Ji-Chun Zhang

Parkinson's disease (PD) is characterized by the accumulation of Lewy bodies (LBs) in the brain, predominantly consisting of aggregated and phosphorylated α‐synuclein (α‐Syn). Consequently, strategies to suppress α‐Syn expression offer substantial therapeutic potential for PD. This study explores heteroduplex oligonucleotides (HDOs), an innovative gene‐silencing technology utilizing DNA/RNA or DNA/DNA hybrids. We designed two HDOs targeting α‐Syn: α‐Syn‐HDO‐1 (DNA/RNA) and α‐Syn‐HDO‐2 (DNA/DNA). Both demonstrated robust silencing of α‐Syn expression in mice. In AAV‐hSyn‐human SNCA‐treated mice, these α‐Syn‐HDOs exerted neuroprotective effects on dopaminergic neurons. Furthermore, they reduced aberrant α‐Syn accumulation in α‐Syn‐HEK293 cells and in mice treated with α‐Syn preformed fibrils (PFFs). The neuroprotective effects of α‐Syn‐HDOs were linked to activation of the brain‐derived neurotrophic factor (BDNF)‐tyrosine kinase B (TrkB) signaling pathway. Moreover, BDNF overexpression diminished abnormal α‐Syn aggregation in both PFFs‐treated α‐Syn‐HEK293 cells and PFFs‐treated mice. These results highlight the capacity of α‐Syn‐HDOs to protect dopaminergic neurons by enhancing BDNF–TrkB signaling through the inhibition of abnormal elevated α‐Syn. Our findings position α‐Syn‐HDOs as promising therapeutic candidates for PD and suggest BDNF as a potential diagnostic biomarker or indicator of treatment efficacy.

Research has implicated disrupted autophagy initiation in the pathophysiology of depression. However, the role of Unc-51-like Kinase 1 (ULK1), a key regulator of autophagy initiation, in depression remains poorly understood. Here, using behavioural, molecular, and genetic approaches, we show that serum ULK1 levels are decreased in both patients with depression and mice susceptible to chronic social-defeat stress, and that both ULK1 and p-ULK1 (Ser-555) are downregulated in the lateral habenula (LHb) of susceptible mice. In addition, ULK1 deficiency in the LHb is sufficient to induce depressive-like behaviours in mice. Conversely, restoration of ULK1 in the LHb, either genetically or pharmacologically, produced antidepressant-like effects. Moreover, ULK1 deficiency specifically in LHb glutamatergic neurons induces neuronal hyperactivity, which contributes to ULK1 deficiency-induced depressive-like behaviours. Mechanistically, LHb glutamatergic neuron-specific ULK1 deficiency upregulates ryanodine receptor 2 (RYR2), which mediates increased stress-evoked presynaptic calcium transients, enhances presynaptic glutamatergic transmission, and neuronal hyperactivity in the LHb, ultimately resulting in depressive-like behaviours. Collectively, our findings suggest that ULK1 deficiency in LHb glutamatergic neurons may contribute to the development and progression of depression and identify ULK1 as a potential target for further investigation in antidepressant therapy development.

Background: Postoperative sleep disturbance (PSD) is common among surgical patients and adversely affects recovery. The benefits of perioperative esketamine on sleep remain incompletely defined. Methods: Randomized controlled trials (RCTs) comparing ketamine or esketamine with saline or other drugs for postoperative sleep quality were identified through a systematic search of PubMed, Embase, Web of Science, and the Cochrane Library until 6 September 2025. The primary outcome was postoperative sleep quality scores, and effect sizes were calculated using the ratio of means (ROM). Secondary outcomes included incidence of PSD, postoperative pain and depression scores, and adverse events. Results: Twenty-three trials including 2868 participants met inclusion criteria. Esketamine improved sleep quality on postoperative day (POD) 1 (ROM, 0.85; 95% CI, 0.80 to 0.90; P < 0.001; I ² = 84%; 21 studies), POD 2 (ROM, 0.73; 95% CI, 0.57 to 0.93; P = 0.01; I ² = 92%; 8 studies), POD 3 (ROM, 0.94; 95% CI, 0.90 to 0.99; P = 0.02; I ² = 25%; 12 studies), and POD 7 (ROM, 0.89; 95% CI, 0.82 to 0.95; P = 0.001; I ² = 36%; 8 studies); no benefit was observed at 1 month. The incidence of PSD was reduced on PODs 1 through 3 (RRs, 0.71, 0.70, and 0.61, respectively; all P ≤ 0.01), with no effect on POD 7. Esketamine also lowered postoperative pain and depression scores. However, it increased drowsiness (RR, 12.64; 95% CI, 6.04 to 26.46; P < 0.001; I ² = 21%). Conclusions: Perioperative esketamine is associated with short-term improvements in postoperative sleep quality and a lower incidence of PSD, alongside reductions in pain and depressive symptoms. However, these benefits are accompanied by an increased risk of drowsiness, and the current evidence does not yet support routine clinical use. Larger multinational trials are warranted.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that poses a significant and growing global health challenge due to its multifactorial origin and complex pathophysiological mechanisms. Modern computational biology provides powerful tools to uncover risk factors from large-scale biomedical datasets, yet distinguishing causality from correlation within such observational data remains a fundamental methodological bottleneck. To address this issue, we implement a two-sample Mendelian randomization (MR) computational framework, employing genetic variants as instrumental variables to infer causality from complex biological traits. This study focuses on evaluating potential causal relationships among key biological markers, specifically Apolipoprotein E4 (ApoE4), brain-derived neurotrophic factor (BDNF), and AD risk. The primary causal inference was conducted using the inverse-variance weighted (IVW) estimator, with a suite of sensitivity analyses, including Mendelian randomization-Egger regression (MR-Egger), weighted median, and Mendelian randomization pleiotropy RESidual sum and outlier (MR-PRESSO) coupled with leave-one-out validation to ensure methodological robustness and mitigate confounding bias. The computational results indicate a statistically significant negative causal effect of genetically instrumented ApoE4 exposure on BDNF levels, suggesting a potential pathway through which ApoE4 influences AD susceptibility. Sensitivity analyses consistently supported the robustness and validity of this causal inference. This work presents a rigorous, data-driven computational pipeline for causal discovery from high-dimensional biomedical data, offering a generalizable methodological framework that can be extended to infer causal networks in other multifactorial disorders.

