ACS Chemical Neuroscience最新文献

Autism spectrum disorder (ASD) is a multifactorial neurodevelopmental condition characterized by impaired sociability, repetitive behaviors, and communication deficits. Animal models have been instrumental in elucidating the mechanisms underlying ASD, with prenatal exposure to valproic acid (VPA) being one of the most widely validated approaches. However, most studies rely on intraperitoneal administration, which poorly reflects human exposure. Here, we investigated the effects of oral prenatal VPA exposure in Wistar rats, focusing on behavioral outcomes, biochemical alterations, and sex-dependent differences. Pregnant females received VPA (500 mg/kg) by gavage on gestational days 11-13, and offspring were monitored from neonatal to juvenile stages. VPA-exposed pups exhibited delayed physical maturation, including postponed eye opening, tooth eruption, and locomotor development, along with reduced body weight gain. In the juvenile phase, VPA impaired sociability, reduced exploratory activity, and increased repetitive self-grooming. Importantly, behavioral effects were sex-specific: males showed more pronounced deficits in social interaction, whereas females exhibited stronger stereotyped and anxiety-like behaviors. Biochemical assays revealed elevated malondialdehyde (MDA) and nitrite levels, consistent with oxidative and nitrosative stress, especially in the hippocampus and PFC. Additionally, VPA-exposed females showed a marked reduction in hippocampal glutathione (GSH), while males exhibited increased glutamate and γ-aminobutyric acid (GABA) levels in the PFC, indicating disrupted excitatory/inhibitory balance. Collectively, our findings demonstrate that oral VPA administration induces autism-like phenotypes and region-specific neurochemical alterations in a sex-dependent manner. This study reinforces the translational validity of the oral VPA model and identifies oxidative stress and neurotransmitter imbalance as potential biomarkers for ASD pathophysiology and therapeutic intervention.

Epigenetic aberrations play a key role in the neuropathogenesis of Parkinson's disease (PD). Herein, we explored the post-translational changes of DNA methyltransferase 1 (DNMT1), an epigenetic marker, in a rotenone model of PD. Rats infused with intranigral rotenone showed impaired locomotor activity and motor coordination in open-field, rotarod, and gait assays. We also noted a depression-like phenotype in the forced swim test (FST). These rotenone-generated motor and nonmotor abnormalities were reversed following peroral administration of urolithin A (UA) at 50 and 100 mg/kg doses. At the molecular level, decreased mRNA/protein expression of the NAD⁺-dependent sirtuin 1 (SIRT1) enzyme was seen in the substantia nigra (SN) of the rotenone-infused group. At the epigenetic level, we observed a decreased expression of DNMT1 and upregulated levels of acetylated DNMT1 (ac-DNMT1) in the SN of rotenone-recipient rats. UA treatment elevated the SIRT1 expression and DNMT1 deacetylation in the SN of rotenone-lesioned rats. However, DNMT1 mRNA expression remained unchanged across the groups. The in-silico binding of the catalytic region of SIRT1 to DNMT1 (over the BAH2 and catalytic domains) and its stability over a 300 ns simulation indicated the importance of SIRT1 in deacetylating DNMT1 protein. This led to UA-mediated elevation of 5-methylcytosine (5-mC) levels, promoting global DNA hypermethylation in the SN and alpha-synuclein (SNCA) promoter region methylation in the striatum. UA treatment also downregulated the SNCA gene expression and α-synuclein levels in rotenone-lesioned rats. These findings indicate that UA treatment may reverse rotenone-induced PD progression through modulation of the SIRT1/ac-DNMT1/5-mC axis within the neuroanatomical framework of the SN.

Photobiomodulation (PBM) is a non invasive technique that utilizes light to modulate cellular processes and promote tissue regeneration. In the context of regenerative therapies, PBM has emerged as a promising approach for enhancing the differentiation of adipose-derived stem cells into neurospheres. This study aimed to investigate the effects of PBM on neurosphere growth, mitochondrial function, and cellular differentiation, focusing on 825 and 525 nm wavelengths and at 5 and 10 J/cm² fluences. Our results demonstrate that PBM modulates neurosphere size and growth kinetics with distinct effects observed at different wavelength and fluence combinations. Notably, 825 nm at 5 J/cm² promoted larger neurospheres with slower growth rates, while 525 nm at 10 J/cm² induced smaller, rapidly differentiating clusters. We also observed wavelength-dependent effects on mitochondrial function and cellular differentiation, accompanied by increased gene expression of β-tubulin III and NeuN levels by Day 11. These findings highlight the multifaceted impact of PBM on cellular behavior, promoting differentiation and modulating mitochondrial function. Our results suggest that PBM has potential as a non invasive approach for stem cell-based therapies aimed at neural repair and regeneration and warrant further investigation into its mechanisms and applications.

