Mol Brain [JOURNAL]
Sun
200 papers
Systemic semaglutide provides a mild vasoprotective and antineuroinflammatory effect in a rat model of ocular hypertensive glaucoma.
Mouhammad ZA, Rombaut A, Bermúdez MYG … +4 more , Vohra R, Tribble JR, Williams PA, Kolko M
Mol Brain · 2025 Jul · PMID 40597179 · Full text
Glaucoma is a neurodegenerative disease affecting retinal ganglion cells (RGCs), with a multifactorial genesis that includes inflammation and vascular dysfunction. Emerging evidence suggests that glucagon-like peptide 1...
Glaucoma is a neurodegenerative disease affecting retinal ganglion cells (RGCs), with a multifactorial genesis that includes inflammation and vascular dysfunction. Emerging evidence suggests that glucagon-like peptide 1 receptor agonist (GLP-1RAs) may serve as promising neuroprotective agents in glaucoma. In this study, we investigated the neuroprotective potential of the GLP-1RA semaglutide (SEM) in a rat model of ocular hypertension (OHT) induced by paramagnetic bead injections in Brown Norwegian rats. Rats were divided into four cohorts, two normotensive (NT) cohorts, and two OHT cohorts, treated with either SEM or saline (HBSS), which served as control. Systemic SEM or HBSS administration was initiated simultaneously with OHT induction. We observed that SEM administration seemed to delay the increase in intraocular pressure (IOP) associated with OHT. Although SEM administration did not improve RGC survival, it significantly improved astrocytic fractal dimension value and lacunarity. In conclusion, our findings suggest that GLP-1RAs may exert neuroprotective effects by delaying IOP elevation and preventing OHT-induced reactive astrocyte and vascular remodeling. These findings highlight the potential of GLP-1RAs for retinal neuroprotection, but further studies are needed to elucidate their applicability in glaucoma.
Distinct composition of different types of Abeta plaques in the pathogenesis of Alzheimer's disease and the role of neutrophil-derived myeloperoxidase.
Sun J, Shao X, Wang X … +6 more , Yin XS, Qiu W, Qian X, Liu F, Chen Y, Ma C
Mol Brain · 2025 Jun · PMID 40545530 · Full text
Alzheimer's disease (AD) is an age-related neurodegenerative disorder. Different types of Aβ plaques are likely to play distinct roles in the brains of patients with AD. In this study, through the combination of patholog...
Alzheimer's disease (AD) is an age-related neurodegenerative disorder. Different types of Aβ plaques are likely to play distinct roles in the brains of patients with AD. In this study, through the combination of pathological techniques and analysis of the human brain database, we discovered that focal Aβ plaques (FAPs), rather than diffuse Aβ plaques (DAPs), are significantly correlated with AD-related neuropathological changes and cognitive impairment. By using laser capture microdissection in conjunction with microproteomics, the protein components of different Aβ plaques were characterized. Bioinformatic analysis indicated that FAP-enriched proteins are associated mainly with immune-related pathways, such as neutrophil extracellular trap formation. We further confirmed that myeloperoxidase (MPO) is significantly upregulated in the AD brain and colocalizes with FAPs but not with DAPs. Immunohistochemical staining demonstrated that neutrophils expressing MPO accumulated in the capillary lumen and brain parenchyma. The number of neutrophils significantly increases in the cortex and hippocampus of AD donors. Our study revealed a potential role for neutrophil-derived MPO in FAPs, providing insights into the pathogenesis mechanisms and potential therapeutic targets of AD.
Effects of vincristine on the properties of low threshold mechanoreceptors and high threshold mechanoreceptors in the hindpaw glabrous skin of mice.
Yamada A, Yamada AI, Ling J … +1 more , Gu JG
Mol Brain · 2025 Jun · PMID 40528215 · Full text
Vincristine is an important chemotherapy drug to treat various types of cancer, but it induces peripheral neuropathy, leading to numbness and mechanical allodynia in the hands and feet of patients. The peripheral neuropa...
