Quantification and Proteomic Characterization of ß-Hydroxybutyrylation Modification in the Hearts of AMPKα2 Knockout Mice.

AMP-activated protein kinase alpha 2 (AMPKα2) regulates energy metabolism, protein synthesis, and glucolipid metabolism myocardial cells. Ketone bodies produced by fatty acid ß-oxidation, especially ß-hydroxybutyrate, are fatty energy-supplying substances for the heart, brain, and other organs during fasting and long-term exercise. They also regulate metabolic signaling for multiple cellular functions. Lysine ß-hydroxybutyrylation (Kbhb) is a ß-hydroxybutyrate-mediated protein posttranslational modification. Histone Kbhb has been identified in yeast, mouse, and human cells. However, whether AMPK regulates protein Kbhb is yet unclear. Hence, the present study explored the changes in proteomics and Kbhb modification omics in the hearts of AMPKα2 knockout mice using a comprehensive quantitative proteomic analysis. Based on mass spectrometry (LC-MS/MS) analysis, the number of 1181 Kbhb modified sites in 455 proteins were quantified between AMPKα2 knockout mice and wildtype mice; 244 Kbhb sites in 142 proteins decreased or increased after AMPKα2 knockout (fold change >1.5 or <1/1.5, p < 0.05). The regulation of Kbhb sites in 26 key enzymes of fatty acid degradation and tricarboxylic acid cycle was noted in AMPKα2 knockout mouse cardiomyocytes. These findings, for the first time, identified proteomic features and Kbhb modification of cardiomyocytes after AMPKα2 knockout, suggesting that AMPKα2 regulates energy metabolism by modifying protein Kbhb.

A regulation strategy of self-assembly molecules for achieving efficient inverted perovskite solar cells.

Self-assembled monolayers (SAMs) have been successfully employed to enhance the efficiency of inverted perovskite solar cells (PSCs) and perovskite/silicon tandem solar cells due to their facile low-temperature processing and superior device performance. Nevertheless, depositing uniform and dense SAMs with high surface coverage on metal oxide substrates remains a critical challenge. In this work, we propose a holistic strategy to construct composite hole transport layers (HTLs) by co-adsorbing mixed SAMs (MeO-2PACz and 2PACz) onto the surface of the H2O2-modified NiOx layer. The results demonstrate that the conductivity of the NiOx bulk phase is enhanced due to the H2O2 modification, thereby facilitating carrier transport. Furthermore, the hydroxyl-rich NiOx surface promotes uniform and dense adsorption of mixed SAM molecules while enhancing their anchoring stability. In addition, the energy level alignment at the interface is improved due to the utilization of mixed SAMs in an optimized ratio. Furthermore, the perovskite film crystal growth is facilitated by the uniform and dense composite HTLs. As a result, the power conversion efficiency of PSCs based on composite HTLs is boosted from 22.26% to 23.16%, along with enhanced operational stability. This work highlights the importance of designing and constructing NiOx/SAM composite HTLs as an effective strategy for enhancing both the performance and stability of inverted PSCs.

Efficient Perovskite Light-Emitting Diodes with Chemically Bonded Contact and Regulated Charge Behavior.

Efficient charge injection and radiative recombination are essential to achieving high-performance perovskite light-emitting diodes (Pero-LEDs). However, the perovskite emission layer (EML) and the electron transport layer (ETL) form a poor physically interfacial contact and non-negligible charge injection barrier, limiting the device performance. Herein, we utilize a phosphine oxide, 2,4,6-tris[3-(diphenylphosphinyl)phenyl]-1,3,5-triazine (PO-T2T), to treat the perovskite/ETL interface and form a chemically bonded contact. Specifically, PO-T2T firmly bonds on the perovskite's surface and grain boundaries through a dative bond, effectively passivating the uncoordinated lead defects. Additionally, PO-T2T has high electron mobility and establishes an electron transport highway to bridge the ETL and EML. As a result, a maximum external quantum efficiency (EQEmax) of 22.06% (average EQEmax of 20.02 ± 1.00%) and maximum luminance (Lmax) of 103286 cd m-2 have been achieved for the champion device. Our results indicate that EML/ETL interface modifications are crucial for the fabrication of highly efficient Pero-LEDs.

