Increased excitatory amino acid transporter 2 levels in basolateral amygdala astrocytes mediate chronic stress-induced anxiety-like behavior.

JOURNAL/nrgr/04.03/01300535-202506000-00024/figure1/v/2024-08-05T133530Z/r/image-tiff The conventional perception of astrocytes as mere supportive cells within the brain has recently been called into question by empirical evidence, which has revealed their active involvement in regulating brain function and encoding behaviors associated with emotions. Specifically, astrocytes in the basolateral amygdala have been found to play a role in the modulation of anxiety-like behaviors triggered by chronic stress. Nevertheless, the precise molecular mechanisms by which basolateral amygdala astrocytes regulate chronic stress-induced anxiety-like behaviors remain to be fully elucidated. In this study, we found that in a mouse model of anxiety triggered by unpredictable chronic mild stress, the expression of excitatory amino acid transporter 2 was upregulated in the basolateral amygdala. Interestingly, our findings indicate that the targeted knockdown of excitatory amino acid transporter 2 specifically within the basolateral amygdala astrocytes was able to rescue the anxiety-like behavior in mice subjected to stress. Furthermore, we found that the overexpression of excitatory amino acid transporter 2 in the basolateral amygdala, whether achieved through intracranial administration of excitatory amino acid transporter 2 agonists or through injection of excitatory amino acid transporter 2-overexpressing viruses with GfaABC1D promoters, evoked anxiety-like behavior in mice. Our single-nucleus RNA sequencing analysis further confirmed that chronic stress induced an upregulation of excitatory amino acid transporter 2 specifically in astrocytes in the basolateral amygdala. Moreover, through in vivo calcium signal recordings, we found that the frequency of calcium activity in the basolateral amygdala of mice subjected to chronic stress was higher compared with normal mice. After knocking down the expression of excitatory amino acid transporter 2 in the basolateral amygdala, the frequency of calcium activity was not significantly increased, and anxiety-like behavior was obviously mitigated. Additionally, administration of an excitatory amino acid transporter 2 inhibitor in the basolateral amygdala yielded a notable reduction in anxiety level among mice subjected to stress. These results suggest that basolateral amygdala astrocytic excitatory amino acid transporter 2 plays a role in in the regulation of unpredictable chronic mild stress-induced anxiety-like behavior by impacting the activity of local glutamatergic neurons, and targeting excitatory amino acid transporter 2 in the basolateral amygdala holds therapeutic promise for addressing anxiety disorders.

Benzo[a]pyrene exposure induces anxiety-like behaviors in the mice through brain metabolic alterations.

The deleterious health impacts of polycyclic aromatic hydrocarbons (PAHs) on the population have been extensively substantiated and acknowledged. Mounting evidence underscores that PAH exposure is closely linked to an elevated risk of mental disorders, particularly in populations experiencing occupational and high-level exposure. In this study, we aimed to investigate the mechanisms underlying anxiety-like behaviors induced by different dosages of PAHs, with a concentrated focus on brain region-specific metabolic alterations in mice using various metabolomics approaches. Male C57BL/6 mice were exposed to benzo[a]pyrene (B[a]P), a typical PAH, through gavage at occupational exposure and EPA toxicologically relevant dosages (2.0 and 20.0 mg/kg/day) for 21 days, respectively. Behavioral assessments revealed that occupational exposure to B[a]P induced anxiety-like behaviors in C57BL/6 mice. Meanwhile, elevated serum norepinephrine and corticotropin-releasing hormone further confirmed the anxiety-inducing effects of B[a]P exposure. Metabolomics analysis uncovered dysregulation across various metabolic pathways following B[a]P exposure, encompassing brain neurotransmitter, organic acid, amino acid, lipid, fatty acid, and cholesterol. Anxiety levels and lipid metabolic abnormalities were notably exacerbated at the higher dosage, despite being only a 10-fold increase. Of particular significance, a decrease in lysophosphatidic acid (LPA) and lysophosphatidylserine (LPS) emerged as pivotal indicators of B[a]P neurotoxicity. Spatial-resolved metabolomics further demonstrated distinctive lipid and metabolite profiles across different brain subregions after exposure to B[a]P. Remarkably, alterations were specifically observed in the anxiety-related brain regions, such as the hippocampus, cortex, white matter, and thalamus, varying with exposure dosages. These findings underscore the significance of brain metabolic abnormalities in the development of mental disorders triggered by B[a]P exposure and highlight the need for establishing precise exposure limits of B[a]P to safeguard public mental health.

