J. Neurosci. Res. [JOURNAL]
Sun
200 papers
Dysregulation of Glial Gap Junction Protein Innexin2 Mediates Seizures and Disrupted Sleep in a Drosophila Model for North Sea Progressive Myoclonus Epilepsy.
Grzeschik NA, Lambrechts RA, van der Zwaag M … +3 more , Eggens-Meijer E, Sibon OCM, Gorter JA
J Neurosci Res · 2025 Nov · PMID 41208742 · Full text
North Sea Progressive Myoclonus Epilepsy (NS-PME) is a rare genetic disease that presents at an early age with progressive ataxia, myoclonus, and epilepsy. The disease is caused by a mutation in the Golgi SNAP receptor 2...
North Sea Progressive Myoclonus Epilepsy (NS-PME) is a rare genetic disease that presents at an early age with progressive ataxia, myoclonus, and epilepsy. The disease is caused by a mutation in the Golgi SNAP receptor 2 gene (GOSR2). However, the consequences of this genetic defect at the cellular level are still unknown. Using a NS-PME Drosophila melanogaster model, it was previously found that knockdown of membrin, the fruit fly GOSR2 ortholog, in glial cells leads to progressive heat-induced seizure-like behavior in adult flies. Upon close inspection, we found NS-PME flies not only show progressive heat-induced seizures but also disrupted sleep architecture (higher number of shorter sleep bouts). Here we asked what glial cellular consequences could be underlying these phenotypes of membrin knockdown. First, we investigate whether these phenotypes are attributed to specific glial types; we found that these phenotypes were partly reproduced with specific knockdown of membrin in perineurial glia only. Next, we show that Innexin2, a gap junction protein specifically expressed in glia, is affected upon membrin knockdown, with an altered expression pattern and reduced protein levels. Finally, glial overexpression of Innexin2 in the background of glial membrin knockdown strongly ameliorates the heat-induced seizure phenotype, disrupted sleep architecture, as well as Innexin2 expression pattern, corroborating the importance of Innexin2 in maintaining neuronal homeostasis in NS-PME. These findings show that dysregulation of Innexin2 at least partially underlies the phenotypes of membrin knockdown in Drosophila melanogaster and could suggest a similar role of Innexin2-like proteins in the human disease NS-PME.
Soluble Epoxide Hydrolase Inhibition Confers Neuroprotection via PPAR-α Activation During Intracerebral Hemorrhage.
Martínez-Torres AM, Navarro-Mabarak C, Morán J
J Neurosci Res · 2025 Nov · PMID 41201160 · Full text
Epoxyeicosatrienoic acids (EETs), are known to possess potent anti-inflammatory and antioxidant neuroprotective properties. However, the molecular mechanisms responsible for these effects are not well understood. In this...
Epoxyeicosatrienoic acids (EETs), are known to possess potent anti-inflammatory and antioxidant neuroprotective properties. However, the molecular mechanisms responsible for these effects are not well understood. In this work, we aimed to evaluate the neuroprotective role of EETs in a hemorrhagic stroke model and the possible involvement of PPAR-α activation in this neuroprotection. Hemorrhagic damage was induced in mice through the intracerebral administration of collagenase VII in the striatum. The neuroprotective effect of EETs was tested in mice by pre-treatments of 2 h with TPPU, an inhibitor of the EETs metabolism. TPPU was administered intraperitoneally at a dose of 0.5, 1.0, or 2 mg/kg. Brain damage was evaluated based on measurements of motor activity, hematoma volume, brain water content, and blood-brain barrier (BBB) permeability. Additionally, the levels of enzymes involved in the oxidative stress balance, such as NADPH oxidase 2 (NOX-2) and superoxide dismutase (SOD), were determined by Western blot analysis. Our results showed that EETs exert neuroprotective effects by significantly decreasing all parameters related to brain damage, improving motor function and promoting an antioxidant state, as evidenced by increased levels of SOD and reduced levels of NOX enzymes. Subsequently, PPAR-α involvement was evaluated through the administration of GW6471, a PPAR-α antagonist. Pre-treating mice with GW6471 for 30 min, reverted all neuroprotective effects, including the observed changes in SOD and NOX levels. Our results demonstrate that EETs confer neuroprotection in hemorrhagic brain injury, and this effect is dependent on PPAR-α activation.
Rolipram-Loaded PgP Nanotherapeutics via Intrathecal Administration Reduces Secondary Injury in a Rat Acute Moderate Contusion SCI Model.
Liao Z, Gao J, Khang MK … +3 more , Webb K, Detloff MR, Lee JS
J Neurosci Res · 2025 Nov · PMID 41192818 · Full text
Spinal cord injury (SCI) triggers complex secondary injury mechanisms, resulting in long-term impacts on sensory and motor function. Rolipram, a phosphodiesterase-4 inhibitor, has shown promise in preserving/restoring cy...
