Tic disorder (TD) is a developmental neurological condition characterized by pathological motor and/or vocal tics. Accumulating evidence suggests that central histamine (HA) participates in the onset and development of TD. Recent research highlights HA’s role in neuroinflammation, and microglia the central resident phagocytes are closely associated with HA in neuroinflammatory conditions. Clinical studies have associated H1 receptor (H1R) antagonist exposure with increased TD risk and symptom severity; however, causal evidence remains limited, and the precise pathogenesis is unclear. This study investigated the HA-H1R pathway and microglial reactivity in a β,β′-iminodipropionitrile (IDPN)-induced mouse model of tic-like behaviors. IDPN‑treated mice showed reduced HA and H1R expression in the hypothalamus. Intraperitoneal administration of the brain-penetrant H1R antagonist diphenhydramine (DPH) induced tic-like stereotyped behaviors in wild-type mice. IDPN-treated mice also showed increased striatal Iba-1 immunoreactivity. Intrastriatal HA injection reduced stereotyped behavior and Iba-1 immunoreactivity in IDPN-treated mice, and these effects were attenuated by DPH pretreatment. These findings support an association between altered HA-H1R signaling and tic-like behaviors in this model and suggest that microglial reactivity may be involved. The results should be interpreted as hypothesis-generating because the study used a pharmacological antagonist approach and did not include genetic H1R manipulation or direct microglia-specific intervention.
The rapid rise in childhood exposure to digital devices has raised concerns about its impact on brain development and its potential link to autism spectrum disorder (ASD). Recent studies have shown that when excessive exposure to digital devices begins during early development (before weaning), it can lead to behavioral disturbances, including hyperactivity and social deficits along with impaired brain neuroplasticity in animal models. This study aimed to investigate whether prolonged excessive audiovisual stimulation (EAVS) after weaning could induce autism-like symptoms in rats. While this model does not fully capture the voluntary nature of human device use, it provides a controlled experimental framework for examining the neurobiological consequences of sensory overstimulation during development. Male rats were exposed to colored lights and cartoon sounds for 6 h daily from postnatal day (PND) 22 to PND 52. Behavioral assessments and 3-D stereological measurement were conducted to evaluate autism-related behaviors and amygdala structure in adolescence. The results revealed increased repetitive behaviors, impaired social interaction, hyperactivity, and significant enlargement of the amygdala, along with an increased number of neurons in its basolateral (BL) and central (CE) subregions. This study suggests that the negative effects of overexposure to digital devices are not limited to infancy. Prolonged exposure to EAVS during childhood can lead to changes in amygdala structure and the emergence of behavioral impairments similar to ASD. Not applicable.
To investigate the regulatory role and molecular mechanisms of the SIRT1-FOXO1 signaling axis in mitophagy, glycolytic metabolism, and inflammatory responses within a lipopolysaccharide (LPS)-induced macrophage inflammation model. An in vitro inflammatory model was established by treating RAW264.7 macrophages with LPS. Mitochondrial membrane potential was assessed using the JC-1 probe. Western Blotting and immunofluorescence were used to analyze the expression of autophagy-related proteins. Inflammatory cytokines and the oxidative stress marker Malondialdehyde (MDA) were measured by ELISA, respectively. Furthermore, lactate production, glucose uptake, ATP levels, and the expression of glycolysis-related proteins were evaluated. Silencing SIRT1 or overexpressing FOXO1 induced the excessive expression of the key mitophagy proteins PINK1 and Parkin, leading to mitochondrial membrane potential dissipation and increased release of inflammatory factors (TNF-α, IL-1β) and MDA. These changes were accompanied by increased glucose uptake, lactate production, elevated ATP levels, upregulation of key glycolysis-related proteins, and acidification of the cellular microenvironment. Rapamycin further enhanced, whereas 3-MA attenuated, the phenotypes triggered by SIRT1-FOXO1 axis imbalance. SIRT1 negatively regulates FOXO1, thereby preventing excessive activation of mitophagy and glycolytic metabolic shift. This action helps maintain mitochondrial functional homeostasis and effectively inhibits the inflammatory response. These findings reveal the crucial negative regulatory role of the SIRT1-FOXO1 axis in LPS-induced macrophage inflammation, suggesting that this pathway may represent a potential therapeutic target for neuroinflammatory diseases such as ischemic stroke.
