Brain Research Bulletin[JOURNAL]
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200 papers
Corrigendum to "The central amygdala as a pathological hub: A multi-level review of pain-emotion comorbidity" [Brain Res. Bull. 236 (2026) 111756].
Xu X, Hu J, Wang Y … +4 more , Zhu Y, Cao Y, Li M, Peng P
Brain Res Bull · 2026 Jul · PMID 42173794 · Publisher ↗
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Neurobiological mechanisms of second-generation antipsychotic-induced obesity: Interactions between ghrelin signaling and neurotransmitter systems.
Zogović N, Despotović A, Marjanović MM … +2 more , Vučićević L, Janjetović K
Brain Res Bull · 2026 Aug · PMID 42173450 · Publisher ↗
Second-generation (atypical) antipsychotics are central to the treatment of schizophrenia and related disorders but are frequently associated with significant metabolic adverse effects, particularly weight gain and obesi...
Second-generation (atypical) antipsychotics are central to the treatment of schizophrenia and related disorders but are frequently associated with significant metabolic adverse effects, particularly weight gain and obesity. These complications can impair treatment adherence and substantially increase the risk of cardiovascular and metabolic comorbidities. Accumulating evidence indicates that antipsychotic-induced metabolic dysregulation arises from complex interactions between central neurotransmitter systems and neuroendocrine regulators of appetite and energy balance. Among these, the orexigenic peptide ghrelin and its receptor, growth hormone secretagogue receptor 1a(GHSR1a), play a key role in linking peripheral metabolic signals with central reward pathways that govern feeding behavior. Ghrelin signaling also functionally interacts with multiple neurotransmitter systems and the hypothalamic-pituitary-adrenal (HPA) axis, all of which are targets of atypical antipsychotics. This narrative review examines the convergence of ghrelin signaling with serotonergic, dopaminergic, histaminergic, and cholinergic pathways involved in appetite regulation. We further consider how sex-dependent differences in ghrelin signaling, antipsychotic pharmacokinetics, and bidirectional interactions with the HPA axis contribute to metabolic vulnerability. In addition, we explore how the pharmacodynamic profiles of second-generation antipsychotics influence these neurochemical and neuroendocrine networks, highlighting shared receptor-level mechanisms that may promote increased food intake and metabolic dysfunction. Integrating insights from neuropharmacology, neuroendocrinology, and psychiatric neuroscience, this review outlines mechanisms underlying antipsychotic-associated obesity and identifies potential targets to mitigate metabolic side effects while preserving therapeutic efficacy.
Exposure to polystyrene microplastics exacerbates hippocampal inflammation and ferroptosis in mice following chronic sleep deprivation.
Gao Y, Zhu X, Wang M … +7 more , Li R, Han W, Deng S, Wei H, Zhu Y, Yu M, Xu Y
Brain Res Bull · 2026 May · PMID 42173449 · Publisher ↗
Chronic sleep deprivation (CSD) is closely associated with impairments in learning and memory, neuroinflammation, and ferroptosis, potentially increasing vulnerability to harmful environmental exposures. Polystyrene micr...
Chronic sleep deprivation (CSD) is closely associated with impairments in learning and memory, neuroinflammation, and ferroptosis, potentially increasing vulnerability to harmful environmental exposures. Polystyrene microplastics (PS-MPs) can induce oxidative stress and inflammation, yet their impact on hippocampal pathology and cognition under CSD remains unclear. Here, we established a mouse model combining oral PS-MPs exposure with CSD and assessed cognition using the novel object recognition (NOR) test, open-field test (OFT), Y-maze, and nest-building. CSD markedly promoted PS-MPs deposition in the hippocampus, and PS-MPs further aggravated CSD-induced cognitive deficits, accompanied by more severe neuronal structural damage and loss. PS-MPs also amplified CSD-induced neuroinflammation, increasing IL-6 and TNF-α, decreasing IL-4 and IL-10, and enhancing microglial activation. In BV2 cells, PS-MPs induced dose-dependent inflammatory responses with SOCS3 downregulation and increased p-STAT3. In addition, PS-MPs further elevated hippocampal ROS, MDA, and Fe²⁺ levels, reduced GSH, and aggravated mitochondrial shrinkage and membrane densification. In BV2 cells, PS-MPs also induced ferroptosis in a dose-dependent manner and suppressed SLC7A11/GPX4 expression. In summary, under CSD conditions, PS-MPs accumulate in the hippocampus and promote microglia-mediated neuroinflammation and ferroptosis through SOCS3/STAT3 and SLC7A11/GPX4 signaling, thereby worsening hippocampal injury and cognitive decline.
