J. Neurosci. Res. [JOURNAL]
Sun
200 papers
The Identification of Mitochondrial-Related Biomarkers of Ruptured Intracranial Aneurysms Based on Bioinformatics Analysis and Machine Learning.
Li Y, Huang D, Wu Z … +2 more , Liu T, Sun P
J Neurosci Res · 2026 Feb · PMID 41588925 · Publisher ↗
Intracranial aneurysms (IAs) are pathological dilatations of cerebral blood vessels, and their rupture can lead to severe mortality and disability. Therefore, identifying those at risk of rupture is of considerable clini...
Intracranial aneurysms (IAs) are pathological dilatations of cerebral blood vessels, and their rupture can lead to severe mortality and disability. Therefore, identifying those at risk of rupture is of considerable clinical significance. We screened 3740 differentially expressed genes (DEGs) in ruptured IA (RIA) versus unruptured IA (UIA) from the GSE13353 dataset. Weighted gene co-expression network analysis (WGCNA) was used to identify RIA-related module genes. After the intersection of DEGs and module genes with mitochondria-related genes (MRGs), MTX1, BCL2A1, BID, UCP2, ME2, VAV1, CYBA, and CYBB were identified as mitochondria-associated signatures of RIA. MTX1 was identified as the key diagnostic biomarker using three machine learning methods. While the diagnostic potential of this eight-gene signature was supported by an independent dataset (GSE122897), experimental validation in clinical and animal models confirmed significant dysregulation of ME2, UCP2, BCL2A1, and CYBA in RIA. Notably, MTX1 showed a consistent but non-significant trend of downregulation in these experimental assays. Immune infiltration analysis revealed a pro-inflammatory and stromal-enriched microenvironment in RIA, characterized by significantly elevated abundances of fibroblasts, smooth muscle cells, and macrophages, and showing distinct correlation patterns between key mitochondrial genes and specific immune and stromal cell populations. The construction of transcription factors and endogenous RNA networks was used to identify the underlying molecular mechanisms. Finally, potential therapeutic drugs such as rosiglitazone were identified by drug prediction, and the molecular docking of ME2 with cryptotanshinone suggested a new therapeutic approach. This study may provide a new strategy for the diagnosis and treatment of RIA targeting mitochondria.
Non-Mammalian Models in Ischemic Stroke Research: Advances, Applications, and Translational Potential.
Mizoguchi T, Tonoki A, Yamaguchi A … +1 more , Itoh M
J Neurosci Res · 2026 Jan · PMID 41559535 · Publisher ↗
Ischemic stroke remains a major global health burden, consistently ranking among the leading causes of mortality and long-term disability. Although rodent models are widely utilized for ischemic stroke research, their li...
Ischemic stroke remains a major global health burden, consistently ranking among the leading causes of mortality and long-term disability. Although rodent models are widely utilized for ischemic stroke research, their limited translational success has driven the pursuit of alternative experimental systems. This review underscores the growing significance of non-mammalian models, particularly zebrafish and Drosophila melanogaster, in advancing ischemic stroke research. Zebrafish offer notable advantages, including high genetic homology with humans, optical transparency, a pronounced capacity for neural regeneration, in vivo live real-time imaging, and behavioral analyses. Photothrombotic and systemic hypoxia paradigms in zebrafish enable detailed investigation of neurovascular injury and recovery processes. Drosophila, characterized by a rapid life cycle and sophisticated genetic toolkit, serves as a valuable model for elucidating hypoxia-induced neuronal damage and stroke-related comorbidities such as sleep disturbances. These models are cost-efficient, ethically advantageous, and well-suited for high-throughput applications. Despite inherent anatomical and physiological disparities, non-mammalian systems provide critical complementary insights into stroke pathogenesis and therapeutic innovation, reinforcing their integration into multi-model research frameworks.
Pharmacological Inhibition of EZH2 by GSK-343 Attenuates Neuroinflammation in a Mouse Model of Spinal Cord Injury.
Kang Y, Mannino D, Bova V … +7 more , Repici A, Maria B, Hasan A, Catalfamo A, Yang J, Lanza M, Filippone A
J Neurosci Res · 2026 Jan · PMID 41557490 · Full text
Spinal cord injury (SCI) is a devastating condition with limited therapeutic options and a strong neuroinflammatory component that exacerbates tissue damage and impairs functional recovery. Enhancer of zeste homolog 2 (E...