MLKL-USP7-UBA52 signaling is indispensable for autophagy in brain through maintaining ubiquitin homeostasis.

Individuals with genetic elimination of MLKL (mixed lineage kinase domain like pseudokinase) exhibit an increased susceptibility to neurodegenerative diseases like Alzheimer disease (AD). However, the mechanism is not yet fully understood. Here, we observed significant compromise in macroautophagy/autophagy in the brains of mlkl knockout (KO) mice, as evidenced by the downregulation of BECN1/Beclin1 and ULK1 (unc-51 like autophagy activating kinase 1). We identified UBA52 (ubiquitin A-52 residue ribosomal protein fusion product 1) as the binding partner of MLKL under physiological conditions. Loss of Mlkl induced a decrease in ubiquitin levels by preventing UBA52 cleavage. Furthermore, we demonstrated that the deubiquitinase (DUB) USP7 (ubiquitin specific peptidase 7) mediates the processing of UBA52, which is regulated by MLKL. Moreover, our results indicated that the reduction of BECN1 and ULK1 upon Mlkl loss is attributed to a decrease in their lysine 63 (K63)-linked polyubiquitination. Additionally, single-nucleus RNA sequencing revealed that the loss of Mlkl resulted in the disruption of multiple neurodegenerative disease-related pathways, including those associated with AD. These results were consistent with the observation of cognitive impairment in mlkl KO mice and exacerbation of AD pathologies in an AD mouse model with mlkl deletion. Taken together, our findings demonstrate that MLKL-USP7-UBA52 signaling is required for autophagy in brain through maintaining ubiquitin homeostasis, and highlight the contribution of Mlkl loss-induced ubiquitin deficits to the development of neurodegeneration. Thus, the maintenance of adequate levels of ubiquitin may provide a novel perspective to protect individuals from multiple neurodegenerative diseases through regulating autophagy.Abbreviations: 4HB: four-helix bundle; AAV: adeno-associated virus; AD: Alzheimer disease; AIF1: allograft inflammatory factor 1; APOE: apolipoprotein E; APP: amyloid beta precursor protein; Aß: amyloid ß; BECN1: beclin 1; co-IP: co-immunoprecipitation; DEGs: differentially expressed genes; DLG4: discs large MAGUK scaffold protein 4; DUB: deubiquitinase; EBSS: Earle's balanced salt solution; GFAP: glial fibrillary acidic protein; HRP: horseradish peroxidase; IL1B: interleukin 1 beta; IL6: interleukin 6; IPed: immunoprecipitated; KEGG: Kyoto Encyclopedia of Genes and Genomes; KO: knockout; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MLKL: mixed lineage kinase domain like pseudokinase; NSA: necrosulfonamide; OPCs: oligodendrocyte precursor cells; PFA: paraformaldehyde; PsKD: pseudo-kinase domain; SYP: synaptophysin; UB: ubiquitin; UBA52: ubiquitin A-52 residue ribosomal protein fusion product 1; UCHL3: ubiquitin C-terminal hydrolase L3; ULK1: unc-51 like autophagy activating kinase 1; UMAP: uniform manifold approximation and projection; UPS: ubiquitin-proteasome system; USP7: ubiquitin specific peptidase 7; USP9X: ubiquitin specific peptidase 9 X-linked.

Astrocyte-mediated regulation of BLAWFS1 neurons alleviates risk-assessment deficits in DISC1-N mice.