Inhibition of C5aR1 alleviates early brain injury after subarachnoid hemorrhage by reducing STAT3 phosphorylation and attenuating neuroinflammation.
Zhang S, Zhao X, Tian Q … +6 more , Liu C, Jiang S, Wang G, Xiang X, Liao J, Li M
Brain Res Bull · 2026 Jul · PMID 42167499 · Publisher ↗
Subarachnoid hemorrhage is a severe type of cerebral hemorrhage, with neuroinflammation being the main driving factor. The C5a-C5aR1 axis can mediate the inflammatory response, but its mechanism of action in SAH remains...
Subarachnoid hemorrhage is a severe type of cerebral hemorrhage, with neuroinflammation being the main driving factor. The C5a-C5aR1 axis can mediate the inflammatory response, but its mechanism of action in SAH remains unclear. We established in vivo and in vitro models of SAH and treated them with the C5aR1 inhibitor PMX53 or the STAT3 inhibitor STAT3-IN-13. We detected C5aR1 expression, levels of inflammatory factors, microglial polarization, and neuronal apoptosis using Western blotting, ELISA, TUNEL, and immunofluorescence. The expression of C5aR1 in the brains of SAH mice (peaking at 24 h) and in the cerebrospinal fluid (CSF) of patients was upregulated, which was associated with poor prognosis. PMX53 can improve neurological function, reduce edema and neuronal apoptosis, and transform microglia from the pro-inflammatory M1 type to the anti-inflammatory M2 type. PMX53 and STAT3-IN-13 inhibit JAK/STAT3-p65 phosphorylation, reduce TNF-α/IL-1β, and increase TGF-β/IL-10. C5a promotes STAT3 phosphorylation through C5aR1, thereby exacerbating neuroinflammation, making C5aR1 a potential therapeutic target.
E-field guided repetitive transcranial magnetic stimulation modulates oscillatory brain activity dynamics in tinnitus.
Schoisswohl S, Langguth B, Neff P … +3 more , Schecklmann M, Kleinjung T, Shabestari PS
Brain Res Bull · 2026 Aug · PMID 42167498 · Publisher ↗
INTRODUCTION: The auditory phantom sound perception tinnitus is accompanied by maladaptive neurophysiological changes. In tinnitus treatment, repetitive transcranial magnetic stimulation (rTMS) is applied to counteract t...
INTRODUCTION: The auditory phantom sound perception tinnitus is accompanied by maladaptive neurophysiological changes. In tinnitus treatment, repetitive transcranial magnetic stimulation (rTMS) is applied to counteract these pathological alterations. Previous work showed that single-session rTMS can induce short-term tinnitus loudness suppression and modulate tinnitus-associated oscillatory brain activity. This study aimed to contribute to this research branch by addressing previous methodological shortcomings, including the absence of neuronavigation and adequate sham control. The objective was to assess tinnitus loudness and ongoing brain activity changes following various brief rTMS protocols, and to characterize modulations related to patient-specific most effective protocols, potentially uncovering electrophysiological markers of tinnitus suppression. METHODS: Three active protocols (1,10,20 Hz; 200 pulses) and one sham protocol (0.1 Hz; 20 pulses) were delivered to the left and right temporo-parietal junction of 22 chronic subjective tinnitus patients using e-field-guided neuronavigation. Resting state EEG was recorded before and after each stimulation, along with tinnitus loudness ratings. Patient-specific protocols eliciting maximal suppression were identified via significant pre-to-post loudness reductions exceeding sham. RESULTS: Right 10 Hz rTMS induced strongest loudness suppressions. Significant and sham-superior EEG modulations were observed after right 10 Hz, right 20 Hz and left 20 Hz. Power increases in the Delta, Theta, Alpha and Gamma frequency bands were mainly observed in frontal and temporal areas but did not correlate with reported tinnitus suppression. In 16 patients it was feasible to identify a protocol inducing significant loudness reduction exceeding sham. Here suppression was associated with increased Alpha activity in the frontal cortex. CONCLUSIONS: Our findings demonstrate that brief rTMS protocols can transiently suppress tinnitus and modulate tinnitus-related oscillatory brain activity dynamics. Frontal Alpha power increases may reflect local enhanced inhibitory processes and reduced tinnitus percept processing, emphasizing frontal Alpha as a potential candidate marker for effective tinnitus suppression.