Spinal cord injury (SCI) triggers complex secondary injury mechanisms, resulting in long-term impacts on sensory and motor function. Rolipram, a phosphodiesterase-4 inhibitor, has shown promise in preserving/restoring cyclic adenosine monophosphate (cAMP) to reduce secondary injury responses, but its clinical application is hindered by poor solubility and systemic side effects. To overcome these challenges, we developed rolipram-loaded poly(lactide-co-glycolide)-graft-polyethylenimine (PgP) nanoparticles (Rm-PgP) to enable localized and sustained drug delivery. In our previous findings, Rm-PgP administered via intraspinal injection restored cAMP levels at the lesion site, and reduced secondary injury after moderate, contusive SCI. In this study, we investigated the effect of single and repeat administration of Rm-PgP by the clinically relevant intrathecal route immediately after injury. We observed that the hydrophobic dye, DiR-loaded PgP (DiR-PgP) was retained in the CNS over 7 days post-injury (DPI). In addition, we observed that both single and repeat Rm-PgP treatment groups showed higher cAMP levels compared to those in the untreated SCI group and only the single treatment group showed a significant difference compared to the untreated SCI group. Lastly, we observed that cAMP restoration in both single and repeat Rm-PgP treatment groups showed higher levels of activated cAMP-response element-binding protein (pCREB) relative to the untreated control. We also observed that both Rm-PgP treatment groups showed reduced inflammatory response, reduced astrogliosis and apoptosis, and increased neuronal survival and spared tissue volume. These findings highlight the neuroprotective efficacy of Rm-PgP by intrathecal administration in mitigating secondary injury during the critical early phase of recovery after SCI.
Characterizing Non-Traumatic Spinal Cord Injury in Neonatal Sprague Dawley Rats.
Ridlen RM, Burke M, Wesley C … +4 more , Le HT, Farrell L, McGrath K, Gorrie CA
J Neurosci Res · 2025 Nov · PMID 41178388 · Publisher ↗
Spinal cord injuries (SCI) can occur from either traumatic or non-traumatic causes. While traumatic spinal cord injury (TSCI), caused by acute external forces, is well-researched, non-traumatic spinal cord injury (NTSCI)...
Spinal cord injuries (SCI) can occur from either traumatic or non-traumatic causes. While traumatic spinal cord injury (TSCI), caused by acute external forces, is well-researched, non-traumatic spinal cord injury (NTSCI), arising from chronic conditions like tumors and infections, is often underreported and misclassified. NTSCI is increasingly recognized as a major cause of SCI globally, particularly affecting the elderly and infants. Despite its prevalence, research on NTSCI remains limited, necessitating new models to understand its pathophysiology. This study introduces a novel, repeatable model for NTSCI in both neonatal (9 days post-partum) and adult rats (9 weeks post-partum), simulating chronic compression injuries. The model uses 3D-printed (PLA) spacers to induce mild-moderate compression in the lower thoracic vertebrae. Six weeks of spinal cord compression resulted in locomotor deficits and cellular changes consistent with hypoxic-ischemic injury due to disrupted blood flow, without significant long-term inflammation or astrogliosis. This versatile model can be easily adapted for different age groups, for graded injury severities, and for different injury durations. It offers a promising avenue for understanding and treating chronic compression NTSCI, addressing a critical gap in current research. This model can be used in future research to test and understand the effectiveness and pathophysiology of decompression and cellular interventions in response to chronic compression NTSCI.
Slc20a2 Deficiency Increases Susceptibility to CNS Demyelination Possibly Through Th17 Cells.
Zhang Y, Wang X, Ren Y … +6 more , Zhang Z, Li Y, Peng Z, Xu C, Cheng L, Zhang X
J Neurosci Res · 2025 Nov · PMID 41163520 · Publisher ↗
Primary familial brain calcification (PFBC) is a rare inherited neurodegenerative disorder characterized by abnormal brain calcium-phosphate (Ca-Pi) deposits along microvessels or inside neuronal cells. Eight genes have...
Primary familial brain calcification (PFBC) is a rare inherited neurodegenerative disorder characterized by abnormal brain calcium-phosphate (Ca-Pi) deposits along microvessels or inside neuronal cells. Eight genes have been linked to PFBC, with the SLC20A2 being the earliest identified. SLC20A2 encodes PiT-2, which is crucial for Pi homeostasis in the cerebrospinal fluid (CSF). In Slc20a2 homozygous knockout (HO) mice, the neurotoxic effects resulting from pathological CSF-Pi accumulation and the unique brain transcriptome suggested that the absence of PiT-2 might lead to myelin abnormalities. However, the myelin morphology and content under Slc20a2 deficiency remained largely unknown, and these were quantitatively investigated in this study. The results indicated no direct demyelination in the brains of Slc20a2-HO mice, but an increased susceptibility to demyelination under the induction of oligodendrocyte-toxic cuprizone (CPZ). The enhanced susceptibility was related to a greater infiltration of Th17 cells in the brain parenchyma, accompanying an exacerbation of brain calcification in Slc20a2 deficiency.
Newborn Auditory Brainstem Response and Sudden Infant Death Syndrome.