Chirality Sensing of Amino Acid Esters by S-2-Methylbutanamido-Substituted m-Phthalic Diamide-Linked Zinc Bisporphyrinate.

To understand the role of an additional coordination site in the linker in chirality sensing, we designed and synthesized an S-2-methylbutanamido-substituted m-phthalic diamide-linked zinc bisporphyrinate, [Zn2(S-MAABis)] and investigated its ability to sense the chirality of amino acid esters. The 1H NMR spectra and the crystal structure showed that the amido oxygen adjacent to the chiral carbon was coordinated with zinc. NMR and UV-vis titration showed that the binding of [Zn2(S-MAABis)] to amino acid esters occurred via two equilibria, forming 1:1 and 1:2 host-guest complexes. The CD spectra suggested that [Zn2(S-MAABis)] can effectively recognize the absolute configuration of amino acid esters. The sign of the CD spectra remained unchanged during the titration, indicating that the corresponding 1:1 and 1:2 host-guest complexes had the same chirality. This is different from previously studied amino-substituted m-phthalic diamide-linked zinc bisporphyrinate [Zn2(AmBis)], which showed chirality inversion during titration. Theoretical calculations indicated that the additional coordination sites (amido or amino) in the 1:1 host-guest complexes played different roles, leading to differences in chirality. Our studies suggest that the introduction of a coordination site can influence the chirality transfer process, but the results of chirality transfers are dependent on the specific binding modes.

Thiazole Functionalization of Thiosemicarbazone for Cu(II) Complexation: Moving toward Highly Efficient Anticancer Drugs with Promising Oral Bioavailability.

In this work, we report the synthesis of a new thiosemicarbazone-based drug of N'-(di(pyridin-2-yl)methylene)-4-(thiazol-2-yl)piperazine-1-carbothiohydrazide (HL) featuring a thiazole spectator for efficient coordination with Cu(II) to give [CuCl(L)]2 (1) and [Cu(NO3)(L)]2 (2). Both 1 and 2 exhibit dimeric structures ascribed to the presence of di-2-pyridylketone moieties that demonstrate dual functions of chelation and intermolecular bridging. HL, 1, and 2 are highly toxic against hepatocellular carcinoma cell lines Hep-G2, PLC/PRF/5, and HuH-7 with half maximal inhibitory concentration (IC50) values as low as 3.26 nmol/mL (HL), 2.18 nmol/mL (1), and 2.54 × 10-5 nmol/mL (2) for PLC/PRF/5. While the free ligand HL may elicit its anticancer effect via the sequestration of bio-relevant metal ions (i.e., Fe3+ and Cu2+), 1 and 2 are also capable of generating cytotoxic reactive oxygen species (ROS) to inhibit cancer cell proliferation. Our preliminary pharmacokinetic studies revealed that oral administration (per os, PO) of HL has a significantly longer half-life t1/2 of 21.61 ± 9.4 h, nearly doubled as compared with that of the intravenous (i.v.) administration of 11.88 ± 1.66 h, certifying HL as an effective chemotherapeutic drug via PO administration.

[FeIIICl(TMPPH2)][FeIIICl4]2: A Stand-Alone Molecular Nanomedicine That Induces High Cytotoxicity by Ferroptosis.