The genetic basis of traits linked to glymphatic system dysfunction (GSd) remains poorly understood. Using Genomic Structural Equation Modeling (Genomic-SEM) and multiple post Genome-Wide Association Studies (GWAS) methods, we identified four potentially genome-wide significant loci and one significant gene (Transmembrane protein 106B, TMEM106B). Transcriptome-wide analyses identified susceptibility gene signaling loci and related component information, and a multigene score assessed GSd risk across chromosomes. Although TMEM106B is linked to neurological disorders, the molecular mechanisms of its missense variants remain unclear. We innovatively integrated AI-powered high-precision structural prediction, protein-model-based dynamics simulation, and thermodynamic stability analysis. This systematically revealed, for the first time, how the TMEM106B mutations (T185I, T185N, and T185S) potentially affect the glymphatic system: by disrupting protein structural integrity and influencing dynamic behavior, ultimately impairing function. Our study provides the first panoramic view of GSd's genetic structure, offering a vital theoretical basis for understanding the glymphatic system dysfunction pathogenesis and identifying new targets for precision medicine and pharmacological interventions.

Human α-synuclein is an intrinsically disordered protein concentrated at presynaptic terminals and strongly linked to Parkinson's disease and other synucleinopathies. Its dynamic C-terminal region mediates interactions with small molecules and metal ions. Here, we used high-resolution nuclear magnetic resonance spectroscopy (NMR) and molecular dynamics (MD) simulations to characterize interactions between the C-terminal α-synuclein construct, the small molecule fasudil, and calcium ions. NMR data show that fasudil and Ca²⁺ bind preferentially to overlapping regions enriched in alternating tyrosine and acidic residues while preserving the protein's disordered nature. Side-chain-resolved spectra indicate distinct driving forces for fasudil and calcium binding. MD simulations reveal that Ca²⁺ modifies the local electrostatic environment, decreasing fasudil interaction frequency through electrostatic screening and steric effects. Despite this, fasudil retains dynamic, reversible contacts with key tyrosine residues. Overall, exposed α-synuclein conformations allow simultaneous, ligand-specific interactions, highlighting side-chain hotspots governing binding in Ca²⁺-rich conditions.

TAR DNA-binding protein 43 (TDP-43) is an essential physiological protein implicated in several fatal neurodegenerative disorders. Interestingly, the nature of TDP-43 aggregates varies across patients and disease conditions, suggesting an underlying heterogeneity in its self-assembly behavior. In this study, we investigated two native-like states of full-length TDP-43: the native dimer (N form) and the native-like oligomer (O form). These are compact, folded states with similar secondary structures but differ in size. We found that the N and O forms respond differently to external perturbations and form distinct self-assemblies under stress conditions. Under electrostatic stress, both N and O forms undergo phase separation but produce condensates with markedly different morphologies and dynamics. The underlying mechanisms driving their phase separation are different. Under thermal stress, both forms convert into amyloid aggregates, but again with clearly different morphologies, biochemical properties, and aggregation pathways. These results demonstrate that multiple conformations of TDP-43 respond to distinct perturbations by assembling into structurally and mechanistically different higher-order assemblies. Our findings highlight how the interplay among the structural state, solvation environment, and self-assembly mechanism governs the heterogeneity of TDP-43 assemblies, offering new insights into their physiological roles and pathological relevance. This study suggests that the heterogeneity observed in patients associated with TDP-43 aggregation may arise from differences in the cellular stresses experienced by the protein and the corresponding assembly mechanisms engaged.

Amyloid-β (Aβ) aggregation into toxic oligomers and fibrils is a hallmark of Alzheimer's disease. The Aβ_16-22 fragment plays a critical role in the early stages of the aggregation of full-length Aβ peptides. Aggregation of Aβ_16-22 is primarily driven by hydrophobic interactions within the LVFF core and electrostatic attraction between flanking residues K16 (+) and E22 (-). To dissect the relative contributions of these forces, we introduced a K16F/E22F double mutation, which eliminates charged residues while enhancing hydrophobicity and aromaticity. This substitution provides a controlled system to evaluate how specific interactions influence aggregation behavior. Using a novel computational protocol, featuring a strategically designed 4-mer system, multiple independent and long-time scale trajectories, and specialized analysis, we directly tracked and comprehensively characterized the oligomerization process. The mutation significantly enhanced both intra- and intermolecular interactions, promoting aggregation. It also altered the oligomerization pathways, as reflected in the distinct distribution across ten possible states formed by four Aβ_16-22 peptides. Furthermore, while the wild-type peptide predominantly formed antiparallel β-sheets, the mutant favored parallel and mixed β-sheet arrangements. These results indicated that increased hydrophobicity and aromaticity facilitate more stable and polymorphic aggregation pathways. Our findings highlight the dominant role of hydrophobic interactions in early-stage Aβ aggregation and emphasize the therapeutic potential of targeting hydrophobic hotspots, such as the LVFF core, while accounting for structural polymorphism rather than focusing solely on disrupting electrostatic interactions.

