Yongchang Chen

Psilocybin holds strong therapeutic promise for treating major depressive disorder. However, the cellular and molecular substrates underlying its action have not been fully elucidated, especially in the primate brain. We combined multimodal MRI, magnetic resonance spectroscopy (MRS), cerebrospinal fluid (CSF) proteomics and metabolomics, and single-nucleus RNA sequencing (snRNA-seq) to map the multiscale temporospatial dynamics induced by a single dose of psilocybin in cynomolgus macaques. Psilocybin increased the integration of the frontoparietal network (FPN) with the default-mode and limbic networks, transiently reduced integration of the FPN with the somatomotor network, and induced global network segregation. Several regions in the cortex, striatum, and thalamus as well as certain of the frontoparietal white matter pathways showed persistent enhancement lasting 1 week. Notably, these changes were accompanied by a CSF multi-omics shift from acute prostaglandin-dominated inflammation to a sustained enrichment of an omega-3 fatty acid-associated anti-inflammatory state together with a bidirectional reorganization of extracellular matrix (ECM)-related signatures, characterized by increased CD44 and decreased fibulin-family proteins. In addition, we found lasting upregulation of TCA-cycle and NAD(P)-dependent redox enzymes. This was further supported by sustained elevations of glutamate/glutamine and total creatine in the dorsolateral prefrontal cortex (dlPFC), which was found using in vivo MRS. At the cellular level, psilocybin promoted HTR2A selective upregulation in deep-layer excitatory neurons along with a widespread enhancement of mitochondrial oxidative phosphorylation centered on the complex I subunit ND3 across diverse excitatory and inhibitory neuronal subtypes in the dorsolateral prefrontal cortex. Glial-state remodeling, including a shift of astrocytes toward ECM remodeling states and microglia toward an anti-inflammatory state, also occurred. Collectively, these findings provide evidence in the primate brain that psilocybin induces functional integration and segregation of brain networks, enhances energy metabolism and synaptic plasticity, and modulates neuroimmune signaling. All the data will be shared as an integrated resource for primate psilocybin research.

Aims: Remyelination failure is a major contributor to progressive neurological disability in multiple sclerosis (MS). Although oligodendrocyte progenitor cells (OPCs) persist in demyelinated lesions, they often fail to differentiate into myelinating oligodendrocytes. This study aimed to determine whether growth differentiation factor 11 (GDF11), a circulating member of the TGF‐β superfamily, regulates oligodendrocyte differentiation, CNS myelination, and remyelination. Methods: The effects of GDF11 were examined using purified mouse OPC cultures, a neonatal developmental myelination model, and two demyelination models: cuprizone‐induced demyelination and experimental autoimmune encephalomyelitis (EAE). OPC differentiation was assessed by immunocytochemistry and morphological analysis. In vivo myelination and remyelination were evaluated using histological, ultrastructural, and behavioral approaches following systemic GDF11 administration. Results: GDF11 directly promoted OPC differentiation and maturation in vitro without affecting proliferation. Systemic GDF11 enhanced developmental myelination in neonatal mice, increasing myelin gene expression, myelinated axon density, and myelin thickness. Although GDF11 did not prevent active demyelination, it significantly accelerated remyelination and functional recovery following cuprizone withdrawal and in the EAE model, and this was accompanied by enhanced oligodendrocyte differentiation and reduced neuroinflammation. Conclusion: These findings identify GDF11 as a circulating regulator of oligodendrocyte maturation and CNS myelin formation and repair, highlighting its therapeutic potential for demyelinating diseases.

Longitudinal multi-omics profiling of a nonhuman primate Rett syndrome (RTT) model reveals early systemic alterations. RTT monkeys exhibited postnatal growth retardation, intestinal structural abnormalities, and low-grade systemic inflammation. Gut microbiome analysis showed delayed microbial maturation and age-discordant dysbiosis, including altered Firmicutes/Bacteroidetes ratios and persistent community restructuring. Fecal metabolomics revealed reduced short-chain fatty acids (SCFAs), disrupted microbe-metabolite networks, and broad alterations in lipid, amino acid, and energy metabolism. Electrocardiogram (ECG) identified prolonged corrected QT interval (QTc) and subclinical cardiac electrophysiological changes. Integrated multi-omics analyses indicate that RTT involves early, coordinated dysregulation across gut microbial, metabolic, immune, and peripheral physiological systems, supporting its characterization as a systemic disorder from the early postnatal stage.

Unraveling the intricate composition and function of the cochlea is paramount to comprehending the mechanisms underlying sound perception and the pathogenesis of auditory disorders. The mammalian cochlea displays a highly organized structure, which contributes to the diversity and complexity of auditory processing. However, the cellular intricacies in non-human primates remain largely unexplored. In the present study, we employed high-throughput transcriptomic sequencing to profile over 36,701 nuclei across virtually all cochlear cell types in both juvenile and adult Macaca fascicularis at single-cell resolution. Our analysis unveiled remarkable heterogeneity both across and within cell types. Despite a largely conserved cellular composition of the cochlea between mouse and macaque species, glial cells exhibited substantial species-specific diversity, while hair cells and spiral ganglion neurons with specialized transcriptional programs were well-mapped onto their murine counterparts, underscoring the similarities that persist despite evolutionary divergence. Furthermore, we constructed a disease map associated with hearing loss, establishing this transcriptomic atlas of the macaque cochlea as an indispensable resource for future investigations in both human and non-human primates.

Mapping the developmental and aging trajectories of brain structures and their underlying cellular and molecular mechanisms is fundamental to understanding the organizational principles of the primate brain. Here, we systematically characterized brain structural, cellular and molecular spatiotemporal dynamics from birth to 18 years of macaques integrating multimodal magnetic resonance imaging and single-cell transcriptomics. Structurally, we found that gray matter volume, cortical surface area, and thickness of macaque brain progressively declined, which is contrary to human brain developmental patterns, but the white matter volume, microstructure, white matter and gray matter complexity steadily increased, reflecting enhanced fiber organization and network integration. Molecularly, the brain undergoes neural optimization and homeostatic maintenance during development and aging, respectively. Importantly, we linked the macroscopic structural trajectories to the molecular developmental and aging patterns to identify the cellular and molecular drivers of brain structure for the first time. In summary, these findings establish a crucial multiscale framework for understanding primate brain development and aging and shed new light on the divergent evolution between macaques and humans. Our work provides a comprehensive and integrated resource that bridges molecular, structural and network-level scales in primate neuroscience.