Vincristine is an important chemotherapy drug to treat various types of cancer, but it induces peripheral neuropathy, leading to numbness and mechanical allodynia in the hands and feet of patients. The peripheral neuropathy is a dose-limiting toxicity of vincristine chemotherapy. How vincristine treatment causes numbness and mechanical allodynia remains incompletely understood. In the present study, we utilized Nav1.8-ChR2 transgenic mice in which Nav1.8-ChR2-positive and Nav1.8-ChR2-negative mechanoreceptors could be characterized using the opto-electrophysiological method. Nav1.8-ChR2-negative Aβ- and Aδ-fiber mechanoreceptors are primarily low-threshold mechanoreceptors (LTMRs). On the other hand, Nav1.8-ChR2-positive Aβ- and Aδ-fiber mechanoreceptors are mainly high-threshold mechanoreceptors (HTMRs). We have shown that the mechanical threshold of Nav1.8-ChR2-negative Aβ-fiber mechanoreceptors, but not Nav1.8-ChR2-negative Aδ-fiber mechanoreceptors, were increased significantly in the animals treated with vincristine. In contrast, the mechanical threshold of Nav1.8-ChR2-positive Aβ-fiber mechanoreceptors were significantly reduced following vincristine treatment. Vincristine treatment did not significantly affect the mechanical sensitivity of Nav1.8-ChR2-positive Aδ- and C-fiber mechanoreceptors. Vincristine treatment also did not affect the opto-sensitivity of Nav1.8-ChR2-positive Aβ-, Aδ-, and C-fiber mechanoreceptors. Our findings suggest that mechanical sensitivity is decreased in Aβ-fiber LTMRs and increased in Aβ-HTMRs following vincristine treatment, providing insights into vincristine-induced numbness and mechanical allodynia.
Chronic voluntary exercise induces plasticity of noradrenaline-activated dopamine D-like receptor signaling.
Kobayashi K
Mol Brain · 2025 Jun · PMID 40524260 · Full text
Physical exercise has lasting positive influence on mental health. However, its cellular substrate remains to be elucidated. Recently, dopamine D-like receptor activation induced by noradrenaline has been suggested to un...
Physical exercise has lasting positive influence on mental health. However, its cellular substrate remains to be elucidated. Recently, dopamine D-like receptor activation induced by noradrenaline has been suggested to underlie exercise-dependent augmentation of antidepressant effects. The present study demonstrates that exercise induces a long-term enhancement of this atypical catecholaminergic signaling. Noradrenaline potentiates hippocampal mossy fiber synaptic transmission by activating D-like receptors in mice. Voluntary exercise by wheel running enhanced this noradrenaline-D-like receptor signaling within 5 days. The enhancement of the noradrenaline-D-like receptor signaling did not require the integrity of noradrenergic fibers and was maintained for more than 2 weeks after cessation of wheel running. Notably, the effect of exercise was more robustly seen in D-like receptor signaling activated by noradrenaline as compared with dopamine, indicating particular responsiveness of the noradrenaline-activated D-like receptor signaling to exercise. These results suggest that exercise could exert lasting influence on brain functioning via plasticity of the hippocampal noradrenaline-D-like receptor signaling.
Recent developments in peptide vaccines against Glioblastoma, a review and update.
Salahlou R, Farajnia S, Alizadeh E … +1 more , Dastmalchi S
Mol Brain · 2025 Jun · PMID 40514725 · Full text
Glioblastoma multiforme (GBM) is the most prevalent invasive CNS tumor, with a high incidence rate and a high likelihood of recurrence in most patients. Despite available treatments, recurrent glioblastoma (rGBM) exhibit...
Glioblastoma multiforme (GBM) is the most prevalent invasive CNS tumor, with a high incidence rate and a high likelihood of recurrence in most patients. Despite available treatments, recurrent glioblastoma (rGBM) exhibits growing resistance to chemotherapy and radiotherapy, which necessitates the development of newer methods of treatment. Peptide vaccines, a type of cancer immunotherapy, have recently attracted attention as a potentially practical therapeutic approach because they target tumor-associated or tumor-specific antigens to generate an effective immune response against cancer cells. These vaccines have been included in several clinical trials, demonstrating their safety and effectiveness by eliciting protective immune responses. However, peptide vaccines for glioblastoma face challenges due to the complex nature of intracranial brain tumors that require innovative approaches and in-depth research to increase their efficacy. The main topics covered in this article include immunological inhibitors and immune characteristics of the CNS and GBM, the basis of immunity, and the significant results of clinical trials of peptide vaccine therapy for GBM. Additionally, it examines the potential causes of the low effectiveness of these vaccines and recommends future research to address the specific challenges associated with immunotherapy in GBM. The evaluation of preliminary phase studies and phase III clinical trials will provide insights into potential immunological responses, biosecurity precautions, and clinical outcomes, guiding future vaccination initiatives to promote higher effectiveness.