The molecular trigger that transduces psychosocial stress into the release of the key pro-inflammatory cytokine interleukin-1β (IL-1β) has been a missing link in stress-related neuropathology. We identify the E3 ubiquitin ligase tripartite motif-containing protein 21 (TRIM21) as this critical upstream regulator. In a rat model of repeated social defeat stress, TRIM21 was upregulated in the hippocampus, brain microvasculature, and peripheral blood mononuclear cells (PBMCs). This upregulation correlated with anxiety-like behavior and cognitive deficits and was more pronounced in females. Mechanistically, TRIM21 directly interacts with and promotes the cleavage of gasdermin D (GSDMD), enabling the formation of membrane pores for the export of mature IL-1β. This TRIM21-GSDMD-IL-1β axis was functional in PBMCs, linking peripheral immune activation to behavioral pathology. In vivo knockdown of TRIM21 systemically attenuated this pathway, reducing IL-1β release and downstream NF-κB activation. This intervention rescued blood-brain barrier integrity, restored hippocampal synaptic density, and attenuated behavioral deficits. Pharmacological inhibition of GSDMD with disulfiram recapitulated the neuroprotective effects of TRIM21 knockdown, validating this axis as a druggable pathway for stress-induced pathology. Using an in vitro neurovascular model, we defined endothelial TRIM21 as a central mediator of this stress-induced inflammatory cascade. These findings establish TRIM21 as a pivotal stress-responsive node, bridging peripheral immune signaling to GSDMD-dependent neuroinflammation and blood-brain barrier disruption, thereby revealing a new mechanistic framework and potential therapeutic target for neuropsychiatric disorders.

N-Benzyl-derived phenethylamines are highly active (psychedelic) 5-HT_2AR (serotonin 2A receptor) agonists used as biochemical tools and on the drug market. The impact of adding an N-benzyl substituent to the tryptamine core structure has scarcely been studied. A recent systematic exploration of N-benzyl-substituted (5-MeO-)tryptamines revealed a surprisingly low activity in a Ca²⁺ mobilization assay for certain analogues. Considering the increased number of reports on biased agonism at the 5-HT_2AR, with particular examples in the group of phenethylamines containing an N-benzyl substituent, a series of 16 of these (5-MeO-)tryptamine derivatives (14 of which containing an N-benzyl group) was evaluated in two additional assays. Specifically, two highly similar yet complementary NanoBiT assays, monitoring the recruitment of β-arrestin 2 (βarr2) or miniGα_q to the 5-HT_2AR, were applied. The functional data allowed assessment of the impact of different substituents on the compounds' 5-HT_2AR activity: (i) the introduction of an N-benzyl group on the (5-MeO-)tryptamine core; (ii) the substitution of the N-benzyl at different positions; and (iii) the presence of a 5-MeO group on the tryptamine core structure. Interestingly, the N-benzyl-substituted (5-MeO-)tryptamines were more active in βarr2 than in the miniGα_q recruitment assay, and biased agonism was assessed by both quantitative and qualitative methods. Aside from the estimation of structure-activity relationships and biased agonism, the current data set allowed for a comparison of the functional data between different assays, hence providing a better understanding of the translatability of results from one assay to the other.

Evaluation of data quality always remains labor-intensive, but it is a critical prerequisite in clinical neuroscience research to ensure the reliability and reproducibility of research outcomes. The unavailability of quality control (QC) pipelines on a single platform for multimodal neuroimaging data has been a limiting factor in extensive brain research. Moreover, existing QC pipelines primarily involve MRI-based data only. In this context, we developed a neuroimaging and neurospectroscopy (NINS) QC platform "NINS_QC" for multimodal neuroimaging (MRI, fMRI, DTI, MRS) and neuropsychological data. NINS_QC is a transparent and user-friendly framework that can be distributed as a standalone or in the form of a downloadable executable file. This allows local processing of multimodal neuroimaging data and is well-suited for environments with stringent data privacy requirements. The presence of metrics-based analysis, along with visual-based assessment, has added one more attribute to this platform.