Behavioral Tests Research Articles

Electroacupuncture effects on trigeminal neuralgia with comorbid anxiety and depression: The role of frequency and acupoint specificity.

This study aimed to investigate the effects of electroacupuncture (EA) at specific acupoints (DU20 and ST36) and different frequencies (2 and 100 Hz) on brain regions associated with trigeminal neuralgia, anxiety, and depression. Chronic trigeminal neuralgia was induced by the chronic constriction of the infraorbital nerve (CION). Anxiety and depression were assessed through behavioral tests. The effects of high-frequency (100 Hz) and low-frequency (2 Hz) EA at DU20 and ST36 were compared using immunofluorescence staining to evaluate their impact on pain, anxiety, depression, and brain activity. CION induced prominent trigeminal neuralgia in mice, accompanied by anxiety- and depression-like behaviors. Two weeks post-CION surgery increased neural activity was observed in the Prl, Cg1, CeA, BLA, TRN, CA3, CA1, vlPAG, PC5, and LPB brain regions, while reduced activity was noted in the PVN, VTA, and LDTgv regions. EA at 100 Hz applied to DU20 and ST36 rapidly alleviated pain and specifically reduced despair behavior, a depressive-like phenotype. In contrast, 2 Hz EA at the same acupoints addressed both anxiety- and depression-like behaviors, modulating a broader range of brain regions, including the PrL, BLA, PVN, VTA, vlPAG, and LDTgv, compared to 100 Hz EA. Repeated 2 Hz EA exclusively at DU20 was sufficient for analgesia and improvement of anxiety and depression, demonstrating a more extensive modulation of brain activity, particularly in the VTA and LDTgv, than EA at ST36. The study reveals that CION induces significant trigeminal neuralgia, accompanied by anxiety and depression, characterized by distinct neural activity patterns. EA at 2 Hz exhibits greater effectiveness in alleviating anxiety and depression, exerting broad modulation across various brain regions. Notably, EA at DU20 demonstrates superior modulation of brain activity and enhanced antidepressant and analgesic effects compared to ST36. These findings provide valuable insights into the nuanced therapeutic effects of EA on the interplay between chronic pain and affective disorders, suggesting potential clinical strategies for intervention.

Aerobic exercise regulates gut microbiota profiles and metabolite in the early stage of Alzheimer's disease.

Aerobic exercise (AE) has been shown to offer significant benefits for Alzheimer's disease (AD), potentially influencing the gut microbiota. However, the impact of changes in intestinal flora in early Alzheimer's disease induced by aerobic exercise on metabolic pathways and metabolites is not well understood. In this study, 3-month-old APP/PS1 and C57BL/6 mice were divided into two groups each: a control group (ADC for APP/PS1 and WTC for C57BL/6) and an aerobic exercise group (ADE for APP/PS1 and WTE for C57BL/6). The exercise groups underwent a 20-week aerobic training program on a motorized treadmill before the behavioral test (both the Morris water maze experiment (MWM) and the eight-arm maze test). Fecal samples were collected to analyze gut microbiota profiles via 16S rRNA gene sequencing. At the same time, the metabolic pathway analysis and the detection of metabolites were carried out. At the phylum level, the ADE group exhibited a significant reduced in the relative abundance of Bacteroidetes compared to the ADC group. At the genus level, both Ileibacterium and Faecalibaculum were found to be more abundant in the ADE group than in the ADC group. Additionally, PICRUSt analysis revealed that lipid metabolism and bile acid metabolism pathways were significantly enriched in the cecal microbiota of mice in the ADE group. The metabolites detected further confirmed the changes in the metabolic pathways mentioned above. Aerobic exercise may modify gut microbiota profiles and metabolites in APP/PS1 mice, thereby potentially playing a beneficial role in delaying cognitive impairment associated with early-stage Alzheimer's disease.