ATP stimulates appetite by enhancing the expression of hypothalamic orexigenic neuropeptides.
Kim N, Kim EK
Mol Brain · 2025 Jun · PMID 40495207 · Full text
Hypothalamic neuropeptides play a pivotal role in regulating appetite and energy homeostasis. Extracellular ATP, a key signaling molecule in the hypothalamus, is associated with neuronal activity and metabolic processes....
Hypothalamic neuropeptides play a pivotal role in regulating appetite and energy homeostasis. Extracellular ATP, a key signaling molecule in the hypothalamus, is associated with neuronal activity and metabolic processes. However, its role in appetite control remains unclear. This study explored how sustained extracellular ATP regulates the expression of hypothalamic orexigenic neuropeptides Agrp and Npy. The administration of ATP alone reduced food intake, body weight, and orexigenic neuropeptide expression in mice. Conversely, inhibition of ATP conversion into AMP using the ectonucleoside triphosphate diphosphohydrolase inhibitor ARL67156 caused a transient increase in these parameters. Prolonged extracellular ATP was shown to upregulate Agrp and Npy expression via purinergic P2X4 receptor (P2X4R) activation in AGRP/NPY-expressing cells. Activation of P2X4R induced CaMKII phosphorylation, which subsequently led to CREB phosphorylation and upregulation of orexigenic neuropeptides. Our findings reveal a mechanism whereby extracellular ATP accumulation promotes appetite through P2X4R-CaMKII-CREB signaling, shedding light on how extracellular ATP impacts hypothalamic appetite control.
Effects of intermittent theta burst stimulation on the inflammatory response and cerebral blood flow in promoting neurovascular repair after ischemic stroke.
Zhang J, Li S, Huang D … +13 more , Fu J, Chen S, Ren N, Yang P, Song D, Bai X, Xie H, Liu G, Yu K, Ng SSM, Wu J, Xiao X, Wu Y
Mol Brain · 2025 Jun · PMID 40490760 · Full text
Secondary injuries from ischemia‒reperfusion in stroke, such as edema and hemorrhagic transformation, can significantly impact brain function. This study investigated the effects of intermittent theta burst stimulation (...
Secondary injuries from ischemia‒reperfusion in stroke, such as edema and hemorrhagic transformation, can significantly impact brain function. This study investigated the effects of intermittent theta burst stimulation (iTBS) on neurological function and cerebral blood flow in a mouse model of ischemia‒reperfusion injury. Laser speckle flowmetry was used to assess changes in cortical blood flow before and after ischemia‒reperfusion. Behavioral assessments were conducted to evaluate motor function recovery. The impact of iTBS on neuronal damage and apoptosis in the peri-infarct area was evaluated via Nissl staining and a TUNEL assay. RNA transcriptome sequencing and immunofluorescence staining were performed to investigate the effects of iTBS on microglial and astrocyte activation and the associated inflammatory response. Our findings demonstrated that iTBS significantly mitigated abnormal perfusion in the infarcted hemisphere, reduced neuronal damage and apoptosis in the peri-infarct area, and enhanced motor function in ischemic mice. Furthermore, iTBS promoted the polarization of microglia and astrocytes toward the anti-inflammatory M2 and A2 phenotypes. Therefore, iTBS provides neurovascular protection by modulating microglial and astrocyte activation and regulating the inflammatory response in the peri-infarct area, thereby improving abnormal cerebral blood flow in both the acute and subacute phases after ischemic brain injury.
Sonication dissociates the synaptic cleft and allows purification of postsynaptic densities with associated postsynaptic membrane.
Dosemeci A, Tao-Cheng JH
Mol Brain · 2025 May · PMID 40448157 · Full text
In the synaptic junction, pre-and post compartments are anchored to each other through trans-synaptic bridges spanning the synaptic cleft. Here we demonstrate that mild mechanical disturbance through sonication dissociat...