To explore the neuroprotective effects and molecular mechanism of the VAMP2-mediated PPAR signaling pathway on neuronal mitophagy using an in vitro seizure-like injury model. A seizure model was established by culturing mouse hippocampal HT22 cells in Mg2+-free medium. siRNA-mediated gene knockdown and lentiviral overexpression were applied to regulate VAMP2 expression. Bioinformatic analysis via GeneCards and STRING was performed to predict the interaction between VAMP2 and the PPAR pathway. Cell phenotypes and molecular alterations were detected by RT-qPCR, Western blotting, flow cytometry, ELISA and immunofluorescence. The PPAR inhibitor GW9662 was used to verify the regulatory relationship between VAMP2 and PPAR signaling. VAMP2 expression was significantly downregulated in Mg2+-free solution -treated neurons. VAMP2 overexpression increased cell viability, inhibited apoptosis and restored mitochondrial membrane potential (p<0.001). VAMP2 upregulated mitophagy-related proteins (LC3-II/I, PINK1, and Parkin), reduced ROS and pro-inflammatory cytokines (IL-1β, TNF-α), and balanced the expression of synaptic proteins NMDAR1 and GABAA1. Bioinformatic and experimental results demonstrated that VAMP2 acts as an upstream regulator to promote the expression and nuclear translocation of PPARα/γ. Blocking PPAR signaling with GW9662 completely abolished the protective effects of VAMP2, leading to impaired mitophagy, mitochondrial dysfunction and synaptic imbalance. A novel VAMP2-PPAR-mitophagy axis was identified in seizure-injured neurons, which maintains mitochondrial integrity and alleviates neuronal damage. Targeting the crosstalk between vesicle trafficking and nuclear receptor signaling may provide potential therapeutic ideas for hyperexcitability-related neurodegenerative disorders. Not applicable. This study reveals that VAMP2 acts as an upstream regulator to activate PPAR signaling and further promote neuronal mitophagy, thereby alleviating epileptic damage. The identified “VAMP2-PPAR-mitophagy” axis provides a novel potential therapeutic target for epilepsy.
The African pygmy hedgehog (Atelerix albiventris) is a terrestrial mammal with well-developed olfactory, visual, and auditory senses. This study presents the first detailed histomorphological and histomorphometric description of the cerebellum and olfactory bulb of the African pygmy hedgehog. Six adult hedgehogs (three males and three females) were examined using standard histological techniques, histomorphometric analysis was performed on representative sections using Fiji/ImageJ software. The cerebellum displayed the classical trilaminar cortical organisation comprising molecular, Purkinje cell, and granular layers overlying a fibrous white matter core. The molecular layer was the thickest cerebellar cortical layer (139.44 ± 5.84 μm), followed by the granular layer (115.67 ± 14.75 μm), while the Purkinje cell layer was the thinnest (23.84 ± 5.30 μm). Distinct cerebellar glomeruli were observed within the granular layer as pale eosinophilic regions interspersed among densely packed granule cells. The olfactory bulb consisted of seven layers: the olfactory nerve layer, glomerular layer, external plexiform layer, mitral cell layer, internal plexiform layer, granule cell layer, and subventricular zone. Histomorphometric analysis revealed that the granule cell layer was the thickest olfactory bulb layer (248.30 ± 16.37 μm), whereas the mitral cell layer (17.74 ± 4.75 μm) and internal plexiform layer (15.74 ± 3.28 μm) were comparatively thin. Mitral, tufted, periglomerular, and granule cells were readily identifiable, reflecting the hedgehog’s reliance on olfaction for behaviours such as foraging and predator avoidance. The cerebellum and olfactory bulb of the African pygmy hedgehog conform to the conserved structural organisation observed in other mammals. The combined histological and histomorphometric findings provide baseline quantitative and qualitative data for comparative neuroanatomical studies and suggest adaptations associated with the species’ sensorimotor and olfactory specialisations.
