Jun Wang

Adolescent depression is undergoing a rapid surge and has become a severe global public health challenge. However, current therapeutic approaches are limited and often accompanied by significant side effects primarily due to the elusive underlying mechanisms. The gut-brain axis has recently gained growing attention for its pivotal roles in neuropsychiatric disorders, particularly the tryptophan (Trp) metabolism by the microbiota. With the 16S rRNA gene sequencing, the abundance of Bacteroidetes, a microbiota phylum that includes several taxa involved in tryptophan metabolism and indole derivative production was significantly reduced in unmedicated adolescents with depression. The in-depth analysis showed that levels of key indole derivatives, including IAA, IPA and IAld, were markedly decreased in depressed patients; crucially, these reductions showed a significant negative correlation with depression severity scores. Consistent with the clinical findings, a similar decline in IAA, IPA, and IAld levels was observed in adolescent mice with depression induced by chronic restraint stress (CRS). Notably, depression-like behaviors in these mice were substantially ameliorated by a high-Trp diet (CRS + 1.19% Trp) and direct supplementation with indole derivatives. In a reciprocal experiment, a low-Trp diet (0.09% Trp) was found to de novo induce depressive behaviors in otherwise healthy mice. Morphological analysis of brain tissue uncovered another critical insight, the microglial cells in CRS mice exhibited hallmark features of overactivation. Remarkably, both the high-Trp diet and indole derivative supplementation exerted consistent protective effects, shown as restored microglial morphology and neurogenesis. Mechanistically, the indole derivatives were shown to activate AhR signaling, which in turn balanced the expression of anti-inflammatory factors (e.g., IL-10, TGF-β) and pro-inflammatory factors (e.g., IL-1β, CD68), thereby remodeling microglial morphology and promoting neurogenesis in hippocampus. A series of loss-of-function and gain-of-function experiments further confirmed AhR’s essential role: the salutary effects of indole derivatives on anti-depression were substantially attenuated in AhR^-/- mice; reciprocally, conditional microglia-specific overexpression of AhR in the hippocampus of CRS mice significantly ameliorated CRS-induced depressive-like changes, accompanied by suppression of microglial activation and upregulation of anti-inflammatory factors. Collectively, the present study revealed a previously unrecognized the microbiota-derived indole derivatives ameliorated CRS-induced adolescent depression via the AhR signaling pathway. These findings highlight that targeting the indole derivative-AhR signaling axis may represent a novel therapeutic strategy for adolescent depression, one with the potential to minimize side effects and address the unmet clinical needs of this vulnerable population.

Epidemiological evidence suggests that developmental arsenic (As) exposure increases behavioral abnormalities in offspring. However, how placental neuroendocrine function and sex-specific responses contribute to these effects remains poorly understood. Here, we demonstrate that maternal As exposure induces trophoblastic damage, vascular disruption, and placental labyrinth thinning, leading to placental dysplasia, fetal growth restriction, and sex-specific behavioral outcomes in offspring. Integrated transcriptomic and neurobehavioral analyses revealed sex-dependent alterations primarily involving neurodevelopmental pathways and transporter dysfunction. Concurrently, neurotransmitter metabolomic profiling identified profound disturbances in tryptophan, tyrosine, and amino acid metabolism in the placenta and fetal brain. Bayesian benchmark dose (BMD) modeling revealed that points of departure (PoDs) followed the rank order, such that metabolomic (mPoDs) < neurobehavioral (nPoDs) < apical (aPoDs). Notably, alterations in the tryptophan pathway were the most sensitive early perturbations observed, with BMDL10 values for 5-hydroxy-l-tryptophan of 3.73 μg/L in females and 4.17 μg/L in males, respectively. Overall, this exploratory framework provides evidence for placental neuroendocrine toxicity of As and highlights its potential relevance for refined environmental risk assessment.

Adolescent depression has rapidly emerged as a critical public health concern, driven by its soaring prevalence, profound functional impairment, and heightened suicide risk. However, the underlying mechanisms remain poorly understood. A growing body of evidence highlights the gut microbiota-brain axis as a key modulator of host emotional function, acting through interconnected immune, metabolic, and neural pathways. In the current work, a clinical study involving first-diagnosed adolescent depression patients was conducted and significant reductions in Roseburia intestinalis ( R.i. ) and its metabolite butyrate were identified. Therefore, we hypothesized that alterations in R.i. and butyrate may be involved in adolescent depression and may serve as novel therapeutic strategy. Intriguingly, transplantation of R.i. obviously retarded the chronic restraint stress (CRS)-induced depression in adolescent mice. Critically, this protective effect was completely abrogated by blocking the G protein-coupled receptor 43 (GPR43). Mechanistically, we delineated a novel “peripheral-central” regulatory cascade: R.i. robustly promoted the expansion of peripheral CD25⁺Foxp3⁺ regulatory T (Treg) cells, alleviating pathological inflammation in both of the colon (peripheral) and brain (central). Reciprocally, depletion of Treg cells completely abolished not only R.i. ’s antidepressant effects but also its anti-inflammatory actions in the colon and brain in vivo. The in vitro study revealed that either the R.i. conditioned or heated culture medium obviously alleviated the LPS+corticosterone induced neuroinflammation in microglial cells, shifting reactive state toward a homeostatic state. Collectively, our study for the first time reveals that R.i. ameliorates adolescent depression-like changes through a GPR43-dependent, Treg-mediated mechanism. Given the unmet clinical need for clinical diagnosis and therapy of adolescent depression, the present study provided the potential translational values for the novel treatments, such as transplantation of R.i. or butyrate supplement, which represent promising therapeutic strategies.