In the synaptic junction, pre-and post compartments are anchored to each other through trans-synaptic bridges spanning the synaptic cleft. Here we demonstrate that mild mechanical disturbance through sonication dissociates the synaptic cleft, and releases PSDs adjoined to the postsynaptic membrane, but devoid of presynaptic elements. It is the first time, to our knowledge, that dissection of the synaptic cleft has been achieved without the use of chemical/enzymatic treatments. This observation suggests that some of the protein-protein interactions involved in the anchoring of pre- and postsynaptic compartments are relatively weak non-covalent associations. We describe a method for the further fractionation of PSDs with the associated postsynaptic membrane. This PSD preparation provides a valuable tool for studies of postsynaptic membrane components, such as glutamatergic receptors, in an environment closer to their native state.
Targeting CD74 in microglia to modulate experimental cerebral ischemia and reperfusion injury: insights from Single-Cell and bulk transcriptomics.
Cao C, Liu T, Peng L … +6 more , Li L, Xu Z, Li X, Chen G, Li H, Bai L
Mol Brain · 2025 May · PMID 40400029 · Full text
Ischemic stroke remains a leading cause of mortality and long-term disability, with reperfusion injury contributing significantly to poor clinical outcomes. Microglia, the primary immune cells of the central nervous syst...
Ischemic stroke remains a leading cause of mortality and long-term disability, with reperfusion injury contributing significantly to poor clinical outcomes. Microglia, the primary immune cells of the central nervous system, play a dual role in ischemic stroke by both exacerbating injury through neuroinflammation and supporting recovery through neuroprotection. This study aimed to explore the role of CD74, a gene upregulated in microglia following ischemia-reperfusion injury. Using single-cell RNA sequencing and bulk RNA sequencing, we identified CD74 as a potential target involved in microglial-mediated neuroinflammation. We observed a significant increase in CD74 expression in microglia following middle cerebral artery occlusion/reperfusion (MCAO/R), which correlated with pro-inflammatory cytokine production and neuroinflammation. Targeted knockdown of CD74 in microglia using CX3CR1Cre/ERT2 mice led to a reduction in infarct volume, inflammatory cytokine levels, and long-term neurological deficits. Behavioral tests showed improved motor coordination, sensory function, and exploratory behavior in CD74 knockdown mice. These results suggest that CD74 is a critical mediator of microglia-driven neuroinflammation, and targeting CD74 may represent a promising therapeutic strategy for reducing ischemic brain injury and promoting recovery after stroke.
DYRK1A modulates fear memory formation via epigenetic modification.
Kang DS, Koo JW
Mol Brain · 2025 May · PMID 40390093 · Full text
Fear memory formation is crucial for survival, with the hippocampus playing a central role. This study investigates the behavioral and molecular aspects of fear memory formation, focusing on Dual-specificity tyrosine pho...
Fear memory formation is crucial for survival, with the hippocampus playing a central role. This study investigates the behavioral and molecular aspects of fear memory formation, focusing on Dual-specificity tyrosine phosphorylation-regulated kinase 1 A (DYRK1A), a protein known to be critical for cognitive functions. Our results demonstrate that DYRK1A expression in hippocampal CA1 pyramidal neurons is downregulated after contextual fear conditioning (CFC). We also observed a decrease in DYRK1A binding to the Maoa promoter, suggesting its involvement in transcriptional regulation during fear memory formation. In subsequent experiments, we modulated DYRK1A expression using viral vectors. DYRK1A overexpression reduced freezing behavior, while knockdown enhanced it. At the molecular level, DYRK1A overexpression resulted in elevated H3K4me3 levels, while knockdown decreased it. These findings indicate that DYRK1A regulates fear memory formation via epigenetic modifications, altering H3K4me3 levels and influencing Maoa transcription in the hippocampus. This research highlights the nuclear role of DYRK1A and suggests its potential as a therapeutic target for neuropsychiatric disorders related to fear and memory.
Gastrin-releasing peptide is essential for generalization of auditory conditioned fear under stress.
Wu Y, Ni X, Mori H … +1 more , Inoue R
Mol Brain · 2025 May · PMID 40375283 · Full text
Fear generalization, which allows animals to respond adaptively to cues similar to original threatening ones, is generally beneficial for survival. However, an inability to distinguish between threat and safety, leading...