Maylott SE, Zeng G, Leung TS … +6 more , Montenegro CS, Barrios A, Malik A, Delgado RE, Delgado CF, Simpson EA
J Neurosci Res · 2025 Nov · PMID 41163517 · Publisher ↗
Sudden infant death syndrome (SIDS)-the sudden and unexplained death of a seemingly healthy infant, < 1 year old-may be associated with abnormalities in the brain regions that underlie breathing and arousal during sleep....
Sudden infant death syndrome (SIDS)-the sudden and unexplained death of a seemingly healthy infant, < 1 year old-may be associated with abnormalities in the brain regions that underlie breathing and arousal during sleep. While post-mortem studies suggest abnormalities in SIDS infants' brainstems, there are no studies of these infants' brainstem function before death. One way to assess the function of the brainstem is with auditory brainstem response (ABR), a routine hearing-screening method that noninvasively measures the brainstem's response to sound. We hypothesized that anomalies in newborns' ABR measures may predict SIDS. We integrated two secondary datasets and examined ABRs of newborns who later died of SIDS (n = 11) compared to a normative sample (n = 198,990), using existing archived records of neonatal ABR results from a sample of newborns born in Florida. As hypothesized, infants who died from SIDS were more likely than non-SIDS infants to have abnormal ABRs as newborns. Children who died of SIDS appeared to have shorter latencies to the trough that follows peak V in the left ear than children without SIDS. However, our expert-rated data failed to replicate this finding, suggesting it is unlikely to reflect a true effect. Understanding the association between SIDS and ABR may facilitate more accurate identification of an infant's risk for SIDS at birth, enabling increased monitoring, which may facilitate interventions and improve survivorship.
Evolution of Axonal Injury in the Closed Head Impact Model of Engineered Rotational Acceleration in Adult Ferrets.
Krieg JL, Antolis K, Hooper C … +7 more , Kapuwelle H, George R, O'Brien WT, McDonald SJ, Leonard AV, Turner RJ, Corrigan F
J Neurosci Res · 2025 Nov · PMID 41163442 · Publisher ↗
Concussion-related symptoms, such as impaired balance, slower processing speed, attention deficits, memory dysfunction, and irritability, are thought to result from diffuse axonal injury (DAI), characterized by selective...
Concussion-related symptoms, such as impaired balance, slower processing speed, attention deficits, memory dysfunction, and irritability, are thought to result from diffuse axonal injury (DAI), characterized by selective damage to white matter axons. Axons subjected to this mechanical stretch injury exhibit diverse pathological changes, including disruption of axonal transport, neurofilament compaction and degradation, myelin sheath disruption, and loss of sodium channels required for action potential generation and propagation. These distinct forms of axonal pathology may evolve differentially over time and preferentially localize to specific white matter tracts. In this study, we employed the clinically relevant ferret model of concussion using the closed head impact model of engineered rotational acceleration (CHIMERA). 55 male ferrets were randomly allocated to sham or injury groups and then to either 24 h, 72 h, or 14d survival time points. We confirmed that axonal transport disruption and neurofilament pathology represent independent processes, with minimal colocalization but a shared peak of around 72 h following injury. Furthermore, we observed a persistent loss of ankyrin-G, a critical anchoring protein for sodium channels at the node of Ranvier, up to 14d postinjury, suggesting that the resultant impairment in axonal transmission may underlie many concussion symptoms. Indeed, injured ferrets displayed significant deficits in balance, working memory, spatial memory, and recognition memory. These findings demonstrate that the CHIMERA model in ferrets recapitulates key axonal pathologies and their associated clinical manifestations following concussion. This model offers a valuable platform for investigating the temporal evolution of axonal injury and developing targeted therapeutic interventions to mitigate concussion-related deficits.
Moderate Chronic Treadmill Exercise Slows Dopaminergic Neuron Loss in a Rat Model of Parkinson's Disease and Alters RNA Content of Circulating Plasma Exosomes.
Citron BA, Guzman M, Shapdoor B … +6 more , Rameshwar P, Sokratian A, Shaikh AL, Mausoof AE, West AB, Delic V
J Neurosci Res · 2025 Oct · PMID 41078024 · Full text
Exercise has been reported to improve outcomes in patients with Parkinson's disease, but the exact biological mechanisms remain incompletely understood. This study was conducted to determine whether chronic moderate trea...