Developing clinically meaningful nanomedicines for cancer therapy requires the drugs to be effective, safe, simple, cheap, and easy to store. In the present work, we report that a simple cationic Fe(III)-rich salt of [FeIIICl(TMPPH2)][FeIIICl4]2 (Fe-TMPP) exhibits a superior anticancer performance on a broad spectrum of cancer cell lines, including breast, colorectal cancer, liver, pancreatic, prostate, and gastric cancers, with half maximal inhibitory concentration (IC50) values in the range of 0.098-3.97 µM (0.066-2.68 µg mL-1), comparable to the best-reported medicines. Fe-TMPP can form stand-alone nanoparticles in water without the need for extra surface modification or organic-solvent-assisted antisolvent precipitation. Critically, Fe-TMPP is TME-responsive (TME = tumor microenvironment), and can only elicit its function in the TME with overexpressed H2O2, converting H2O2 to the cytotoxic •OH to oxidize the phospholipid of the cancer cell membrane, causing ferroptosis, a programmed cell death process of cancer cells.

Prefrontal GABAA(δ)R Promotes Fear Extinction through Enabling the Plastic Regulation of Neuronal Intrinsic Excitability.

Extinguishing the previously acquired fear is critical for the adaptation of an organism to the ever-changing environment, a process requiring the engagement of GABAA receptors (GABAARs). GABAARs consist of tens of structurally, pharmacologically, and functionally heterogeneous subtypes. However, the specific roles of these subtypes in fear extinction remain largely unexplored. Here, we observed that in the medial prefrontal cortex (mPFC), a core region for mood regulation, the extrasynaptically situated, δ-subunit-containing GABAARs [GABAA(δ)Rs], had a permissive role in tuning fear extinction in male mice, an effect sharply contrasting to the established but suppressive role by the whole GABAAR family. First, the fear extinction in individual mice was positively correlated with the level of GABAA(δ)R expression and function in their mPFC. Second, knockdown of GABAA(δ)R in mPFC, specifically in its infralimbic (IL) subregion, sufficed to impair the fear extinction in mice. Third, GABAA(δ)R-deficient mice also showed fear extinction deficits, and re-expressing GABAA(δ)Rs in the IL of these mice rescued the impaired extinction. Further mechanistic studies demonstrated that the permissive effect of GABAA(δ)R was associated with its role in enabling the extinction-evoked plastic regulation of neuronal excitability in IL projection neurons. By contrast, GABAA(δ)R had little influence on the extinction-evoked plasticity of glutamatergic transmission in these cells. Altogether, our findings revealed an unconventional and permissive role of extrasynaptic GABAA receptors in fear extinction through a route relying on nonsynaptic plasticity.SIGNIFICANCE STATEMENT The medial prefrontal cortex (mPFC) is one of the kernel brain regions engaged in fear extinction. Previous studies have repetitively shown that the GABAA receptor (GABAAR) family in this region act to suppress fear extinction. However, the roles of specific GABAAR subtypes in mPFC are largely unknown. We observed that the GABAAR-containing δ-subunit [GABAA(δ)R], a subtype of GABAARs exclusively situated in the extrasynaptic membrane and mediating the tonic neuronal inhibition, works oppositely to the whole GABAAR family and promotes (but does not suppress) fear extinction. More interestingly, in striking contrast to the synaptic GABAARs that suppress fear extinction by breaking the extinction-evoked plasticity of glutamatergic transmission, the GABAA(δ)R promotes fear extinction through enabling the plastic regulation of neuronal excitability in the infralimbic subregion of mPFC. Our findings thus reveal an unconventional role of GABAA(δ)R in promoting fear extinction through a route relying on nonsynaptic plasticity.

The Addition of an Ultra-Small Amount of Black Phosphorous Quantum Dots Endow Self-Healing Polyurethane with a Biomimetic Intelligent Response.

This study explores new applications of black phosphorus quantum dots (BPQDs) by adding them to self-healing material systems for the first time. Self-healing polyurethane with an ultra-small amount of BPQDs has biomimetic intelligent responsiveness and achieves balance between its mechanical and self-healing properties. By adding 0.0001 wt% BPQDs to self-healing polyurethane, the fracture strength of the material increases from 3.0 to 12.3 MPa, and the elongation at break also increases from 750% to 860%. Meanwhile, the self-healing efficiency remains at 98%. The addition of BPQDs significantly improves the deformation recovery ability of the composite materials and transforms the surface of self-healing polyurethane from hydrophilic to hydrophobic, making it suitable for applications in fields such as electronic skin and flexible wearable devices. This study provides a simple and feasible strategy for endowing self-healing materials with biomimetic intelligent responsiveness using a small amount of BPQDs.

