Neurosci. Lett. [JOURNAL]
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200 papers
Mini Review: How circular RNAs participate in neuro-degeneration.
Biswas S, Bagchi A
Neurosci Lett · 2025 Oct · PMID 40789433 · Publisher ↗
Circular RNAs have important implications in the onsets of various neurodegenerative diseases. Their broad functionalities involve miRNA sponging and binding to RBPs. Some circular RNAs have protein-coding potentials thr...
Circular RNAs have important implications in the onsets of various neurodegenerative diseases. Their broad functionalities involve miRNA sponging and binding to RBPs. Some circular RNAs have protein-coding potentials through specialized mechanisms. These products have varied functional implications in neurodegenerative diseases. However, the exact mechanisms of their involvement are not yet fully understood. This review gives an overview of the roles of the circular RNAs and their derived protein products in the onsets of neurodegenerative diseases.
Aβ-damaged neural stem cells migration and differentiation through Wnt3a/β-catenin pathway: Protective effects of 17β-E2.
Yang Y, Zhang L, Zhao Y … +3 more , Chen Z, Wang P, Yang Z
Neurosci Lett · 2025 Oct · PMID 40784614 · Publisher ↗
Alzheimer's disease (AD) is a widespread central nervous system degenerative disease in the elderly population. This study aims to uniquely targets this sex-specific vulnerability by investigating the effects of 17β-E2 o...
Alzheimer's disease (AD) is a widespread central nervous system degenerative disease in the elderly population. This study aims to uniquely targets this sex-specific vulnerability by investigating the effects of 17β-E2 on the differentiation and migration capabilities of Aβ-damaged NSCs and its potential mechanisms-a critical gap for female-focused AD therapies. Primary NSCs isolated from neonatal SD rats were treated with Aβ25-35 (60 μM) to mimic AD pathology, followed by 17β-E2 (100 nM) with or without BX795 (a Wnt3a/β-catenin inhibitor). Results showed that Aβ significantly suppressed Wnt3a, LRP6, and β-catenin mRNA/protein levels while increasing GSK-3β expression. 17β-E2 treatment reversed these effects, enhancing phosphorylated GSK-3β (Ser9) and β-catenin, which were abolished by BX795. Transwell assays demonstrated that 17β-E2 rescued Aβ-damaged migration deficits, accompanied by elevated p-MLC and Cdc42 protein levels. Furthermore, 17β-E2 promoted neuronal differentiation, increasing MAP2 + and βIII-tubulin + cells with enhanced dendritic complexity, whereas BX795 counteracted these benefits. These findings indicate that 17β-E2 mitigates Aβ-damaged NSCs dysfunction by activating the Wnt3a/β-catenin pathway via GSK-3β phosphorylation, highlighting its therapeutic potential for AD by enhancing neurogenesis and NSC mobility.
The dysregulation of high glucose-induced iPSC-neural stem cells differentiation by caspase-1.
Chung HH
Neurosci Lett · 2025 Oct · PMID 40784613 · Publisher ↗
Maternal diabetes (MD) increases the risk for neurodevelopmental disorders and leads to neural tube defects (NTDs) which are severe anomalies of the nervous system. In order to elucidate the etiology and pathological mec...
Maternal diabetes (MD) increases the risk for neurodevelopmental disorders and leads to neural tube defects (NTDs) which are severe anomalies of the nervous system. In order to elucidate the etiology and pathological mechanisms causing NTDs in MD and try to search for new therapeutic strategies as well, the exposure of induced pluripotency stem cell (iPSC)-neural stem cells (NSCs) to high glucose (HG) may be associated with fetal progressive deterioration of neuronal functions in utero ultimately leading to MD-related NTDs. In the present study, although HG (25 mM) had no effect on the viability of undifferentiated iPSC-NSCs compared with the positive control mannitol (25 mM), HG attenuated iPSC-NSCs cell proliferation and induced the presence of decreased βIII-tubulin and neurite network length during 7-day neuronal differentiation, resulting in the inability of nerve-to-nerve connections to communicate effectively. Compared with mannitol, HG actually reduced gene and protein expressions of iPSC-NSCs differentiation marker βIII-tubulin on day 7. Moreover, HG increased protein expressions of caspase-1 during 7-day neuronal differentiation compared with mannitol, indicating the critical role of caspase-1 in HG-mediated neuronal inflammation. Thus, the present study indicated that HG-induced impairment in iPSC-NSCs differentiation was mediated by decreased βIII-tubulin, shorter neurite network length and increased caspase-1 expressions, which provided a direction for the clarification of MD-induced NTDs.