Ginkgolide B alleviates Parkinson's disease in rats by resisting oxidative stress and inflammatory response and activating PI3K/Akt signaling pathway

This study explored the alleviative effect of ginkgolide B on Parkinson's disease (PD) in rats. PD model was established in 20 rats, which were then randomly divided into model and treatment group, 10 rats in each group. Other 10 rats were selected as control group. The treatment group was treated with ginkgolide B for four weeks. After treatment, compared with model group, in treatment group the behavior test and learning and memory test indexes were improved, the substantia nigra superoxide dismutase and glutathione peroxidase levels were increased, the substantia nigra malondialdehyde and inflammatory factor levels were decreased, and the substantia nigra phosphorylated phosphatidylinositol-3 kinase (p-PI3K)/phosphatidylinositol-3 kinase (PI3K) and phosphorylated serine-threonine protein kinase (p-Akt)/serine-threonine protein kinase (Akt) ratios were increased (all p<0.05). Ginkgolide B can alleviate PD in rats. The action mechanisms may be related to its resisting oxidative stress and inflammatory response and activating PI3K/Akt signaling pathway.

Triaxial behavior and microstructural insights of loose sandy soil stabilized with alkali activated slag

This study investigates the mechanical and microstructural properties of loose sandy soil stabilized with alkali-activated Ground Granulated Blast Furnace Slag (GGBFS). To examine the effects of varying GGBFS contents, curing times, and confining pressures on mechanical behavior, undrained triaxial and unconfined compressive strength (UCS) tests were conducted. Microstructural analyses using FE-SEM, EDX, and FTIR were performed to elucidate the nature and development of cementation. The results of mechanical behavior demonstrate that even with limited GGBFS content (1–6%), the treated samples exhibited significant improvements in strength, stiffness, and energy absorption, underscoring the efficiency of alkali-activated GGBFS as a soil stabilizer. Moreover, mechanical parameters from triaxial tests revealed a nearly constant internal friction angle with increasing GGBFS content and curing duration, while cohesion showed remarkable enhancement. A strong linear correlation between UCS and cohesion was also identified, enabling cost-effective estimation of shear strength parameters. These findings highlight the potential of alkali-activated GGBFS for improving granular soils, offering practical implications for sustainable geotechnical applications, particularly in road construction.

Blocking the p38 MAPK Signaling Pathway in the Rat Hippocampus Alleviates the Depressive-like Behavior Induced by Spinal Cord Injury.

Patients with spinal cord injury (SCI) may develop depression, which can affect their rehabilitation. However, the underlying mechanism of depression in SCI patients remains unclear. Previous studies have revealed increased p38 MAPK phosphorylation in the rat hippocampus after SCI, accompanied by depression-like behaviors. However, the role of the p38 MAPK signaling pathway in SCI-induced depression remains unclear. In this study, we used an aneurysm clip-induced rat SCI model to investigate whether p38 MAPK phosphorylation in the hippocampus is associated with depression-like behaviors in rats after SCI. Behavioral testing revealed that SB203580, a p38 MAPK signaling inhibitor, reduced depression-like behaviors. Western blotting and morphological analyses showed that SB203580 inhibited the activation of microglia and astrocytes in the hippocampus after SCI. Additionally, SB203580 reduced the expression of tumor necrosis factor α and increased p38 MAPK phosphorylation and the number of bromodeoxyuridine-positive cells in the hippocampus. These findings suggest that SB203580 can inhibit hippocampal remodeling and the neuroimmune response in the rat hippocampus after SCI. Therefore, the phosphorylation of p38 MAPK in the hippocampus plays a key role in the depression-like behaviors induced by SCI. The inhibition of p38 MAPK phosphorylation may represent a mechanism to protect against hippocampal injury induced by SCI.

Malnutrition exacerbating neuropsychiatric symptoms on the Alzheimer's continuum is relevant to the cAMP signaling pathway: Human and mouse studies.