Astrocyte inhibition impacts metaplasticity in the hippocampal CA area following traumatic brain injury.
Rezagholizadeh A, Tavassoli Z, Saeedi N … +3 more , Janahmadi M, Sayyah M, Hosseinmardi N
Brain Res Bull · 2026 Jul · PMID 42162698 · Publisher ↗
Traumatic Brain Injury (TBI) is an important contributing factor to cognitive impairment, frequently linked to disturbances in synaptic plasticity and metaplasticity. Astrocytes, as essential regulators of synaptic funct...
Traumatic Brain Injury (TBI) is an important contributing factor to cognitive impairment, frequently linked to disturbances in synaptic plasticity and metaplasticity. Astrocytes, as essential regulators of synaptic function, are crucial for sustaining brain circuit activity in both normal and pathological states. Post-TBI, astrocytes reveal reactive alterations that manifest both advantageous and harmful impacts on synaptic plasticity and cognitive performance. This study examines the involvement of astrocytes in traumatic brain injury-induced synaptic dysfunction in the hippocampal CA area, seeking to elucidate processes that connect astrocyte reactivity to synaptic transmission and plasticity which might provide insights into cognitive deficits subsequent to TBI and guide prospective therapy strategies. Following the establishment of a traumatic brain injury model via the controlled cortical impact (CCI) method in male Wistar rats, both short-term and long-term synaptic plasticity were examined through field potential recordings. Our findings indicated that TBI significantly diminished baseline synaptic responses (P < 0.05, two-way ANOVA) and reduced LTP (P < 0.001, unpaired t-test) while enhancing LTD in the hippocampus CA area (P < 0.01, unpaired t-test). Astrocytic inhibition by Fluorocitrate (FC) intensified LTP deficits (P < 0.01, two-way ANOVA) and prevented LTD augmentation (P < 0.01, two-way ANOVA) in TBI rats. In sham animals, FC had no significant effect on baseline synaptic responses or paired-pulse ratios. These findings emphasize the dual function of reactive astrocytes in synaptic plasticity post-TBI, wherein astrocyte malfunction leads to maladaptive plasticity.
Inflammation in treatment-resistant depression: From mechanisms to therapeutics.
Wu S, Gao X, Zhou Y … +7 more , Lin Z, Chen C, Luo J, Liu X, Lin L, Shao H, Liu S
Brain Res Bull · 2026 Jul · PMID 42162697 · Publisher ↗
Depression is a prevalent and debilitating mental disorder, imposing a leading global public health burden. First-line monoamine-based antidepressants are ineffective in a substantial proportion of patients, many of whom...
Depression is a prevalent and debilitating mental disorder, imposing a leading global public health burden. First-line monoamine-based antidepressants are ineffective in a substantial proportion of patients, many of whom develop treatment-resistant depression (TRD). Emerging evidence strongly implicates inflammation in the pathophysiology of TRD, with a heightened inflammatory profile observed in patients who respond poorly to conventional therapies. Consequently, targeting inflammatory pathways represents a promising novel therapeutic strategy for TRD. This review examines the interplay between inflammation and TRD, elucidates the mechanisms by which inflammation contributes to depression, and evaluates current anti-inflammatory interventions and their regulatory mechanisms. A particular focus is placed on the pivotal role of tumor necrosis factor-alpha (TNF-α) in the pathogenesis of TRD and the potential of anti-TNF-α monoclonal antibodies as a targeted treatment. We propose that TNF-α serves not only as a promising therapeutic target but also as a valuable biomarker for TRD treatment. These perspectives may pave the way for precision medicine in TRD and inspire novel therapeutic approaches for depression.
Corrigendum to 'Deletion in exon 5 of the SNCA gene and exposure to rotenone leads to oligomerization of α-synuclein and toxicity to PC12 cells' [Brain Research Bulletin 90 (2013) 127-131].
Ma KL, Song LK, Long WA … +6 more , Yuan YH, Zhang Y, Song XY, Niu F, Han N, Chen NH
Brain Res Bull · 2026 Jul · PMID 42161784 · Publisher ↗
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Corrigendum to "The facial skin reflects as much as it speaks: Associations between skin condition and whole-brain fractional anisotropy" [Brain Res. Bull. 111611].
Kokubun K, Yuan D, Nemoto K … +1 more , Yamakawa Y
Brain Res Bull · 2026 Jul · PMID 42156286 · Publisher ↗
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Sensorimotor network hyperactivity and impaired psychomotor performance associated with cumulative occupational stress in firefighters.