The present experimental study was designed to evaluate the potential neuroprotective effects of urapidil during the acute phase (24 hours) of spinal cord ischemia–reperfusion injury in a rat model, with a focus on early functional, biochemical, histopathological, and immunohistochemical changes. Rats were randomly assigned to four experimental groups (n = 6 per group): Control (CR), Sham (SH), Ischemia–Reperfusion (IR), and Ischemia–Reperfusion + Urapidil (IR+URA). Spinal cord ischemia was induced by infrarenal abdominal aortic clamping for 30 minutes followed by reperfusion. Urapidil was administered before ischemia and after reperfusion in the IR+URA group. Motor function was evaluated 24 hours after reperfusion using the Tarlov scoring system, and biochemical, histopathological, and immunohistochemical analyses were performed. Data were analyzed using one-way analysis of variance (ANOVA) followed by Duncan’s multiple comparison test, which was selected due to its greater sensitivity in exploratory studies with small sample sizes. A p-value < 0.05 was considered statistically significant. Motor function was significantly impaired in the IR group compared with all other groups, whereas the IR+URA group demonstrated preserved motor performance comparable to the CR and SH groups. Urapidil administration significantly increased antioxidant activity, as reflected by elevated glutathione peroxidase levels, and reduced inflammatory markers including TNF- α and IL-1 β . Histopathological and immunohistochemical findings showed marked neuronal degeneration, apoptosis, oxidative stress, and inflammation in the IR group, which were notably attenuated by URA treatment. In this experimental spinal cord ischemia–reperfusion model, urapidil treatment was associated with improved early motor performance, increased glutathione peroxidase (GPx) activity, and reduced levels of the pro-inflammatory cytokines TNF- α and IL-1 β during the acute reperfusion period. These changes occurred alongside favorable histopathological findings; however, given the short follow-up duration and the limited scope of apoptotic assessment, the results should be considered preliminary and interpreted as hypothesis-generating.
Current treatments for spinal muscular atrophy have significantly improved patient prognosis, but still fall short of a full cure, particularly when administered after symptom onset. To improve future therapies, it is essential to identify the early pathological events that currently limit treatment efficacy. Here we have investigated the vulnerability and maturation of intramuscular motor axons in the SmnΔ7 mouse model of spinal muscular atrophy using a panel of cranial muscles with differing susceptibility to disease. We demonstrate that although there is intermuscular heterogeneity in neuromuscular junction pathology, they are united by a common loss of motor axons. We show that the timing of motor axon loss differs between muscles, but that motor axon loss precedes structural denervation and can occur by postnatal day 1 in highly vulnerable muscles. Electron microscopy of intramuscular axons revealed that axonal maturation and myelination are grossly normal prior to subsequent postnatal degeneration. We note that axons lack the traditional morphological correlates of axon degeneration but can be visualised using antibodies which detect degenerating neurofilaments. Treatment with SMN-upregulating therapy SMN-C8 at best preserves intramuscular axons when administered before the onset of degeneration but is unable to reverse damage or promote regeneration once axon loss has occurred. Collectively this data demonstrates that SMN-upregulating therapy can prevent motor axon loss, but the capacity is limited by the number of intramuscular axons which remain at the time of treatment onset. This work highlights the importance of developing complementary therapies which can promote motor axon regeneration to act in synergy with SMN-upregulating compounds.
The present fMRI study investigated which subregions of the visual word recognition network contribute to morphologically structured word form processing in Korean. Participants performed two separate lexical decision tasks in the scanner. In the Eojeol task, stimuli were three-syllable words composed of a disyllabic noun plus a case particle, whereas in the Noun task, stimuli were disyllabic (DSN) and trisyllabic (TSN) nouns. Behaviorally, reaction time was significantly longer in the Eojeol condition than in both DSN and TSN conditions, indicating greater processing demands for morphologically complex words, while accuracy did not differ across conditions. At the neural level, ROI analyses revealed that Eojeol processing elicited stronger activation than simple nouns in specific nodes of the visual word recognition related system, including the left inferior frontal gyrus (pars opercularis), anterior perisylvian cortex, anterior superior temporal sulcus, and anterior inferior temporal gyrus. These findings suggest that morphologically complex word recognition in Korean recruits additional resources within the visual word recognition network, highlighting the role of anterior fronto-temporal subregions in combining content and functional morphemes into unified lexical representations. Morphologically complex words recruited anterior fronto-temporal language network. pSTS and lingual gyrus involved domain-general lexical and orthographic operations. Used Eojeols as cross-linguistic evidence for morphologically complex word recognition.