Exercise has been reported to improve outcomes in patients with Parkinson's disease, but the exact biological mechanisms remain incompletely understood. This study was conducted to determine whether chronic moderate treadmill exercise prevents dopaminergic neuron loss and Lewy body-like inclusion burden in a preclinical model of PD. This study also sought to identify plasma exosome bound "exerkines" with potential to induce neuroprotective brain adaptations. Benefits of exercise are thought to be achieved in part through nucleic acids, lipids, and peptides termed exerkines abundant during exercise. These exerkines can induce cell-specific exercise adaptations culminating in neuroprotection. Membrane-free exerkines are subject to degradation in blood and may not effectively cross the blood-brain barrier to induce brain adaptations to exercise, limiting their inter-organ signaling potential. This led us to hypothesize that exerkines, bioactive RNAs in particular, may be selectively packaged into exosomes and released into plasma during exercise. Exosomes are small extracellular vesicles, selectively packaged and released by cells, with likely important differences in composition at rest, during injury and disease, and in response to exercise. Exosomes have been demonstrated to play a major role in inter-organ communication. Chronic exercise was found to provide neuroprotection to dopaminergic neurons in the substantia nigra pars compacta, without affecting Lewy body-like inclusion burden in the nigra or the striatum. Plasma exosomal RNA was isolated from age-matched exercising and sedentary non-PD rats and sequenced. We report 27 unique RNAs upregulated in the exosomes of exercisers, 3 mRNAs with clear neuroprotective potential.
Single-Cell RNA-Seq and Machine Learning Reveal Key Feature Genes of Astrocyte in Perioperative Neurocognitive Disorders.
Zhao L, Chen Z, Ma X … +1 more , Chi X
J Neurosci Res · 2025 Oct · PMID 41074638 · Publisher ↗
Perioperative neurocognitive disorder (PND) is common in older patients after anesthesia and surgery, significantly increasing morbidity and mortality. However, the role of astrocytes in its pathogenesis remains limitedl...
Perioperative neurocognitive disorder (PND) is common in older patients after anesthesia and surgery, significantly increasing morbidity and mortality. However, the role of astrocytes in its pathogenesis remains limitedly understood. Here, we analyzed 9976 and 9484 single-cell transcriptomes from hippocampal cells of aged mice undergoing PND surgery or sham operation, focusing on astrocytes. We identified 13 distinct clusters corresponding to nine cell types, including astrocytes, microglia, neurons, oligodendrocytes, and other relevant cell populations. Specifically, five astrocyte subclusters were identified, with cluster 0 being the most abundant. Its proportion decreased by 5.51% in the PND surgery condition, showing the largest difference between the groups. Functional enrichment analysis revealed that astrocytes are involved in crucial neurodevelopmental processes and pathways associated with nervous system development and synaptic regulation. Pseudotime analysis placed cluster 0 at the early stage of differentiation, suggesting it as a key responsive population. Gene co-expression network further identified modules with peak activity in cluster 0. By intersecting cluster 0 markers with differentially expressed genes (DEGs) and applying machine learning methods, including LASSO, XGBoost, and Random Forest, we pinpointed four feature genes Dbp, PISD, Id4, and Tsc22d3 with differential expression patterns between surgery and control conditions. Transcription factor activity analysis highlighted distinct regulatory networks in astrocytes, providing insights into their functional differences in response to PND surgery. These findings offer a detailed aged hippocampal landscape of astrocyte dynamics and intercellular communication, contributing to our understanding of neuroinflammation and cognitive dysfunction following surgical stress.
RETRACTION: Antibodies Directed Against Rubella Virus Induce Demyelination in Aggregating Rat Brain Cell Cultures.
J Neurosci Res · 2025 Oct · PMID 41013901 · Publisher ↗
C. Besson Duvanel, P. Honegger and J.-M. Matthieu, "Antibodies Directed Against Rubella Virus Induce Demyelination in Aggregating Rat Brain Cell Cultures," Journal of Neuroscience Research 65, no. 5 (2001): 446-454, http...
C. Besson Duvanel, P. Honegger and J.-M. Matthieu, "Antibodies Directed Against Rubella Virus Induce Demyelination in Aggregating Rat Brain Cell Cultures," Journal of Neuroscience Research 65, no. 5 (2001): 446-454, https://doi.org/10.1002/jnr.1173. The above article, published online on 28 August 2001 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor-in-Chief, Lawrence S. Sherman, and Wiley Periodicals LLC. The retraction has been agreed upon following an investigation into concerns raised by a third party. The article purports a homology between amino acid sequences of myelin oligodendrocyte glycoprotein (MOG) and the rubella virus E2 glycoprotein. However, further analysis has demonstrated that the referenced sequences are not present in the mature MOG proteins. The authors did not respond to address the concerns and did not provide their original data. As a result, the editors consider the conclusions of this article to be unsupported.
Focused Ultrasound-Induced Peripheral Nerve Blockade: Duration of Changes to Thermal Withdrawal Latency and Nerve Structure After Focused Ultrasound Application to the Sciatic Nerve in a Rat Model of Acute Pain.
Gao G, Thomas Z, Kantarci H … +5 more , Pacharinsak C, Zuchero JB, Pauly KB, Yeomans DC, Anderson TA
J Neurosci Res · 2025 Sep · PMID 40990106 · Publisher ↗
Focused ultrasound (FUS) holds potential to inhibit peripheral nerves to manage pain. We previously found FUS parameters resulting in changes to nerve structure and reversible increased mechanical withdrawal threshold as...