Suh C, Lee H, Jeong H … +5 more , Joo Y, Shim Y, Choi Y, Lyoo IK, Yoon S
Brain Res Bull · 2026 Jul · PMID 42155813 · Publisher ↗
Firefighters face chronic occupational stressors including trauma exposure, sleep disruption, and substantial physical demands that can compromise brain function and cognition. Despite increasing concern regarding stress...
Firefighters face chronic occupational stressors including trauma exposure, sleep disruption, and substantial physical demands that can compromise brain function and cognition. Despite increasing concern regarding stress-related cognitive decline in this population, limited evidence is available on whether occupational stress is associated with alterations in resting-state networks (RSNs) or whether such neural changes relate to cognitive outcomes. This study investigated occupational stress-related alterations in functional connectivity (FC) across major RSNs and examined their associations with cognitive performance in firefighters. Ninety-eight actively employed firefighters and 98 demographically matched non-firefighter controls underwent resting-state functional magnetic resonance imaging. RSN-specific FC was derived using independent component analysis. Group comparisons identified significantly higher FC within the sensorimotor network (SMN) in firefighters relative to controls (family-wise error-corrected P < 0.05). Within the firefighter group, both longer cumulative duration of emergency duties (β = 0.45, P = 0.013) and higher alcohol use levels (β = 0.37, P = 0.003) were independently associated with increased SMN connectivity. Moreover, SMN hyperconnectivity was significantly correlated with poorer psychomotor performance (β = -0.19, P = 0.023), indicating potential behavioral consequences. These findings provide evidence that chronic occupational stress and maladaptive coping behaviors such as alcohol misuse may contribute to functional reorganization of the SMN in firefighters which may be linked to diminished psychomotor efficiency. The results highlight a potential neurobiological mechanism through which occupational stress influences cognitive functioning and underscore the need for early identification of at-risk individuals and targeted interventions to mitigate cumulative stress burdens in this vulnerable occupational group.
Longitudinal changes of BOLD-CSF coupling and its association with the clinical assessments in subcortical ischemic stroke.
Li Y, Zhou X
Brain Res Bull · 2026 Jul · PMID 42155812 · Publisher ↗
PURPOSE: Stroke is a leading cause of long-term disability globally, with motor deficits being the most prevalent and disabling consequence. However, the neural mechanisms underlying post-stroke motor recovery remain poo...
PURPOSE: Stroke is a leading cause of long-term disability globally, with motor deficits being the most prevalent and disabling consequence. However, the neural mechanisms underlying post-stroke motor recovery remain poorly understood. This longitudinal study aimed to explore dynamic changes in BOLD-CSF coupling in patients with ischemic subcortical stroke receiving antiplatelet plus citicoline therapy, and evaluate its association with motor function. METHOD: Resting-state fMRI was performed on eighteen patients before treatment and one month post-treatment, while twenty healthy controls completed a single scan. Global and motor region-specific (precentral gyrus, supplementary motor area (SMA)) BOLD-CSF coupling coefficients were computed, with motor and neurological functions assessed via Fugl-Meyer Assessment, Neurological Deficit Scale, and Modified Barthel Index. RESULTS: At baseline, stroke patients exhibited significant alterations in global BOLD-CSF coupling, as well as in regional coupling within the precentral gyrus and supplementary motor area (SMA), compared with healthy controls. Following targeted treatment, stroke patients showed significant improvements in these disrupted global and regional BOLD-CSF coupling measures relative to baseline. By contrast, no significant changes in BOLD-CSF coupling were detected in subregions of the inferior frontal gyrus. Notably, regional BOLD-CSF coupling in the precentral gyrus and SMA strongly correlated with clinical scores. CONCLUSION: These findings indicate that antiplatelet plus citicoline therapy promotes BOLD-CSF coupling restoration, and regional BOLD-CSF coupling in the SMA and precentral gyrus may serve as a neuroimaging biomarker for post-stroke motor recovery.
Fearful faces in peripheral vision: The vestigial auriculomotor system as an indicator of affective processing.
Renz L, Vargas RA, Qiu Z … +4 more , Grün T, Corona-Strauss FI, Pegna AJ, Strauss DJ
Brain Res Bull · 2026 Jul · PMID 42144024 · Publisher ↗
The human auriculomotor system responsible for orienting the pinna has been named a "neural fossil" considering its vestigial nature. However, it remains a subject of interest in cognitive research and has been shown to...