Differential cholinergic modulation of parafascicular thalamic neurons.
Vázquez-Vázquez HA, Ortega A, Parrado Y … +3 more , Laville A, Tapia D, Galarraga E
Neurosci Lett · 2025 Oct · PMID 40784612 · Publisher ↗
The parafascicular (PF) thalamic nucleus participates in functions such as arousal, consciousness, learning, and behavioral flexibility, which are linked to its projections to the striatum and receives strong cholinergic...
The parafascicular (PF) thalamic nucleus participates in functions such as arousal, consciousness, learning, and behavioral flexibility, which are linked to its projections to the striatum and receives strong cholinergic input from the pedunculopontine nucleus. Using electrophysiological recordings, we identified two neuronal populations based on their afterhyperpolarization potential (AHP) characteristics: Brief AHP neurons and Prolonged AHP neurons. Only Prolonged AHP neurons were modulated by cholinergic receptor activation, which reduced AHP amplitude and duration, and increased their firing frequency. These effects were associated with SK-type calcium-activated potassium channels and specifically activated by M1 type muscarinic receptors. Together, these findings indicate clear differential cholinergic modulation in the PF thalamic nucleus, which may be related to its functional roles.
Prevention of memory impairment and hippocampal injury with blarcamesine in an Alzheimer's disease model.
Maurice T
Neurosci Lett · 2025 Oct · PMID 40784611 · Publisher ↗
Alzheimer's disease (AD) is the most common dementia, with rising global prevalence, still incomplete pathogenetic understanding and very limited effective therapies. Recent advances in biomarker identification of Aβ pep...
Alzheimer's disease (AD) is the most common dementia, with rising global prevalence, still incomplete pathogenetic understanding and very limited effective therapies. Recent advances in biomarker identification of Aβ peptides and phospho-tau protein, and in anti-Aβ immunotherapy are suggesting that more early intervention will be more effective. Alternative therapeutic strategies to anti-Aß immunotherapy have received comparably less attention, yet one specific approach toward upstream neuroprotection by improvement of intracellular calcium homeostasis, activation of endogenous neuroprotection and restoration of autophagy through sigma-1 receptor activation recently demonstrated positive clinical data with oral blarcamesine in a phase IIb/III trial in 508 patients with early AD. AD-preventive approaches beyond lifestyle interventions become attractive candidates when meeting criteria of: (i) record of effective early intervention in mild disease, (ii) record of human safety, (iii) ease of administration, (iv) scalability to population level, (v) relative cost-effectiveness considering longer-term preventive use at population level. Here, we assessed blarcamesine's efficacy at preventing memory impairment and brain oxidative injury in the mouse preclinical model induced by intracerebroventricular injection of aggregated Aβ peptide, that permitted a clean preventive approach before administration of the pathology-inducing amyloidogenic Aβ fragment. We observed significant preventions of Aβ-induced memory impairments, for both spatial working and contextual long-term memories, and of Aβ-induced increase in lipid peroxidation in the mouse hippocampi. These new insights, together with blarcamesine's clinical record in early AD render blarcamesine an attractive candidate for AD pharmacological prevention.
Hormonal and histological impacts of valproate in PTZ-kindled male rats: a focus on 5HT1A receptors.