Kinetically and thermodynamically controlled one-pot growth of gold nanoshells with NIR-II absorption for multimodal imaging-guided photothermal therapy.

Since the successful clinical trial of AuroShell for photothermal therapy, there is currently intense interest in developing gold-based core-shell structures with near-infrared (NIR) absorption ranging from NIR-I (650-900 nm) to NIR-II (900-1700 nm). Here, we propose a seed-mediated successive growth approach to produce gold nanoshells on the surface of the nanoscale metal-organic framework (NMOF) of UiO-66-NH2 (UiO = the University of Oslo) in one pot. The key to this strategy is to modulate the proportion of the formaldehyde (reductant) and its regulator / oxidative product of formic acid to harness the particle nucleation and growth rate within the same system. The gold nanoshells propagate through a well-oriented and controllable diffusion growth pattern (points → facets → octahedron), which has not been identified. Most strikingly, the gold nanoshells prepared hereby exhibit an exceedingly broad and strong absorption in NIR-II with a peak beyond 1300 nm and outstanding photothermal conversion efficiency of 74.0%. Owing to such superior performance, these gold nanoshells show promising outcomes in photoacoustic (PA), computed tomography (CT), and photothermal imaging-guided photothermal therapy (PTT) for breast cancer, as demonstrated both in vitro and in vivo.

Separation and determination of triadimefon and its metabolites triadimenol enantiomers in fruit puree by supercritical fluid chromatography.

A method was established for the separation and determination of triadimefon and its metabolite triadimenol enantiomer residues in major complementary fruit puree for infants and young children (banana puree, pineapple puree, and grape puree) by supercritical fluid chromatography. After the samples were extracted with acetonitrile and purified with a solid phase extraction cartridge, Acquity Trefoil CEL2 chiral chromatographic column was adopted for separation, and gradient elution was conducted at the flow rate of 1.0 ml/min under the mobile phase of supercritical carbon dioxide - 0.5% ammonia methanol, the detection wavelength was 220 nm and quantification was conducted with the external standard method. The limits of quantitation of triadimefon and triadimenol enantiomers were both 0.05 mg/kg, the linear ranges were 0.5-50 mg/L, and the linear correlation coefficients were greater than 0.9993. The recoveries in the spiked samples at 0.05, 0.2, and 3.0 mg/kg were from 80.1 to 106%, and the relative standard deviation reached 3.3-7.6%. The method is efficient, rapid, reproducible, and environmentally friendly, enabling accurate analysis of pesticide enantiomers, which can detect the enantiomer residues of triadimefon and its metabolite triadimenol in major complementary fruit puree for infants and young children.

Conductive Phosphine Oxide Passivator Enables Efficient Perovskite Light-Emitting Diodes.

Recently, surface passivation has been proved to be an essential approach for obtaining efficient and stable perovskite light-emitting diodes (Pero-LEDs). Phosphine oxides performed well as passivators in many reports. However, the most commonly used phosphine oxides are insulators, which may inhibit carrier transport between the perovskite emitter and charge-transporter layers, limiting the corresponding device performance. Here, 2,7-bis(diphenylphosphoryl)-9,9'-spirobifluorene (SPPO13), a conductive molecule with two phosphine oxide functional groups, is introduced to modify the perovskite emitting layer. The bifunctional SPPO13 can passivate the nonradiative defects of perovskite and promote electron injection at the interface of perovskite emitter and electron-transporter layers. As a result, the corresponding Pero-LEDs obtain a maximum external quantum efficiency (EQE) of 22.3%. In addition, the Pero-LEDs achieve extremely high brightness with a maximum of around 190 000 cd/m2.