The human auriculomotor system responsible for orienting the pinna has been named a "neural fossil" considering its vestigial nature. However, it remains a subject of interest in cognitive research and has been shown to be modulated by attention, motivation, and affection. This study explores audiovisual integration in an emotion recognition paradigm by examining this pinna-orienting system, focusing on peripheral vision. 23 participants were evaluated in an experimental paradigm requiring discrimination between fearful and neutral facial expressions at three eccentricities (22.5°, 45°, and 67.5°) in the peripheral visual field. Post-auricular muscle (PAM) activity was measured in response to an auditory chirp presented at 260 ms after visual stimulation, the analysis considering eccentricity, facial emotion, and recognition accuracy. We adopt a broader perspective on the post-auricular muscle function by examining both the PAM reflex elicited by a sound and PAM's ongoing activity outside the audio stimulus. The recognition rates in the emotion discrimination task exceeded chance level for the 22.5° and 45° eccentricities. Electromyographic spike activity of the post-auricular muscle was measured and revealed reduced myographic spiking activity in the interval between face stimulus presentation and onset of auditory stimuli. Correctly identified fearful faces elicited a significantly higher PAM reflex compared to neutral faces at the most outer eccentricity (67.5°). In regard to previous studies reporting attenuated activity for stimuli of negative valence, specifically angry faces, these findings raise questions about the origin of the modulation. We propose that the PAM reflex may not be exclusively modulated by emotional valence, but be part of a broader threat-avoidance strategy. We further discuss the possibility that reduced spiking activity after visual stimulation is indicative of increased receptivity to subsequent auditory cues. The observations offer a novel perspective on the pinna-orienting system in emotional processing and attentional mechanisms, providing an exploratory account that encourages further investigation of the underlying causes.
From brainstem arousal to cortical prediction: A circuit-based framework for active flavor inference.
Hong YS, Park YS
Brain Res Bull · 2026 Jul · PMID 42142600 · Publisher ↗
Flavor perception exhibits substantial variability across physiological and contextual states, yet how peripheral gustatory signals are transformed into these subjective experiences remains incompletely understood. Tradi...
Flavor perception exhibits substantial variability across physiological and contextual states, yet how peripheral gustatory signals are transformed into these subjective experiences remains incompletely understood. Traditional models of taste processing have largely focused on bottom-up sensory relay from peripheral receptors to cortical regions, and have limited capacity to explain this variability across physiological and contextual conditions. To bridge this gap, this study proposes Active Flavor Inference (AFI) as a conceptual framework that reinterprets gustatory processing in light of predictive coding and interoceptive regulation. AFI conceptualizes flavor perception not as an isolated sensory outcome, but as an active inferential process arising from functional interactions among brainstem arousal circuits, thalamic gating mechanisms, and cortical networks, through which sensory evidence, physiological state, and higher-order predictions are integrated. Drawing on converging evidence from animal models and human neuroimaging, we propose that ascending sensory signals and descending regulatory influences converge through distributed architectures rather than single linear pathways. Ultimately, AFI provides a structured framework to interpret state-dependent flavor distortions in clinical contexts and generates experimentally testable predictions to guide future high-resolution gustatory research.
Exploring post-stroke depression: Exosomal proteomics reveals underlying mechanisms and potential plasma biomarkers.
Yue X, Zhang M, Li J … +5 more , Zhang H, Zhang C, Li R, Ding N, Zhang P
Brain Res Bull · 2026 Aug · PMID 42142599 · Publisher ↗
BACKGROUND: As the most common psychiatric complication following stroke, post-stroke depression (PSD) lacks effective biomarkers for diagnosis. This study aims to identify potential biomarkers for PSD through proteomics...
BACKGROUND: As the most common psychiatric complication following stroke, post-stroke depression (PSD) lacks effective biomarkers for diagnosis. This study aims to identify potential biomarkers for PSD through proteomics analysis of plasma exosomes. METHODS: Patients with acute ischemic stroke were grouped according to the Hamilton Depression Rating Scale (HAMD). Exosomes were isolated and purified from plasma samples using size exclusion filtration combined with ultracentrifugation. Differentially expressed proteins (DEPs) were screened and subjected to functional analysis and identification using direct data-independent acquisition (direct-DIA) proteomics and bioinformatics approaches. RESULT: A total of 111 significantly differentially expressed proteins were identified between the two groups, including 44 upregulated and 67 downregulated. GO and KEGG enrichment analyses revealed that the upregulated proteins were significantly enriched in the complement and coagulation cascades. Protein-protein interaction network analysis further identified PLG, HRG, and CPB2 as core network nodes. ROC curve analysis demonstrated favorable predictive efficacy for the combined detection of these three proteins, and their expression levels were positively correlated with HAM-D scores. These findings were validated by ELISA in an independent cohort. CONCLUSION: These results suggest that the complement and coagulation pathways may be involved in the pathophysiological process of post-stroke depression (PSD), in which key proteins such as PLG, HRG, and CPB2 are likely to play important roles.
