Activating Lobule VI PCTH+-Med Pathway in Cerebellum Blocks the Acquisition of Methamphetamine Conditioned Place Preference in Mice.

Cerebellum has been implicated in drug addiction; however, its underlying cellular populations and neuronal circuitry remain largely unknown. In the current study, we identified a neural pathway from tyrosine hydroxylase (TH)-positive Purkinje cells (PCTH+) in cerebellar lobule VI to calcium/calmodulin-dependent protein kinase II (CaMKII)-positive glutamatergic neurons in the medial cerebellar nucleus (MedCaMKII), forming the lobule VI PCTH+-MedCaMKII pathway in male mice. In naive male mice, inhibition of PCTH+ neurons activated Med neurons. During conditioned place preference (CPP) training, exposure to methamphetamine (METH) inhibited lobule VI PCTH+ neurons while excited MedCaMKII neurons in mice. Silencing MedCaMKII using a tetanus toxin light chain (tettox) suppressed the acquisition of METH CPP in mice but resulted in motor coordination deficits in naive mice. In contrast, activating lobule VI PCTH+ terminals within Med inhibited the activity of Med neurons and subsequently blocked the acquisition of METH CPP in mice without affecting motor coordination, locomotor activity, and sucrose reinforcements in naive mice. Our findings identified a novel lobule VI PCTH+-MedCaMKII pathway within the cerebellum and explored its role in mediating the acquisition of METH-preferred behaviors.

Comparison of dye-based and probe-based RT-LAMP in detection of canine astrovirus.

A rapid and sensitive assay is essential for reliable surveillance and diagnosis of canine astrovirus (CaAstV). In this study, two real-time reverse transcription loop-mediated isothermal amplification (RT-LAMP) assays with high sensitivity, rapidity, and reliability were developed using fluorescence dye and FRET-based assimilating probes for real-time detection of CaAstV. These assays specifically amplified the ORF2 gene of CaAstV and did not amplify any sequences from canine enterovirus. The limit of detection (LOD) of both the probe-based and dye-based RT-LAMPs was 100 copies/µL. Fluorescence signals were generated within 30 min for the lowest concentration of a standard RNA sample, which was significantly faster than that achieved by real-time fluorescence quantitative PCR (qRT-PCR) assay. When clinical samples were tested, the positive and negative agreement of the dye-based RT-LAMP assay with qRT-PCR was 87.5% (14/16) and 93.55% (29/31), respectively. The positive and negative agreement of the probe-based RT-LAMP assay with qRT-PCR was 94.11% (16/17) and 96.55% (28/29), respectively. The RT-LAMP assays developed in this study showed strong potential for use as an on-site diagnostic assay for rapid, specific, and reliable detection of CaAstV in clinical samples.

Fine-Regional Role of the Claustrum in Anxiety and Higher Sensitivity to Cocaine in Adolescent Cocaine-Exposed Male Mice during Adulthood.

Adolescent cocaine exposure (ACE) induces anxiety and higher sensitivity to substances abuse during adulthood. Here, we show that the claustrum is crucial for controlling these psychiatric problems in male mice. In anxiety-like behavioral tests, the CaMKII-positive neurons in the median portion of the claustrum (MClaustrum) were triggered, and local suppression of these neurons reduced the anxiety-like behavior in ACE mice during adulthood. In contrast, the CaMKII-positive neurons in the anterior portion of the claustrum (AClaustrum) were more activated in response to subthreshold dose of cocaine induced conditioned place preference (CPP), and local suppression of these neurons blocked the acquisition of cocaine CPP in ACE mice during adulthood. Our findings for the first time identified the fine-regional role of the claustrum in regulating the anxiety and susceptibility to cocaine in ACE mice during adulthood, extending our understanding of the claustrum in substance use disorder.

METH exposure alters sperm DNA methylation in F0 mice and mPFC transcriptome in male F1 mice.

