Spinal cord injury after cardiac arrest (CA) can cause devastating neurological deficits, including paraplegia. Although lumbar spinal cord injury is clinically important, regional comparisons remain limited. In this study, we examined region-associated vulnerability of the thoracic and lumbar spinal cord using a rat model of asphyxial CA (ACA). Adult male Sprague-Dawley rats underwent sham surgery or ACA, and thoracic and lumbar spinal cord tissues were collected 24 h after return of spontaneous circulation (ROSC) from ACA survivors with hindlimb paralysis. Histopathological analysis demonstrated significantly fewer surviving neurons in the lumbar compared with the thoracic spinal cord after ACA. The lumbar spinal cord also showed higher BAX/BCL2 ratios and cleaved caspase-3 expression, together with increased phosphorylation of NF-κB and mitogen-activated protein kinases, including p38, extracellular signal-regulated kinase (ERK), and c-Jun N-terminal kinase (JNK). Exploratory transcriptomic comparison between ACA-L and ACA-T identified 292 upregulated and 187 downregulated DEGs. Enrichment analyses indicated that upregulated DEGs were associated with extracellular matrix-receptor interaction, focal adhesion, integrin signaling, and PI3K-Akt signaling, whereas downregulated DEGs were associated with nervous system development and myelination. Collectively, these findings demonstrate region-dependent molecular and histopathological alterations at 24 h after ROSC, with a more pronounced injury-associated inflammatory and apoptosis-related profile in the lumbar spinal cord of paralyzed ACA survivors.

Why do brain circuits differ among species of the same or different classes of vertebrates? Answers to this question are critical in determining brain organization and evolution. Investigations in mammals and in certain model systems have been the main focus of these studies. Among the areas that have commonly been investigated are cell death, synaptic pruning, and synapse organizing proteins. Whether these same or even other factors sculpt similar circuits in other vertebrates such as reptiles is unknown. The present study examined the development of a well defined circuit in crocodiles and compared it with a similar circuit in mammals. In mammals, cortical areas project directly back to the same dorsal thalamic nucleus that provides its input. However, in reptiles, pallial regions in receipt of dorsal thalamic input do not project directly back to dorsal thalamic nuclei. Instead, pallial areas in reptiles project to the basal nuclei, similar, in part, to the striatum of mammals. The basal nuclei then project back to the dorsal thalamus. This suggested the possibility that this circuit might have been lost in reptiles or perhaps added in mammals. To determine which of these two possibilities might be the case, the development of this circuit in Alligator embryos and juvenile crocodiles was investigated. The results indicate that cell death caused the loss of this circuit in crocodiles and is the likely explanation for this difference. However, a distinction between neuronal death and axonal re-modelling could not be determined.

Multiple system atrophy (MSA) is a progressive neurodegenerative disease characterized by parkinsonism, cerebellar ataxia, and autonomic dysfunction. Recently, a close relationship of neuroinflammation to MSA pathogenesis was identified. Studies in mouse models of MSA have indicated that peripheral-type myeloid cells and endogenous microglia promote neuroinflammation in MSA. However, their distinct roles in MSA pathogenesis remain unknown. We performed immunohistochemical analyses of brain tissues obtained at autopsy from patients with MSA and age-matched controls to examine the putamen and cerebellar white matter with antibodies against CCR2 (a chemokine receptor expressed by monocyte-lineage cells), TMEM119 for microglia, and fibrinogen for blood-brain barrier (BBB) leakage. The CCR2-immunopositive area was significantly increased in both regions in MSA patients compared to controls (putamen, p = 0.0043; cerebellar white matter, p = 0.0438); however, the TMEM119-immunopositive area showed no significant between-group difference (putamen, p = 0.4220; cerebellar white matter, p = 0.8152). The densities of CCR2-immunopositive areas in the putamen and cerebellar white matter were positively correlated (Pearson's r = 0.7325, p = 0.0248). In the putamen, fibrinogen immunoreactivity and perivascular leakage were increased and showed a distribution similar to that of CCR2 immunostaining (p = 0.0398). These findings suggest that CCR2-immunopositive myeloid cell accumulation in regions with BBB dysfunction may involve recruitment of peripheral monocyte-lineage cells.