Malnutrition correlates with neuropsychiatric symptoms (NPSs) in Alzheimer's disease (AD); however, the potential mechanism underlying this association remains unclear. Baseline and longitudinal associations of nutritional status with NPSs were analyzed in 374 patients on the AD continuum and 61 healthy controls. Serum biomarkers, behavioral tests, cerebral neurotransmitters, and differentially gene expression were evaluated in standard and malnourished diet-fed transgenic APPswe/PSEN1dE9 (APP/PS1) mice. Poor nutritional status and increased cerebral blood flow in the midbrain and striatum were associated with severe general NPSs and subtypes, especially depression, anxiety, and apathy. APP/PS1 mice fed a malnourished diet showed poor nutritional status, depression- and anxiety-like behaviors, altered neurotransmitter levels, and downregulated c-Fos expression in the midbrain and striatum; these were associated with suppressed cyclic adenosine monophosphate (cAMP) signaling pathway. Malnutrition exacerbating NPSs is relevant to suppressed cAMP pathway in the midbrain and striatum, suggesting the potential for targeted nutritional interventions to mitigate NPSs in the AD continuum. Poor nutritional status linked to general and specific neuropsychiatric symptom (NPS) deterioration. Malnutrition affects NPSs, usually involving the midbrain and striatum. Malnourished diet induces depression- and anxiety-like behaviors in APP/PS1 mice. Malnutrition exacerbates NPSs associated with cAMP signaling pathway in the midbrain and striatum.

The Antidepressant Effect of Resveratrol Is Related to Neuroplasticity Mediated by the ELAVL4-Bdnf mRNA Pathway

Resveratrol, a plant-derived polyphenol, exhibits significant antidepressant effects and notably enhances neuroplasticity in neurological diseases. However, whether the antidepressant function of resveratrol is related to neuroplasticity remains uncertain, and the underlying mechanisms is poorly understood. This study aims to investigate the role and mechanism of resveratrol in neuroplasticity in depression. Here, we adopted the chronic unpredictable mild stress (CUMS) model and resveratrol intervention by oral gavage. Thereafter, behavioral tests confirmed resveratrol’s antidepressant effect, and Nissl staining, Golgi staining, and Western blotting (WB) were employed to assess the neuronal plasticity. Moreover, proteomic analysis and WB were used to screen and identify the key proteins. To investigate the downstream target of ELAV-like RNA-binding protein 4 (ELAVL4) (one of candidate genes), the RNA Interactome Database and the National Center for Biotechnology Information databases were utilized to predict the targets of ELAVL4. Finally, Quantitative PCR, WB, and Immunofluorescence were used to verify the prediction. Our results indicate that resveratrol alleviates CUMS-induced depressive-like behaviors accompanied by the restoration of impaired hippocampal neuroplasticity. Then, proteomic analysis shows that 351 differentially expressed proteins (DEPs) decrease after CUMS, while 24 DEPs increase remarkably with the resveratrol treatment. Among which, ELAVL4 is downregulated by CUMS, simultaneously increasing after resveratrol intervention, which acts as a protective protein in this process. Finally, brain-derived neurotrophic factor (Bdnf) mRNA is predicted to be the potential target of ELAVL4 and validated by molecular technologies. In conclusion, our findings demonstrate that resveratrol’s antidepressant efficacy is closely associated with ELAVL4, an RNA-binding protein, a mediated neuroplasticity pathway, potentially intersecting with the Bdnf mRNA. Overall, this research sheds light on the role of the ELAVL4-Bdnf mRNA pathway through neuroplasticity in resveratrol’s antidepressant action, which provides an mRNA regulation perspective for the development of novel antidepressants and understanding depression pathology.

Varenicline Attenuates Memory Impairment in Amyloid-Beta-Induced Rat Model of Alzheimer's Disease.

Alzheimer's disease (AD) is the most prevalent neurodegenerative disorder characterized by cognitive decline. Despite extensive research, therapeutic options remain limited. Varenicline, an α4β2 nicotinic acetylcholine receptor agonist, shows promise in enhancing cognitive function. This study aimed to evaluate varenicline's effect on memory and hippocampal activity in rat model of AD. Forty-eight adult male Wistar rats were randomly assigned to control, sham, AD, and varenicline (0.1, 1, and 3mg/kg/po for 14 days) groups. AD was induced by intracerebroventricular (i.c.v.) injection of 4µl amyloid-beta (Aβ)1-42 (1µg/µl). Spatial learning and memory, hippocampal synaptic function, and CA1 electrophysiological activity were evaluated using appropriate methods. Barnes maze and T-maze behavioral tests revealed that varenicline, particularly at 1mg/kg, significantly improved spatial memory compared to the AD group. Western blot analysis showed varenicline's ability to upregulate synaptic proteins PSD-95, synaptophysin, and GAP-43 in the hippocampus, with the most significant effects observed at 1mg/kg. Electrophysiological recordings demonstrated that varenicline at 1mg/kg enhanced hippocampal long-term potentiation (LTP), indicating improved synaptic plasticity. Single-unit recordings showed an increase in spike count with varenicline administration. These findings suggest that varenicline, particularly at 1mg/kg, ameliorates memory deficits in AD rats possibly through modulation of synaptic proteins and enhancement of hippocampal LTP and electrical activity. Further investigations are warranted to elucidate varenicline's precise mechanisms of action in alleviating AD-induced cognitive deficits and its potential as a therapeutic intervention for AD-related cognitive impairment.

