, an anti-atretic miRNA, was significantly elevated by TGF-β1 in sow granulosa cells (GCs). Quantitative detection, correlation analysis, luciferase reporter assays, and chromatin immunoprecipitation confirmed that TGF-β1 induces miR-184 transcription in a SMAD4-dependent manner, with SMAD4 acting as a transcriptional activator that directly binds to the miR-184 promoter under TGF-β1 stimulation. RNA-seq and bioinformatics analysis revealed that the target genes of miR-184 are enriched in the TGF-β pathway, with TGF-β1 being feedback-induced by miR-184. In vivo and in vitro mechanistic analyses revealed that miR-184, a small-activating RNA (saRNA), activates TGF-β1 transcription by binding to its promoter and forming an RNA-induced transcriptional activation complex with AGO2, CTR9, DHX9, and RNA polymerase II. Consequently, a novel positive feedback loop (TGF-β1/SMAD4/miR-184) was identified. In vitro GC and follicle culture systems validated the anti-apoptotic/atretic functions of this loop. Moreover, comparative analyses showed that the levels of TGF-β1 and miR-184 in the follicles of high-fertility sows were significantly higher than those in low-fertility sows. Our findings highlight the critical role of the interaction between TGF-β1 and miR-184 in inhibiting GC apoptosis and follicular atresia, providing potential targets for improving follicular development and sow fertility.
The central cholinergic system regulates diverse neurological functions, learning, attention, arousal, sleep, emotion regulation and behavior control. As a close evolutionary relative of primates, the tree shrew is a valuable comparative model for neurobiological investigation. However, the anatomical distribution of choline acetyltransferase-immunoreactive (ChAT-ir) neurons in its brain remains poorly characterized. Using ChAT immunofluorescence, we systematically mapped the whole-brain distribution and morphology of ChAT-ir neurons in the tree shrew and compared them with those in the mouse. In the neocortex, ChAT-ir neurons were absent in the tree shrew, whereas the mouse showed sparse cortical labeling. Semi-quantitative analyses of subcortical regions revealed the overall distribution was largely conserved, whereas the tree shrew exhibited higher ChAT-ir neuronal density in the trochlear and prepositus nuclei compared to mice. ChAT-ir neurons were detected in the suprachiasmatic and supraoptic nuclei in the hypothalamus in the tree shrew but not in the mouse. Tree shrew ChAT-ir neurons showed greater dendritic complexity in the caudate nucleus, medial septum, pedunculopontine/dorsal tegmental nuclei, and prepositus nucleus, while the horizontal limb of the diagonal band and oculomotor nuclei exhibited similar complexity across species. In the putamen, the tree shrew has more complex distal dendrites but less complex proximal branches than mice. ChAT-ir neurons displayed a rostral-to-caudal density gradient in the caudate, while mice showed largely uniform distributions of ChAT-, CB-, PV-, and CR-positive neurons across the medial and lateral sides of the caudate putamen. These findings provide a comprehensive mapping of ChAT-ir neurons in the tree shrew brain, highlighting significant interspecies differences and offering a structural framework for investigating cholinergic roles in diverse neural functions.
Viviparity has independently evolved multiple times in teleosts, leading to diverse modes of maternal nutrient provisioning. In black rockfish ( Sebastes schlegelii), embryos gain dry weight during gestation, supported by a placental connection that facilitates maternal-fetal nutrient transfer. Although prior studies have outlined the morphology and evolutionary convergence of the black rockfish placental analogue, its full architecture and underlying molecular mechanisms remain unresolved. Here, we show that the maternal component of the placental analogue, derived from ovarian follicular tissue, consists of a vascularized outer layer and a glandularized inner layer, organized into a sac-like structure. At the molecular level, this transformation involves epithelial-mesenchymal interactions, angiogenesis, and immune responses. We observed exosome-like structures surrounding the placental analogue and isolated ovarian exosomes for characterization. These findings suggest active crosstalk between developing embryos and the maternal ovary, which may underlie the observed changes. Subsequent proteomic and transcriptomic analyses revealed that these exosomes carry diverse functional cargos, including hepatocyte growth factor b ( hgfb) mRNA. Ovarian cells efficiently internalize exosomes, upregulating hgfb mRNA and protein expression and secretion, which in turn reprograms gene expression and promotes angiogenesis-related placentation. Together, these results elucidate the molecular underpinnings of ovarian placentation in black rockfish and offer valuable perspectives on the oviparity-to-viviparity transition in fish evolution.