Intracranial aneurysm (IA) rupture is a life-threatening event. While inflammation is implicated, the cellular mechanisms associated with progression from stable lesion to rupture remain poorly defined at single-cell resolution. We performed single-cell RNA sequencing (scRNA-seq) on a mouse model spanning sham, formed, and ruptured IA stages. Computational analyses included trajectory inference, cell-cell communication analysis, and metabolic scoring. Key findings were validated using human IA bulk RNA-seq data and protein-level assays on matched clinical tissues. Our single-cell atlas revealed a progressive “inflammatory-lytic” microenvironment marked by immune cell infiltration and vascular smooth muscle cell (VSMC) depletion. We identified a metabolically specialized VSMC subpopulation (VSMC_0) that was selectively lost in formed and ruptured aneurysms. Pseudotime analysis indicated VSMC differentiation blockade, associated with downregulation of the structural genes actin alpha2, smooth muscle (ACTA2) and prolyl 4-hydroxylase subunit alpha2 (P4HA2), which correlated with irregular aneurysm shape a strong clinical predictor of rupture risk. Cell communication analysis positioned VSMC_0 as a signaling hub to macrophages, suggesting a feed-forward inflammatory loop. These findings were validated in human IAs tissues. Our study identifies VSMC phenotypic dysregulation as a key correlate of IA instability, linking molecular deficits to clinical rupture predictors. This reframes IA as a disorder of vascular cellular identity and communication, revealing potential therapeutic targets for aneurysm stabilization.
Traumatic brain injury (TBI) is a severe neurological condition associated with complex pathological cascades. Transforming growth factor-β2 (TGF-β2) is a pleiotropic cytokine that participates in multiple cellular events in the central nervous system; however, its potential protective role and molecular mechanisms in the context of TBI-induced neuronal injury have not been fully elucidated. In this study, we observed that TGF-β2 expression was markedly increased following TBI, with peak expression at day 7 post-injury. Using an in vitro LPS-induced inflammatory model, we found that exogenous TGF-β2 treatment significantly reduced the expression of pro-inflammatory factors TNF-α, IL-1β, and IL-6, as assessed by qRT-PCR, Western blot, and ELISA. Co-culture of neurons with conditioned medium from LPS-stimulated astrocytes revealed that TGF-β2 overexpression indirectly attenuated neuronal apoptosis and enhanced neuronal viability, as demonstrated by CCK-8, TUNEL staining, and molecular analyses. Mechanistic investigations suggested that the anti-inflammatory and anti-apoptotic effects of TGF-β2 may be mediated through activation of the Smad3 signaling pathway. Consistently, in vivo experiments indicated that TGF-β2 overexpression alleviated motor dysfunction and reduced neuronal apoptosis in a TBI mouse model. Collectively, these findings provide evidence for a protective role of TGF-β2 in inflammatory neuronal injury and offer insights into potential molecular targets for TBI therapeutic development.