Fear generalization, which allows animals to respond adaptively to cues similar to original threatening ones, is generally beneficial for survival. However, an inability to distinguish between threat and safety, leading to the overgeneralization of fear to non-threatening stimuli, is maladaptive and is implicated in anxiety disorders such as post-traumatic stress disorder (PTSD). The neuropeptide gastrin-releasing peptide (GRP) is known to modulate fear memory under stress, yet its role in response to intense aversive stimuli remains less understood. In this study, we used GRP knockout (Grp) mice to examine the role of GRP in enhancing fear responses to conditioned stimulus (10 kHz tone, CS+) and non-conditioned stimulus (2 kHz tone, CS-) in a model of auditory fear conditioning with high-intensity footshocks following single acute restraint stress (RS). Our findings reveal that GRP is required not only for enhanced response to CS+ but also for generalized fear responses to CS-. Furthermore, we observed that infusion of GRP into the auditory cortex (AC) of Grp mice restores freezing behavior in response to CS- and fear generalization. Additionally, GRP in the AC is essential for the generalization of CS+ responsive neurons to respond to CS- during fear memory retrieval. These results highlight a novel role for GRP in the mechanisms underlying maladaptive fear in highly stressful situations, offering potential new targets for treating anxiety-related disorders.
Phosphorylated septin 3 delocalizes from the spine base and facilitates endoplasmic reticulum extension into spines via myosin-Va.
Ageta-Ishihara N, Mizukami M, Kinoshita I … +5 more , Asami Y, Nishioka T, Bito H, Kaibuchi K, Kinoshita M
Mol Brain · 2025 May · PMID 40375097 · Full text
Cytoskeletal remodeling drives morphological changes. Septin cytoskeleton assembles into hetero-oligomers. We previously demonstrated that late-phase long-term potentiation (L-LTP) induces smooth endoplasmic reticulum (s...
Cytoskeletal remodeling drives morphological changes. Septin cytoskeleton assembles into hetero-oligomers. We previously demonstrated that late-phase long-term potentiation (L-LTP) induces smooth endoplasmic reticulum (sER) extension into dendritic spines via septin 3 (SEPT3), contributing to greater postsynaptic Ca responses and enhanced activation of synaptically induced Ca signaling. Sept3 mice exhibit a reduced number of sER-containing spines and show impaired long-term spatial/object memory despite normal short-term memory. Additionally, SEPT3 binds the motor protein myosin-Va (MYO5A) upon elevated Ca²⁺ concentrations, facilitating sER extension from the dendritic shaft into the spine. MYO5A localizes on the sER membrane, while SEPT3 remains at the spine base, accumulating on sER upon electroconvulsive stimulation (ECS). However, the mechanism underlying SEPT3's delocalization from the spine base and its cooperative role with MYO5A in sER extension remains unclear. In this study, we demonstrate that SEPT3 is phosphorylated in a stimulation-dependent manner. Phosphorylation at Thr211 releases SEPT3 from the spine base, enabling sER extension with constitutively active MYO5A mutant (MYO5A-CCtr). These findings provide molecular insight into the role of SEPT3 phosphorylation in regulating sER dynamics that sustain long-term spine activation.
Synergistic actions of corticosterone and BDNF on rat hippocampal LTP.
Thacker JS, Ralph LT, Koek L … +6 more , Abbasian A, Bettio LB, Smith AE, Georgiou J, Christie BR, Collingridge GL
Mol Brain · 2025 May · PMID 40355868 · Full text
Exercise evokes many physiological changes, including the release of hormones and growth factors that are known to improve cognition via unknown mechanisms. Here, we have compared the ability of two physiologically relev...
Exercise evokes many physiological changes, including the release of hormones and growth factors that are known to improve cognition via unknown mechanisms. Here, we have compared the ability of two physiologically relevant factors, corticosterone (CORT) and brain-derived neurotrophic factor (BDNF), to affect long-term potentiation (LTP) in the hippocampus. Using a compressed theta-burst stimulation (cTBS) protocol, we found that CORT has no effect on LTP, BDNF enhances LTP and combined CORT + BDNF treatment results in significantly greater LTP. We also find that CORT + BDNF, but not either compound alone, results in phosphorylation of protein kinase A (PKA). These findings show that BDNF and CORT act synergistically to enhance LTP at these synapses, potentially via a PKA-dependent mechanism. Such a synergistic action could underlie the positive cognitive effects of exercise.
Chlorpromazine directly inhibits Kv1.3 channels by facilitating the inactivation of channels.
Park SI, Hwang S, Lee Y … +5 more , Lee HY, Kim S, Hong J, Jo SH, Choi SY
Mol Brain · 2025 May · PMID 40340862 · Full text
Kv1.3 channels in microglia are pivotal in regulating neuroinflammation. The antipsychotic chlorpromazine (CPZ) demonstrates anti-inflammatory effects by decreasing Kv1.3 activity in mPFC microglia. However, the precise...