Anillin (Ani)/Scraps has a well-characterized function in cytokinesis and has recently been shown to play a role in the nervous system. Ani is expressed in neuroblasts, axons, and neuromuscular junctions in the Drosophila larval nervous system, and pan-neuronal ani knockdown impairs both larval and adult behaviors. However, despite the expression of ani in glial cells, its function in these cells remains unclear. In the present study, we therefore investigated the role of ani in Drosophila glial cells by performing pan-glial ani knockdown and assessing the subsequent effects on larval and adult behaviors. Ani was expressed in a subset of glial cells, including in the central and peripheral nervous systems, and expression levels varied across individual cells. Pan-glial knockdown of ani significantly impaired larval and adult locomotion, larval learning ability, and adult activity; however, it did not affect lifespan. Although ani depletion decreased the number of glial cells in the central nervous system, it did not disrupt neuropil formation. In the peripheral nervous system, ani knockdown increased the total length of neuromuscular junctions. Subtype-specific knockdown analyses suggested that Ani functions in endoreplicating subperineurial and wrapping glia to support larval locomotion. The results also suggested a possible role for Ani in astrocyte-like and ensheathing glia, although the evidence is inconclusive. In contrast, Ani did not appear to have an obvious role in cortex glia or actively proliferating perineurial glia for larval locomotion. Together, these findings indicate that ani exerts both canonical and non-canonical roles in Drosophila glial cells.

The cerebellum's involvement in non-motor functions, such as emotional and cognitive processes, has been gaining attention. The functional topography of the cerebellum remains inconclusive, and both clinical and preclinical studies have aimed to identify it to achieve a better understanding of cerebellar neurophysiology and its influence on other brain structures in different functions. The aim of this study was to analyze activation in cerebellar lobules IV-V, VI and VII under different context and temporal conditions of an inhibitory avoidance (IA) task, and to assess the association between c-Fos expression in these lobules and in other brain regions involved in emotional and memory processing. Thirty-three naïve Swiss Albino mice were exposed to the IA box for 1, 4, and 8 days. After the final exposure of each group to the evaluation apparatus, euthanasia was performed, followed by transcardiac perfusion and brain removal. Immunofluorescence analysis of c-Fos in pre-established structures was performed. Significant c-Fos/DAPI ratio was observed in cerebellar lobules IV-V and VI in animals that performed IA task for 4 days. No significant difference in c-Fos expression was found in the other regions of interest. Spearman's Correlation Coefficient test did not indicate any associations between the c-Fos/DAPI ratios across the regions of interest. These results suggest that cerebellar lobules IV-V and VI may be differentially recruited during the IA task, although their specific involvement in emotional and emotional memory processing remains to be determined.

Neuroinflammation mediated by microglial activation plays a critical role in Parkinson's disease (PD), with the NLRP3 inflammasome contributing to dopaminergic neurodegeneration. Varlitinib, a clinically developed pan-human epidermal growth factor receptor inhibitor, has been investigated as an anticancer agent; however, its therapeutic potential in PD remains unknown. Here, we evaluated the neuroprotective effects of varlitinib in in vitro and in vivo PD models. BV2 microglial cells were stimulated with α-synuclein and 1-methyl-4-phenylpyridinium and treated with varlitinib. Varlitinib significantly improved cell viability, reduced lactate dehydrogenase release, and suppressed IL-1β and IL-18 production. Co-treatment with the selective NLRP3 inhibitor MCC950 produced no additional anti-inflammatory effects, suggesting that NLRP3 inflammasome signaling contributes, at least in part, to varlitinib's actions. In a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced mouse model of PD, varlitinib significantly improved motor performance, reduced microglial activation in the substantia nigra and striatum, and preserved tyrosine hydroxylase-positive dopaminergic neurons. Collectively, these findings support varlitinib as a potential drug-repurposing candidate for PD.

Amyloid-β (Aβ) accumulation impairs hippocampal neural stem cell (NSC) function, but whether Aβ biases NSC lineage commitment toward the astrocytic lineage remains unclear. In this study, primary hippocampal NSCs from neonatal Sprague-Dawley rats were treated with 60 μM Aβ25-35 fragment, close to the 48-h half-maximal inhibitory concentration (IC50 ≈ 57.8 μM) determined by a CCK-8 assay. After 48 h, the proportions of Nestin[+] and 5-ethynyl-2'-deoxyuridine (EdU)[+] cells were significantly decreased (P < 0.01 and P < 0.001, respectively). After 7 days of differentiation, the proportion of glial fibrillary acidic protein (GFAP)[+] cells was significantly increased (P < 0.001). GFAP[+] cells exhibited an increased number of processes but shortened process length. Western blotting confirmed decreased Nestin and increased GFAP protein levels (both P < 0.01). Network-based bioinformatics screening identified 124 overlapping genes between Aβ-related targets and NSC-associated genes, with the PI3K-Akt pathway most highly enriched; validation showed a reduced p-Akt/Akt ratio (P < 0.01), decreased p-GSK-3β (Ser9) and β-catenin levels (P < 0.001), and upregulated total GSK-3β (P < 0.05). Taken together, these findings indicate that Aβ25-35 inhibits NSC proliferation and promotes astrocytic lineage differentiation, at least partly through suppression of the PI3K/Akt/GSK-3β/β-catenin pathway.