Considerable individual variations in empathic abilities have been observed, but the contributing factors and underlying neural mechanisms remain poorly understood. Dominance hierarchy is a fundamental phenomenon in grouped animals and human beings, which has a profound impact on mental health and behaviors. Here, we show that social rank modulates empathic pain responses, with subordinate mice displaying significantly stronger empathic pain than dominant counterparts. Our findings reveal that the glutamatergic projection from the anterior cingulate cortex (ACC) to the nucleus accumbens core (NAcC) is critical for the development of empathic pain in subordinate mice. Selective activation of the ACC-NAcC pathway enhances empathic pain intensity in dominant mice, whereas inhibition of the pathway attenuates such responses in subordinate mice. Through synaptic molecular screening, we identified Galntl6 as a key regulator of enhanced synaptic glutamate transmission from ACC to D1-type medium spiny neurons (D1 MSNs) in the NAcC. Collectively, these findings provide a framework for understanding the neural basis of the impact of social status on empathic pain.

Arketamine, the ( R )-enantiomer of ( R,S )-ketamine, shows even greater rapid and sustained antidepressant-like effects in rodent models compared to esketamine, yet the underlying mechanisms remain unclear. In this study, we used the chronic social defeat stress (CSDS) model to investigate how arketamine exerts its antidepressant-like effects. We found that activating cAMP response element–binding protein (CREB) at S133 and methyl-CpG–binding protein 2 (MeCP2) at S421 drives the transcription of brain-derived neurotrophic factor (BDNF), contributing to arketamine’s antidepressant-like effects. Furthermore, microglia-derived BDNF enhances excitatory synaptic transmission in the infralimbic (IL) region of the medial prefrontal cortex (mPFC), mediating the antidepressant-like effects of arketamine in CSDS-susceptible mice. Last, microglia-derived BDNF can activate mPFC (IL) neurons projecting to the nucleus accumbens (NAc) shell, contributing to arketamine’s antidepressant-like effects. These findings highlight the essential role of microglial BDNF in modulating NAc-projecting mPFC neurons, which contribute to the antidepressant-like effects of arketamine.

Rationale 18β-Glycyrrhetinic acid (18β-GA) exhibits antidepressant-like effects in mice, but the underlying mechanisms remain unclear. Objective This study aimed to explore the role of serum polyunsaturated fatty acids in the antidepressant-like effects of 18β-GA. Results 18β-GA exerted antidepressant-like effects in mice susceptible to chronic social defeat stress (CSDS). These effects were associated with increased serum levels of docosahexaenoic acid (DHA), neuroprotectin D1 (NPD1), and N-docosahexaenoylethanolamide (DEA), alongside decreased levels of 14,15-dihydroxyeicosatrienoic acid (DHET). Additionally, 18β-GA restored the suppressed brain-derived neurotrophic factor (BDNF)-tyrosine kinase B (TrkB) signaling pathway and reduced the elevated pro-inflammatory cytokine levels in CSDS-susceptible mice. Conclusions This study demonstrates that the antidepressant-like effects of 18β-GA in CSDS-susceptible mice are closely associated with DHA and its metabolites.

Ketamine exhibits rapid and sustained antidepressant effects. As decreased myelination has been linked to depression pathology, changes in myelination may be a pivotal mechanism underlying ketamine’s long-lasting antidepressant effects. Although ketamine has a long-lasting facilitating effect on myelination, the precise roles of myelination in ketamine’s sustained antidepressant effects remain unknown. In this study, we employed spatial transcriptomics (ST) to examine ketamine’s lasting effects in the medial prefrontal cortex (mPFC) and hippocampus of mice subjected to chronic social defeat stress and identified several differentially expressed myelin-related genes. Ketamine’s ability to restore impaired myelination in the brain by promoting the differentiation of oligodendrocyte precursor cells (OPCs) into mature oligodendrocytes was demonstrated. Moreover, we showed that inhibiting the expression of myelin-associated oligodendrocytic basic protein (Mobp) blocked ketamine’s long-lasting antidepressant effects. We also illustrated that α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) signaling mediated ketamine’s facilitation on myelination. In addition, we found that the (R)-stereoisomer of ketamine showed stronger effects on myelination than (S)-ketamine, which may explain its longer-lasting antidepressant effects. These findings reveal novel mechanisms underlying the sustained antidepressant effects of ketamine and the differences in antidepressant effects between (R)-ketamine and (S)-ketamine, providing new insights into the role of myelination in antidepressant mechanisms.