Assessing and responding to threats is vital in everyday life. Unfortunately, many mental illnesses involve impaired risk assessment, affecting patients, families, and society. The brain processes behind these behaviors are not well understood. We developed a transgenic mouse model (disrupted-in-schizophrenia 1 [DISC1]-N) with a disrupted avoidance response in risky settings. Our study utilized single-nucleus RNA sequencing and path-clamp coupling with real-time RT-PCR to uncover a previously undescribed group of glutamatergic neurons in the basolateral amygdala (BLA) marked by Wolfram syndrome 1 (WFS1) expression, whose activity is modulated by adjacent astrocytes. These neurons in DISC1-N mice exhibited diminished firing ability and impaired communication with the astrocytes. Remarkably, optogenetic activation of these astrocytes reinstated neuronal excitability via D-serine acting on BLAWFS1 neurons' NMDA receptors, leading to improved risk-assessment behavior in the DISC1-N mice. Our findings point to BLA astrocytes as a promising target for treating risk-assessment dysfunctions in mental disorders.

Boosting Reinforcement Learning via Hierarchical Game Playing With State Relay.

Due to its wide application, deep reinforcement learning (DRL) has been extensively studied in the motion planning community in recent years. However, in the current DRL research, regardless of task completion, the state information of the agent will be reset afterward. This leads to a low sample utilization rate and hinders further explorations of the environment. Moreover, in the initial training stage, the agent has a weak learning ability in general, which affects the training efficiency in complex tasks. In this study, a new hierarchical reinforcement learning (HRL) framework dubbed hierarchical learning based on game playing with state relay (HGR) is proposed. In particular, we introduce an auxiliary penalty to regulate task difficulty, and one training mechanism, the state relay mechanism, is designed. The relay mechanism can make full use of the intermediate states of the agent and expand the environment exploration of low-level policy. Our algorithm can improve the sample utilization rate, reduce the sparse reward problem, and thereby enhance the training performance in complex environments. Simulation tests are carried out on two public experiment platforms, i.e., MazeBase and MuJoCo, to verify the effectiveness of the proposed method. The results show that HGR significantly benefits the reinforcement learning (RL) area.

Influence maximization based on threshold models in hypergraphs.

Influence maximization problem has received significant attention in recent years due to its application in various domains, such as product recommendation, public opinion dissemination, and disease propagation. This paper proposes a theoretical analysis framework for collective influence in hypergraphs, focusing on identifying a set of seeds that maximize influence in threshold models. First, we extend the message passing method from pairwise networks to hypergraphs to accurately describe the activation process in threshold models. Then, we introduce the concept of hypergraph collective influence (HCI) to measure the influence of nodes. Subsequently, we design an algorithm, HCI-TM, to select the influence maximization set, taking into account both node and hyperedge activation. Numerical simulations demonstrate that HCI-TM outperforms several competing algorithms in synthetic and real-world hypergraphs. Furthermore, we find that HCI can be used as a tool to predict the occurrence of cascading phenomena. Notably, we find that the HCI-TM algorithm works better for larger average hyperdegrees in Erdös-Rényi hypergraphs and smaller power-law exponents in scale-free hypergraphs.

The Central Nervous Mechanism of Stress-Promoting Cancer Progression.

Evidence shows that stress can promote the occurrence and development of tumors. In recent years, many studies have shown that stress-related hormones or peripheral neurotransmitters can promote the proliferation, survival, and angiogenesis of tumor cells and impair the body's immune response, causing tumor cells to escape the "surveillance" of the immune system. However, the perception of stress occurs in the central nervous system (CNS) and the role of the central nervous system in tumor progression is still unclear, as are the underlying mechanisms. This review summarizes what is known of stress-related CNS-network activation during the stress response and the influence of the CNS on tumors and discusses available adjuvant treatment methods for cancer patients with negative emotional states, such as anxiety and depression.

Facile immobilization of graphene nanosheets onto PBO fibers via MOF-mediated coagulation strategy: Multifunctional interface with self-healing and ultraviolet-resistance performance.