Alzheimer’s disease (AD), the most common form of dementia, is characterized by cholinergic dysfunction and early impairments in episodic and recognition memory. Although retrieval failure represents a hallmark of cognitive decline in AD, the task- and phase-specific molecular mechanisms underlying cholinergic-dependent memory retrieval remain poorly defined. This study investigated whether acute muscarinic cholinergic blockade disrupts the retrieval phase of recognition memory. We also examined the associated regulation of hippocampal calcium/calmodulin-dependent protein kinase II (CaMKII) isoforms α and β, together with extracellular signal-regulated kinase (ERK) signaling. Adult male SWR/J mice were trained in the NOR paradigm and administered scopolamine (1 mg/kg, i.p.) or saline 30 min prior to the retrieval phase. Recognition memory performance was assessed using the discrimination index and exploratory preference. Immediately following behavioral testing, hippocampal tissue was collected for Western blot analysis of phosphorylated and total CaMKII-α, CaMKII-β, and ERK. Scopolamine significantly impaired recognition memory retrieval, as evidenced by a reduced discrimination index and decreased preference for the novel object, without diminishing overall exploratory activity. At the molecular level, scopolamine-induced cholinergic inhibition selectively decreased hippocampal phosphorylation of both CaMKII-α and CaMKII-β while increasing ERK phosphorylation, with no significant changes in total protein expression of any kinase. These findings identify a retrieval-specific, scopolamine-induced molecular signature of cholinergic inhibition in the hippocampus, characterized by concurrent suppression of both CaMKII isoform activities (α and β) alongside dissociable ERK hyperactivation. By extending prior molecular observations from aversively motivated paradigms to an ethologically relevant model of recognition memory, this study provides mechanistic insight into how cholinergic dysfunction contributes to memory retrieval deficits and suggests that cholinergic signaling maintains the functional (CaMKII-α) and structural (CaMKII-β) dimensions of hippocampal memory retrieval machinery through coordinated kinase activation.
Intracerebral hemorrhage (ICH) is a health challenge resulting in death or disability. Iron overload has been identified as one of post-ICH damaging factors. However, the impact of iron overload, as well as the underlying mechanisms, on neural stem/progenitor cells (NSPCs) remains unknown. In this study, we found that iron overload induced significant NSPC death in a dose-dependent manner. Interestingly, iron overload increased the number of early and late apoptotic cells and the expression of caspase-3 in NSPCs. Moreover, iron overload was highly correlated with enhanced intracellular reactive oxygen species (ROS) generation and loss of mitochondrial integrity. Further, iron overload activated mTOR signaling and downregulated AMP-activated protein kinase (AMPK) phosphorylation. Importantly, drugs that eliminate ROS or activate AMPK prevented this event, as well as apoptosis of NSPCs. These results indicate that post-ICH iron overload in the brain induces excessive ROS generation and leads to NSPC death by regulating mTOR and AMPK signaling.
Extensive research with rodent models has shown detrimental effects of early-life adversity (ELA) on behavioral (e.g., impulsive behavior, anxiety, and depression) and neurobiological processes (e.g., alterations of neuroendocrine processes and maturation of brain areas). However, heterogeneous methodologies, including types and variations of ELA manipulations could have contributed to inconsistent findings across studies. Recent research indicates that the combination of the two most widely implemented rodent ELA protocols, Maternal Separation (MS) and Limited Bedding/Nesting (LBN), produces consistent and robust behavioral effects. We assessed the effects of combined MS-LBN on four processes linked to both ELA and behavioral disorders in later stages of life: incentive salience of reward cues, and impulsive choice, action, and persistence/perseverance. Sixteen male Sprague Dawley rats were divided in groups of combined MS-LBN during postnatal days 2–21 and without ELA. They were exposed to an Autoshaping Pavlovian conditioning task (AUT), a delay-discounting task (DDT), and acquisition and extinction of a multiple schedule of reinforcement with long and short Variable Intervals (VI) across a span of 18 weeks. Compared to the No-ELA group, ELA rats displayed higher goal-tracking during the AUT (higher nose-poking in the food-delivery location), higher impulsive choice during test and 7-week re-test of the DDT (preference for the smaller-sooner reinforcer over the larger-later), and less efficient responding during the long-interval schedule of reinforcement (more unnecessary responses per pellet). Associations between autoshaping and reinforcement-schedule performance were identified, with ELA moderating the relationship between sign tracking and efficiency during training and persistence/perseverance during extinction. Combined MS-LBN was associated with task-specific changes in reward-related and impulsive behavior in male rats. These complex patterns of disruptions across behavioral processes adds further support to the notion that combined ELA protocols are promising robust models of adverse rearing in humans, which often entails multiple stressors. Not applicable.