RATIONALE: Methamphetamine (METH) exposure has toxicity in sperm epigenetic phenotype and increases the risk for developing addiction in their offspring. However, the underlying transgenerational mechanism remains unclear. OBJECTIVES: The current study aims to investigate the profiles of sperm epigenetic modifications in male METH-exposed mice (F0) and medial prefrontal cortex (mPFC) transcriptome in their male first-generation offspring (F1). METHODS: METH-related male F0 and F1 mice model was established to investigate the effects of paternal METH exposure on reproductive functions and sperm DNA methylation in F0 and mPFC transcriptomic profile in F1. During adulthood, F1 was subjected to a conditioned place preference (CPP) test to evaluate sensitivity to METH. The gene levels were verified with qPCR. RESULTS: METH exposure obviously altered F0 sperms DNA methylated profile and male F1 mPFC transcriptomic profile, many of which being related to neuronal system and brain development. In METH-sired male F1, subthreshold dose of METH administration effectively elicited CPP, along with more mPFC activation. After qPCR verification, Sort1 and Shank2 were at higher levels in F0 sperm and F1 mPFC. CONCLUSIONS: Our findings put new insights into paternal METH exposure-altered profiles of F0 sperm DNA methylation and male F1 mPFC transcriptomics. Several genes, such as Sort1 and Shank2, might be used as potential molecules for further research on the transgenerational vulnerability to drug addiction in offspring by paternal drug exposure.

Paternal methamphetamine exposure induces higher sensitivity to methamphetamine in male offspring through driving ADRB1 on CaMKII-positive neurons in mPFC.

Paternal abuse of drugs, such as methamphetamine (METH), elevates the risk of developing addiction in subsequent generations, however, its underlying molecular mechanism remains poorly understood. Male adult mice (F0) were exposed to METH for 30 days, followed by mating with naïve female mice to create the first-generation mice (F1). When growing to adulthood, F1 were subjected to conditioned place preference (CPP) test. Subthreshold dose of METH (sd-METH), insufficient to induce CPP normally, were used in F1. Selective antagonist (betaxolol) for ß1-adrenergic receptor (ADRB1) or its knocking-down virus were administrated into mPFC to regulate ADRB1 function and expression on CaMKII-positive neurons. METH-sired male F1 acquired sd-METH-induced CPP, indicating that paternal METH exposure induce higher sensitivity to METH in male F1. Compared with saline (SAL)-sired male F1, CaMKII-positive neuronal activity was normal without sd-METH, but strongly evoked after sd-METH treatment in METH-sired male F1 during adulthood. METH-sired male F1 had higher ADRB1 levels without sd-METH, which was kept at higher levels after sd-METH treatment in mPFC. Either inhibiting ADRB1 function with betaxolol, or knocking-down ADRB1 level on CaMKII-positive neurons (ADRB1CaMKII) with virus transfection efficiently suppressed sd-METH -evoked mPFC activation, and ultimately blocked sd-METH-induced CPP in METH-sired male F1. In the process, the p-ERK1/2 and ΔFosB may be potential subsequent signals of mPFC ADRB1CaMKII. The mPFC ADRB1CaMKII mediates paternal METH exposure-induced higher sensitivity to drug addiction in male offspring, raising a promising pharmacological target for predicting or treating transgenerational addiction.

A Recombinase-Aided Amplification Assay for the Detection of Chlamydia felis.

Chlamydia felis is an important zoonotic agent for humans and various animals. A recombinase-aided amplification (RAA) assay was developed for detecting C. felis. RAA can be performed in a closed tube at 39°C within 30 min. The detection limit was 10.6 copies of the C. felis plasmid DNA per reaction. No positive signals for other pathogens were detected. The coincidence rate of RAA and conventional PCR was 95.24% (20/21) and 100% (96/96) for positive and negative samples, respectively. The established RAA assay is a simple, rapid, highly sensitive, and specific method for detecting C. felis.

Gegen-Qinlian decoction-A traditional Chinese medicine formula-Alleviates methamphetamine withdrawal induced anxiety by targeting GABAergic interneuron-pyramidal neuron pathway in mPFC.