Association between choroid plexus enlargement and impaired glymphatic function in relapsing-remitting multiple sclerosis.
Kong L, Yan Z, Zhu Q … +3 more , Ding S, Wang X, Li Y
Brain Res Bull · 2026 Jul · PMID 42142598 · Publisher ↗
BACKGROUND AND OBJECTIVES: Although the glymphatic system and choroid plexus (CP) have been studied in MS, their longitudinal evolution remains poorly understood. Therefore, we aim to characterize glymphatic system funct...
BACKGROUND AND OBJECTIVES: Although the glymphatic system and choroid plexus (CP) have been studied in MS, their longitudinal evolution remains poorly understood. Therefore, we aim to characterize glymphatic system function and CP alterations and their longitudinal evolution in relapsing-remitting multiple sclerosis (RRMS), and to examine the relationship with other clinical variables. METHODS: Ninety-two patients with RRMS and forty healthy controls (HCs) were recruited. The diffusion tensor imaging analysis along the perivascular space (DTI-ALPS) index and the normalized volume of the choroid plexus (CPV) were compared between the two groups in baseline and follow up. Furthermore, their correlations with white matter lesion (WML) and cortical lesion volume were investigated in the RRMS group. RESULTS: RRMS patients exhibited a significantly lower ALPS index (p = 0.001) and a larger CPV (p < 0.001) compared to HCs. A lower ALPS index was associated with larger CPV (p = 0.011), greater WML volume (p < 0.001) and cortical lesion volume (p = 0.004), and longer disease duration (p = 0.022). Furthermore, larger CPV was correlated with greater cortical lesion volume (p = 0.037). In the follow-up group, the CPV slightly increased (p = 0.02), while the ALPS index showed no significant change. CONCLUSION: Impaired glymphatic system function and enlarged CP volume may contribute to the pathological mechanisms underlying MS. Moreover, CP enlargement may persist throughout the course of MS. DTI-ALPS index and CP volume are potential imaging biomarkers, and the CP may be a promising therapeutic target in MS.
DEL-1 relieves bone cancer pain by targeting IL-17-triggered ferroptosis and astrocyte activation in the spinal cord.
Pang J, Wang X, Tian H … +4 more , Wang N, Xia J, Wang J, Gao W
Brain Res Bull · 2026 Jul · PMID 42140592 · Publisher ↗
OBJECTIVE: The core cytokine IL-17 plays a role in initiating local inflammation and stimulating the release of pro-inflammatory factors. The endogenous immune balance regulator developmental endothelial locus-1 (DEL-1)...
OBJECTIVE: The core cytokine IL-17 plays a role in initiating local inflammation and stimulating the release of pro-inflammatory factors. The endogenous immune balance regulator developmental endothelial locus-1 (DEL-1) helps maintain immune homeostasis and modulates nociceptive signaling pathways. Currently, the roles and regulatory mechanisms of IL-17 and DEL-1 in bone cancer pain remain poorly understood. This study aims to investigate the effects of IL-17 and DEL-1 in alleviating bone cancer pain and to explore the specific signaling pathways involved in their regulation. METHODS: The relevant data sets of patients with bone cancer pain and animal models were obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases. Differentially Expressed Genes (DEGs) analysis, functional enrichment analysis and immune cell infiltration analysis were used to evaluate the activation of IL-17 signaling pathway in bone cancer pain. The regulatory effect of DEL-1 on IL-17 and its mechanism of relieving pain were further verified by behavioral tests, virus vector-mediated DEL-1 overexpression, and immunofluorescence staining in the bone cancer pain mouse model. RESULTS: The DEGs results showed that IL-17 was significantly activated in the bone cancer pain group, accompanied by the infiltration of immune cells. In animal experiments, the expression of IL-17 was significantly up-regulated in the spinal cord of bone cancer pain mice, while the expression of DEL-1 was down-regulated. After overexpressing DEL-1, the pain behavior of bone cancer pain mice was significantly relieved, and the expression of IL-17 and the activation of astrocytes were reduced. In addition, DEL-1 overexpression could effectively inhibit the characteristics of ferroptosis in the spinal cord, including ROS accumulation, lipid peroxidation, and elevated iron ion levels. CONCLUSION: For the first time, it was revealed that DEL-1 alleviated bone cancer pain by inhibiting IL-17-induced ferroptosis of astrocytes. This finding provides a new molecular target for the treatment of bone cancer pain, especially the intervention of DEL-1 and ferroptosis pathway may become a new therapeutic strategy.