Spinal cord injury (SCI) is a devastating condition with limited therapeutic options and a strong neuroinflammatory component that exacerbates tissue damage and impairs functional recovery. Enhancer of zeste homolog 2 (EZH2), a histone methyltransferase and core component of the Polycomb Repressive Complex 2 (PRC2), has emerged as a key regulator of epigenetic modifications involved in neuroinflammation. In this study, we investigated the potential neuroprotective effects of GSK-343, a selective EZH2 inhibitor, in a murine model of SCI induced by extradural compression. Female adult CD1 mice received intraperitoneal injections of GSK-343 (1, 5, or 10 mg/kg) at 1- and 6-h post-injury. After 24 h, spinal cord tissues were collected and analyzed. GSK-343 treatment significantly reduced histological damage, neuronal demyelination, and the expression of pro-inflammatory markers, likely through modulation of the TRAF6/NF-κB signaling pathway. Moreover, EZH2 inhibition attenuated innate immune responses, as evidenced by the reduction in mast cell infiltration, microglial activation, and MCP-1 levels. These findings support the therapeutic potential of EZH2 inhibition as a novel epigenetic strategy to counteract neuroinflammation and promote early neuroprotection following SCI.
The Functional Epididymal Amyloid Cystatin-Related Epididymal Spermatogenic (CRES) is a Component of the Mammalian Brain Extracellular Matrix.
Gomez A, Tran UT, Grozdanov PN … +1 more , Cornwall GA
J Neurosci Res · 2026 Jan · PMID 41557487 · Full text
CRES is the defining member of a reproductive subgroup of family 2 cystatins of cysteine protease inhibitors. We previously showed that CRES and other subgroup members are part of a highly plastic amyloid-containing extr...
CRES is the defining member of a reproductive subgroup of family 2 cystatins of cysteine protease inhibitors. We previously showed that CRES and other subgroup members are part of a highly plastic amyloid-containing extracellular matrix (ECM) with host defense functions in the mouse epididymal lumen. Based on parallels between the epididymis and the brain, we hypothesized that CRES and CRES amyloids might also function within the brain including the ECM. Here we show that CRES is produced by hippocampal neurons and astrocytes in the male and female mouse and human brain. Further, approximately 50% of hippocampal astrocytes from aged mice, like the aged human donor samples, had significantly reduced levels of CRES compared to younger mice, suggesting an age-related decline in CRES could contribute to altered brain function. Immunofluorescence experiments showed CRES colocalized with the ECM markers phosphacan and wisteria floribunda agglutinin indicating that CRES is part of the ECM. CRES monomer and high molecular weight SDS-resistant forms were found in insoluble fractions of the hippocampus, cortex, cerebellum, and midbrain and bound to the protein aggregation disease (PAD) ligand, which preferentially binds amyloids but not protein monomers, suggesting a population of CRES normally exists in the brain as an amyloid structure. Collectively, our studies demonstrate that CRES/CRES amyloid is present in the mammalian brain and may contribute to ECM structure and function.
G Protein-Coupled Receptor Kinase 5 (GRK5) Modulates Nociceptin/Orphanin FQ Opioid (NOP) Receptor Desensitization in Rat Sympathetic Neurons.
Farrag M, Soliman M, Mahmoud S … +4 more , Miller L, Herold PB, Brandt K, Ruiz-Velasco V
J Neurosci Res · 2026 Jan · PMID 41531179 · Full text
Stimulation of nociceptin/orphanin FQ peptide (NOP) opioid receptors by the endogenous ligand nociceptin (Noc) leads to voltage-gated Ca channel inhibition or G protein inwardly rectifying K channel activation. One mecha...
Stimulation of nociceptin/orphanin FQ peptide (NOP) opioid receptors by the endogenous ligand nociceptin (Noc) leads to voltage-gated Ca channel inhibition or G protein inwardly rectifying K channel activation. One mechanism of G protein-coupled receptor (GPCR) desensitization occurs when G protein-coupled receptor kinases (GRK) phosphorylate the agonist-bound receptors. In the continued presence of an agonist, Gβγ recruits GRK to the plasma membrane where GPCR are then phosphorylated by GRK. The purpose of this study was to identify the GRK subtype responsible for desensitization of the Noc-mediated Ca current inhibition in rat stellate ganglion (SG) neurons. We observed that GRK2 and GRK5 are expressed in SG neurons. Further, silencing either GRK subtype alone or together employing siRNA did not overtly alter their Noc pharmacological profile. We assessed NOP receptor desensitization employing a protocol where the peak Ca current inhibition was measured during intermittent application of high Noc concentrations in the continued presence of the IC Noc concentration. With this approach, we observed complete Ca current desensitization in neurons transfected with either scrambled or GRK2 siRNA following exposure to high Noc concentrations. On the other hand, full desensitization of the Ca currents was not observed in neurons in which GRK5 was silenced alone or with GRK2. That is, coupling of NOP receptors with Ca channels was still observed following application of high Noc concentration. These results suggest that GRK5 plays a key role in the mechanism that mediates NOP receptor desensitization in SG neurons.
The Subcellular Localization of the Cystic Fibrosis Transmembrane Conductance Regulator in the Chicken Retina Suggests Multiple Roles in Retinal Function.
Leviskas B, Gleason E
J Neurosci Res · 2026 Jan · PMID 41511863 · Publisher ↗
Protein function is influenced by multiple factors including cell type and subcellular localization. The cystic fibrosis transmembrane conductance regulator (CFTR) is well investigated in epithelial tissues, where life t...