The surface of poly (p-phenylene benzobisoxazole) (PBO) fibers with self-healing and ultraviolet (UV)-resistance performance play the key role in prolonging their service lifespan. Although great advances have been made in the single aspect of above two properties, integration of self-healing and anti-UV performance into the surface of PBO fiber is still a challenge. In this study, the coagulation strategy mediated by metal-organic framework (MOF) is proposed to construct the multifunctional surface of PBO fibers. The spindle-like iron (III)-based MOF (MIL-88B-NH2) nanocrystals are firstly immobilized onto the surface of PBO-COOH through hydrothermal reaction, then serving as the medium layer to further immobilize sufficient graphene oxide (GO) nanosheets. Benefitting from the favorable near-infrared (NIR, 808 nm) photothermal conversion performance of GO nanolayers, the monofilament composite-PBO@Fe-MIL-88B-NH2-GO-TPU (thermoplastic polyurethane) exhibited a stable and high self-healing efficiency (approximately 80%) within five cycle times. Meanwhile, the cooperative adsorption and shielding weaken effects of MOF-GO nanolayers enabled PBO fibers with excellent anti-UV properties that are superior to much reported literatures after 96 h aging time and eventually increased by 75% compared with untreated PBO fiber. In view of the varieties and multifunctionalities of MOFs and carbon nanomaterials, MOF-mediated coagulation strategy would provide guidance for preparing multifunctional composite materials.

Activation of dopaminergic VTA inputs to the mPFC ameliorates chronic stress-induced breast tumor progression.

AIMS: Chronic stress plays an important role in promoting the progression and migration of cancers. However, little is known of any direct impact on tumor progression related to the regulation of emotion-related circuitry. The aim of this study was to explore the neural-circuit mechanisms underlying stress-induced progression of cancers and the impact of emotion-related regulation of circuitry on tumor growth. METHODS: Optogenetic manipulation was applied to unpredictable chronic mild stress (UCMS)-treated mice bearing breast tumor cell. The stress-related hormones, tumor-related cytokines, the tyrosine hydroxylase (TH)-positive neurons and their fibers, dopamine receptor-positive cells, and anxiety level were measured using ELISA, immunohistochemical staining, fluorescence in situ hybridization, and behavioral test, respectively. RESULTS: By investigating breast cancer mouse models with a chronic mild stress model, optogenetic stimulation, and behavioral analysis, we show that chronic stress induced anxiety-like behavior in mice and increased serum concentration of norepinephrine and corticosterone, hormones closely related to stress and anxiety. Optogenetic activation of VTA TH terminals in the mPFC rescued anxiety-like behavior induced by chronic stress. Chronic stress resulted in marked progression of breast tumors, and repetitive optogenetic activation of VTA TH terminals in the mPFC significantly attenuated stress-induced progression of breast cancers and reduced serum concentration of norepinephrine and corticosterone. Furthermore, there was a positive correlation between serum norepinephrine or corticosterone concentration and tumor size. CONCLUSIONS: These findings indicate a positive role of an emotion regulation circuit on the progression of breast cancer and reveal a link between stress, emotion regulation, and the progression of breast cancers. Our findings provide new insights pertinent to therapeutic interventions in the treatment of breast cancers.

Chronic optogenetic manipulation of basolateral amygdala astrocytes rescues stress-induced anxiety.

Chronic exposure to stressors can disrupt normal brain function and induce anxiety-like behavior and neurobiological alterations in the basolateral amygdala (BLA). Here, we showed that unpredictable chronic mild stress (UCMS) induced anxiety-like behavior, lowered glutamatergic neuronal activity and reactive astrocytes in the BLA. Using optogenetic tools, we found that activation of BLA glutamatergic neurons did not rescue anxiety-like behavior in stressed mice. In contrast, however, optogenetic activation of the BLA astrocytes relieved stress-induced anxiety, and, interestingly, chronic optogenetic manipulation fully restored the UCMS-induced behavioral and neurobiological dysfunctions, including anxiety-like behavior, lower c-Fos expression in the BLA, S100 overexpression in the BLA, and higher serum corticosterone concentration. Thus, our findings suggest that chronic manipulation of BLA astrocytes is a potential therapeutic intervention target for pathological anxiety.