Evaluation of the Control Efficacy of Bt Maize Expressing Cry1Ab and Vip3Aa Proteins Against Agrotis ypsilon (Rottemberg)

Bt maize is the main means to control many lepidopteran pests in the world, but its control efficacy against Agrotis ypsilon (Rottemberg), an important insect pest of maize seedlings, remains unclear until now. The interaction between the insect and Bt transgenic maize events (DBN9936 (expressing Cry1Ab), DBN9501 (expressing Vip3Aa), and DBN3601T (expressing Cry1Ab and Vip3Aa)) was investigated using bioassay and insect behavioral tests. The results show that the Cry1Ab contents in different tissues of DBN9936 were 47.78–82.60 μg·g−1, and the Vip3Aa contents in DBN9501 were 15.29–27.78 μg·g−1. The contents of Cry1Ab and Vip3Aa in DBN3601T were 32.08–79.08 and 10.16–17.52 μg·g−1, respectively. There was no significant difference in total Bt protein content between the leaves and stems; however, that the content in both was significantly higher than that in the roots. The larvae were most sensitive to the Vip3Aa protein, and the corrected mortalities of larvae feeding on DBN9501 and DBN3601T were greater than 89.65% at the seedling stage, significantly higher than those feeding on DBN9936 (16.46–76.13%). The corrected mortalities of the third to the fifth instar larvae feeding on Bt maize root were as follows: DBN3601T (54.00–96.60%) > DBN9501 (24.67–70.88%) > DBN9936 (6.67–53.31%). The results of behavioral tests for Bt/non-Bt maize plant selection indicated that the larvae mainly fed on non-Bt maize while showing antifeedant behavior toward Bt maize, and the moth preferred to lay eggs on undamaged or slightly damaged Bt maize. It is concluded that DBN3601T maize has a strong control efficacy for A. ypsilon, which can play an important role in building an integrated pest management strategy for the insect.

A Behavioral Screening Method for Predicting PTSD-like Phenotypes: Novel Application to Female Rats.

Only a small percentage of trauma-exposed subjects develop PTSD, with females being twice as likely. Most rodent models focus on males and fail to account for inter-individual variability in females. We tested a behavioral PTSD model in female rats to distinguish between susceptible and resilient individuals. In Experiment 1, female rats underwent footshocks paired with social isolation, a PTSD risk factor. They were re-exposed to the conditioned context to test memory retention, and assessed in the Elevated Plus Maze (EPM) and Social Interaction (SI) tests for anxiety and social behavior. Footshock-exposed rats showed fear memory retention up to 16 days, indicated by elevated freezing behavior during re-exposure. They also exhibited reduced exploration in the EPM and less SI time compared to controls. In Experiment 2, we classified rats into normal responders, susceptible, and resilient groups based on locomotor activity after trauma, correlating with memory retention and anxiety. Unlike existing models focused on males and lacking predictive variables before trauma, our method identifies PTSD-like susceptibility and resilience in female rats by using exploratory behavior as a predictor before trauma exposure. Exploratory activity in a novel environment after trauma and before extinction is a reliable predictor of PTSD-like phenotypes and differentiates between susceptible and resilient female rats.