Cisplatin-induced neurotoxicity is driven in part by neuroinflammation and oxidative injury in vulnerable brain regions. Glycine has anti-inflammatory and antioxidant properties that may offer neuroprotection against chemotherapy-related brain damage. Twenty-five adult male BALB/c mice were randomized into five groups (n = 5/group) Group 1 received cisplatin for 14 days; Group 2 received cisplatin plus glycine for 14 days; Group 3 received cisplatin for 28 days; Group 4 received cisplatin for 14 days followed by glycine for 14 days; and Group 5 received cisplatin for 28 days with glycine introduced from day 14 to day 28. Cisplatin was administered intraperitoneally at 3 mg/kg every fourth day, and glycine was given subcutaneously at 1 g/kg daily. The primary outcome was serum TNF-α measured by ELISA. Secondary outcomes were neuronal integrity and optical density in the hippocampus and frontal cortex assessed by Nissl staining. Data were analyzed using one-way ANOVA with Tukey post-hoc testing. Serum TNF-α levels differed significantly among groups (F = 230.422, p < 0.001). Mean TNF-α concentrations were 150.0 pg/mL in Group 1, 130.2 pg/mL in Group 2, 201.4 pg/mL in Group 3, 159.4 pg/mL in Group 4, and 171.0 pg/mL in Group 5. Prolonged cisplatin exposure (Group 3) produced the highest TNF-α levels, whereas concurrent glycine administration during the 14-day regimen (Group 2) resulted in the lowest levels. Compared with the 28-day cisplatin group, both delayed glycine treatment (Group 4) and glycine introduced during the second half of cisplatin exposure (Group 5) were associated with lower TNF-α concentrations. Histological analysis demonstrated reduced Nissl staining intensity and neuronal preservation in cisplatin-only groups, particularly Group 3, whereas glycine-treated groups showed better preservation of neuronal architecture and optical density in the hippocampus and frontal cortex. Glycine attenuated cisplatin-induced neuroinflammation and preserved neuronal integrity in the hippocampus and frontal cortex of mice. These findings support further preclinical evaluation of glycine as a low-cost adjuvant strategy to reduce chemotherapy-associated neurotoxicity.
Abstract Due to delayed symptoms and dependence of behavioral assessment, early diagnosis of autism spectrum disorder remains challenging. Identification of multivariate biomarker for the etiological mechanisms of ASD may enhance diagnostic accuracy. Multivariable logistic regression combines many predictors into a single risk score (linear predictor), resulting in an optimised ROC curve that enhances diagnostic accuracy over individual markers. The method comprises modelling a binary result, determining the likelihood, and visualising ROC based on the projected probabilities, which often improves individual marker AUCs. In the present study a diagnostic performance for a biomarker panel reflecting glutamatergic dysfunction, oxidative stress, and neuroinflammation was evaluated. Plasma levels of glutaminase, 8-isoprostane, and prostaglandin E₂ (PGE₂) obtained from 44 children with ASD and 40 age-matched controls were evaluated using receiver operating characteristic (ROC) analysis, both individually and in combined ROC models. Glutaminase showed significant negative correlations with both 8-isoprostane and PGE₂, whereas a positive correlation was observed between 8-isoprostane and PGE₂. All the three-biomarker showed good diagnostic performance for ASD on its own with statistically significant ( p = 0.001) values of AUC of 0.830 for glutaminase, AUC of 0.815 for 8-Isoprostane and AUC of 0.818 for PGE₂. However combined ROC modeling substantially improved diagnostic accuracy by achieving high apparent discriminative performance with AUC value of 0.977 with 92.3% sensitivity and 100.0% specificity. In conclusion, the diagnostic usefulness of independent glutaminase, 8-isoprostane, and prostaglandin E₂ (PGE₂) biomarkers may be enhanced by combining ROC. Combined markers show strong apparent discriminating power in a case-control method, but estimates are biassed towards optimism and are not diagnostic. Comprehensive assay validation, calibration, and clinically representative cohorts (including females and relevant differentials) are required for replication.