Protein function is influenced by multiple factors including cell type and subcellular localization. The cystic fibrosis transmembrane conductance regulator (CFTR) is well investigated in epithelial tissues, where life threatening symptoms stem from its dysfunction. A postsynaptic neuronal role was previously established by the Gleason lab where CFTR regulation of cytosolic Cl in retinal amacrine cells was shown. Other work from our lab showed that disruption of the synaptic vesicle cycle reduced action of CFTR, suggesting CFTR associates with synaptic vesicles. Here, we evaluate the hypothesis that CFTR localizes to the synapse with possible presynaptic function. To address this, the cellular and subcellular CFTR localization in mature chicken retina was examined using fluorescence light microscopy and immunogold-labeled transmission electron microscopy. CFTR labeling was detected throughout the retina, including photoreceptor outer segments and in the mitochondria rich region of the photoreceptor inner segment termed the ellipsoid. Synaptic labeling was found in both synaptic plexiform layers, pre-and post-synaptically. A subset of amacrine cells were strongly labeled and labeling was also found in Müller cells and in axons of the nerve fiber layer. Addressing whether the activity of CFTR plays a role in presynaptic function, amacrine cells were recorded using the whole cell voltage clamp method. Spontaneous postsynaptic quantal currents were recorded and found to increase in frequency upon pharmacological inhibition of CFTR suggesting that under normal circumstances, CFTR serves to limit the rate of spontaneous synaptic vesicle fusion. This work provides evidence CFTR might have multiple functions in the retina including synaptic transmission regulation.
Tryptophan Hydroxylase: A Target for the Correction of Affective and Neurodegenerative Disorders.
Sviridova VM, Absalyamova MT, Karpenko MN … +1 more , Ivleva IS
J Neurosci Res · 2026 Jan · PMID 41493885 · Publisher ↗
Tryptophan hydroxylase (TPH) is a key enzyme in the biosynthesis of serotonin, a neurotransmitter involved in the regulation of mood, emotional state, sleep, appetite, digestion, and cognitive functions. It plays a key r...
Tryptophan hydroxylase (TPH) is a key enzyme in the biosynthesis of serotonin, a neurotransmitter involved in the regulation of mood, emotional state, sleep, appetite, digestion, and cognitive functions. It plays a key role in the creation of a sense of well-being, reduction of anxiety and control of the response to stress. Imbalances in its levels are associated with many disorders, notably depression, anxiety disorders and migraines. This review examines the structural and functional aspects of the regulation of TPH activity with an emphasis on its isoforms, TPH1 and TPH2, which are responsible for serotonin synthesis in peripheral tissues and in neurons, respectively. Approaches to TPH regulation at the gene, protein, and enzymatic activity levels are discussed. The role of TPH in the pathogenesis of affective disorders such as depression, anxiety, attention deficit hyperactivity disorder and posttraumatic stress disorder is also discussed. Approaches to modulating TPH activity are proposed, including, for example, using calpain inhibitors.
The Effect of Magic Mushroom (Psilocybe azurescens) on Social Interaction, Anxiety- and Depressive-Like Behaviors in Male Rats; the Role of Neuroinflammation, Oxidative Stress, and Neurotrophic Factors.
Moghadam H, Akbari P, Beirami E … +3 more , Nabavifard S, Ameli A, Valian N
J Neurosci Res · 2026 Jan · PMID 41493855 · Publisher ↗
Psilocybin-containing mushrooms, commonly known as magic mushrooms, strongly affect mood, cognition, and behavior. Psilocybe azurescens is a species of psilocybin mushrooms that contains the main active compounds psilocy...
Psilocybin-containing mushrooms, commonly known as magic mushrooms, strongly affect mood, cognition, and behavior. Psilocybe azurescens is a species of psilocybin mushrooms that contains the main active compounds psilocybin and psilocin. Psilocybin mushrooms have been used since ancient times to improve the quality of life. However, their adverse effects have been less studied. This study aimed to investigate, for the first time, the effect of oral consumption of P. azurescens on social behavior, anxiety- and depressive-like behaviors in rats. The underlying mechanisms of these behaviors were also studied. Male Wistar rats received three doses of P. azurescens (10, 100, and 250 mg/kg) by gavage every other day for 14 days. Social interaction, anxiety- and depressive-like behaviors were assessed using the three-chamber, elevated plus maze, and forced swimming tests, respectively. Protein levels of neurotrophic (BDNF and GDNF), neuroinflammatory (IL-6 and TNFα), and oxidative stress (ROS and SOD) factors were measured in the hippocampus, prefrontal cortex (PFC), and amygdala by ELISA technique. The results showed that P. azurescens significantly increased anxiety- and depressive-like behaviors and disrupted social interaction behavior in rats. These effects were accompanied by increased neuroinflammation and oxidative stress and decreased neurotrophic factors in the hippocampus, PFC, and amygdala. This study suggests that the high doses of P. azurescens can cause mood disorders by increasing inflammatory responses and oxidative stress and decreasing the expression of neurotrophic factors.
