Ming-Li Li’s research while affiliated with Kunming Institute of Zoology and other places

Background Deciphering the functionality and dynamics of brain networks across different regions and age groups in non-human primates (NHPs) is crucial for understanding the evolution of human cognition as well as the processes underlying brain pathogenesis. However, systemic delineation of the cellular composition and molecular connections among multiple brain regions and their alterations induced by aging in NHPs remain largely unresolved. Methods In this study, we performed single-nucleus RNA sequencing on 39 samples collected from 10 brain regions of two young and two aged rhesus macaques using the DNBelab C4 system. Validation of protein expression of signatures specific to particular cell types, brain regions, and aging was conducted through a series of immunofluorescence and immunohistochemistry staining experiments. Loss-of-function experiments mediated by short hairpin RNA (shRNA) targeting two age-related genes (i.e., VSNL1 and HPCAL4) were performed in U251 glioma cells to verify their aging effects. Senescence-associated beta-galactosidase (SA-β-gal) staining and quantitative PCR (qPCR) of senescence marker genes were employed to assess cellular senescence in U251 cells. Results We have established a large-scale cell atlas encompassing over 330,000 cells for the rhesus macaque brain. Our analysis identified numerous gene expression signatures that were specific to particular cell types, subtypes, brain regions, and aging. These datasets greatly expand our knowledge of primate brain organization and highlight the potential involvement of specific molecular and cellular components in both the regionalization and functional integrity of the brain. Our analysis also disclosed extensive transcriptional alterations and cell–cell connections across brain regions in the aging macaques. Finally, by examining the heritability enrichment of human complex traits and diseases, we determined that neurological traits were significantly enriched in neuronal cells and multiple regions with aging-relevant gene expression signatures, while immune-related traits exhibited pronounced enrichment in microglia. Conclusions Taken together, our study presents a valuable resource for investigating the cellular and molecular architecture of the primate nervous system, thereby expanding our understanding of the mechanisms underlying brain function, aging, and disease.

Aging is an intricate process involving interactions among multiple factors, which is one of the main risks for chronic diseases, including Alzheimer's disease (AD). As a member of cysteine protease, cathepsin S (CTSS) has been implicated in inflammation across various diseases. Here, we investigated the role of neuronal CTSS in aging and AD started by examining CTSS expression in hippocampus neurons of aging mice and identified a significant increase, which was negatively correlated with recognition abilities. Concurrently, we observed an elevation of CTSS concentration in the serum of elderly people. Transcriptome and fluorescence‐activated cell sorting (FACS) results revealed that CTSS overexpression in neurons aggravated brain inflammatory milieu with microglia activation to M1 pro‐inflammatory phenotype, activation of chemokine C‐X3‐C‐motif ligand 1 (CX3CL1)—chemokine C‐X3‐C‐motif receptor 1 (CX3CR1) axis and janus kinase 2 (JAK2)—signal transducer and activator of transcription 3 (STAT3) pathway. As CX3CL1 is secreted by neurons and acts on the CX3CR1 in microglia, our results revealed for the first time the role of neuron CTSS in neuron–microglia “crosstalk.” Besides, we observed elevated CTSS expression in multiple brain regions of AD patients, including the hippocampus. Utilizing CTSS selective inhibitor, LY3000328, rescued AD‐related pathological features in APP/PS1 mice. We further noticed that neuronal CTSS overexpression increased cathepsin B (CTSB) activity, but decreased cathepsin L (CTSL) activity in microglia. Overall, we provide evidence that CTSS can be used as an aging biomarker and plays regulatory roles through modulating neuroinflammation and recognition in aging and AD process.