Kv1.3 channels in microglia are pivotal in regulating neuroinflammation. The antipsychotic chlorpromazine (CPZ) demonstrates anti-inflammatory effects by decreasing Kv1.3 activity in mPFC microglia. However, the precise mechanism of CPZ's effect in the mPFC remains unclear, given that CPZ is known to inhibit dopamine receptors and the mPFC contains various cell types with dopamine receptors. In this study, we investigate how CPZ inhibits Kv1.3 channels using human Kv1.3 channel-expressing Xenopus laevis oocytes. CPZ directly inhibits Kv1.3 channel currents in a concentration-dependent manner. The CPZ-mediated Kv1.3 channel inhibition is not voltage-dependent, and CPZ accelerates Kv1.3 channel inactivation without significantly affecting its activation. Our findings suggest that CPZ directly blocks Kv1.3 channels without involving other ion channels or receptors, including dopamine receptors, thereby contributing to the understanding of its neuroinflammation-suppressing mechanism.
GAS reduced inflammatory responses in activated microglia by regulating the Ccr2/Akt/Gsk-3β pathway.
Shi H, Shi J, Wang Z … +7 more , Zuo H, Guo T, Zheng H, Xiao R, Zhang X, Yang S, Li J
Mol Brain · 2025 May · PMID 40329396 · Full text
Hypoxic-ischemic brain damage (HIBD) is a significant cause of neonatal death and neurological dysfunction. Following this injury, activated microglia can lead to a series of inflammatory responses. Gastrodin (GAS), a po...
Hypoxic-ischemic brain damage (HIBD) is a significant cause of neonatal death and neurological dysfunction. Following this injury, activated microglia can lead to a series of inflammatory responses. Gastrodin (GAS), a polyphenol extracted from the Chinese herbal medicine Gastrodia elata Blume, has demonstrated antioxidant and anti-inflammatory effects. This study investigated the neuroprotective impact of GAS in HIBD mice model and in BV2 cells subjected to oxygen-glucose deprivation (OGD) treatment. Expression of various members of the Ccr2/Akt/Gsk-3β, including Ccl2, Ccr2, Akt, p-Akt, Gsk-3β, p-Gsk-3β and inflammatory factors TNF-α and IL-1β in activated microglia was assessed by Western blotting, immunofluorescence, and qRT-PCR in HIBD in postnatal mice, and in OGD-induced BV2 microglia in vitro with or without GAS treatment. The present results showed that GAS effectively reduces the expression of Ccl2 and Ccr2, increases the phosphorylation levels of Akt and Gsk-3β, and decreases the expression of the TNF-α and IL-1β. Additionally, we have shown that inhibition of Ccr2 by RS102895 increased the expression of p-Akt and p-Gsk-3β, and attenuate production of proinflammatory mediators in activated microglia. Of note, the expression of p-Akt, p-Gsk-3β, TNF-α and IL-1β remained unchanged after the combination of gastrodin and RS102895. Taken together, we conclude that GAS can play a protective role in reducing the neuroinflammatory response after HIBD. It is suggested that this is mainly through up-regulating the Akt/Gsk-3β signaling pathway via the Ccr2 receptor in the present experimental paradigm.
Hes5 astrocytes potentiate primary afferent Aδ and C fiber-mediated excitatory synaptic transmission to spinal lamina I neurons.
Kagiyama I, Uchiyama S, Tsuda M
Mol Brain · 2025 Apr · PMID 40289116 · Full text
Astrocytes are critical in regulating synaptic transmission in the central nervous system (CNS). The spinal dorsal horn (SDH) is a crucial region that processes and integrates somatosensory information from the periphery...
Astrocytes are critical in regulating synaptic transmission in the central nervous system (CNS). The spinal dorsal horn (SDH) is a crucial region that processes and integrates somatosensory information from the periphery and transmits it to the brain. Our previous work demonstrated that stimulation of an astrocyte population in the SDH, characterized by the expression of hairy and enhancer of split 5 (Hes5), causes pain hypersensitivity. However, the mechanism by which Hes5 astrocytes modulate synaptic transmission in the SDH remains unclear. In this study, using electrophysiological and cell type-specific functional manipulation approaches, we found that chemogenetic stimulation of Hes5 SDH astrocytes enhanced Aδ and C fiber-mediated excitatory postsynaptic currents in lamina I neurons. A pharmacological blockade of the glycine binding site of N-methyl-D-aspartate (NMDA) receptors prevented the astrocytic enhancement. These findings suggest that Hes5 astrocytes in the SDH enhance synaptic transmission from primary afferent nociceptors to lamina I neurons by potentiating NMDA receptor activity.