Modulation of Magnetic Resonance Spectroscopy Levels of Glutamate and GABA by Ketamine in Treatment-Resistant Depression.
Njau S, Zavaliangos-Petropulu A, Joshi S … +6 more , Brooks J, O'Neill J, Roger WP, Norris V, Espinoza RT, Narr KL
J Neurosci Res · 2026 Jan · PMID 41473990 · Publisher ↗
Ketamine has emerged as a highly effective intervention for treatment-resistant depression (TRD). Though it acts as a non-competitive antagonist of excitatory N-methyl-D-aspartate receptors (NMDAR), widely expressed in t...
Ketamine has emerged as a highly effective intervention for treatment-resistant depression (TRD). Though it acts as a non-competitive antagonist of excitatory N-methyl-D-aspartate receptors (NMDAR), widely expressed in the brain, including on inhibitory γ-aminobutyric acid (GABA)-ergic cells, the mechanisms of its antidepressant action are less clear. To investigate the links between glutamate and GABA neurotransmission and the clinical benefits of ketamine, we used proton magnetic resonance spectroscopy (H-MRS) to measure both glutamate and GABA levels in the dorsal anterior cingulate cortex (dACC) in 60 participants with TRD before (~within 1 week), and 24 h after a 40-min intravenous infusion with 0.5 mg/kg of racemic (R,S)-ketamine. The 17-item Hamilton Depression Rating Scale (HDRS) was used as the primary measure of clinical improvement, and a 50% or greater improvement in HDRS ratings was used to define treatment responders. Ketamine increased mean dACC glutamate levels in responders only 24 h after treatment (n = 25, p = 0.01). Further, lower glutamate levels at baseline predicted greater improvements in HDRS scores at 24 h post treatment (p < 0.0001). However, GABA levels remained stable after treatment irrespective of response status (p = 0.90). Metabolites associated with neuronal integrity (tNAA), metabolic function (tCr), and membrane turnover (tCho), which may serve as complementary biological evidence of ketamine-induced plasticity, also increased with treatment (all p < 0.01). Results provide evidence of sustained enhancements of neurotransmission or other glutamate-related metabolic effects following subanesthetic ketamine in responders and a potential role of ACC glutamate levels as a biomarker of responsivity to ketamine.
Cortical Hierarchy Collapse in Alzheimer's Disease: Connectome Gradient Compression as a Potential Biomarker.
Zhao MT, Gong Q, Chen R … +2 more , Jiao Y, Alzheimer's Disease Neuroimaging Initiative
J Neurosci Res · 2025 Dec · PMID 41423431 · Publisher ↗
This investigation centered on Alzheimer's disease (AD), a progressive neurodegenerative disorder characterized by memory impairment and cognitive decline. Functional connectome gradient analysis was utilized to investig...
This investigation centered on Alzheimer's disease (AD), a progressive neurodegenerative disorder characterized by memory impairment and cognitive decline. Functional connectome gradient analysis was utilized to investigate alterations in the hierarchical architecture of brain networks in AD. The study cohort consisted of 222 subjects, encompassing 111 AD patients and 111 normal controls (NC). Connectome gradients were computed via a dimensionality reduction technique based on diffusion map embedding and analyzed at both the region of interest (ROI) and network levels. Additional connectome gradient metrics, including network median distance and gradient eccentricity, were calculated, and the relationship between connectome gradients and rich-club organization was assessed. These connectome gradient values were subsequently correlated with clinical cognitive scores. The results demonstrated a significant reduction in the principal gradient range in AD patients. At the network level, gradient values exhibited an increase in the somatomotor (SMN) and visual networks (VIS), while decreasing in the default mode (DMN) and frontoparietal networks (FPN) relative to controls. Analyzes of network mean distance and gradient eccentricity further revealed compression of the brain cortical hierarchy in AD patients. Furthermore, rich-club analyzes indicated a reduction in the gradient value difference between hub and peripheral nodes in AD patients. Finally, clinical correlation analysis revealed a positive correlation between the degree of cognitive impairment and the degree of compression of the brain cortical hierarchy. These findings provide a novel perspective on the study of brain network organization in AD patients, contributing to a more comprehensive understanding of the neural mechanisms underlying Alzheimer's disease.
Repetitive Blast Exposure Drives Chronic Pain in Female Rats.
Wright A, Murphy SF, VandeVord PJ
J Neurosci Res · 2025 Dec · PMID 41411066 · Full text
Clinical studies have established that repeated blast traumatic brain injury (rbTBI) can result in chronic pain conditions, with outcomes exhibiting notable sex-dependent differences. However, limited preclinical rbTBI m...
