Biology subjects

Zhang, T. Y.

Publications and source records attributed to Zhang, T. Y..

6 recordsLinked to original sources

bioRxiv2026

Sex-specific hormone-sensitive regulatory architecture in adolescence as a scaffold for depression vulnerability

Adolescence is a critical developmental period during which sex differences in depression risk emerge, yet the underlying molecular mechanisms remain unclear. Here, we integrated longitudinal transcriptomic, epigenomic, and gene regulatory network analyses to characterize sex-specific regulatory dynamics of the brain across adolescence under normative conditions and elucidate how baseline molecular differences may shape later vulnerability. We observed that immediate early genes exhibited the strongest sex-biased signals, with males and females showing opposing developmental trajectories, suggesting a role in sex-specific stress-responsive programs. Across analyses, a consistent pattern emerged: males showed stronger activity-dependent neuronal signatures, whereas females showed stronger stress- and immune-related signatures. Extending these findings to a disease context using single-nucleus chromatin accessibility data, we identified hormone-responsive regulatory elements enriched in depression-associated regions, with sex- and cell type-specific links to genetic risk. Grounded in established models of sex-specific stress responses, these findings offer a developmental regulatory framework for understanding the differential presentation of, and vulnerability to, depression.

genomics↗

bioRxiv2025

Insulin modulates mPFC gene expression and emotional behavior in a sex-specific manner following fetal growth restriction

Exposure to prenatal adversity (e.g., stress, malnutrition) is a major risk factor for lifelong vulnerability to neuropsychiatric and metabolic disorders, and alterations in the function of peripheral hormones in the brain are suggested as a possible and unexplored mechanism. Although insulin is well known for its peripheral metabolic functions, it also influences brain development and emotional regulation, particularly within the medial prefrontal cortex (mPFC). Here, we identify insulin signaling as a key mechanistic link between prenatal stress and long-term alterations in brain function and behavior. Using a validated rat model of prenatal adversity (prenatal food restriction, FR), we found that insulin administration selectively modulates gene expression in FR animals at P0, P21 and P90, affecting pathways involved in neurodevelopment and stress regulation, such as Wnt/{beta}-catenin signaling. Targeted insulin infusion into the mPFC of adult animals reversed behavioral phenotypes induced by FR in a sex- and context-dependent manner, decreasing emotional reactivity to environmental cues. These findings offer novel insight into the neurodevelopmental role of insulin and suggest that insulin signaling may serve as a therapeutic target to mitigate the long-term brain and behavioral consequences of prenatal adversity.

genomics↗

bioRxiv2025

Muscle-specific increased expression of JAG1 improves skeletal muscle phenotype in dystrophin-deficient mice.

Therapeutic strategies for Duchenne Muscular Dystrophy (DMD) will likely require complementary approaches. One possibility is to explore genetic modifiers that improve muscle regeneration and function. The beneficial effects of the overexpression of Jagged-1 were described in escaper golden retriever muscular dystrophy (GRMD) dogs that had a near-normal life and validated in dystrophin-deficient zebrafish (1). To clarify the underlying biology of JAG1 overexpression in dystrophic muscles, we generated a transgenic mouse (mdx5cv-JAG1) model that lacks dystrophin and overexpresses human JAG1 in striated muscles. Skeletal muscles from mdx5cv-JAG1 and mdx5cv mice were studied at one, four, and twelve-month time points. JAG1 expression in mdx5cv-JAG1 increased by three to five times compared to mdx5cv. Consequently, mdx5cv-JAG1 muscles were significantly bigger and stronger than dystrophic controls, along with an increased number of myofibers. Proteomics data show increased dysferlin in mdx5cv-JAG1 muscles and an association of Nsd1 with the phenotype. Our data supports the positive effect of JAG1 overexpression in dystrophic muscles. Significance StatementDuchenne Muscular Dystrophy (DMD) patients present a progressive decline in motor function. DMD is caused by mutations in the DMD gene that lead to the absence of dystrophin - an essential component of muscle cells. However, dystrophin-deficient dogs overexpressing JAG1 had a normal lifespan with remarkable motor function. In this study, we increased expression of human JAG1 in mouse skeletal muscles lacking dystrophin to explore mechanisms responsible for these benefits. Our observations show that overexpression of JAG1 counterbalances the lack of dystrophin by generating bigger and stronger muscles as the mouse ages. Moreover, our proteomics dataset suggests a role of dysferlin in the phenotype. Therefore, our study supports the exploration of JAG1 in pre-clinical models.

physiology↗

bioRxiv2025

Perinatal environmental enrichment affects murine neonates' brain structure before their active engagement with environment