Focused ultrasound (FUS) holds potential to inhibit peripheral nerves to manage pain. We previously found FUS parameters resulting in changes to nerve structure and reversible increased mechanical withdrawal threshold as well as reversible inhibition of motor and non-pain sensory fibers. However, as behaviors were only followed for 4 weeks and structure for 2 weeks, the duration of increased thermal withdrawal latency and changes to nerve structure were undetermined. We investigated the duration of increased thermal withdrawal latency and nerve structure alterations after FUS application in an acute pain model. FUS was applied directly to the rat sciatic nerve prior to hindpaw (HP) incision; animal behaviors (thermal and mechanical nociceptive thresholds, HP extension and flexion) were assessed for 12 weeks and nerve structure was assessed for 28 weeks. The primary outcome was the change in HP thermal withdrawal latency. Secondary outcomes were the changes to sciatic nerve structure and HP mechanical withdrawal threshold, extension, and flexion. Compared with controls, after FUS application, animals had increased thermal nociceptive thresholds until week 9, increased mechanical nociceptive thresholds until week 2, decreased HP motor response until week 3.5, and decreased HP plantar sensation until week 4. Nerve ultrastructure changes may have persisted until week 24. In this new longer-term follow-up study, after invasive FUS application to the sciatic nerve in a rodent model of acute incisional pain, we determined the duration of changes to thermal hyperalgesia, mechanical hyperalgesia, motor, and non-pain sensory responses, and changes to nerve structure.
Combination of Treadmill Training and Inosine Enhance Nerve Regeneration and Functional Recovery After Mice Sciatic Nerve Transection.
Taboada TB, Heringer LDS, de Oliveira CLF … +8 more , da Rosa GV, Pestana FM, Cardoso R, Cardoso FSDS, Cavalcanti RR, Ramalho BDS, Martinez AMB, de Almeida FM
J Neurosci Res · 2025 Sep · PMID 40956018 · Full text
Peripheral nerve injuries are a major cause of disability, leading to significant sensorimotor impairment and functional loss. These injuries can result from traumatic or non-traumatic events, with severe cases posing th...
Peripheral nerve injuries are a major cause of disability, leading to significant sensorimotor impairment and functional loss. These injuries can result from traumatic or non-traumatic events, with severe cases posing therapeutic challenges. Neurorrhaphy is the gold standard for treating injuries where the gap between nerve stumps is less than 3 cm, while autografting is used for larger gaps. Despite various therapeutic approaches aimed at enhancing peripheral nerve regeneration, restoring pre-injury function remains difficult in clinical practice, prompting the exploration of experimental therapies. This study examined the effects of treadmill training and inosine treatment on sciatic nerve regeneration after transection in mice. Male C57/Bl6 mice (8-12 weeks) underwent sciatic nerve transection, with the proximal and distal stumps sutured to a polylactic acid tubular graft, creating a 3 mm gap. The mice were treated with saline or inosine (70 mg/mL) for 1 week, followed by treadmill exercise starting in the second week. The exercise protocol involved treadmill speeds of 6-12 m/min, three times per week for 10 min, continuing for 8 weeks. Functional recovery was assessed weekly using the Sciatic Functional Index, pinprick test, and Von Frey electronic analgesiometer. At the end of the study, electrophysiological tests and morphologic analysis were performed. The results showed that the combination of inosine with treadmill training significantly accelerated functional recovery and nerve regeneration, suggesting that this combined approach may offer a promising alternative for improving recovery outcomes in cases of peripheral nerve injury.
Characterization of a Ferret Model of Traumatic Brain Injury due to Under-Vehicle Blast, Controlled Cortical Impact, or Blast Plus Impact.
Goodfellow MJ, Hrdlick AL, Piskoun B … +11 more , Proctor JL, Rangghran P, Shaughness MC, Vesselinov A, Xu S, Gullapalli RP, Leiste UH, Fourney WL, Miller CHT, Cantu JC, Fiskum G
J Neurosci Res · 2025 Sep · PMID 40948389 · Full text
Under-vehicle blast (UVB) generated from landmines is a unique traumatic brain injury (TBI) mechanism affecting warfighters. UVB hyperacceleration can result in injury independent of impact; however, a secondary impact i...
Under-vehicle blast (UVB) generated from landmines is a unique traumatic brain injury (TBI) mechanism affecting warfighters. UVB hyperacceleration can result in injury independent of impact; however, a secondary impact injury can also occur. To date, translation of findings from rodent TBI models to improved patient outcomes has been unsuccessful, perhaps due to neuroanatomical differences between humans and rodents, including white-to-gray matter ratio and cortical gyrification. To address this modeling difference, a UVB model was developed in ferrets, the brains of which more closely resemble humans. Male ferrets underwent UVB-alone (Blast), controlled cortical impact (CCI)-alone, combined UVB + CCI (BCCI), or craniotomy (Sham) procedures. Neurobehavioral assays were optimized and used to assess mood, memory, and motor control. Blast and BCCI ferrets underwent neuroimaging at baseline and 7 days post-injury. All ferrets were euthanized by terminal perfusion with paraformaldehyde on day 7 for histologic analysis. Results indicate that UVB alters cortical metabolites and induces blood-brain barrier (BBB) disruption. CCI leads to BBB disruption and cortical diffuse axonal injury, but this is not exacerbated by combination with UVB. BCCI does result in several alterations in key cortical metabolites indicative of increased neuronal injury, oxidative stress, and glial activation as well as impaired neurotransmission and energy generation. Additionally, BCCI significantly increases hyperactivity and impairs spatial memory. Anxiety-like behavior, mood, and motor function approached statistical significance. Taken together, we provide a military-relevant model of UVB in a gyrencephalic animal, the ferret, that may be applied in future investigations into TBI pathophysiology and potential treatment.