Gut microbiome modulation of opioid reinforcement in preclinical models: Microbial regulation of reward and motivation.
Aburahma A, Canfield JR, Sprague JE … +1 more , Fernandez AM
Brain Res Bull · 2026 Jul · PMID 42134481 · Publisher ↗
Emerging evidence indicates that the gut microbiome modulates opioid-related behaviors through bidirectional communication with mesolimbic reward circuitry. Preclinical studies show that antibiotic-induced microbiome dep...
Emerging evidence indicates that the gut microbiome modulates opioid-related behaviors through bidirectional communication with mesolimbic reward circuitry. Preclinical studies show that antibiotic-induced microbiome depletion, germ-free conditions, and developmental microbial disruption alter opioid reward and reinforcement in animal models. Rather than uniformly increasing or decreasing opioid responsivity, microbiome disruption produces paradigm-specific and stage-dependent effects across distinct components of reinforcement learning. Reduced microbial diversity is associated with decreased production of short-chain fatty acids (SCFAs), altered gut barrier integrity, and enhanced peripheral immune signaling. These changes converge on the ventral tegmental area (VTA) and nucleus accumbens (NAc), modifying dopaminergic transmission and transcriptional plasticity within reward-related circuits. Notably, microbiome depletion reduces morphine conditioned place preference, whereas, in separate paradigms, it increases fentanyl self-administration and motivational responding under progressive ratio schedules, revealing a dissociation between hedonic reward and reinforcement processes. SCFA supplementation can partially rescue reward-related phenotypes, supporting a mechanistic role for microbial metabolites. Across reinforcement paradigms, microbiome status emerges as a dynamic regulator of opioid reinforcement rather than a simple modulator of reward magnitude. Importantly, antibiotic exposure, which is common during infectious disease treatment of individuals with opioid use disorder (OUD), may represent a clinically relevant and underappreciated modifier of reinforcement sensitivity and relapse risk. This review uniquely integrates microbiome disruption, stress sensitivity, negative affect, and neuroimmune priming during protracted abstinence to highlight antibiotic exposure as an overlooked but actionable factor in OUD recovery.
Tetramethylpyrazine improving cerebral microcirculation in Alzheimer's Disease mice.
Wu Q, Cui X, Liu X … +4 more , Yuan X, Wang P, Li H, Xiu R
Brain Res Bull · 2026 Jul · PMID 42134480 · Publisher ↗
Cerebrovascular dysfunction plays a crucial role in the development and progression of Alzheimer's Disease (AD). Tetramethylpyrazine, a bioactive alkaloid monomer derived from Chinese herbal medicine Chuanxiong (Ligustic...
Cerebrovascular dysfunction plays a crucial role in the development and progression of Alzheimer's Disease (AD). Tetramethylpyrazine, a bioactive alkaloid monomer derived from Chinese herbal medicine Chuanxiong (Ligusticum chuanxiong), has been demonstrated to improve tissue microcirculation. However, direct in vivo monitoring of cerebral microcirculation is still challenging due to the presence and thickness of the skull. In this study, we constructed a visualized mouse cranial window and utilized photoacoustic microscopy, laser speckle imaging, and Laser Doppler flowmetry to investigate the effect of Tetramethylpyrazine on cortical microvascular function in normal mice, AD mice, and Tetramethylpyrazine-treated AD mice. Our results revealed impaired cerebral microvascular perfusion in AD mice, including significant reductions in blood flow velocity, oxygen saturation, and metabolic rate of oxygen. Tetramethylpyrazine treatment improved cortical microvascular function in AD mice, with endothelium-derived microvascular signals playing a key role in microvascular rhythmic motion. These findings suggest that Tetramethylpyrazine has the ability to enhance cortical microcirculation in AD mice through multiple mechanisms, particularly through endothelial improvement. Tetramethylpyrazine may serve as a potential candidate drug for AD treatment, and photoacoustic microscopy holds promise in the clinical observation of cortical microcirculation in AD.