Icaritin alleviates motor impairment and osteoporosis in Parkinson’s disease mice via the ER-PI3K/Akt pathway

This study investigates the role of flavonoid Icaritin (ICT) in estrogen-deficient ovariectomized (OVX) female mice by activating the Estrogen receptor (ER)/ Phosphatidylinositol 3-kinase (PI3K)/Protein kinase B (Akt) signaling pathway, potentially delaying Parkinson’s disease (PD) progression post-castration. Seventy-five 8-week-old C57BL/6J female mice underwent ovariectomy, followed by MPTP (20 mg/kg) injection for 7 days. ICT (20 mg/kg) was administered for 14 days, and motor function was assessed using various behavioral tests. Serum estradiol, FSH, LH levels were measured by ELISA, and the expression of PI3K/Akt signaling and apoptosis proteins was analyzed by Western blot. Bone mineral density was assessed via dual-energy X-ray absorption, and histology of the uterus and femur was performed. Results showed that ICT alleviated MPTP-induced motor deficits, increased serum estradiol, and improved uterine atrophy. At the molecular level, ICT activated the PI3K/Akt pathway, reduced apoptosis, and mitigated PD symptoms and osteoporosis induced by OVX. These findings suggest ICT may offer therapeutic potential in managing OVX-induced motor dysfunction and PD.

Bone marrow mesenchymal stem cells derived cytokines associated with AKT/IAPs signaling ameliorate Alzheimer’s disease development

BackgroundAlzheimer’s disease (AD) is a progressive neurodegenerative condition affecting around 50 million people worldwide. Bone marrow-derived mesenchymal stem cells (BMMSCs) have emerged as a promising source for cellular therapy due to their ability to differentiate into multiple cell types and their paracrine effects. However, the direct injection of BMMSCs can lead to potential unpredictable impairments, prompting a renewed interest in their paracrine effects for AD treatment. The specific mechanism and central role of cytokines in this process have not been fully elucidated.MethodsMouse BMMSCs were isolated, validated, and then transplanted intracerebrally into APP/PS1 female mice. The behavioral tests, including open-field test, novel object recognition test, and Morris water maze were performed, followed by β-amyloidosis plaque and neuron apoptosis analyses. Then the tissue RNA sequencing and mBMMSC cytokine analysis were performed. A cytokine antibody array for BMMSCs and the brain slice models were performed with AD model tissues were used to elucidate the molecular mechanisms. Finally, APP/PS1 mice were administrated with cytokine mixture for cognitive recovery.ResultsOur results demonstrated that BMMSCs significantly improved cognitive function, reduced beta-amyloid plaque deposition, and decreased apoptotic neurons through the activation of the AKT signaling pathway. Using a cytokine antibody array, we identified three highly expressed AKT pathway regulated neuroprotective factors in BMMSCs: IGF1, VEGF, and Periostin2. These cytokines were found to upregulate inhibitors of apoptosis family proteins (IAPs) and suppress Caspase-3 activity in brain slices induced with beta amyloidosis (Aβ), okadaic acid (OA), and lipopolysaccharide (LPS). When injection of this cytokine mixture to APP/PS1 mice also resulted in a mitigation of cognitive impairment.ConclusionsThese findings suggest that the secretory factors IGF1, VEGF, and Periostin2 derived from BMMSCs play a crucial role in neuroprotection by modulating the AKT/IAPs pathway to restore neuronal function. These cytokine sets could be a potential therapeutic strategy for AD and lay the groundwork for promising clinical applications.

Early functional and structural hippocampal impairment in a bilateral common carotid artery stenosis mouse model.

Subcortical ischemic vascular dementia (SIVD) is a common subtype of vascular dementia. Currently, the bilateral common carotid artery stenosis (BCAS) mouse model is the most suitable SIVD rodent model. In this study, we investigated the functional and structural impairments in the hippocampus 1 month after BCAS. We used behavioral tests, laser speckle flowmetry, long-term potentiation, histochemical staining, molecular experiments, and voxel-based morphometry to evaluate the hippocampal impairments. Behavioral studies revealed that BCAS mice exhibited worse performance. Laser speckle flowmetry detected an obvious decrease in cerebral blood flow. The synaptic plasticity of the perforant path-dentate gyrus pathway was inhibited. Decreased fractional anisotropy and increased mean diffusivity were detected in the hippocampus via diffusion tensor imaging data. A reduction in gray matter volume, which was most prominent in the hippocampus and its surrounding areas, was detected via voxel-based morphometry analysis. Impairments in cell morphology and myelin integrity were validated using histochemical staining and molecular biology techniques. In addition, the numbers of GFAP+ astrocytes and Iba1+ microglia increased in the hippocampus. Overall, our study demonstrates early functional and structural impairments in the hippocampus contributing to learning and memory deficits after 1 month of BCAS, indicating that the hippocampus is vulnerable to chronic cerebral ischemia.