Shojaei M, Nazemi S, Khazaei M … +5 more , Negah SS, Sobhani B, Rezaei M, Khakshour E, Mohammad-Zadeh M
Neurosci Lett · 2025 Oct · PMID 40780638 · Publisher ↗
INTRODUCTION: The occurrence of seizures and the use of valproate (VPA) both have sexual and hormonal side effects and ultimately cause infertility in males and females. Also, since VPA increases serotonin levels, it pla...
INTRODUCTION: The occurrence of seizures and the use of valproate (VPA) both have sexual and hormonal side effects and ultimately cause infertility in males and females. Also, since VPA increases serotonin levels, it plays a role in the development of hormonal disorders in both sexes. Our aim was to investigate the role of 5-HT1A receptors in the impact of VPA on hormonal and cellular changes in pentylenetetrazol (PTZ)-kindled rats. MATERIALS AND METHODS: Fifty male rats were divided into placebo (saline), PTZ + Saline, PTZ + VPA, PTZ + NAD, and PTZ + VPA + NAD groups. Hormone assays and histological examinations were performed at the end of kindling or after the fifteenth injection. FINDINGS: Changes in sex hormones due to epilepsy and VPA use in males decreased testosterone and increased estradiol. Progesterone increased in the kindled group and decreased in kindled rats receiving VPA. Histological changes due to kindling were observed, as were decreases in the number of spermatogonia, primary spermatocytes, Sertoli and Leydig cells, and seminiferous tubules; the diameter of seminiferous tubules was also smaller than in the saline group. CONCLUSION: The obtained results showed that the changes effected by the investigated drugs (VPA and NAD) increased when the receptor antagonist was injected with VPA. Therefore, maybe the activation of the 5-HT1A receptors has a protective effect in terms of the control of serotonin levels. When the 5HT1A receptor is inactive, the side effects caused by valproate become more pronounced.
Modeling Alzheimer's disease in mice: Gonadectomy combined with bilateral hippocampus dentate gyrus injection of Aβ oligomers.
Li Y, Gao Q, Zhuang C … +6 more , Zhou Y, Chang Z, Zhao Y, Zhu S, Liu Y, Zhang B
Neurosci Lett · 2025 Oct · PMID 40774420 · Publisher ↗
BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder that accounts for almost half of all dementia cases globally and is progressively increasing. Etiology includes heredity, genetic factors, aging, and n...
BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disorder that accounts for almost half of all dementia cases globally and is progressively increasing. Etiology includes heredity, genetic factors, aging, and nutrition, but sex hormones also play a key role. Reliable animal models of AD are the basis for gaining insight into the pathophysiological mechanisms of AD and for developing and evaluating novel therapeutic strategies for preclinical AD. NEW METHOD: This study described and evaluated a model mimicking features of late-onset AD by combining gonadectomy with bilateral hippocampal dentate gyrus Aβ injections in mice. RESULTS: As demonstrated by the Morris water maze test, Nissl staining, TUNEL, and EDU labeling, this method produced the mouse model of AD with decreased learning memory capacity accompanied by decreased neuronal function in the hippocampus, increased apoptotic neurons in hippocampus CA1 area and decreased regenerative neurons in hippocampus dentate gyrus area. COMPARISON WITH EXISTING METHODS: Existing AD models often overlook the physiological feature of sex hormone deficiency in late-onset AD and fail to fully account for the neuroprotective effects of sex hormones, which may lead to false-positive results in neuroprotection-related assessments. The model in this study simulates low sex hormone levels through gonadectomy and is combined with bilateral hippocampal dentate gyrus injection of Aβ oligomers, overcoming the limitations of single-factor models and more effectively simulating the pathophysiological characteristics of sex hormone deficiency and Aβ deposition in late-onset AD. CONCLUSIONS: The model effectively simulated the pathophysiological state of late-onset AD. In both sexes, most of these indications of dysfunction were significantly more pronounced in gonadectomized animals compared to gonadally intact controls. SIGNIFICANCE STATEMENT: In this study, a mouse model of late-onset Alzheimer's disease, developed by combining gonadectomy with Aβ injection into the bilateral hippocampal dentate gyrus, accurately simulates the pathophysiological processes of sex hormone deficiency and Aβ deposition in patients, thereby providing a robust platform to explore nervous system structural and functional changes in late-onset AD and evaluate potential preventive drugs. Moreover, this dual-factor model provides novel insights into the synergistic interaction between sex hormone deficiency and Aβ pathology, offering a physiologically relevant platform for studying late-onset AD.