Early life experiences shape individuals. Environmental enrichment, an experimental paradigm used to study the effect of increased environmental complexity and novelty in animal models, has long been recognised for its broad effect on nervous system function and behaviour. In adult rodents, structural changes in the brain due to enriched environments are well documented, notably in the hippocampus. However, the effect of environmental enrichment on the developing brain during early life is not well understood. This study aims to investigate how environmental enrichment affects brain development during the critical perinatal period, and how such effects compare to those observed during adulthood. We use high-resolution MRI to measure the brain structure of mouse neonates at postnatal day 7, born either in an enriched or a standard environment. We show that rodents exhibit brain structure differences as early as postnatal day 7. However, the regional changes observed differ from those in adulthood: hippocampal changes are limited, but changes in the hindbrain, the dorsal striatum, and the medial habenula are strong. Given the lack of direct interaction between neonates and the environment at P7, we hypothesised that maternal care may mediate these effects. We show that maternal care differs between enriched and standard environments, that maternal care correlates with brain structure changes in the neonates, and that maternal care and enriched environment affect brain structure similarly. This suggests that early changes in brain structure due to environmental enrichment are at least partly mediated by maternal care. This study provides novel insight into the differential effect of enriched environment on early brain development in rodents.

neuroscience↗

bioRxiv2024

Resting-state fMRI reveals altered functional connectivity associated with resilience and susceptibility to chronic social defeat stress in mouse brain

Chronic stress is a causal antecedent condition for major depressive disorder and associates with altered patterns of neural connectivity. There are nevertheless important individual differences in susceptibility to chronic stress. How stress-induced alterations in functional connectivity amongst depression-related brain regions associates with resilience and susceptibility to chronic stress is largely unknown. We used resting-state functional magnetic resonance imaging (rs-fMRI) to examine functional connectivity between established depression-related regions in susceptible (SUS) and resilient (RES) adult mice following chronic social defeat stress (CSDS). Seed-seed FC analysis revealed that the ventral dentate gyrus (vDG) exhibited the greatest number of group differences in functional connectivity with targeted brain regions. SUS mice showed greater functional connectivity between the vDG and subcortical regions compared to both control (CON) or RES groups. Whole brain vDG seed-voxel analysis supported seed-seed findings in SUS mice and indicated significantly decreased connectivity between the vDG and anterior cingulate area compared to CON mice. Interestingly, RES mice exhibited enhanced connectivity between the vDG and anterior cingulate area compared to SUS mice. Moreover, RES mice showed greater connectivity between the infralimbic prefrontal cortex and the nucleus accumbens shell. These findings indicate unique differences in functional connectivity patterns in SUS and RES mice that could represent a neurobiological basis for vulnerability for stress-induced depression.

neuroscience↗

bioRxiv2020

Enantiomers of Chloroquine and Hydroxychloroquine Exhibit Different Activities Against SARS-CoV-2 in vitro, Evidencing S-Hydroxychloroquine as a Potentially Superior Drug for COVID-19

In all of the clinical trials for COVID-19 conducted thus far and among those ongoing involving chloroquine or hydroxychloroquine, the drug substance used has invariably been chloroquine (CQ) diphosphate or hydroxychloroquine (HCQ) sulfate, i.e., the phosphoric or sulfuric acid salt of a racemic mixture of R- and S-enantiomer (50/50), respectively. As a result, the clinical outcome from previous CQ or HCQ trials were, in fact, the collective manifestation of both R and S- enantiomers with inherent different pharmacodynamic and pharmacokinetic properties, and toxicity liabilities. Our data for the first time demonstrated the stereoselective difference of CQ and HCQ against live SARS-CoV-2 virus in a Biosafety Level 3 laboratory. S-chloroquine (S-CQ) and S-hydroxychloroquine (S-HCQ) significantly more active against SARS-CoV-2, as compared to R-CQ and R-HCQ, respectively. In addition, Mpro, as one of the critical enzymes for viral transcription and replication, also exhibited an enantioselective binding affinity toward the S-enantiomers. The most significant finding from this study is the pronounced difference of the two enantiomers of CQ and HCQ observed in hERG inhibition assay. The IC50 value of S-HCQ was higher than 20 M against hERG channel, which was much less active over all tested CQ and HCQ compounds. Moreover, S-HCQ alone did not prolong QT interval in guinea pigs after 3 days and 6 days of administration, indicating a much lower cardiac toxicity potential. With these and previous findings on the enantio-differentiated metabolism, we recommend that future clinical studies should employ S-HCQ, substantially free of the R-enantiomer, to potentially improve the therapeutic index for the treatment of COVID-19 over the racemic CQ and HCQ.

biochemistry↗