Nanoscale Two-Dimensional FeII- and CoII-Based Metal-Organic Frameworks of Porphyrin Ligand for the Photodynamic Therapy of Breast Cancer.

The delivery of biocompatible reagents into cancer cells can elicit an anticancer effect by taking advantage of the unique characteristics of the tumor microenvironment (TME). In this work, we report that nanoscale two-dimensional FeII- and CoII-based metal-organic frameworks (NMOFs) of porphyrin ligand meso-tetrakis (6-(hydroxymethyl) pyridin-3-yl) porphyrin (THPP) can catalyze the generation of hydroxyl radicals (•OH) and O2 in the presence of H2O2 that is overexpressed in the TME. Photodynamic therapy consumes the generated O2 to produce a singlet oxygen (1O2). Both •OH and 1O2 are reactive oxygen species (ROS) that inhibit cancer cell proliferation. The FeII- and CoII-based NMOFs were non-toxic in the dark but cytotoxic when irradiated with 660 nm light. This preliminary work points to the potential of porphyrin-based ligands of transition metals as anticancer drugs by synergizing different therapeutic modalities.

Benzothieno[3,2-b]thiophene-Based Noncovalent Conformational Lock Achieves Perovskite Solar Cells with Efficiency over 24.

Organic semiconductors with noncovalently conformational locks (OSNCs) are promising building blocks for hole-transporting materials (HTMs). However, lack of satisfied neighboring building blocks negatively impacts the optoelectronic properties of OSNCs-based HTMs and imperils the stability of perovskite solar cells (PSCs). To address this limitation, we introduce the benzothieno[3,2-b]thiophene (BTT) to construct a new OSNC, and the resulting HTM ZS13 shows improved intermolecular charge extraction/transport properties, proper energy level, efficient surface passivation effect. Consequently, the champion devices based on doped ZS13 yield an efficiency of 24.39 % and 20.95 % for aperture areas of 0.1 and 1.01 cm2 , respectively. Furthermore, ZS13 shows good thermal stability and the capability of inhibiting I- ion migration, thus, leading to enhanced device stability. The success in neighboring-group engineering can triggered a strong interest in developing thienoacene-based OSNCs toward efficient and stable PSCs.

In situ siloxane passivation of colloidal lead halide perovskite via hot injection for light-emitting diodes.

All-inorganic cesium lead halide perovskite (CsPbX3; X = Cl, Br) nanocrystals (NCs) are synthesized via a modified hot injection method using 3-mercaptopropyltrimethoxysilane (MPTMS), together with oleic acid and oleylamine, for in situ passivation of the surface defects. The surface chemistry, revealed by Fourier transform infrared spectroscopy (FTIR) and x-ray photoelectron spectroscopy (XPS) techniques, shows an absence of Si-O-Si network and C-O groups on these in situ passivated CsPbX3 NCs, denoted as InMP-CsPbX3, which is in strong contrast to the counterpart NCs obtained via a postsynthesis exchange strategy. The x-ray diffraction (XRD) pattern indicates a lattice structure significantly strained from the cubic structure. The synthesis of these InMP-CsPbX3 NCs is highly reproducible, and the colloids are stable in nonpolar solvents. The emission wavelength of CsPb(Cl/Br)3 mixed halide perovskite NCs is tuned from 405 nm to 508 nm by reducing the nominal Cl/Br ratio, while the photoluminescence quantum yield (PLQY) is greatly enhanced over the whole spectral range. More importantly, the InMP-treatment is among the few strategies that are promising for electroluminescence in light-emitting diodes.

Vacuum-Induced Guest N,N'-Diethylformamide Binding in a Metastable Cd5-Based Metal-Organic Framework.