Astragaloside IV ameliorates autism-like behaviors in BTBR mice by modulating Camk2n2-dependent OXPHOS and neurotransmission in the mPFC.

Autism spectrum disorder (ASD) represents a multifaceted set of neurodevelopmental conditions marked by social deficits and repetitive behaviors. Astragaloside IV (ASIV), a natural compound derived from the traditional Chinese herb Astragali Radix, exhibits robust neuroprotective effects. However, whether ASIV can ameliorate behavioral deficits in ASD remains unknown. This work aimed to determine the efficacy and molecular mechanisms of ASIV in ASD. The autistic BTBR T + tf/J (BTBR) mice were used in this study. Behavioral tests were performed to assess the ASD-like phenotypes. The neurotransmitter levels and synaptic transmission were evaluated by high-performance liquid chromatography and whole-cell patch-clamp recordings, respectively. Molecular biological techniques, immunostaining, and RNA-sequencing (RNA-seq) were combined to uncover the underlying molecular mechanisms. Our study showed that both social impairment and repetitive behaviors were significantly improved after ASIV treatment in a dose-dependent manner in BTBR mice. The ASIV treatment normalized the neurotransmitter levels (GABA and glutamate) and their corresponding vesicular transporters (vGAT, vGLUT1) in the medial prefrontal cortex (mPFC). Furthermore, the excitation-inhibition imbalance in layer V of mPFC was reversed after ASIV administration. Mechanistically, bulk RNA-seq and PPI network analysis identified Camk2n2 as the crucial bridging gene regulating oxidative phosphorylation and neurotransmission. Camk2n2 overexpression in the mPFC abolished the beneficial effects of ASIV on autistic symptoms in BTBR mice via the Camk2/CREB pathway. The evidence demonstrates that ASIV may become a promising treatment option for ASD and implies that targeting the Camk2n2/Camk2/CREB axis is warranted to investigate these ASD individuals further.

Unraveling the neuroprotective effect of perampanel and lacosamide combination in the corneal kindling model for epilepsy in mice.

Scientific evidence to guide clinicians on the use of different antiseizure drugs in combination therapy is either very limited or lacking. In this study, the impact of lacosamide and perampanel alone and in combination was tested in corneal kindling model in mice, which is a cost-effective mechanism for screening of antiseizure drugs. The impact of lacosamide (5 mg/kg) and perampanel (0.125 mg/kg) alone and their combination was tested in corneal kindling process (3-mA current for 3 s applied twice daily for consecutive 12 days) in male BALB/c mice. Post-kindling, mice were subjected to a battery of behavioral tests assessing anxiety, memory, and depression-like behaviors. Brain tissues were then harvested for analysis of oxidative stress biomarkers. Our results showed that the combination therapy of lacosamide and perampanel was more effective in reducing seizure progression than monotherapy of these drugs. Animals treated with combination therapy showed significant behavioral improvements, as reduced anxiety and depression were noticed, and their cognitive abilities were notably better compared to animals of all other groups. Moreover, biochemical assays of isolated brains from combination-treated group revealed lesser amount of oxidative stress. In addition, outcomes of dual regime were comparable to the phenytoin in seizure control but showed superior benefits in mitigation of kindling-prompted behavioral dysfunction and oxidative stress. This study suggests that the lacosamide and perampanel combination therapy worked noticeably better in halting the corneal kindling process in mice and improved the epilepsy-associated psychiatric disorders that might be due to antioxidant effects of both drugs.