Abstract Background Parkinson’s disease (PD) is a progressive neurodegenerative disorder strongly associated with dopaminergic neuronal degeneration and alpha-synuclein pathology. Paraquat (PQ) has been implicated in Parkinsonian neurodegeneration; however, the influence of age on susceptibility to PQ-induced neuropathology remains insufficiently characterized. Aim This study investigated age-dependent effects of paraquat exposure on neurobehaviour, substantia nigra histomorphology, and serum alpha-synuclein levels in male Wistar rats. Methods Sixty-three male Wistar rats were assigned into juvenile, young adult, and adult age categories, each further subdivided into control, PQ-treated, and PQ+recovery groups. Paraquat (10 mg/kg, intraperitoneally) was administered twice weekly for three weeks. Recovery groups were maintained for a two-month post-exposure period. Neurobehavioral assessments were conducted to evaluate locomotor and anxiety-related functions. Serum and nigral alpha-synuclein concentrations were quantified using enzyme-linked immunosorbent assay (ELISA), while histological examination of the substantia nigra was performed to assess neuronal integrity. Results Adult rats exhibited a significant reduction in locomotor activity following PQ exposure ( p = 0.020) and showed more prominent histopathological alterations within the substantia nigra compared with juvenile and young-adult animals. Although improvement in tissue architecture was observed following paraquat withdrawal, residual alterations persisted, particularly in adults. Nigral alpha-synuclein concentrations did not differ significantly among treatment groups in any age cohort. Serum alpha-synuclein levels were similarly unchanged in most groups, except for a reduction observed in recovering young-adult animals ( p = 0.039). Conclusion Age influences vulnerability to PQ-induced neurotoxicity, with adult animals showing greater susceptibility to behavioral and histological damage. However, serum total alpha-synuclein levels did not consistently parallel central neuropathology, suggesting limited reliability as a standalone peripheral biomarker of PQ-induced Parkinsonism.
The CHRNA7 gene, located on chromosome 15q13.3, encodes the α7 nicotinic acetylcholine receptor (α7 nAChR) subunit and lies within a genomic region characterized by high recombination rates and associations with multiple neuropsychiatric disorders. Within this region, the human specific gene CHRFAM7A arose through partial duplication, rearrangement, and fusion between CHRNA7 and FAM7A. The direct CHRFAM7A allele has been shown to negatively regulate α7 nAChR function. The inverted allele (CHRFAM7AΔ2bp), harboring a two-base pair deletion in exon 6, is linked to schizophrenia, bipolar disorder, and other psychiatric conditions. In this study, we investigated how the presence of the CHRFAM7AΔ2bp allele alters the cellular proteome. Using high-throughput proteomic analysis by liquid chromatography-electrospray ionization tandem mass spectrometry (LC-ESI-MS/MS), we characterized protein expression in neuronal progenitors differentiated from isogenic human induced pluripotent stem cell (iPSC) lines representing CHRFAM7AΔ2bp and CHRFAM7A-null genotypes. Comparative analysis identified 129 differentially expressed proteins enriched in pathways related to extracellular matrix organization, collagen biosynthesis, and cell adhesion. Functional assays further demonstrated differences in matrix adhesion between CHRFAM7A-null and CHRFAM7AΔ2bp-derived progenitors. These results suggest that the CHRFAM7AΔ2bp variant influences cellular structure through modulation of adhesion matrix-interaction proteins. This work provides insight into molecular mechanisms that may underlie increased neurodisease vulnerability associated with this genotype.