A three-dimensional (3D) metal-organic framework (MOF) of [Et2NH2]2[Cd5(BTB)4(DEF)2]·4.75DEF (1; H3BTB = benzene-1,3,5-tribenzoic acid and DEF = N,N'-diethylformamide) sustained by symmetrical Z-shaped Cd5 secondary building units (SBUs) with an intrinsically metastable host framework has been prepared and characterized. Upon gentle vacuum (800 Pa) at 50 °C, some encapsulated DEF solvates are released, leading to pore-shape changes and Cd2+ coordination geometry distortion. This is followed by DEF solvate migration to only one end of the SBU with concomitant symmetry breaking. Additional time under vacuum promoted further structural distortion and topology changes as authenticated by single-crystal X-ray diffraction studies. This work was initially inspired by unusual gas adsorption isotherms and points to the potentially complicated, nonspectator role of coordinative solvents such as DEF during MOF activation.

Synergistic photothermal-photodynamic-chemotherapy toward breast cancer based on a liposome-coated core-shell AuNS@NMOFs nanocomposite encapsulated with gambogic acid.

A multifunctional nanoplatform with core-shell structure was constructed in one-pot for the synergistic photothermal, photodynamic, and chemotherapy against breast cancer. In the presence of gambogic acid (GA) as the heat-shock protein 90 (HSP90) inhibitor and the gold nanostars (AuNS) as the photothermal reagent, the assembly of Zr4+ with tetrakis (4-carboxyphenyl) porphyrin (TCPP) gave rise to the nanocomposite AuNS@ZrTCPP-GA (AZG), which in turn, further coated with PEGylated liposome (LP) to enhance the stability and biocompatibility, and consequently the antitumor effect of the particle. Upon cellular uptake, the nanoscale metal - organic framework (NMOF) of ZrTCPP in the resulted AuNS@ZrTCPP-GA@LP (AZGL) could be slowly degraded in the weak acidic tumor microenvironment to release AuNS, Zr4+, TCPP, and GA to exert the synergistic treatment of tumors via the combination of AuNS-mediated mild photothermal therapy (PTT) and TCPP-mediated photodynamic therapy (PDT). The introduction of GA serves to reduce the thermal resistance of the cell to re-sensitize PTT and the constructed nanoplatform demonstrated remarkable anti-tumor activity in vitro and in vivo. Our work highlights a facile strategy to prepare a pH-dissociable nanoplatform for the effective synergistic treatment of breast cancer.

Research method of rapid determination of chiral pesticide fenpropathrin enantiomers in fruit and vegetable puree by supercritical fluid chromatography.

A method is first established for the separation and determination of fenpropathrin enantiomer residues in apple puree, strawberry puree, and tomato puree considered a supplementary food for infants by supercritical fluid chromatography. After the sample was extracted with acetonitrile and cleaned up by a solid-phase extraction column, then it was separated by a CHIRALPAK AD-3 chiral column with gradient elution at a flow rate of 1.5 mL/min using methanol and supercritical carbon dioxide as the mobile phase, detected by ultraviolet detector at 230 nm wavelength and quantified with the external standard method. The limits of quantification of the two fenpropathrin enantiomers were both 0.2 mg/kg, the linear ranges were 1.0-20.0 mg/L with linear correlation coefficients greater than 0.9992, the recoveries in the spiked samples at 0.2, 0.4 and 2.0 mg/kg were from 80.6 to 105%, and the relative standard deviation reached 2.6-7.7%. This method has the advantages of convenient operation, good resolution, and environmental protection, which can satisfy the requirement of determination for fenpropathrin enantiomer residues in fruit and vegetable puree as supplementary food for infants.

New Insights into the Pivotal Role of the Amygdala in Inflammation-Related Depression and Anxiety Disorder.