Clinical studies have established that repeated blast traumatic brain injury (rbTBI) can result in chronic pain conditions, with outcomes exhibiting notable sex-dependent differences. However, limited preclinical rbTBI models have systematically investigated the behavioral and neuropathological outcomes of female subjects. In the present study, adult female rats were subjected to repeated blast exposures, and the subsequent development of chronic pain-related behaviors and neuropathological changes was assessed. Repeated blast events induced robust mechanical and thermal hypersensitivity beginning 48 h post-injury and persisted through 12 weeks, accompanied by anxiety and depressive-like behaviors at the chronic time point. These behavioral alterations were associated with increased glial activity, as evidenced by Glial Fibrillary Acidic Protein (GFAP) and Ionized Calcium-Binding Adaptor Molecule 1 (IBA-1) in the frontal cortex and posterior nucleus regions at 12 weeks following injury. Notably, expression levels of neuropeptide markers, Calcitonin Gene-Related Peptide (CGRP) and Substance P (SP), remained unchanged. Collectively, these findings suggest that chronic pain behaviors following rbTBI in females are mediated primarily by sustained glial activation rather than neuropeptide dysregulation.
Frequency and Timing-Dependent Effects of Ultrasound on Neural Responses: Comparative Analysis With Whisker Stimulation in Rats.
Yuan Y, Liu T, Wang J
J Neurosci Res · 2025 Dec · PMID 41399905 · Publisher ↗
This study explores whether ultrasound can induce short-term synaptic plasticity (STP)-like effects at the systems level by modulating cortical excitability and sensory responsiveness. We designed a temporally shifted se...
This study explores whether ultrasound can induce short-term synaptic plasticity (STP)-like effects at the systems level by modulating cortical excitability and sensory responsiveness. We designed a temporally shifted sensory paradigm to test how ultrasound frequency (1, 2, and 4 MHz), inter-stimulus interval (10, 25, and 100 ms), and stimulation order (ultrasound-whisker vs. whisker-ultrasound) affect cortical responses in the rat barrel cortex. Thirty Sprague-Dawley rats underwent an identical experimental protocol. Electrocorticography (ECoG) signals were recorded from the C2 barrel column, and neural responses were assessed by peak amplitude, latency, and power spectral density. Whisker stimulation alone evoked strong cortical responses, significantly greater than ultrasound stimulation. Notably, when ultrasound preceded whisker stimulation by 25 ms, subsequent whisker responses were significantly enhanced, suggesting the existence of a cortical "excitability window" for neuromodulation. This facilitation effect was absent with time intervals of 10 and 100 ms. Mechanistically, ultrasound may modulate membrane tension and activate mechanosensitive ion channels to transiently lower the activation threshold of cortical neurons. These findings reveal that ultrasound can temporally enhance cortical excitability and sensory responsiveness in a frequency- and timing-dependent manner. Our results provide systems-level evidence of STP-like neuromodulation and provide the potential of ultrasound as a noninvasive method for dynamic control of sensory processing.
Cannabidiol as a Neuroprotective Agent in Acrylamide-Induced Neurotoxicity: Effects on Oxidative Stress, Inflammation, and Cholinergic Function in Male Mice.
Atsopardi K, Mesiakaris K, Sotiropoulos I … +2 more , Margarity M, Poulas K
J Neurosci Res · 2025 Dec · PMID 41395773 · Full text
The neuroprotective potential of cannabidiol (CBD) was assessed in a mouse model of acrylamide-induced neurotoxicity. Acrylamide (AA), an environmental and dietary pollutant, is known to cross the blood-brain barrier and...
The neuroprotective potential of cannabidiol (CBD) was assessed in a mouse model of acrylamide-induced neurotoxicity. Acrylamide (AA), an environmental and dietary pollutant, is known to cross the blood-brain barrier and induce oxidative stress, inflammation and neurotoxic effects. Male C57BL/6 mice were randomly assigned to four groups: Control (Con), Acrylamide (AA), Cannabidiol (CBD), and a combination treatment (AA + CBD). The AA group received acrylamide (10 mg/kg, i.p.) daily for 5 days. CBD was administered (10 mg/kg, i.p.) for 10 days in the CBD and AA + CBD groups. In the AA + CBD group, acrylamide (10 mg/kg, i.p.) was co-administered during the last 5 days of CBD treatment. Behavioral outcomes were analyzed using the open field test, revealing that CBD mitigated anxiety-like behavior induced by acrylamide, enhancing movement and center exploration. Further, CBD treatment modulated oxidative stress responses, reducing MDA levels and partially restoring antioxidant markers (GSH, SOD, and CAT) in the hippocampus and striatum. Inflammatory markers were also assessed, revealing that acrylamide elevated pro-inflammatory cytokines TNF-α and IL-6. Notably, CBD co-treatment reduced TNF-α levels in the hippocampus and cortex and attenuated IL-6 levels in the cortex and striatum, suggesting an anti-inflammatory effect. Additionally, CBD modulated neuroplasticity by increasing BDNF levels in the hippocampus, counteracting the reduction caused by acrylamide. CBD also influenced cholinergic activity by restoring Ach levels and altering AChE activity across brain regions. Findings suggest that CBD exhibits neuroprotective properties by reducing oxidative stress, inflammation and cholinergic dysregulation, thereby offering a promising therapeutic approach for mitigating pollutant-induced neurotoxicity and potentially treating neurodegenerative disorders.