Abstract Background Despite neuroinflammation being an initially protective response made by the central nervous system (CNS), as it becomes chronic, it can lead to neuronal damage since the cytokines which are released by microglia potentialize cellular death due to excitotoxicity, and this, in turn, promotes the release of pro-inflammatory mediators, feeding this way a self-sustaining cycle of neuroinflammatory response, which favor subsequent neurodegeneration. Given the fact that until this moment, there are not any therapeutic alternatives able to stop the neurodegeneration, the objective of the present work was to evaluate the putative neuroprotector effect of taurine, a partial glycinergic ionotropic receptor agonist, and also a GABA A receptor agonist, in a neuroinflammation animal model. Method For this intent, the oral taurine administration was evaluated on mnemonic impairing caused by LPS induced neuroinflammation in male Wistar rats. Such effects were investigated on recent and late spatial long-term memory and aversive memory in the behavioural tasks Morris water maze (MWM) and context fear conditioning (CFC), respectively. In addition, we investigated the effect of orally administered taurine on hippocampal neuronal density and on hippocampal levels of TNF-α and IL-4. Results Taurine, when orally administered for 30 days, in the doses of 20 and 200 mg/kg, was able to reverse the mnemonic impairment caused by neuroinflammation on recent and remote spatial long-term memory, and in the dose of 200 mg/kg, it also was able to do the same on aversive long-term memory. In the doses of 20 and 200 mg/kg, taurine was also able to reverse the LPS-induced increase in hippocampal TNF-α levels. Conclusion Taurine, when orally administered in a pathological context characterized by neuroinflammatory background, as it was induced in this work, can perform a dose-dependent neuroprotective effect, probably by acting in an excitotoxic scenario in which the activation of hyperpolarizing receptors can be welcomed.
Cerebral toxoplasmosis is a common opportunistic parasitic infection of the CNS caused by the Toxoplasma gondii parasite. Host immunosuppression can affect disease outcomes. To explore the changes in the cerebral cortical ultrastructure accompanying the infection in different immune-altered models and to find an effective treatment against the infection, we tested the possible therapeutic effect of clofazimine (CFZ) (the FDA-approved antimycobacterial drug) against the infection using 60 male CD1 Swiss Albino mice divided into 6 groups: 3 dexamethasone (DEX)- treated groups (DEX-only, DEX-infected, and DEX-infected-treated), and 3 streptozotocin (STZ)-induced type 1 diabetic groups (STZ-only, STZ-infected, STZ-infected-treated). The worst ultrastructural changes were observed in the diabetic and diabetic-infected groups, characterized by a significant increase in neuronal apoptotic and necrotic nuclei (P < 0.05) and changes in the numbers and structure of glial cells compared to the DEX and DEX-infected groups. CFZ (at a dose of 10 mg/kg/day for 3 days starting on 45th day post infection) significantly improved cortical neuronal ultrastructural changes in both models (P < 0.05), reduced microglial numbers, increased astrocyte numbers, and restored brain capillary integrity and axonal growth, in addition to significantly reducing mature cyst numbers in both models (P < 0.05). However, the drug didn’t reduce the number of atrophic and necrotic cysts in the infected-treated groups. So, in our study, CFZ showed preclinical promise in treating experimental cerebral toxoplasmosis and reducing the parasitic cyst burden, highlighting the adverse impact of the host’s altered immune status on brain tissue and the course of the infection, especially in diabetes.
The intersection of age- and experience-dependent processes influence learning throughout development, and developmental learning can have long-term effects on behavior. Phosphorylation of ribosomal protein S6 phosphorylation (pS6) is required in active ribosomes, and new protein synthesis is a conserved mechanism that supports long term memory formation. As such, pS6 fluctuations in brain regions processing experience can provide insight into shifts in the ability for learning and memory. Juvenile male and female zebra finch songbirds (Taeniopygia guttata) perform sensory song learning in ways that affect their adult behaviors. As adults, both sexes perform song recognition learning. Both juvenile and adult types of sensory learning invoke the auditory forebrain. Prior reports established a pS6 song response in the auditory forebrain in Posthatch day 30 juvenile males but not females, and not in younger birds. This was intriguing because the experience-dependent pS6 increase tracked with the onset of the critical period for juvenile sensory song learning in males, and behavioral data indicated that females also effectively learn at P30, though they may not have a critical period. Further, by adulthood (> Posthatch day 90), both male and female auditory forebrains showed an equivalent increase in pS6 after hearing song in patterns consistent with effective recognition learning. Here, to further test the relationships between a crucial molecular marker of active learning processes and the developmental trajectory of juvenile sensory song learning and the emergence of adult-like song recognition learning, we assessed the effect of age and sex, as well as the absence of tutor experience, a manipulation that extends the critical period for developmental learning in males, on the phosphorylation of S6 within the auditory forebrain. Outcomes highlight the complexity of molecular mechanisms across developmental learning and reveal questions to be addressed by further inquiry.