Overexpressing GPX4 attenuates cognitive decline in chronic cerebral hypoperfusion via suppression of ferroptosis-driven neuroinflammation and white matter injury.
Liu Z, Huang H, Duan Q … +9 more , Du C, Li Y, Xing Y, He P, Ma G, Zhang Y, Nie K, Gao Y, Wang L
Brain Res Bull · 2026 Jul · PMID 42134479 · Publisher ↗
Chronic cerebral hypoperfusion (CCH), a core pathological mechanism of vascular cognitive impairment, induces cognitive deficits closely associated with ferroptosis; however, previous studies have not focused on hippocam...
Chronic cerebral hypoperfusion (CCH), a core pathological mechanism of vascular cognitive impairment, induces cognitive deficits closely associated with ferroptosis; however, previous studies have not focused on hippocampus-specific microglial damage. In this study, we systematically investigated the mechanism of Gpx4-regulated ferroptosis on cognitive function, neuroinflammation, and white matter damage by constructing a mouse model of CCH with microglia-specific overexpression of glutathione peroxidase 4 (Gpx4) and by establishing a model of microglial oxygen-glucose deprivation (OGD) in vitro. We found that Gpx4 overexpression in CCH mice significantly attenuated hippocampal ferroptosis, preserved the integrity of white matter fiber bundles, and inhibited the expression of inflammatory factors IL-1β, IL-6, TNF-α, CCL3, and CCL2 (with the most significant decrease in CCL2). In vitro, we demonstrated that intervention of OGD microglia with ferrostatin-1 (Fer-1), a ferroptosis inhibitor, or Gpx4 overexpression could reduce microglial death, intracellular iron ion aggregation, and lipid peroxidation. The present study reveals that selective modulation of microglial Gpx4 in the hippocampus mitigates CCH-induced cognitive dysfunction through a cause-effect axis: ferroptosis suppression functions as the primary trigger that attenuates neuroinflammation, thereby conferring downstream protection on white matter microstructure. These findings support the pharmacological activation of Gpx4 expression to improve vascular cognitive impairment.
Mechanistic insights into cortical network entrainment by tACS and tDCS: A computational modeling approach.
Agnihotri SK, Cai J
Brain Res Bull · 2026 Jul · PMID 42128142 · Publisher ↗
Non-invasive brain stimulation techniques such as transcranial alternating current stimulation (tACS) and transcranial direct current stimulation (tDCS) are increasingly explored for modulating large-scale brain oscillat...
Non-invasive brain stimulation techniques such as transcranial alternating current stimulation (tACS) and transcranial direct current stimulation (tDCS) are increasingly explored for modulating large-scale brain oscillations associated with cognition, sleep, and neuropsychiatric disorders. However, the network-level mechanisms underlying their differential effects on synchronization and excitatory-inhibitory (E/I) dynamics remain poorly understood. This study investigates how tDCS, tACS, and algorithmically guided tACS (ALGO-tACS) influence phase synchronization, intrinsic frequency modulation, phase-amplitude coupling (PAC), and E/I balance in a large-scale cortical network model. A biologically plausible network of 1000 Izhikevich neurons (800 excitatory, 200 inhibitory) was simulated to generate intrinsic delta (3 Hz) oscillations. Stimulation protocols included continuous depolarizing and hyperpolarizing tACS, tDCS, and adaptive ALGO-tACS, matched to intrinsic network phase and frequency. Depolarizing tACS enhanced intrinsic delta-band power (∼3-4 Hz) and elevated PLV (∼0.99), indicating effective phase entrainment. In contrast, hyperpolarizing tACS disrupted synchrony and reduced oscillatory power. tDCS enhanced PAC (MI: 0.0180), indicating stronger delta-gamma coupling, but reduced PLV and overall coherence. ALGO-tACS combined near-perfect PLV (∼0.99), strong delta coherence, and the highest PAC (MI: 0.0183), reflecting superior adaptive modulation of network dynamics. Cross-coherence analysis revealed that tACS and ALGO-tACS preserved low-frequency coherence across excitatory-inhibitory populations, while tDCS disrupted higher-frequency synchrony. These findings demonstrate that phase- and frequency-matched stimulation, especially ALGO-tACS, optimizes network synchronization and cross-frequency coupling, preserving E/I balance. This mechanistic framework supports the development of personalized, closed-loop neuromodulation strategies targeting sleep, cognition, and neuropsychiatric disorders.
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