Neonatal Freeze Lesion-Induced Cortical Malformation Alters Hippocampal Gene Expression and Leads to Persistent Cognitive and Emotional Deficits in Adult Male Wistar Rats.
Zubareva OE, Kovalenko AA, Sinyak DS … +4 more , Postnikova TY, Subkhankulov MR, Sabirova ER, Zaitsev AV
J Neurosci Res · 2025 Sep · PMID 40874645 · Publisher ↗
Cortical malformations, including microgyria, are often associated with neurodevelopmental comorbidities such as epilepsy and cognitive impairments in humans. To investigate how early cortical disruption leads to persist...
Cortical malformations, including microgyria, are often associated with neurodevelopmental comorbidities such as epilepsy and cognitive impairments in humans. To investigate how early cortical disruption leads to persistent behavioral impairments, we employed a neonatal neocortical focal freeze lesion (FFL) model of polymicrogyria in male Wistar rats. Unilateral cortical lesions were induced at postnatal day 0 (P0), and molecular changes in hippocampal gene expression (glutamatergic signaling: Grin1, Grin2a, Grin2b, Gria1, Gria2; neuroinflammation: Nlrp3, Il1b, Il1rn; glial markers: Gfap, Aif1; neurotrophic factors: Bdnf, Fgf2) were analyzed at P21. Behavioral outcomes, including locomotor activity, exploratory behavior, anxiety-like behavior, social interaction, and recognition memory, were assessed in adulthood (P70-P90). Neonatal cortical lesions induced subregion-specific alterations in hippocampal gene expression: Grin2b and Gria1 expression decreased in the ipsilateral dorsal hippocampus, while Grin2a, Bdnf, and Fgf2 increased in the contralateral ventral hippocampus. These molecular changes were associated with subsequent cognitive deficits (impaired recognition memory) and emotional dysregulation (heightened anxiety-like behavior) in adult rats, alongside reduced exploratory activity. Basic motor functions and sociability remained unaffected, and seizure susceptibility (assessed via maximal electroshock threshold) was unchanged, highlighting the specificity of the observed impairments. Our findings suggest a potential mechanistic link between early-life cortical malformations with microgyrus formation, dysregulation of hippocampal synaptic plasticity and neurotrophic signaling, and persistent neurobehavioral deficits. These results underscore the translational relevance of the freeze lesion model for studying the neurodevelopmental trajectory of cortical malformation-related comorbidities.
Investigating Atypical Neural Dynamics and Gene Expression in Temporal Lobe Epilepsy: Insights From Co-Activation Patterns.
Qin L, Qin B, Pan L … +7 more , Zhou Q, Hu H, Su S, Sun Y, Pang X, Chen Z, Zheng J
J Neurosci Res · 2025 Sep · PMID 40873228 · Publisher ↗
Temporal lobe epilepsy (TLE) is a focal epilepsy extensively examined through advanced neuroimaging techniques to elucidate its pathophysiological mechanisms. This study investigates the differences in dynamic brain acti...
Temporal lobe epilepsy (TLE) is a focal epilepsy extensively examined through advanced neuroimaging techniques to elucidate its pathophysiological mechanisms. This study investigates the differences in dynamic brain activity and gene expression in TLE patients. Resting-state functional magnetic resonance imaging (rs-fMRI) data were collected from 60 TLE patients and 30 healthy controls (HC). Dynamic amplitude of low-frequency fluctuations (dALFF) was employed to identify regions with dALFF variance differences, which were then designated as regions of interest (ROIs). Co-activation patterns (CAP) was constructed to compare brain dynamic changes. Pearson's correlation analysis and pathway enrichment analysis were used to explore the potential molecular mechanisms associated with atypical neural dynamics in TLE. Five CAP states were identified from the rs-fMRI data. Compared to HC, TLE with cognitive normal (TLE-CN) and TLE with cognitive impairment (TLE-CI) patients exhibited atypical state-specific temporal characteristics, including number of states (counts), fraction of time, persistence, resilience, and transition probability (TP) between states. Importantly, dynamic indicators of CAP states were significantly correlated with cognitive performance. Furthermore, 2752 genes were significantly associated with atypical dynamic brain states in TLE, with these genes primarily enriched in synapse-related pathways. This study offers novel insights into atypical neural dynamics from a temporal perspective. The brain network dynamics defined by CAP analysis deepen our understanding of the neurobiological underpinnings of TLE and TLE-CI, revealing a link between atypical neural architecture and gene expression in TLE.