Methamphetamine (Meth) withdrawal elicits anxiety, which is a public health concern with limited therapeutic options. Previous studies implied a strong correlation between mPFC and Meth withdrawal. Here, we examined the role of Gegen-Qinlian decoction (GQD) in Meth withdrawal anxiety and explored potential therapeutic targets in mPFC. We found that intra-gastric administration of GQD during the withdrawal period efficiently alleviated anxiety-like behaviours in Meth-withdrawn mice. Further, GQD could restore Meth withdrawal-triggered pathway of GABAergic interneurons (GABA IN)-pyramidal neurons (PN) in the mPFC of Meth-withdrawn mice, especially the prelimbic cortex (PrL) sub-region and PV-positive GABA IN. While, GQD had no obvious effects on the glial cells in the mPFC of Meth-withdrawn mice. By transcriptomic analysis and validation of several gene candidates, we found that genes in the MAPK signalling pathway, especially those related to heat shock proteins, including Hspa1a, Hspa1b and Hspb1, might be GQD-targeting genes in mPFC to treat Meth withdrawal anxiety, as indicated that these genes were up-regulated by Meth withdrawal but rescued by GQD in mPFC. Collectively, our findings identified for the first time that GQD could efficiently alleviate Meth withdrawal anxiety, partially through regulating the local GABA IN-PN pathway and transcriptomic profile of mPFC. The present study confirms that TCM, such as GQD, will be a desirable therapeutic approach in the treatment of drug addiction and related emotional deficits.

mPFC DUSP1 mediates adolescent cocaine exposure-induced higher sensitivity to drug in adulthood.

Adolescent cocaine abuse increases the risk for developing addiction in later life, but the underlying molecular mechanism remains poorly understood. Here, we establish adolescent cocaine-exposed (ACE) male mouse models. A subthreshold dose of cocaine (sdC) treatment, insufficient to produce conditioned place preference (CPP) in adolescent mice, induces CPP in ACE mice during adulthood, along with more activated CaMKII-positive neurons, higher dual specificity protein kinase phosphatase-1 (Dusp1) mRNA, lower DUSP1 activity, and lower DUSP1 expression in CaMKII-positive neurons in the medial prefrontal cortex (mPFC). Overexpressing DUSP1 in CaMKII-positive neurons suppresses neuron activity and blocks sdC-induced CPP in ACE mice during adulthood. On the contrary, depleting DUSP1 in CaMKII-positive neurons activates more neurons and further enhances sdC-induced behavior in ACE mice during adulthood. Also, ERK1/2 might be a downstream signal of DUSP1 in the process. Our findings reveal a role of mPFC DUSP1 in ACE-induced higher sensitivity to the drug in adult mice. DUSP1 might be a potential pharmacological target to predict or treat the susceptibility to addictive drugs caused by adolescent substance use.

Gegen-Qinlian decoction alleviates anxiety-like behaviors in methamphetamine-withdrawn mice by regulating Akkermansia and metabolism in the colon.

BACKGROUND: Anxiety is a prominent withdrawal symptom of methamphetamine (Meth) addiction. Recently, the gut microbiota has been regarded as a promising target for modulating anxiety. Gegen-Qinlian decoction (GQD) is a classical Traditional Chinese Medicine applied in interventions of various gut disorders by balancing the gut microbiome. We aim to investigate whether GQD could alleviate Meth withdrawal anxiety through balancing gut microbiota and gut microenvironment. METHODS: Meth withdrawal anxiety models were established in mice. GQD were intragastric administrated into Meth-withdrawn mice and controls. Gut permeability and inflammatory status were examined in mice. Germ-free (GF) and antibiotics-treated (Abx) mice were used to evaluate the role of gut bacteria in withdrawal anxiety. Gut microbiota was profiled with 16s rRNA sequencing in feces. Metabolomics in colon tissue and in Akkermansia culture medium were performed. RESULTS: Meth withdrawal enhanced anxiety-like behaviors in wild-type mice, and altered gut permeability, and inflammatory status, while GQD treatment during the withdrawal period efficiently alleviated anxiety-like behaviors and improved gut microenvironment. Next, we found Germ-free (GF) and antibiotics-treated (Abx) mice did not develop anxiety-like behaviors by Meth withdrawal, indicating the essential role of gut bacteria in Meth withdrawal induced anxiety. Then, it was observed that gut microbiota was greatly affected in Meth-withdrawn mice, especially the reduction in Akkermansia. GQD can rescue the gut microbiota and reverse Akkermansia abundance in Meth-withdrawn mice. Meanwhile, GQD can also restore the Meth-impaired Akkermansia growth in vitro. Further, GQD restored several common metabolite levels both in colon in vivo and in Akkermansia in vitro. CONCLUSIONS: We revealed a novel effect of GQD on Meth withdrawal anxiety and identified its pharmacological target axis as "Akkermansia-Akkermansia metabolites-gut metabolites-gut microenvironment". Our findings indicated that targeting gut bacteria with TCM, such as GQD, might be a promising therapeutic strategy for addiction and related withdrawal symptoms.