Pentylenetetrazole (PTZ)-induced kindling is an established model for investigating seizure mechanisms and evaluating the efficacy of antiepileptic drugs. Novel drug delivery systems, such as nanoparticles, offer improved therapeutic outcomes by enhancing brain bioavailability and reducing adverse effects. This study investigated the effects of chitosan-encapsulated carbamazepine nanoparticles on seizure activity in PTZ-kindled mice compared with the free form of the drug. Male BALB/c mice were divided into three groups: PTZ-kindled control, PTZ + free carbamazepine, and PTZ + chitosan-encapsulated carbamazepine. Seizure stage, Stage latencies 1 and 4, seizure duration, and mortality were assessed using a modified Racine scale. The results showed that while free carbamazepine temporarily reduced seizure stage, its effect diminished over time. In contrast, the chitosan-encapsulated formulation significantly reduced seizure stage, seizure duration, prolonged latencies, and completely prevented seizure-induced mortality. Characterization of the optimized nanoparticles revealed a mean particle size of 65 nm, a polydispersity index (PDI) of 0.21, a zeta potential of -34.5 mV, and an entrapment efficiency of 55.35 %, indicating favorable stability and delivery properties. Overall, this study demonstrates that chitosan‑based nanoencapsulation of carbamazepine enhances its antiepileptic efficacy in a PTZ‑kindling model, suggesting its promise as a potential therapeutic strategy for epilepsy.

The prevalence of depressive symptoms among college students continues to rise. It has been shown that individuals with higher psychological resilience generally exhibit fewer depressive symptoms. The aim of this study is to examine potential associations between psychological resilience and depressive symptoms in college students and to explore the statistical mediating role of brain activation in this relationship. 140 college students received functional near infrared spectroscopy (fNIRS) scans while completing a verbal fluency task (VFT). Psychological scales, oxyhemoglobin (HbO) concentration, partial correlation and mediation analyses were processed. Partial correlation analysis showed that psychological resilience was significantly negatively associated with depressive symptoms. The activation of HbO in the left dorsolateral prefrontal cortex (DLPFC; CH23), right DLPFC (CH3), and right orbitofrontal cortex (OFC; CH6) were significantly positively correlated with psychological resilience and negatively correlated with depressive symptoms. Further mediation analyses demonstrated a significant indirect association between psychological resilience and depressive symptoms through activation in the left DLPFC (CH23). The findings suggest that the left DLPFC may be involved in the relationship between psychological resilience and depressive symptoms in college students. Future longitudinal or intervention studies are needed to further clarify the causal relationships among these variables.

Exposure to traumatic events induces persistent alterations in defensive behavior that extend beyond associative fear memories, including heightened responses to novel stimuli (stress sensitivity) and sustained defensive states in neutral contexts (stress sensitization). While serotonergic psychedelics such as psilocybin have been shown to facilitate fear extinction in associative paradigms, their effects on trauma-induced non-associative stress adaptations remain poorly understood. Here, we developed a behavioral paradigm in mice that dissociates contextual fear recall from stress sensitivity and stress sensitization within the same subjects. Male C57BL/6J mice were exposed to an acute foot-shock stressor, followed by assessment of trauma recall, administration of psilocybin (1 mg/kg) or vehicle, and subsequent evaluation of responses to a novel auditory stimulus and context. Trauma-exposed mice displayed robust associative fear and increased freezing in response to a novel auditory stimulus, consistent with enhanced stress sensitivity. However, psilocybin did not significantly alter this stimulus-evoked response. In contrast, psilocybin produced bidirectional, experience-dependent effects on stress sensitization - it reduced baseline freezing in non-traumatized mice but increased freezing in trauma-exposed animals when re-exposed to a novel context in the absence of a stimulus. Together, these findings demonstrate that psilocybin does not uniformly attenuate trauma-related behaviors, but instead modulates non-associative defensive responses in a manner dependent on prior experience. This work highlights the importance of distinguishing between associative and non-associative components of fear and suggests that psychedelic-induced plasticity may amplify latent trauma-related states under certain conditions.

Understanding the factors that modulate social reward has important implications for conditions characterized by social dysfunction, including autism spectrum disorder and social anxiety disorder. Social isolation is particularly relevant, given rising rates of subjective loneliness and social disconnection in the United States. The present study investigated the impacts of isolation on social reward by testing the effects of single- versus pair-housing on social conditioned place preference (sCPP) in adult male and female Sprague-Dawley rats. Across a ten-day paradigm with eight conditioning days, rats were trained in a two-chamber apparatus in which one chamber was repeatedly paired with a same-sex, weight-matched littermate, while the other chamber served as an unpaired control. Pair-housed rats were co-housed with their conditioning partner for the duration of the study. Single-housed, but not pair-housed, rats of both sexes developed a significant preference for the social-paired chamber. These findings indicate that housing condition modulated sCPP expression in adult male and female rats.