Effects of Small Conductance Ca-Activated Potassium Channel Agonists on SLEs in Varied Epilepsy Models, From Animal Slices to Pharmacoresistant Human Tissue.
Raza ML, Haq RU, Heinemann U
J Neurosci Res · 2025 Sep · PMID 40873202 · Publisher ↗
To assess the impact of SK channel agonists on seizure-like events (SLEs) in various seizure models in slices of the temporal cortex obtained from pharmacoresistant patients. SLEs were triggered by applying 4-aminopyridi...
To assess the impact of SK channel agonists on seizure-like events (SLEs) in various seizure models in slices of the temporal cortex obtained from pharmacoresistant patients. SLEs were triggered by applying 4-aminopyridine (100 μM) to slices of the entorhinal cortex taken from both normal and pilocarpine-treated rats. Additionally, SLEs were induced in slices of the temporal cortex obtained from individuals who had undergone epilepsy surgery. In the case of human slices, SLEs were also provoked by increasing potassium levels along with the administration of either 4-AP (100 μM) or bicuculline (50 μM). The activation of SK2/3 channels by the compound CYPPA (n = 8) effectively prevented SLEs in slices from the brains of normal rats, pilocarpine-treated rats (n = 8), and in human cortex slices (n = 9) when SLEs were triggered by 4-AP. In human temporal cortex slices, CYPPA also demonstrated efficacy in preventing SLEs induced by an elevation in potassium concentration combined with bicuculline application (n = 5). SKA-31, exhibited efficacy in slices from normal rats (n = 8), rats treated with pilocarpine (n = 8), and in human slices (n = 7) when SLEs were provoked by 4-AP. However, its effectiveness was limited when applied to human tissue slices exposed to bicuculline and elevated potassium levels. The SK1 channel activator GW-542573X displayed only moderate anticonvulsant effects in the models under investigation. SK2 channels showed the highest effectiveness across the different epilepsy models. Sensitivity to the SK3 channel activator was found to be more pronounced compared to the other two activators studied.
Enoxaparin Improves Outcomes in Cerebral Infarction Rats by Reducing Microcirculatory Thrombosis and Hypoperfusion.
Li Y, Zheng D, Xiong L … +1 more , Wang J
J Neurosci Res · 2025 Aug · PMID 40787845 · Publisher ↗
Microcirculatory disturbances may play an important role in futile recanalization. This study investigated the early factors affecting the prognosis of cerebral infarction in rats and whether low-molecular-weight heparin...
Microcirculatory disturbances may play an important role in futile recanalization. This study investigated the early factors affecting the prognosis of cerebral infarction in rats and whether low-molecular-weight heparin improves microcirculation disorders. We used a male rat middle cerebral artery occlusion (MCAO) model with 90 min transient MCAO (tMCAO) or permanent MCAO (pMCAO) ischemia, and analyzed after 24 h. Cortical blood flow was monitored using laser speckle blood flow imaging. Furthermore, 1.5 mg/kg Enoxaparin (Enox) was administered 30 min before ischemia or 1 h post-reperfusion. The tMCAO group received saline. Our results showed that the proportion of moderate and severe (M&S) injuries was 54.2% in tMCAO rats, 100% in pMCAO rats, and reduced to 25% in the enoxaparin pre-ischemic (Enox-pre) group. The reperfusion rats had persistent hypoperfusion and the lowest blood flow after 1 h post-reperfusion. The 1 and 24 h post-reperfusion cortical blood flow was negatively correlated with infarct volume and neurological scores. The Enox-pre group had higher blood flow than the tMCAO group at 1 h post-reperfusion (p < 0.05). Enox-pre reduced fibrin deposition after 1 h post-reperfusion (p < 0.01), improved microvascular patency after 1 and 24 h (p < 0.01), and decreased Evans blue leakage after 24 h (p < 0.001). We concluded that 50% of the futile recanalization rate also exists in rats with recanalization 1.5 h post-infarction. The degree of reperfusion blood flow recovery significantly affects cerebral infarction outcomes. Enox-pre reduces the proportion of poor outcomes by reducing early microthrombus formation, enhancing microcirculation, increasing reperfusion blood flow, and mitigating blood-brain barrier (BBB) disruption.
PPP1R15A Promotes Apoptosis, Autophagy, and Inflammatory Response to Exacerbate Ischemic Stroke Through Activation of TLR4/NF-κB Pathway.
Liu L, Li J, Yin P … +2 more , Kong S, Li J
J Neurosci Res · 2025 Aug · PMID 40751334 · Publisher ↗
Ischemic stroke (IS) is a prevalent and serious neurological disorder, and is one of the major contributors to mortality and disability worldwide. The activation of autophagy and the inflammatory response following cereb...