Effects of Repetitive Transcranial Magnetic Stimulation Combined With Cognitive Training of Response Inhibition on Task-Related Oscillatory Activity.
Xu X, Moffa AH, Xu M … +4 more , Cao TV, Loo CK, Martin DM, Nikolin S
J Neurosci Res · 2025 Dec · PMID 41395757 · Publisher ↗
Repetitive transcranial magnetic stimulation (rTMS) combined with cognitive training (CT) has been explored as a potential novel method to improve response inhibition, but its neural mechanisms remain unclear. This study...
Repetitive transcranial magnetic stimulation (rTMS) combined with cognitive training (CT) has been explored as a potential novel method to improve response inhibition, but its neural mechanisms remain unclear. This study investigated the effects of rTMS + CT on oscillatory activity across different frequency bands and theta-gamma phase-amplitude coupling during the Stroop task. Sixty healthy participants were randomly assigned to receive four sessions of either active or sham prolonged intermittent theta burst stimulation (iTBS) + CT. Each session involved iTBS over both the right inferior frontal cortex and the pre-supplementary motor area, with participants completing the Stop Signal training task first, followed by the Go/No-Go training task. The Stroop task was administered before and immediately after the intervention while electroencephalography was recorded. There was a significant group effect on the change in beta desynchronization during incongruent trials (t = -2.03, p = 0.048), with a significant decrease observed in the active group (p = 0.03) and no change in the sham group (p = 0.83). Additionally, changes in gamma synchronization differed between groups for congruent trials (t = 2.28, p = 0.03), though neither group showed a significant pre-post change (p > 0.05). Our study suggests that four sessions of iTBS + CT may modulate beta and gamma oscillations during the Stroop task, potentially enhancing motor inhibition and processing speed in response inhibition. These results provide neurophysiological insights into the neural mechanisms through which rTMS + CT may enhance response inhibition.
Self-Processing Circuits Among Depressed Youth After Amygdala Neurofeedback Cued to the Self-Face.
Oh S, Hosseini-Kamkar N, Santana-Gonzalez C … +5 more , Ranatunga J, Nguyen GH, Maurice M, Young K, Quevedo K
J Neurosci Res · 2025 Dec · PMID 41387341 · Full text
Major depressive disorder is a significant health concern among adolescents due to its link to suicide and lifetime impairments. Current treatments yield limited success, but real-time functional magnetic resonance imagi...
Major depressive disorder is a significant health concern among adolescents due to its link to suicide and lifetime impairments. Current treatments yield limited success, but real-time functional magnetic resonance imaging (RT-fMRI) neurofeedback (NF) is a promising intervention. We tested the effects of RT-fMRI neurofeedback on the modulation of neural circuitry underlying self-referential processing and emotion regulation in youth trying to up-regulate the amygdala-hippocampus (AMYHIPP) complex. We examined amygdala functional connectivity during a self-other face recognition task before and after RT-fMRI NF from the AMYHIPP complex. (1) Depressed youth showed higher bilateral amygdala to anterior cingulate cortex (ACC), superior temporal and frontal gyri connectivity compared to controls, who showed lower connectivity before NF. Yet after NF, this pattern reversed, with depressed youth showing lower bilateral amygdala connectivity than controls. (2) Depressed youth showed increased right amygdala-cuneus connectivity while controls showed increased left amygdala-cuneus connectivity during self-other face recognition. (3) Lower right amygdala-cuneus connectivity was linked to improved rumination. Higher left amygdala-cuneus connectivity was linked to improved depression. (4) Shifts of less right versus left amygdala to superior middle temporal gyri connectivity after neurofeedback, and of more right versus left amygdala to middle frontal gyrus after NF, were linked to higher AMYHIPP engagement during training. This is suggestive of NF training effects upon implicit versus explicit emotion circuits. Caution is necessary regarding the meaning of symptoms to circuits associations and putative mechanisms of neurofeedback training given the lack of a placebo group.
Disrupted Transcriptional Networks in Mammalian Cells Stably Over-Expressing Pathogenic Atrophin-1.
Nuga O, Pourhadi M, Rausch JP … +1 more , Todi SV
J Neurosci Res · 2025 Dec · PMID 41355374 · Publisher ↗
Dentatorubral-Pallidoluysian Atrophy (DRPLA) is a dominant neurodegenerative disease caused by CAG triplet repeat expansion in ATN1, which encodes the transcriptional co-repressor Atrophin-1. DRPLA features motor, cognit...