Methamphetamine (Meth) abuse leads to cognitive impairment, with the hippocampus being severely affected. However, the precise cellular mechanisms underlying Meth-induced hippocampal damage remain unclear. This study utilizes single-nucleus RNA sequencing (snRNA-seq) to investigate the transcriptional changes in mouse hippocampal neurons after acute Meth exposure. We analyze 36,376 nuclei isolated from the hippocampus of acute Meth-treated and control mice, revealing significant alterations in excitatory neuron transcriptomes. Notably, oxidative phosphorylation (OXPHOS) and peroxisome pathways were prominently activated. Five distinct excitatory neuron subtypes were identified across different hippocampal regions, with the dorsal-ventral (DG) region exhibiting the most pronounced changes in gene expression, inflammatory response, reactive oxygen species (ROS) signaling, and OXPHOS activity. High-dimensional weighted correlation network analysis (hdWGCNA) reveals five modules endowed with functional roles in recognizing-associated pathways. Furthermore, it provides insights into intercellular communication and transcriptional regulation patterns within the hippocampus after Meth exposure. In conclusion, this study offers a comprehensive understanding of Meth’s impact on hippocampal transcriptomes and may guide the development of therapeutic strategies for acute Meth-induced neurotoxicity.

Methamphetamine (Meth), a psychostimulant drug of the amphetamine type, is widely abused and highly neurotoxic. Meth exposure leads to neuronal necroptosis, and the mitochondrial dysfunction may be involved. However, the underlying mechanisms remain poorly understood. Here, we found that Meth significantly elicited the formation of the RIPK1–RIPK3–MLKL necrosome complex. Intriguingly, the activated MLKL (p-MLKL) translocated to the mitochondrial membrane and displayed pore-forming activity, manifesting as the penetration of MLKL in the cell membranes of the mitochondria, which caused decreased mitochondrial membrane potential, ATP generation, and mitochondrial DNA (mtDNA) and increased mitochondrial ROS (mtROS) generation, which finalized neuronal necroptosis. Notably, MLKL activation and translocation seem to depend on the RIPK1–RIPK3 axis since these adverse effects can be substantially ameliorated by disruption of the necrosome complex formation by the necroptotic inhibitor 1 (Nec-1), which also markedly impeded the MLKL mitochondrial membrane translocation. Finally, to delineate the effects of pore formation-associated ROS generation, specific blockage of mtROS retarded the Meth-induced neuronal necroptosis. In conclusion, our study reveals for the first time that MLKL mitochondrial membrane translocation may be involved in Meth-induced neuronal necroptosis. Therefore, impeding MLKL translocation might provide a novel therapeutic strategy for Meth-induced neurotoxicity.

Developmental exposure to arsenic (As) has been linked to irreversible adverse health outcomes in offspring. However, the underlying molecular mechanisms remain a mystery. Here, maternal mice were exposed to As via drinking water. Subsequently, the hippocampi of their offspring were collected at different developmental stages to explore the dynamic changes during hippocampal maturation and the effects of As. Time-series RNA-seq analysis revealed a significant temporal correlation between As neurodevelopmental toxicity and the mRNA expression profile of the hippocampal region during critical postnatal developmental windows. Further, downregulation of genes associated with neurogenesis and telomere maintenance was observed. Notably, dynamic changes in hippocampal telomeres were observed in response to As exposure, with critically shortened telomeres inhibiting neural stem cells (NSCs) proliferation, impairing neuroblast maturation, and reducing the number and size of neurospheres. Additionally, the populations of BrdU⁺ and MAP2⁺ cells were decreased while GFAP⁺ cells were increased, indicating a decline in NSCs stemness. Furthermore, As exposure significantly impaired dendritic complexity in the hippocampus of mice, altered dendritic spine morphology, and disrupted synaptic ultrastructure, ultimately leading to cognitive impairment. These findings highlight the importance of analyzing telomere dynamics in environmental toxicology and offer insights into the neurotoxic mechanisms of maternal As on offspring development.

Background: Methamphetamine (Meth) is a potent psychoactive stimulant that triggers complex neurotoxicity characterized by autophagy‐associated neuronal death. However, the potential mechanisms remain poorly understood. This study aimed to decipher the Meth‐induced neuronal necroptosis involving mitochondrial defect‐initiated excessive mitophagy caused by aberrant presenilin‐associated rhomboid‐like (PARL) cleavage of PTEN‐induced kinase 1 (PINK1) and phosphoglycerate mutase family member 5 (PGAM5). Methods and Results: With the transcriptome analysis, Meth exposure significantly affected autophagy, mitophagy, and necroptosis pathways; meanwhile, the proteomic analysis revealed a marked decline in the level of PARL, which led to an imbalance in intramembrane proteolysis of PINK1 and PGAM5. In behavioral tests, Meth administration elicited pronounced cognitive decline in mice, accompanied by decreased neuronal numbers, massive autophagosomes, and mitochondrial fragmentation, and these processes can be dramatically reversed by knockin of PARL and knockdown of PGAM5 in the mouse hippocampus, molecularly manifesting as decreased necrosome formation and phosphorylated mixed lineage kinase domain‐like (p‐MLKL) mitochondrial membrane translocation, and improved autophagic flux. Conclusion: In summary, these findings collectively underscore the key roles of the PARL‐PGAM5 axis in Meth‐mediated neuronal necroptosis and that targeting this axis may provide promising therapeutic strategies for mitigating Meth‐induced neurotoxicity.