While alterations in cortical thickness have been widely observed in individuals with alcohol dependence, knowledge about cortical thickness-based structural covariance networks is limited. This study aimed to explore the topological disorganization of structural covariance networks based on cortical thickness at the single-subject level among patients with alcohol dependence. Structural imaging data were obtained from 61 patients with alcohol dependence during early abstinence and 59 healthy controls. The single-subject structural covariance networks were constructed based on cortical thickness data from 68 brain regions and were analyzed using graph theory. The relationships between network architecture and clinical characteristics were further investigated using partial correlation analysis. In the structural covariance networks, both patients with alcohol dependence and healthy controls displayed small-world topology. However, compared to controls, alcohol-dependent individuals exhibited significantly altered global network properties characterized by greater normalized shortest path length, greater shortest path length, and lower global efficiency. Patients exhibited lower degree centrality and nodal efficiency, primarily in the right precuneus. Additionally, scores on the Alcohol Use Disorder Identification Test were negatively correlated with the degree centrality and nodal efficiency of the left middle temporal gyrus. The results of this correlation analysis did not survive after multiple comparisons in the exploratory analysis. Our findings may reveal alterations in the topological organization of gray matter networks in alcoholism patients, which may contribute to understanding the mechanisms of alcohol addiction from a network perspective.

There is inconsistent evidence for an association of obesity with white matter microstructural alterations. Such inconsistent findings may be related to the cumulative effects of obesity and alcohol dependence. This study aimed to investigate the possible interactions between alcohol dependence and overweight/obesity on white matter microstructure in the human brain. A total of 60 inpatients with alcohol dependence during early abstinence (44 normal weight and 16 overweight/obese) and 65 controls (42 normal weight and 23 overweight/obese) were included. The diffusion tensor imaging (DTI) measures [fractional anisotropy (FA) and radial diffusivity (RD)] of the white matter microstructure were compared between groups. We observed significant interactive effects between alcohol dependence and overweight/obesity on DTI measures in several tracts. The DTI measures were not significantly different between the overweight/obese and normal-weight groups (although widespread trends of increased FA and decreased RD were observed) among controls. However, among the alcohol-dependent patients, the overweight/obese group had widespread reductions in FA and widespread increases in RD, most of which significantly differed from the normal-weight group; among those with overweight/obesity, the alcohol-dependent group had widespread reductions in FA and widespread increases in RD, most of which were significantly different from the control group. This study found significant interactive effects between overweight/obesity and alcohol dependence on white matter microstructure, indicating that these two controllable factors may synergistically impact white matter microstructure and disrupt structural connectivity in the human brain.

Background: DSM-5 proposes the concept of bipolar disorder with “mixed features ”, which is of great benefit to clinical practice. However, the clinical management of BD with mixed features is more challenging.This investigation examined the prescribing patterns and factors influencing guidelines disconcordance for the acute treatment of bipolar disorder with mixed features in mainland China. Methods:This real-world study enrolled 688 patients with acute bipolar disorder through the National Bipolar Pathway Survey Replication (BIPAS-R). We used CUDOS-M and MINI-M scales based on DSM-5 criteria to improve the sensitivity of screening for bipolar disorder with mixed features. Guideline inconsistency judgments were determined by comparison with the Canadian Network for Mood and Anxiety Treatments(CANMAT) guidelines for treatment recommendations for bipolar disorder with mixed features. Logstic regression was used to analyze the influencing factors of guideline disconcordance. Results: Among 688 cases of acute bipolar disorder, 235 cases (34.2%) were (hypo) mania with mixed features and 213 cases (30.9%) were depression with mixed feature. Without considering the order of treatment, the inconsistency rates of (hypo) mania and depression with mixed features with the guidelines were 29.4% and 55.4%, respectively. (Hypo) mania with mixed features BD-II (OR=0.52; 95% CI 0.29-0.93), age at study entry > 24 years (OR=2.4; 95% CI 1.3-4.3), and the number of episodes > 4 in the past year in depression with mixed features (OR=1.9; 95% CI 1.08-3.6), which increased the risk of treatment disconcordance of guidelines. Conclusions:Our findings suggest that BD with mixed features is more common.