The absence of Neuroligin-1 shapes wake/sleep architecture, rhythmic and arrhythmic activities of the electrocorticogram in female mice.
Areal CC, Lemmetti N, Leduc T … +4 more , Bourguignon C, Lina JM, Bélanger-Nelson E, Mongrain V
Mol Brain · 2025 Apr · PMID 40269933 · Full text
Associated to glutamatergic neurotransmission, Neuroligin-1 (NLGN1) is a synaptic adhesion molecule with roles in the regulation of behavioral states and cognitive function. It was shown to shape electrocorticographic (E...
Associated to glutamatergic neurotransmission, Neuroligin-1 (NLGN1) is a synaptic adhesion molecule with roles in the regulation of behavioral states and cognitive function. It was shown to shape electrocorticographic (ECoG) activity during wakefulness and sleep in male mice, including aperiodic activity under baseline conditions. Given that the expression of Neuroligins (Nlgn) differs between sexes, we here aim to characterize the impact of the absence of NLGN1 on the wakefulness and sleep architecture, rhythmic and arrhythmic activity dynamics, and responses to sleep deprivation in female animals. Nlgn1 knockout (KO) female mice and wild-type (WT) female littermates were implanted with ECoG electrodes, and ECoG signals were recorded for 48 hours comprising a 24-hour baseline, followed by a 6-hour sleep deprivation and 18 hours of undisturbed recovery (REC). Time spent in wakefulness, slow wave sleep (SWS) and paradoxical sleep (PS), and their alternation were interrogated, and ECoG activities were quantified using a standard spectral analysis and a multifractal analysis. Nlgn1 KO females spent more time in PS during the light period under baseline in comparison to WT females. This difference was observed along with more PS bouts and a shorter overall PS bout duration, indicative of a fragmented PS. Additionally, Nlgn1 KO females displayed less ECoG power between 8 and 13 Hz during wake, less power between 1.25 and 3.5 Hz during PS, and more between 2.5 and 3.75 Hz during SWS in comparison to WT. Under both baseline and REC, NLGN1 absence in females was significantly associated with a higher value of the most prevalent Hurst exponent (Hm) during SWS, which points to a higher persistence across scales of ECoG aperiodic activity. Indications for alterations in the daily dynamics of the Dispersion of Hurst exponents around Hm were also found during SWS in KO females. The present study highlights differences in wake/sleep architecture, and in periodic (rhythmic) and aperiodic (arrhythmic/multifractal) activities in female mice lacking NLGN1. These findings provide additional support to a role for NLGN1 in shaping the ECoG organization, in particular during sleep, and will help understanding the origin of sleep disturbances in neuropsychiatric diseases.
Heterogeneity in pericyte inflammatory responses across age and species highlight the importance of human cell models.
Stevenson TJ, Lee K, Li S … +3 more , Montgomery JM, Lee KY, Dragunow M
Mol Brain · 2025 Apr · PMID 40251678 · Full text
Pericytes in the central nervous system are essential for maintaining blood-brain barrier function, regulating blood flow, modulating immune responses, and interacting closely with surrounding cells of the neurovascular...
Pericytes in the central nervous system are essential for maintaining blood-brain barrier function, regulating blood flow, modulating immune responses, and interacting closely with surrounding cells of the neurovascular unit to support brain homeostasis. Increasing evidence has highlighted their involvement in age-related neuroinflammation, where their dysfunction may contribute to sustained inflammatory states associated with neurodegenerative disorders. Here, we compared inflammatory responses to lipopolysaccharide (LPS) in primary cerebral pericytes from neonatal and adult mice and adult humans. Our findings indicate that neonatal mouse pericytes display heightened inflammatory activation, with elevated levels of ICAM-1 and several cytokines, compared to adult mouse pericytes reflecting a more reactive phenotype. In contrast, adult mouse pericytes exhibited a significantly reduced cytokine release profile, suggesting lower responsiveness. Notably, while cytokine secretion patterns in adult human pericytes, in part, mirrored those in neonatal mouse pericytes, nitric oxide production, which was observed in mouse pericytes, was absent in the human cells. These results underscore species- and age-dependent variations in cellular behavior, emphasizing the importance of utilizing human brain cell systems when conducting research on neuroinflammation. Understanding these distinctions is vital for designing accurate studies and developing targeted therapies for neuroinflammatory conditions.