Dopamine receptor 1 on CaMKII-positive neurons within claustrum mediates adolescent cocaine exposure-induced anxiety-like behaviors and electro-acupuncture therapy.

Adolescent cocaine exposure (ACE) increases risk of developing psychiatric problems such as anxiety, which may drive relapse in later life, however, its underlying molecular mechanism remains poorly understood. Methods: ACE male mice model were established by exposing to cocaine during adolescent period. Elevated plus maze (EPM) were used to assess anxiety-like behaviors in mice. Within claustrum, local injection of SCH-23390, a specific antagonist for dopamine receptor 1 (D1R), or D1R knocking-down virus were used to regulate D1R function or expression on CaMKII-positive neurons (D1RCaMKII) in vivo. Electro-acupuncture (EA) treatment was performed at acupoints of Baihui and Yintang during withdrawal period. Results: We found that ACE mice exhibited anxiety-like behaviors, along with more activated CaMKII-positive neurons and increased D1RCaMKII levels in claustrum during adulthood. Inhibiting D1R function or knocking-down D1RCaMKII levels in claustrum efficiently reduced claustrum activation, and ultimately suppressed anxiety-like behaviors in ACE mice during adulthood. EA treatment alleviated ACE-evoked claustrum activation and anxiety-like behaviors by suppressing claustrum D1RCaMKII. Conclusion: Our findings identified a novel role of claustrum in ACE-induced anxiety-like behaviors, and put new insight into the D1RCaMKII in the claustrum. The claustrum D1RCaMKII might be a promising pharmacological target, such as EA treatment, to treat drug-induced anxiety-like behaviors.

Specific Inhibition of Interpeduncular Nucleus GABAergic Neurons Alleviates Anxiety-Like Behaviors in Male Mice after Prolonged Abstinence from Methamphetamine.

Anxiety is one of the most common withdrawal symptoms of methamphetamine (METH) abuse, which further drives relapse to drugs. Interpeduncular nucleus (IPN) has been implicated in anxiety-like behaviors and addiction, yet its role in METH-abstinence-induced anxiety remains unknown. Here, we found that prolonged abstinence from METH enhanced anxiety-like behaviors in male mice, accompanied by more excited IPN GABAergic neurons, as indicated by the increased c-fos expression and the enhanced neuronal excitability by electrophysiological recording in the GABAergic neurons. Using the designer receptors exclusively activated by designer drugs method, specific inhibition of IPN GABAergic neurons rescued the aberrant neuronal excitation of IPN GABAergic neurons and efficiently reduced anxiety-like behaviors, whereas it did not induce depression-like behaviors in male mice after prolonged abstinence from METH. These findings reveal that IPN GABAergic neurons should be a promising brain target to alleviate late withdrawal symptoms from METH with few side effects.SIGNIFICANCE STATEMENT Prolonged abstinence from METH triggers IPN GABAergic neurons and ultimately increases anxiety in male mice. Suppressing IPN GABAergic neurons rescues METH abstinence-induced aberrant neuronal excitation of IPN GABAergic neurons and efficiently reduces anxiety in mice.

Sex-specific metabolic signatures in methamphetamine addicts.

Methamphetamine (METH) is a commonly abused addictive psychostimulant, and METH-induced neurotoxic and behavioural deficits are in a sex-specific manner. However, there is lack of biomarkers to evaluate METH addiction in clinical practice, especially for gender differences. We utilized ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) to detect the serum metabolomics in METH addicts and controls, specially exploring the sex-specific metabolic alterations by METH abuse. We found that many differently expressed metabolites in METH addicts related to metabolisms of amino acid, energy, vitamin and neurological disorders. Further, METH abuse caused different patterns of metabolomics in a sex-specific manner. As to amino acid metabolism, L-phenylalanine, L-tryptophan and L-histidine in serum of male addicts and betaine in serum of female addicts were significantly changed by METH use. In addition, it seemed that purine and pyrimidine-related metabolites (e.g., xanthosine and adenosine 5'-monophosphate) in male and the metabolites of hormone (e.g., cortisol) and folate biosynthesis (e.g., 7,8-dihydrobiopterin and 4-hydroxybenzoic acid) in female were more sensitive to METH addiction. Our findings revealed that L-glutamic acid, L-aspartic acid, alpha-ketoglutarate acid and citric acid may be potential biomarkers for monitoring METH addiction in clinic. Considering sex-specific toxicity by METH, the metabolites of purine and pyrimidine metabolism in male and those of stress-related hormones in female may be used to facilitate the accurate diagnosis and treatment for METH addicts of different genders.