Early-life adversity alters inhibitory circuit maturation across developing brain systems, but most studies have focused on corticolimbic regions involved in emotional and cognitive regulation. Whether early adversity also reshapes inhibitory extracellular matrix architecture in primary sensory cortex remains less clear. Here, we examined the effects of maternal separation on parvalbumin-positive (PV+) interneurons and Wisteria floribunda agglutinin-labeled perineuronal nets (PNNs) in the mouse primary somatosensory barrel cortex (S1BF), a highly organized sensory region in which laminar position carries clear developmental and functional significance. Mice underwent daily maternal separation from postnatal day 1 to 14, and PV/PNN anatomical features were analyzed in young adulthood. PV density, PNN density, PV/PNN co-labeled cell density, and PNN-only density were quantified across layers 2/3, 4, and 5/6 of S1BF. Maternal separation did not alter PV+ interneuron density in any cortical layer. Instead, its effects were selective to PNN-related measures in layer 4, where both PNN density and PV/PNN co-labeled cell density were significantly increased. By contrast, PNN structures not associated with PV cells remained unchanged, indicating that the increase in PNN density was predominantly associated with PV-labeled interneurons. These findings show that maternal separation does not produce a generalized loss of PV-PNN architecture in barrel cortex. Rather, early adversity selectively enhances PV-associated PNN organization in the principal thalamorecipient layer of S1BF. This layer-specific pattern suggests that early-life stress may alter the timing or distribution of plasticity and stabilization within primary sensory circuits, with potential consequences for how tactile information is filtered and integrated during cortical maturation.

Alzheimer's disease (AD) is characterized by amyloid-beta (Aβ) deposition, yet the mechanisms underlying Aβ-induced neuronal damage remain elusive. Emerging evidence implicates ferroptosis, an iron-dependent form of regulated cell death, in AD pathology. We hypothesized that dysfunction of the Nrf2 pathway critically links Aβ deposition to neuronal ferroptosis and cognitive decline. In this study, AD progression in APP/PS1 mice was associated with progressive cognitive impairment, Aβ accumulation, and neurodegeneration. Aged APP/PS1 mice exhibited marked suppression of the Nrf2 antioxidant pathway, accumulation of reactive oxygen species, and prominent hallmarks of ferroptosis, including elevated DMT1 and TfR expression, accompanied by reduced GPX4 and xCT expression. Remarkably, genetic overexpression of Nrf2 significantly ameliorated cognitive impairment, attenuated neuronal and synaptic loss, and concurrently reduced Aβ deposition, oxidative stress, and neuronal ferroptosis. These findings demonstrate that Aβ accumulation is associated with impaired Nrf2 signaling during AD progression, leading to oxidative stress, neuronal ferroptosis, and cognitive dysfunction. Collectively, these findings suggest that activation of the Nrf2 pathway exerts robust protective effects against AD-like pathology, highlighting its potential as a therapeutic strategy for AD.

Chronic microglial activation and the resulting neuroinflammatory cascade drive Alzheimer's disease (AD) progression. Systemic lipopolysaccharide (LPS) triggers robust microglial responses and is linked to neurodegenerative disorders, yet the full spectrum of neuroinflammatory and neuronal changes associated with chronic peripheral endotoxemia remains incompletely characterized. We hypothesized that sustained peripheral endotoxemia establishes a neuroinflammatory environment characterized by microglial activation, mitochondrial dysfunction, and neuronal apoptosis, accompanied by amyloid precursor protein (APP) accumulation. We analyzed public transcriptomic datasets for inflammatory signatures associated with LPS exposure in BV2 microglia (GSE18740) and mouse brain tissue (GSE3253). HT22 neurons were exposed to conditioned medium from LPS-stimulated BV2 cells, and apoptotic markers were measured. Adult rats received repeated systemic LPS injections over six months to model chronic endotoxemia; brain sections were then analyzed by immunohistochemistry for CD68 (microglial activation), cleaved caspase-3 (apoptosis), and APP. Inflammatory-related pathways were consistently upregulated across datasets. Conditioned medium from activated microglia increased neuronal apoptosis. Both LPS-treated microglial cells and HT22 neurons cultured with BV2-conditioned medium exhibited increased reactive oxygen species production and reduced mitochondrial membrane potential. The endotoxemia model exhibited cortico-hippocampal microgliosis, elevated cleaved caspase-3, and APP accumulation. These results support the hypothesis that peripheral endotoxemia probably propagates microglial hyperactivation, which subsequently promotes neuronal apoptosis and APP accumulation. Whether modulation of the inflammation-related pathways identified here can attenuate this microglia-mediated neurodegeneration warrants dedicated investigation.