The mechanism of alpha-lipoic acid regulating dopaminergic neuronal damage in Parkinson's disease through the Nrf2/HMOX1 pathway.
Wang J, Hou J, Du M … +3 more , Hou X, Wang Y, Cheng H
Neurosci Lett · 2025 Oct · PMID 40763886 · Publisher ↗
OBJECTIVE: Parkinson's disease (PD) is a neurodegenerative disorder distinguished by the progressive loss of dopaminergic neurons in the substantia nigra (SN). This study explored the mechanism by which alpha-lipoic acid...
OBJECTIVE: Parkinson's disease (PD) is a neurodegenerative disorder distinguished by the progressive loss of dopaminergic neurons in the substantia nigra (SN). This study explored the mechanism by which alpha-lipoic acid (ALA) modulates dopaminergic neuronal damage via the nuclear factor erythroid-2-related factor 2 (Nrf2)/heme oxygenase-1 (HMOX1) pathway. METHODS: A PD mouse model was established using 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), followed by ALA and the Nrf2 inhibitor (ML385) treatment. Motor and cognitive functions were evaluated via behavioral tests. Tyrosine hydroxylase- and dopamine transporter-positive cells in SN, and the lipid peroxidation (LPO; DATBODIPY581/591 C11) level in dopaminergic neurons were quantified by immunohistochemistry and immunofluorescence, respectively. Levels of glutathione, malondialdehyde, Fe, and reactive oxygen species, and ferroptosis-related proteins, nuclear/cytoplasmic Nrf2, and HMOX1 expression were determined by kits and Western blot. RESULTS: MPTP reduced total movement distance, average movement speed, and platform crossings while increasing pole-climbing time, resting time, and escape latency of mice, confirming successful PD model establishment. PD mice exhibited elevated LPO, Fe, and ferroptosis in dopaminergic neurons in SN, indicating dopaminergic neuronal ferroptosis in SN of PD mice. ALA treatment reversed these effects, reducing dopaminergic neuronal ferroptosis in SN and improving motor and cognitive functions of PD mice. Mechanistically, ALA activated the Nrf2/HMOX1 pathway by promoting Nrf2 nuclear translocation. The Nrf2/HMOX1 pathway inactivation promoted dopaminergic neuronal ferroptosis in SN and partially reversed ALA's beneficial effects. CONCLUSION: ALA regulates HMOX1 expression by facilitating Nrf2 nuclear translocation, thereby reducing Fe accumulation, inhibiting dopaminergic neuronal ferroptosis in SN, eventually alleviating motor, memory, and cognitive dysfunctions in PD mice.
Intranasal insulin administration shows limited tau-targeted effects in early-stage APP/PS1 Alzheimer's mice.
Mao YF, Chen L, Liu JY … +3 more , Guo ZY, Lu PL, Chen YX
Neurosci Lett · 2025 Oct · PMID 40759310 · Publisher ↗
Brain insulin signaling deficits contribute to multiple pathologicalfeatures of Alzheimer's disease (AD).Intranasal insulin has demonstrated therapeutic potential, but its underlying mechanisms remain unclear. This study...
Brain insulin signaling deficits contribute to multiple pathologicalfeatures of Alzheimer's disease (AD).Intranasal insulin has demonstrated therapeutic potential, but its underlying mechanisms remain unclear. This study investigated whether intranasal insulinmodulates tau pathology in early-stage APPswe/PS1dE9 (APP/PS1) mice.After six weeks of treatment, no significant changes in total or phosphorylated tau levels were observed. However, there was a trend toward improvement in dysregulated signaling pathways associated with tau kinases. These findings suggest that the protective effect of nasal insulin in early AD may not primarily be against tau-related neurotoxicity.