A novel cholinergic projection from the lateral parabrachial nucleus and its role in methamphetamine-primed conditioned place preference.

Drug relapse is a big clinical challenge in the treatment of addiction, but its neural circuit mechanism is far from being fully understood. Here, we identified a novel cholinergic pathway from choline acetyltransferase-positive neurons in the external lateral parabrachial nucleus (eLPBChAT) to the GABAergic neurons in the central nucleus of the amygdala (CeAGABA) and explored its role in methamphetamine priming-induced reinstatement of conditioned place preference. The anatomical structure and functional innervation of the eLPBChAT-CeAGABA pathway were investigated by various methods such as fluorescent micro-optical sectioning tomography, virus-based neural tracing, fibre photometry, patch-clamp and designer receptor exclusively activated by a designer drug. The role of the eLPBChAT-CeAGABA pathway in methamphetamine relapse was assessed using methamphetamine priming-induced reinstatement of conditioned place preference behaviours in male mice. We found that the eLPBChAT neurons mainly projected to the central nucleus of the amygdala. A chemogenetic activation of the eLPBChAT neurons in vitro or in vivo triggered the excitabilities of the CeAGABA neurons, which is at least in part mediated via the cholinergic receptor system. Most importantly, the chemogenetic activation of either the eLPBChAT neurons or the eLPBChAT neurons that project onto the central nucleus of the amygdala decreased the methamphetamine priming-induced reinstatement of conditioned place preference in mice. Our findings revealed a previously undiscovered cholinergic pathway of the eLPBChAT-CeAGABA and showed that the activation of this pathway decreased the methamphetamine priming-induced reinstatement of conditioned place preference.

Pathogenicity and Immunogenicity of a Serially Passaged Attenuated Genotype 2c Porcine Epidemic Diarrhea Virus Cultured in Suspended Vero Cells.

In this study, one G2c-subtype strain of porcine epidemic diarrhea virus (PEDV) (SHXX1902 strain) was isolated from clinical samples in suspended Vero cells, which was different from the genotype of the commercial AJ1102 vaccine. As a result, we determined the pathogenicity of different passages' isolates (SHXX1902 strain) and compared the immunogenicity of G2c-subtype strain (SHXX1902 strain) with the commercial AJ1102 vaccine. The viral titer reached 107 50% tissue culture infectious dose (TCID50)/ml, which met the requirement for seed virus replication during vaccine development. Five-day-old piglets were orally infected with viruses from passages P5 and P35 to determine the pathogenicity and immunogenicity of different passages. Pregnant sows were immunized with inactivated SHXX1902-P5 or the commercial AJ1102 vaccine (first immunized with an attenuated vaccine and then boosted with an inactivated vaccine) to study the influence of the culture method on the immunogenicity of the strain. The median pig diarrhea dose (PDD50) and the median lethal dose (LD50) of the P5 virus were 102.00 and 102.84 TCID50/ml, respectively. All five piglets infected with the SHXX1902-P5 virus shed the virus 24 h after vaccination, whereas only two of the five piglets treated with the SHXX1902-P35 virus shed the virus 48 h after vaccination. The SHXX1902-P35 virus was partially attenuated in the 5-day-old piglets. Inactivated SHXX1902-P5 induced PEDV-specific immunoglobulin G (IgG) antibody responses equivalent to those induced by AJ1102 after infection in sow serum. However, the IgA titer induced by AJ1102 was much higher than that induced by inactivated SHXX1902-P5 since the boost immunization. On days 5 and 7 after farrowing, the IgA titers were similar among the immunized groups. Our study highlights that serial passage can lead to the attenuation of G2c-subtype strain. The immunogenicity of the inactivated strain was similar to the commercial vaccine. Our observation helped conceptualize appropriate study designs for the PEDV vaccine.