The effects of early-life whisker deprivation on adolescent behavior in C57BL/6J mice.

Whisker deprivation at different stages of early development results in varied behavioral outcomes. However, there is a notable lack of systematic studies evaluating the specific effects of whisker deprivation from postnatal day 0 (P0) to P14 on adolescent behavioral performance in mice. To investigate these effects, C57BL/6J mice underwent whisker deprivation from P0 to P14 and were subsequently assessed at 5 weeks of age using a battery of tests: motor skills were evaluated using open field test; emotional behavior was evaluated using a series of anxiety- and depression-related behavioral tests; cognitive function was examined via novel location and object recognition tests; and social interactions were analyzed using three-chamber social interaction test. Results show that early-life whisker deprivation impairs social discrimination, as evidenced by reduced interaction preference for novel mice, while not impacting general motor abilities, cognitive performance in novel object and location recognition, or anxiety- and depression-related behaviors during adolescence. The treatment effects were consistent across sexes, with no significant differences observed between control and experimental groups within each sex. These findings contribute to a comprehensive understanding of the behavioral impacts during adolescence resulting from early-life whisker deprivation and provide valuable criteria for selecting appropriate whisker deprivation models in future research.

Manganese exposure induces parkinsonism-like symptoms by Serpina3n-TFEB-v/p-ATPase signaling mediated lysosomal dysfunction

Manganese (Mn) is a neurotoxin that has been etiologically linked to the development of neurodegenerative diseases in the case of overexposure. It is widely accepted that overexposure to Mn leads to manganism, which has clinical symptoms similar to Parkinson’s disease (PD), and is referred to as parkinsonism. Astrocytes have been reported to scavenge and degrade extracellular α-synuclein (α-Syn) in the brain. However, the mechanisms of Mn-induced neurotoxicity associated with PD remain unclear. Serpina3n is highly expressed in astrocytes and has been implicated in several neuropathologies. The role Serpina3n plays in Mn neurotoxicity and PD pathogenesis is still unknown. Here, we used wild-type and Serpina3n knockout (KO) C57BL/6 J mice with i.p. injection of 32.5 mg/kg MnCl2 once a day for 6 weeks to elucidate the role of Serpina3n in Mn-caused neurotoxicity regarding parkinsonism pathogenesis. We performed behavioral tests (open field, suspension and pole-climbing tests) to observe Mn-induced motor changes, immunohistochemistry to detect Mn-induced midbrain changes, and Western blot to detect Mn-induced changes of protein expression. It was found that Serpina3n KO markedly alleviated Mn neurotoxicity in mice by attenuating midbrain dopaminergic neuron damage and ameliorating motor deficits. Furthermore, using immunofluorescence colocalization analysis, Western blot and quantitative real-time PCR on Mn-treated C8-D1A cells, we found that Serpina3n KO significantly improved astrocytic α-Syn clearance by suppressing Mn-induced lysosomal dysfunction. Reduced transcription factor EB (TFEB)-v/p-ATPase signaling is responsible for the impairment of the lysosomal acidic environment. These novel findings highlight Serpina3n as a detrimental factor in Mn neurotoxicity associated with parkinsonism, capture the novel role of Serpina3n in regulating lysosomal function, and provide a potential target for antagonizing Mn neurotoxicity and curing parkinsonism in humans.

Differential impacts of germline and adult aggrecan knockout in PV+ neurons on perineuronal nets and PV+ neuronal function.