Intracerebral administration of Wnt7a improves memory performance and increases synaptophysin expression in the 3xTg-AD mouse model.
Colín-Martínez E, Arias C
Neurosci Lett · 2025 Oct · PMID 40754181 · Publisher ↗
Wnt signaling has emerged as an important pathway involved in the expression of some Alzheimeŕs disease hallmarks. In the adult brain, Wnt signaling regulates synaptic structure and function and has a role in synaptogene...
Wnt signaling has emerged as an important pathway involved in the expression of some Alzheimeŕs disease hallmarks. In the adult brain, Wnt signaling regulates synaptic structure and function and has a role in synaptogenesis, synaptic transmission and memory formation; therefore, its activation could have therapeutic implications in this neurodegenerative disease. In this study we aimed to investigate the effects of chronic infusion of recombinant Wnt7a protein on improving memory performance and the expression of plasticity markers in a female 3xTg-AD mouse model. To this end, we analyzed behavioral outcomes through the open field and object place recognition tasks and changes in pre- and postsynaptic proteins and the neurotrophin VGF. We found a positive effect of Wnt7a on the recovery of spatial memory and the upregulation of the presynaptic marker synaptophysin, demonstrating its potential beneficial use in alleviating cognitive deficits in patients with Alzheimeŕs disease.
Genetic analysis of TMEM230 variants in Han Chinese patients with Parkinson's disease.
Deng X, Zheng W, Xu H … +6 more , Yang Y, Song Z, Xiang Q, Yang H, Deng H, Yuan L
Neurosci Lett · 2025 Oct · PMID 40744139 · Publisher ↗
Parkinson's disease (PD) is a common neurodegenerative disorder characterized by bradykinesia, rigidity, tremor, and gait disturbance. The transmembrane protein 230 gene (TMEM230) was initially identified as a disease-ca...
Parkinson's disease (PD) is a common neurodegenerative disorder characterized by bradykinesia, rigidity, tremor, and gait disturbance. The transmembrane protein 230 gene (TMEM230) was initially identified as a disease-causing gene in autosomal dominant PD while the role of TMEM230 in PD remains controversial. This study investigated the genetic role of TMEM230 variants in PD. Whole exome sequencing and Sanger sequencing were performed on a cohort of 518 unrelated PD patients (388 sporadic and 130 familial) and 539 age- and sex-matched controls. Identified TMEM230 variants were analyzed based on frequency assessments, bioinformatics prediction tools, and conservation analysis. The three-dimensional structures of the wild-type and mutated proteins were modeled using SWISS-MODEL and Missense3D, with visualization using PyMOL. Statistical analysis was performed to evaluate the association between TMEM230 variants and PD. Eight rare heterozygous TMEM230 variants were identified in sporadic PD patients and controls, including seven missense variants and a synonymous variant. Bioinformatics prediction analyses suggested that p.Gly16Trp and p.Arg23Gln were likely to have a damaging role, supporting their potential involvement in PD pathogenesis. The prevalence of TMEM230 missense variants was significantly higher in PD cases compared to controls (1.93 % vs. 0.37 %, P = 0.017, odds ratio = 5.29, 95 % confidence interval: 1.15-24.24). This study enhances the understanding of the genetic landscape of TMEM230 in the Han Chinese PD population and implies that TMEM230 may function as an autosomal dominant disease-causing gene of PD with low penetrance, or as a susceptibility gene, though the pathogenicity of TMEM230 variants is warranted by further investigation.
Delayed administration of rapamycin inhibits glial scar formation through upregulating matrilin-3 in an autophagy-dependent manner in ischemic stroke.
Guo Y, Qin A, Sun L … +8 more , He J, Shan Y, Wang X, Zhang T, Li M, Ma Y, Qiao S, Zhang H
Neurosci Lett · 2025 Oct · PMID 40744138 · Publisher ↗
Glial scar formation is one of the major pathological mechanisms following ischemic stroke. Rapamycin is a potent specific mTOR inhibitor and an autophagy activator. Although it has neuroprotective effects against acute...