Sex-specific neurobehavioural outcomes and brain stimulation pattern in adult offspring paternally exposed to methamphetamine.

Paternal methamphetamine (METH) exposure results in long-term behavioural deficits in the sub-generations with a sex difference. Here, we aim to investigate the sex-specific neurobehavioural outcomes in the first-generation offspring mice (F1 mice) paternally exposed to METH prior to conception and explore the underlying brain mechanisms. We found that paternal METH exposure increased anxiety-like behaviours and spatial memory deficits only in female F1 mice and caused depression-like behaviours in the offspring without sex-specific differences. In parallel, METH-sired F1 mice exhibited sex-specific brain activity pattern in response to mild stimulus (in water at room temperature for 3 min). Overall, paternal METH exposure caused a blunting phenomenon of prelimbic cortex (PrL), infralimbic cortex (IL) and nucleus accumbens (NAc) core in both male and female F1 mice, as indicated by the decreased c-Fos levels under mild stimulus. Of note, the activity of central nucleus of the amygdala (CeA) by mild stimulus was triggered in male but suppressed in female F1 mice, whereas the neurons of orbitofrontal cortex (OFC), cingulate cortex (Cg1), NAc shell, medial habenula (mHb), dorsal hippocampal CA1 (dCA1) and ventral hippocampal CA1 (vCA1) were only blunted in female F1 mice. Taken together, the distinct brain stimulation patterns between male and female F1 mice might contribute to the sex-specific behavioural outcomes by paternal METH exposure, which indicate that sex differences should be considered in the treatment of offspring paternally exposed drugs.

Drainage of senescent astrocytes from brain via meningeal lymphatic routes.

Recent progress on the central lymphatic system has greatly increased our understanding of how the brain maintains its own waste homeostasis. Here, we showed that perivascular spaces and meningeal lymphatic vessels form a functional route for clearance of senescent astrocytes from the aging brain. Blocking meningeal lymphatic drainage by ligation of the deep cervical lymph nodes impaired clearance of senescent astrocytes from brain parenchyma, subsequently increasing neuroinflammation in aged mice. By contrast, enhancing meningeal lymphatic vessel diameter by a recombinant adeno-associated virus encoding mouse vascular endothelial growth factor-C (VEGF-C) improved clearance of senescent astrocytes and mitigated neuroinflammation. Mechanistically, VEGF-C was highly expressed in senescent astrocytes, contributing themselves to migrate across lymphatic vessels along C-C motif chemokine ligand 21 (CCL21) gradient by interacting with VEGF receptor 3. Moreover, intra-cisternal injection of antibody against CCL21 hampered senescent astrocytes into the lymphatic vessels and exacerbated short memory defects of aged mice. Together, these findings reveal a new perspective for the meningeal lymphatics in the removal of senescent astrocytes, thus offering a valuable target for therapeutic intervention.

Comparison of Serum Triiodothyronine with Biomarkers for Alzheimer's Disease Continuum in Euthyroid Subjects.

BACKGROUND: Accumulating studies have implicated thyroid dysfunction in the pathogenesis of Alzheimer's disease (AD). OBJECTIVE: This study aimed to explore the association between thyroid hormone (TH) levels and cerebrospinal fluid (CSF) biomarkers for AD continuum among euthyroid subjects. METHODS: In all, 93 clinically euthyroid subjects with a cognitive decline were included in this prospective cross-sectional study and were divided into groups with abnormal AD biomarkers (belonging to the "Alzheimer's continuum"; A+ patients) and those with "normal AD biomarkers" or "non-AD pathological changes" (A-patients), according to the ATN research framework classification for AD. A partial correlation analysis of serum thyroid-stimulating hormone (TSH) or TH levels with CSF biomarkers was conducted. The predictor for A+ patients was analyzed via binary logistic regressions. Finally, the diagnostic significance of individual biochemical predictors for A+ patients was estimated via receiver operating characteristic curve analysis. RESULTS: Serum total triiodothyronine (TT3) and free triiodothyronine (FT3) levels were found to affect the levels of CSF amyloid-ß (Aß)42 and the ratios of Aß42/40. Further, FT3 was found to be a significant predictor for A+ via binary logistic regression modeling. Moreover, FT3 showed a high diagnostic value for A+ in euthyroid subjects. CONCLUSION: Even in a clinical euthyroid state, low serum FT3 and TT3 levels appear to be differentially associated with AD-specific CSF changes. These data indicate that serum FT3 is a strong candidate for differential diagnosis between AD continuum and non-AD dementia, which benefits the early diagnosis and effective management of preclinical and clinical AD patients.