Dentatorubral-Pallidoluysian Atrophy (DRPLA) is a dominant neurodegenerative disease caused by CAG triplet repeat expansion in ATN1, which encodes the transcriptional co-repressor Atrophin-1. DRPLA features motor, cognitive, and epileptic symptoms and shares pathogenic mechanisms with other polyglutamine (polyQ) disorders, including protein misfolding, impaired autophagy, and transcriptional dysregulation. To understand disease mechanisms, we performed RNA-seq on HEK293T cells stably over-expressing wild-type or pathogenic ATN1. Cells expressing pathogenic ATN1 exhibited a distinct transcriptomic profile, including disruptions in synaptic organization, extracellular matrix remodeling, ion channel expression, and neurotransmission. Several genes tied to neurodevelopmental, neurodegenerative, and oncogenic pathways were fully activated or silenced. Dysregulated pathways also included inflammation, chromatin remodeling, stress responses, and redox imbalance. Heat shock protein expression changes suggested proteotoxic stress and impaired protein quality control, with some findings conserved in a previously reported Drosophila melanogaster model of DRPLA. The transcriptomic signatures that we describe here expand understanding of the normal functions of ATN1 and the biology of disease of DRPLA.
Male-Specific Ventromedial Hypothalamic Nucleus Glutamate Decarboxylase (GAD)-2/GAD65 Regulation of Counterregulatory Transmitter Marker Gene Expression and Peripheral Hormone Profiles.
Pasula MB, Sapkota S, Yadav R … +1 more , Briski KP
J Neurosci Res · 2025 Dec · PMID 41325999 · Publisher ↗
The amino acid neurotransmitter gamma-aminobutyric acid (GABA) reportedly acts by unidentified ventromedial hypothalamic mechanisms to suppress hypoglycemia-associated counterregulatory endocrine function in male rats. P...
The amino acid neurotransmitter gamma-aminobutyric acid (GABA) reportedly acts by unidentified ventromedial hypothalamic mechanisms to suppress hypoglycemia-associated counterregulatory endocrine function in male rats. Present studies addressed the premise that GABAergic transmission of ventromedial hypothalamic nucleus (VMN) origin may regulate dorsomedial VMN (VMNdm) growth hormone-releasing hormone (Ghrh)/steroidogenic factor-1 (SF-1) neuron counterregulatory signaling to control this hormone outflow. VMN glutamate decarboxylase-2 (GAD2/GAD) gene knockdown increased basal but inhibited insulin-induced hypoglycemia (IIH)-associated augmentation of corticosterone and glucagon secretion, while suppressing growth hormone secretion regardless of glucose status. Multiplex qPCR analysis of laser-catapult-microdissected VMNdm Ghrh-immunoreactive neurons showed that GAD2 siRNA pretreatment intensified IIH-associated upregulation of mRNAs that encode the counterregulatory-enhancing neurochemicals nitric oxide and glutamate, and exacerbated hypoglycemic downregulation of GAD1, GAD2, and SF-1 transcription. VMN GAD2 gene silencing augmented hypoglycemic enhancement of Ghrh neuron 5'-AMP-activated protein kinase alpha-1 and alpha-2 gene expression. VMN GAD2 gene knockdown exacerbated both positive lactate receptor and negative estrogen receptor transcriptional reactivity to IIH. Study outcomes provide novel evidence for bidirectional, glucose status-specific VMN GABAergic control of corticosterone and glucagon secretion in male rats, which is not documented in the other sex. Data verify GABA regulation of VMN dorsomedial Ghrh neuron metabolic and hormonal signal reception, energy screening, and counterregulatory neurochemical release. Further effort is needed to characterize the impact of GABA-dependent neurotransmission by this discrete VMN neuron population on neural circuitries that govern glucose homeostasis.
Propofol Alleviates Depression-Like Behavior and Cognitive Disorder in Learned Helplessness Model Mice via Regulating Synaptic Function.
Wang J, Xiang J, Han X … +2 more , Liang J, Shang X
J Neurosci Res · 2025 Dec · PMID 41325982 · Publisher ↗
Propofol, an anesthetic known for its safety, efficacy and neuroprotective properties, has potential novel antidepressant effects. However, its specific mechanisms still require further elucidation. Presently, we establi...
Propofol, an anesthetic known for its safety, efficacy and neuroprotective properties, has potential novel antidepressant effects. However, its specific mechanisms still require further elucidation. Presently, we established a learned helplessness (LH) depression model to investigate the effects of propofol treatment on depression-like impairment. Thirty adult male C57BL/6j mice were randomly divided into three groups: control group (CON), model group (LH), and propofol group (PRO), with 10 mice per group. Behavioral analyses were conducted using weight measurement, sucrose preference test (SPT), forced swim test (FST), tail suspension test (TST), and Morris water maze test (MWM). Subsequently, HE staining was performed to examine pathological changes in the hippocampal region. Western blotting was conducted to assess changes in Notch signaling pathway components, synaptic plasticity-related proteins, and proteins in the glutamate system. Immunofluorescence was used to detect expression changes of NICD, SYP, and DCX. Hippocampal glutamate concentration was determined using a glutamate assay kit. Consequently, stressed mice exhibited pronounced depressive behaviors and decreased spatial learning and memory, accompanied by significant neuronal death in the dentate gyrus of the hippocampal region and reduced levels of neuronal regeneration as well as synaptic plasticity. Additionally, glutamate reuptake function was impaired in depression, manifested specifically as increased glutamate concentrations in the hippocampal region and neuronal glutamate transmission levels. Meaningfully, propofol upregulated Notch signaling pathway activity and improved glutamate reuptake function significantly resulting in enhanced adult hippocampal neurogenesis and synaptic plasticity. These findings demonstrated the effectiveness of propofol as a potential antidepressant and contributed to discovering novel antidepressant drugs.