Depression and anxiety disorders are the two most prevalent psychiatric diseases that affect hundreds of millions of individuals worldwide. Understanding the etiology and related mechanisms is of great importance and might yield new therapeutic strategies to treat these diseases effectively. During the past decades, a growing number of studies have pointed out the importance of the stress-induced inflammatory response in the amygdala, a kernel region for processing emotional stimuli, as a potentially critical contributor to the pathophysiology of depression and anxiety disorders. In this review, we first summarized the recent progress from both animal and human studies toward understanding the causal link between stress-induced inflammation and depression and anxiety disorders, with particular emphasis on findings showing the effect of inflammation on the functional changes in neurons in the amygdala, at levels ranging from molecular signaling, cellular function, synaptic plasticity, and the neural circuit to behavior, as well as their contributions to the pathology of inflammation-related depression and anxiety disorders. Finally, we concluded by discussing some of the difficulties surrounding the current research and propose some issues worth future study in this field.

Association Between Common Vaginal Infections and Cervical Non-Human Papillomavirus (HPV) 16/18 Infection in HPV-Vaccinated Women.

BACKGROUND: How vaginal infections such as bacterial vaginosis, Candida spp, and Trichomonas vaginalis affect persistence of human papillomavirus (HPV) infection is not well established. Our study aimed to evaluate the association between common vaginal infections and cervical non-HPV16/18 infection, as risk factors associated with persistence of nonvaccine HPV types will become increasingly relevant in the setting of HPV vaccination. METHODS: We performed an analysis in 2039 AS04-HPV16/18-vaccinated women enrolled in a phase II/III trial in China, who were HPV DNA negative at month 0 and 6 and had at least 1 subsequent follow-up visit. Vaginal infections were detected in liquid-based cytology according to the diagnostic criteria of the Bethesda System. Associations between vaginal infections and incident and 6-month persistent non-HPV16/18 infections in the cervix were evaluated using generalized estimating equations, adjusting for the age at initial vaccination, as well as HPV types in the persistence analysis. RESULTS: Study visits with any vaginal infection had a statistically significant increased risk of incident non-HPV16/18 infection compared to those without vaginal infections (odds ratio [OR], 1.44 [95% confidence interval {CI}, 1.09-1.92]). However, vaginal infections were not associated with 6-month persistent non-HPV16/18 infection (OR, 1.02 [95% CI, .62-1.69]). CONCLUSIONS: Our study suggests that common vaginal infections are not associated with persistence of non-HPV16/18 infection among HPV16/18-vaccinated women.

Neuroinflammation induces anxiety- and depressive-like behavior by modulating neuronal plasticity in the basolateral amygdala.

Increasing evidence indicates that excessive inflammatory responses play a crucial role in the pathophysiology of psychiatric diseases, including depression and anxiety disorders. The dysfunctional neural plasticity in amygdala has long been proposed as the vital cause for the progression of psychiatric disorders. However, the effect of neuroinflammation on the functional changes of the amygdala remains largely unknown. Here, by using a mouse model of inflammation induced by lipopolysaccharide (LPS) injection, we investigated the effect of LPS-induced neuroinflammation on the synaptic and non-synaptic plasticity in basolateral amygdala (BLA) projection neurons (PNs) and their contribution to the LPS-induced anxiety- and depressive-like behavior. The results showed that LPS treatment led to the activation of microglia and production of proinflammatory cytokines in the BLA. Furthermore, LPS treatment increased excitatory but not inhibitory synaptic transmission due to the enhanced presynaptic glutamate release, thus leading to the shift of excitatory/inhibitory balance towards excitatory. In addition, the intrinsic neuronal excitability of BLA PNs was also increased by LPS treatment through the loss of expression and function of small-conductance, calcium-activated potassium channel. Chronic fluoxetine pretreatment significantly prevented these neurophysiological changes induced by LPS, and alleviated anxiety and depressive-like behavior, indicating that LPS-induced neuronal dysregulation of BLA PNs may contribute to the development of psychiatry disorders. Collectively, these findings provide evidence that dysregulation of synaptic and non-synaptic transmission in the BLA PNs may account for neuroinflammation-induced anxiety- and depressive-like behavior.