Electroacupuncture alleviates spatial memory deficits in METH withdrawal mice by enhancing astrocyte-mediated glutamate clearance in the dCA1.

Methamphetamine (METH) elicits endogenous glutamate (Glu) in the brain, which could partially explain METH-induced memory deficits. Here, we investigated the therapeutic effects of electroacupuncture (EA) on spatial memory deficits in METH withdrawal mice and its potential synaptic mechanisms. We found that EA at acupoints 'Baihui' and 'Yintang' ameliorated the impaired spatial memory in METH withdrawal mice. In parallel, EA attenuated the Glu levels in vivo and suppressed the neuronal activities within dCA1 of METH withdrawal mice, as indicated by the decreasing c-Fos levels and the amplitude of mEPSP. In the dCA1, EA decreased A1-like astrocytes but increased astrocytic glutamatergic transporting molecules including glutamate transporter 1 and glutamine synthase. However, EA seemed to have no effects on presynaptic Glu transmission from the dCA3, as evidenced by the similiar levels of c-Fos in the dCA3 neurons, synaptic vesicular markers of dCA3 neural terminals and values of paired-pulse ratio in the dCA1 neurons between EA-treated and sham EA-treated METH withdrawal mice. These findings suggest that EA might normalize the dCA1 Glu levels at least in part through enhancing astrocyte-mediated Glu clearance. Taken together, astrocytes might be a novel target for developing therapeutic interventions against the impaired memory behaviours in METH users, and EA represents a promising non-invasive therapeutic strategy for the management of drug-caused memory deficits.

The Role of Thyroid Function in Alzheimer's Disease.

The thyroid gland is crucial for the regulation of metabolism, growth, and development of various tissues, organs, systems, including the central nervous system. Recent studies have implicated the role of thyroid dysfunction in the etiology of Alzheimer's disease (AD), while AD leads to a significant increase in the prevalence of thyroid dysfunction. In this review, we have analyzed the role of thyroid function in the pathophysiology of AD as well as its biomarkers. The present review aims to provide encouraging targets for early screening of AD risk factors and intervention strategies.

Astrocyte-selective STAT3 knockdown rescues methamphetamine withdrawal-disrupted spatial memory in mice via restoring the astrocytic capacity of glutamate clearance in dCA1.

Methamphetamine (METH) is a common abused drug. METH-triggered glutamate (Glu) levels in dorsal CA1 (dCA1) could partially explain the etiology of METH-caused abnormal memory, but the synaptic mechanism remains unclear. Here, we found that METH withdrawal disrupted spatial memory in mice, accompanied by the increases in Glu levels and postsynaptic neuronal activities at dCA1 synapses. METH withdrawal weakened the capacity of Glu clearance in astrocytes, as indicated by increasing the A1-like astrocytes and phosphorylated signal transducer and activator of transcription 3 (p-STAT3), decreasing the Glu transporter 1(GLT-1, also known as EAAT2 or SLC1A2), Glu-aspartate-transporter (GLAST also known as EAAT1 or SLC1A3) and astrocytic glutamine synthase (GS), but failed to affect the presynaptic Glu release from dCA3 within dCA1. Moreover, we identified that in vitro A1-like astrocytes exhibited an increased STAT3 activation and the impaired capacity of Glu clearance. Most importantly, selective knockdown of astrocytic STAT3 in vivo in dCA1 restored the astrocytic capacity of Glu clearance, normalized Glu levels at dCA1 synapses, and finally rescued METH withdrawal-disrupted spatial memory in mice. Thus, astrocytic Glu clearance system, especially STAT3, serves as a novel target for future therapies against METH neurotoxicity.