Construction of Anti-Ultraviolet "Shielding Clothes" on Poly( p-phenylene benzobisoxazole) Fibers: Metal Organic Framework-Mediated Absorption Strategy.

A metal-organic framework (MOF)-mediated adsorption strategy is first developed for improving the anti-ultraviolet (UV) properties of poly( p-phenylene benzobisoxazole) (PBO) fibers. In this work, UIO-66 was successfully anchored onto the surface of PBO fibers by one-step microwave-assisted heating method. The experimental results showed an obviously enhanced surface energy (91.1%), roughness (268.4%), interfacial shear strength (49.0%), and anti-UV properties (66.7%) compared to pristine PBO fibers. The anti-UV dye (tartrazine) was further immobilized onto the surface of PBO fibers via an adsorption strategy mediated by UIO-66. Interestingly, the PBO@tartrazine fibers demonstrated superior anti-UV performance (further up to 81.5%) compared to PBO@UIO-66 fibers. The extraordinary anti-UV properties of PBO@tartrazine fibers could be rationally ascribed to the synergistic effects of UIO-66 and tartrazine molecules. Considering the diversities and functionalities of MOFs and targeted materials, our work indicates that the MOF-mediated adsorption strategy would promisingly endow PBO fibers with other desired performance and applications such as solar-thermal transition and self-healing abilities.

Light triggered interfacial damage self-healing of poly(p-phenylene benzobisoxazole) fiber composites.

The interfacial microcracks in the resin matrix composites are difficult to be detected and repaired. However, the self-healing concept provides opportunities to fabricate composites with unusual properties. In the present study, photothermal conversion Ag-Cu2S nanoparticles were immobilized onto poly(p-phenylene benzobisoxazole) (PBO) fibers via a polydopamine chemistry. Benefitting from the photothermal effects of Ag-Cu2S, the obtained PBO fibers (Ag-Cu2S-PBO) efficiently converted the light energy into heat under Xenon lamp irradiation. Then, single PBO fiber composites were prepared using thermoplastic polyurethane as the matrix. It was found that the interfacial damage caused by single fiber pull-out was simply self-healed by Xe light irradiation. This wonderful interfacial damage self-healing property was mainly attributed to the in situ heating generation via photothermal effects of Ag-Cu2S in the composite interface. This paper reports a novel strategy to construct advanced composites with light-triggered self-healing properties, which will provide inspiration for preparing high performance composite materials.

Fabrication of a graphene/C60 nanohybrid via γ-cyclodextrin host-guest chemistry for photodynamic and photothermal therapy.

The wonderful chemical structures and characteristics of low-dimensional carbon materials have exciting applications in life sciences. In the present study, we developed a facile strategy to conjugate C60 with graphene via host-guest chemistry for targeted phototherapy. A versatile carrier based on folic acid-functionalized graphene (GO-FA) and comprising γ-cyclodextrin (γ-CD) at its surface was assembled via π-π interaction, creating hybrid structures with drug storage and tumor targeting properties. This γ-CD-modified graphene (GO-FA/Py-γ-CD) is capable of hosting pristine C60 molecules for the fabrication of a GO-FA/Py-γ-CD/C60 nanohybrid. The hybridization of GO-FA, γ-CD, and C60 hinders the aggregation of C60, promotes cellular uptake, enhances light absorption, and finally demonstrates enhanced phototherapy effects of GO-FA/Py-γ-CD/C60. Under Xe lamp irradiation (2 W cm-2) for 4 min, GO-FA/Py-γ-CD/C60 simultaneously causes heating and intracellular ROS production, which further significantly reduces the cell viability to 16.2% at low content of loading (30 µg mL-1). Moreover, it represents an excellent tumor killing efficiency, better than that of the other reported graphene/C60 nanohybrids; thus, this material is suitable for applications in phototherapy of cancer.