Ischemic stroke (IS) is a prevalent and serious neurological disorder, and is one of the major contributors to mortality and disability worldwide. The activation of autophagy and the inflammatory response following cerebral ischemia are crucial in the progression of IS. Protein phosphatase 1 regulatory subunit 15A (PPP1R15A), as a stress-responsive protein, has been proven to be closely associated with autophagy. Nevertheless, the molecular mechanism of PPP1R15A in IS remains to be fully understood. Our study screened PPP1R15A as a candidate gene by bioinformatics analysis of the differentially expressed genes (DEGs) in IS and autophagy-related genes (ARGs). Functionally, experiments uncovered that down-regulation of PPP1R15A alleviated oxygen-glucose deprivation/reoxygenation (OGD/R)-mediated inhibition of cell viability and promotion of LDH release, cell apoptosis, autophagy, and inflammation in A172 and SH-SY5Y cells. Simultaneously, silencing PPP1R15A ameliorated the IS progression in the middle cerebral artery occlusion and reperfusion (MCAO/R) rat model. Furthermore, PPP1R15A activated the toll-like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB) pathway in vivo and in vitro. Rescue experiments indicated that TLR4 inhibitors TAK-242 and NF-κB inhibitors BAY-11-7082 effectively alleviated the malignant progression of IS mediated by overexpression of PPP1R15A. Our data illustrated that PPP1R15A promoted OGD/R-induced cytotoxicity, apoptosis, autophagy, and inflammation by activating the TLR4/NF-κB pathway.
The Impact of Ketogenic Diet Consumption on the Sporadic Alzheimer's Model Through MT1/MT2 Regulation.
Cimen YA, Elibol B, Korkmaz ND … +4 more , Yuzgulec M, Kinsiz B, Kutlu S, Ustunova S
J Neurosci Res · 2025 Aug · PMID 40751333 · Publisher ↗
Melatonin and its receptors play a primary role in regulating circadian rhythms, which are frequently disrupted in patients with Alzheimer's disease (AD). Furthermore, there is increasing evidence that the use of a ketog...
Melatonin and its receptors play a primary role in regulating circadian rhythms, which are frequently disrupted in patients with Alzheimer's disease (AD). Furthermore, there is increasing evidence that the use of a ketogenic diet (KD) delays the onset of AD. Therefore, we aimed to investigate whether KD has an ameliorative effect on AD through the regulation of melatonin receptors. In this study, male Sprague-Dawley rats were divided into three groups: sham, AD, and KD. At the end of KD supplementation, behavioral parameters were determined by the Morris Water Maze. Melatonin levels, protein expression levels, and immunoreactivity of MT1-MT2 in thehippocampus and striatum were determined by ELISA, Western blotting, and immunofluorescence staining, respectively. As a result, KD improved memory decline in AD rats. Also, KD increased melatonin levels in the hippocampus but did not affect striatum melatonin levels. MT1 expression tended to increase in the hippocampus of the AD group, while MT2 expression decreased. On the contrary, KD treatment increased both MT1 and MT2 expressions. In the striatum, there was no change in MT1 expression in the AD and KD groups, but MT2 expression increased in the AD group compared with the sham group and was suppressed in the KD group. In addition, KD treatment reduced streptozotocin-induced apoptosis and neuroinflammation in the hippocampus and striatum. Our results suggest that KD may improve AD-associated inflammation and apoptosis by altering melatonin levels and the expression of MT2 receptors in the hippocampus and striatum. Therefore, KD may be a promising preventive and therapeutic option for AD.
RETRACTION: Aberrant Dynamic Network Connectivity Changes in Comorbid Depression and Overweight/Obesity: Insights From the Triple Network Model.
J Neurosci Res · 2025 Aug · PMID 40751330 · Publisher ↗
Zhang, Z.-Q., Liao, D., Guo, Z.-P., Song, S.-S., and Liu, X.-J. Aberrant Dynamic Network Connectivity Changes in Comorbid Depression and Overweight/Obesity: Insights From the Triple Network Model. Journal of Neuroscience...
Zhang, Z.-Q., Liao, D., Guo, Z.-P., Song, S.-S., and Liu, X.-J. Aberrant Dynamic Network Connectivity Changes in Comorbid Depression and Overweight/Obesity: Insights From the Triple Network Model. Journal of Neuroscience Research 102, no. 12 (2024): e70001, https://doi.org/10.1002/jnr.70001. The above article, published online on 29 November 2024 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by agreement between the journal Editor-in-Chief, Lawrence S. Sherman; and Wiley Periodicals, LLC. The retraction has been agreed upon after the authors informed the editors that their findings on dynamic functional network connectivity, as presented in Figures 3-7, were not adequately independently validated, thereby undermining the reliability and reproducibility of the results. Furthermore, their ethical approval process was not fully compliant with the standard guidelines. The corresponding author contacted the journal and asked for a retraction, but the authors did not respond when asked to agree to the final retraction wording. The editors consider the results and conclusion of this article to be invalid.
About
- Frequency
- Sun
- Papers found
- 200
- RSS feed
- Subscribe