Divergent disruptive effects of soluble recombinant tau assemblies on synaptic plasticity in vivo.
Yang Y, Ondrejcak T, Hu NW … +2 more , Klyubin I, Rowan MJ
Mol Brain · 2025 Apr · PMID 40251677 · Full text
Neurofibrillary tangles (NFTs), composed of tau protein fibrils, together with brain inflammation and synaptic loss, are neuropathological hallmarks of several neurodegenerative diseases, including Alzheimer's disease. C...
Neurofibrillary tangles (NFTs), composed of tau protein fibrils, together with brain inflammation and synaptic loss, are neuropathological hallmarks of several neurodegenerative diseases, including Alzheimer's disease. Compared with tau fibrils, more water-soluble assemblies of either recombinant or patient-derived tau have been reported to exert relatively potent rapid synaptotoxic effects, including inhibition of synaptic long-term potentiation (LTP) in the hippocampus. Less is known regarding the action of exogenous tau soluble assemblies on the opposite form of synaptic plasticity, long-term depression (LTD). We compared the synaptic plasticity actions of two relatively standard preparations of soluble recombinant tau assemblies, (i) fibril-derived soluble sonicated tau aggregates (SτAs) and (ii) oligomer-enriched tau (oTau) prepared from monomers. Consistent with previous findings, intracerebroventricular injections of either SτAs or oTau acutely inhibited high-frequency stimulation-induced LTP at CA3-to-CA1 synapses in the anaesthetized rat hippocampus. However, LTP inhibition by oTau, but not SτAs, was prevented by co-injection with the conformational anti-tau monoclonal antibody, TOMA1. Furthermore, in contrast to SτAs, which inhibited LTD, injection of oTau potently facilitated LTD, decreasing the threshold for LTD induction by low-frequency stimulation. To test the role of pro-inflammatory cytokines in mediating the disruptive effects of the two forms of soluble tau on synaptic plasticity we pre-injected etanercept, a decoy receptor for tumor necrosis factor alpha (TNFα). Etanercept reduced the disruption of synaptic plasticity by oTau but not by SτAs. Moreover, injection of exogenous TNFα mimicked the facilitation of LTD by oTau, consistent with a role of this pro-inflammatory cytokine in LTD facilitation.These data provide evidence that preparations of soluble tau containing either monomer- or fibril-derived assemblies disrupt LTP and LTD via different mechanisms. Intriguingly, when oTau and SτAs were applied together, LTD block predominated. Thus, if similar synaptotoxic soluble tau assemblies are present together later during the disease process, as seems likely, inhibition of synaptic weakening processes is predicted to predominate. Equally, reducing TNFα would be expected to be more effective when the monomer-derived soluble tau assemblies are the dominant synaptotoxic species. We conclude that oTau and SτAs provide useful means to explore ways of targeting different synaptotoxic soluble tau species in tauopathies.
Intravenous infusion of mesenchymal stem cells increased axonal signal intensity in the rubrospinal tract in spinal cord injury.
Hirota R, Sasaki M, Teramoto A … +3 more , Yamashita T, Kocsis JD, Honmou O
Mol Brain · 2025 Apr · PMID 40241097 · Full text
Limited spontaneous recovery occurs after spinal cord injury (SCI). However, current knowledge indicates that multiple forms of axon growth in spared axons can lead to circuit reorganization. Intravenous infusion of mese...
Limited spontaneous recovery occurs after spinal cord injury (SCI). However, current knowledge indicates that multiple forms of axon growth in spared axons can lead to circuit reorganization. Intravenous infusion of mesenchymal stem cells (MSCs) provides functional improvements after SCI with an increased axonal network. In this study, we examined how intravenous infusion of MSCs facilitates axonal connections in the rubrospinal tract (RST), one of the significant descending tracts, using AAV neuronal tracing techniques. Our finding demonstrated that infused MSCs significantly enhanced axonal signal intensity in the RST, not only around the injury site but also in the rostral and caudal regions, suggesting that neural circuit reorganization is facilitated.
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