Serum miR-598-3p as a Diagnostic and Prognostic Biomarker for Traumatic Brain Injury: Involvement in Modulating Microglial Inflammation.
Lei Y, Shen G, Wang Z … +5 more , Pan Y, Zhang Z, Liu Y, Sui H, Yuan C
J Neurosci Res · 2025 Dec · PMID 41317310 · Publisher ↗
Traumatic brain injury (TBI) results from external mechanical forces causing brain dysfunction. Dysregulated microRNAs (miRNAs) have been implicated in TBI pathophysiology, but the role of miR-598-3p remains unclear. Thi...
Traumatic brain injury (TBI) results from external mechanical forces causing brain dysfunction. Dysregulated microRNAs (miRNAs) have been implicated in TBI pathophysiology, but the role of miR-598-3p remains unclear. This study aimed to evaluate the diagnostic and prognostic value of miR-598-3p in TBI and explore its regulatory effects on inflammation in an LPS-induced microglial injury model. Serum miR-598-3p levels were measured via RT-qPCR in 137 TBI patients and 120 controls. ROC curves assessed its diagnostic and prognostic utility. TBI severity was classified by Glasgow Coma Scale (GCS) scores, and outcomes were evaluated using the Glasgow Outcome Scale (GOS). In vitro, LPS-treated BV2 microglia were transfected with a miR-598-3p inhibitor to analyze inflammatory cytokine levels. miR-598-3p expression was significantly elevated in TBI patients versus controls (p < 0.001) and increased progressively with injury severity. ROC analysis demonstrated high diagnostic accuracy for distinguishing TBI severity (AUC = 0.892/0.905) and predicting poor prognosis (AUC = 0.891, sensitivity = 83.33%, specificity = 90.36%). High miR-598-3p expression correlated with elevated Marshall grades, neural injury markers (S100B, GFAP), and pro-inflammatory cytokines (IL-6, TNF-α). Multivariate analysis identified miR-598-3p as an independent risk factor for poor outcomes (OR = 5.03, p < 0.01). miR-598-3p inhibition attenuated LPS-induced IL-6/TNF-α secretion (p < 0.01). Serum miR-598-3p demonstrates clinical utility as a biomarker for TBI diagnosis, severity grading, and prognostic evaluation. Its observed association with amplified microglial inflammatory responses suggests a potential mechanism involving regulation of neuroinflammation pathways.
Fiber Distribution and Myelination of Dopaminergic Neurons in the Medial Forebrain Bundle of a Rodent Depression Model.
Duan Z, Tong Y, Weng X … +2 more , Coenen VA, Döbrössy MD
J Neurosci Res · 2025 Nov · PMID 41241948 · Full text
It has been hypothesized that the rapid/long-lasting antidepressant action observed following medial forebrain bundle DBS in clinical trials of Treatment-Resistant Depression patients could partially be driven by modulat...
It has been hypothesized that the rapid/long-lasting antidepressant action observed following medial forebrain bundle DBS in clinical trials of Treatment-Resistant Depression patients could partially be driven by modulation of the midbrain-to-forebrain dopaminergic fibers. The study investigated the spatial distribution and myelination status of dopaminergic fibers within the rodent equivalent structure in a preclinical depression model, the Flinders Sensitive Line (FSL). Fixed, sliced brain sections were double stained with anti-tyrosine hydroxylase/anti-dopamine-β-hydroxylase antibodies to distinguish dopaminergic from noradrenergic fibers, and with anti-tyrosine hydroxylase/anti-myelin antibodies to specifically investigate myelination. Quantification was done at six predefined segments. The dopaminergic fibers coursing through the medial forebrain bundle were small diameter, unmyelinated and mainly restricted to the dorsolateral quadrant on the AP axis. Analyses across six predefined planes revealed significantly fewer dopaminergic fibers in FSL males (vs control males, and vs. FSL females) at AP -2.8 mm, the segment corresponding to the medial forebrain bundle DBS target in the rat. No differences were observed elsewhere along the medial forebrain bundle. Previously reported differences in stimulation-evoked dopamine release in the FSLs could be due to differences in the numbers of recruited dopaminergic fibers.
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