Perineuronal nets (PNNs) are a condensed form of extracellular matrix primarily found around parvalbumin-expressing (PV+) interneurons. The postnatal maturation of PV+ neurons is accompanied with the formation of PNNs and reduced plasticity. Alterations in PNN and PV+ neuron function have been described for mental disorders such as schizophrenia and autism. The formation of PNNs is highly dependent on aggrecan, a proteoglycan encoded by the ACAN gene, but it remains unknown if it is produced by the PV+ neurons themselves. Thus, we established a knockout (KO) mouse model (ACANflx/PVcre) and an adeno-associated virus to specifically eliminate aggrecan production from PV+ neurons, in the germline or adult animals, respectively. The germline KO (ACANflx/PVcre) eliminated the expression of PNNs labeled by Wisteria floribunda agglutinin (WFA), the most commonly used PNN marker. Surprisingly, electrophysiological properties of PV+ interneurons and ocular dominance plasticity of adult ACANflx/PVcre mice were similar to controls. In contrast, AAV-mediated ACAN knockout in adult mice increased ocular dominance plasticity. Moreover, in vivo Chondroitinase ABC treatment of KO mice resulted in reduced firing rate of PV+ cells and increased frequency of spontaneous excitatory postsynaptic currents (sEPSC), a phenotype associated with chABC treatment of WT animals. These findings suggest that compensatory mechanisms may be activated during development in response to the germline loss of aggrecan. Indeed, qPCR of bulk tissue indicates that other PNN components, including neurocan and tenascin-R, are expressed at higher levels in the KO animals. Finally, behavioral testing revealed that ACANflx/PVcre mice had similar long-term memory as controls in the Morris water maze. However, they employed bolder search strategies during spatial learning and showed lower level of anxiety-related behavior in an open field and zero maze.

Paraquat neurotoxicity: Oxidative stress and neuronal dysfunction in the ascidian brain.

Paraquat (PQ) is a widely used herbicide; however, it has been linked to various diseases, including an increased risk of developing Parkinsonism. To study this, invertebrates such as ascidians have been used. They have a simple nervous system and are considered an emerging model for the study of neurodegenerative diseases. Here, we investigated the effects of PQ in the brain of the ascidian Styela plicata. We performed behavioral tests, assessed morphology, and monitored oxidative stress and the expression of tyrosine hydroxylase (TH) and caspase-3 (Casp 3) using immunofluorescence. In the presence of PQ, siphon movement was reduced and cortical thickness was increased. In addition, an observed increase in ROS was detected, along with attenuated SOD and CAT activities and increased LPO production. Interestingly, PQ downregulated the expression of TH and upregulated that of Casp 3. We conclude that PQ-induced oxidative stress leads to the death of catecholaminergic neurons in the S. plicata brain.

Mitigation of Neuroinflammation and Oxidative Stress in Rotenone-Induced Parkinson Mouse Model through Liposomal Coenzyme-Q10 Intervention: A Comprehensive In-vivo Study.

Parkinson's disease (PD) stands as the sec most prevalent incapacitating neurodegenerative disorder characterized by deterioration of dopamine-producing neurons in the substantia nigra. Coenzyme Q10 (CoQ10) has garnered attention as a potential antioxidant, anti-inflammatory agent and enhancer of mitochondrial complex-I activity. This study aimed to examine and compare the effectiveness of liposomal and non-encapsulated CoQ10 in rotenone induced-PD mouse model over a 21-day treatment duration. 30 mice were divided into 5 equal groups: Group I (mice receiving normal saline), Group II (rotenone was administered to mice), Group III (standard CoQ10 was given to mice), Group IV (mice were treated with non-encapsulated CoQ10) and Group V (mice were treated with CoQ10 Liposomes). Motor performance, the preservation of dopaminergic neurons, levels of neuroinflammation, oxidative stress, neurotransmitter levels, RT-qPCR analysis of PD-linked genes and histopathology were evaluated. The Liposomal CoQ10 group exhibited superior outcomes in behavioral tests such as reduced anxiety in the open field test, enhanced balance and coordination in beam balance test and improved cognitive performance in Y-maze test. Liposomal Coenzyme Q10 displayed pronounced antioxidative effects, evidenced by a significant (p < 0.001) increase in superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH) activities. In contrast, the non-encapsulated CoQ10 group showed a delayed response in mitigating the inflammation and oxidative stress. CoQ10 Liposomes demonstrated superior efficacy (p < 0.0001) in restoring dopamine and noradrenaline levels, reducing acetylcholinesterase activity, and downregulating Synuclein Alpha (SNCA) gene expression (0.722-fold change) compared to oral CoQ10, highlighting its potential in suppressing PD symptoms. The results of this study indicated that the liposomal CoQ10 effectively averted motor impairments, memory lapses, oxidative stress, as well as neuroinflammation triggered by rotenone.