Glial scar formation is one of the major pathological mechanisms following ischemic stroke. Rapamycin is a potent specific mTOR inhibitor and an autophagy activator. Although it has neuroprotective effects against acute ischemic stroke, it is unknown whether delayed administration of rapamycin can reduce ischemic stroke-induced pathogenesis such as glial scar formation, independent on its effects of acute administration. We recently reported that matrilin-3, an extracellular matrix component, provides neuroprotection in ischemic stroke by suppressing astrocyte-mediated neuroinflammation and glial scar formation. Here, in rat models of middle cerebral artery occlusion and reperfusion (I/R), rapamycin was administered for consecutive 7 or 14 days starting at day 1 post-reperfusion; and in an oxygen-glucose deprivation and reoxygenation (OGD/Re)-induced primary astrocyte or human astrocyte injury model, rapamycin was given upon reoxygenation. We found that rapamycin improved I/R-mediated rats' neurological dysfunction, accompanied by reduced glial scar formation and neuronal loss. To our surprise, rapamycin increased the levels of matrilin-3 in the peri-infarct region of rats and in OGD/Re-treated astrocytes associating with restoring autophagic flux. In contrast, the autophagy inhibitors wortmannin and bafilomycin A1 blocked autophagic flux, decreased the levels of matrilin-3 and enhanced glial scar formation, respectively. Overexpression of matrilin-3 significantly reduced the glial scar formation. Mechanistically, rapamycin could decrease the ADAMTS-4 and ADAMTS-5 levels, two hydrolases responsible for the breakdown of matrilin-3, thus upregulating the matrilin-3 levels. Our results reveal that delayed administration of rapamycin suppresses the glial scar formation by upregulating the astrocytic matrilin-3 related to restoring autophagic flux in ischemic stroke.
miR-423-3p alleviates sevoflurane-induced learning and memory dysfunction and nerve damage via negative regulation of GPX4.
Qiu L, Zhang L, Fan B … +1 more , Luo X
Neurosci Lett · 2025 Oct · PMID 40730318 · Publisher ↗
BACKGROUND: Sevoflurane anesthesia, while widely used, is associated with several side effects including the potential for nerve damage. MicroRNAs are disrupted in patients with sevoflurane anesthesia, including miR-423-...
BACKGROUND: Sevoflurane anesthesia, while widely used, is associated with several side effects including the potential for nerve damage. MicroRNAs are disrupted in patients with sevoflurane anesthesia, including miR-423-3p. However, the association between miR-423-3p and neurological damage remains to be elucidated. AIM: To investigate the effect of miR-423-3p on the rats after sevoflurane anesthesia and related molecular mechanisms. METHODS: RT-qPCR was utilized to quantify the levels of miR-423-3p, GPX4 and oxidative stress indicators in rat hippocampus. Cognitive function was assessed through the Morris water maze and novel object recognition tests. ELISA was applied to detect the levels of inflammatory factors. RESULTS: In the Sev group, miR-423-3p expression was significantly elevated, while GPX4 expression was markedly reduced. Down-regulated miR-423-3p negatively regulated GPX4 to shorten escape latency while increasing crossing times of the platform, time spend in the target quadrant, relative occupancy of exploring new objects and time to explore new objects. Furthermore, down-regulated miR-423-3p reduced ROS and MDA levels and increased GSH levels in nerve-injured rats, which could be reversed by inhibited GPX4. miR-423-3p inhibition reduced the levels of NLRP3, Caspase-1, IL-8, and IL-1β, which could be rescued by inhibition of GPX4. CONCLUSION: Down-regulation of miR-423-3p attenuated cognitive deficits in nerve-injured rats. Moreover, repressed miR-423-3p mitigated oxidative stress and inflammation by negatively regulating GPX4.
Enriched environment during adulthood temporarily ameliorates aggression induced by post-weaning social isolation in rats.
Sanada T, Ichisaka S, Hata Y
Neurosci Lett · 2025 Oct · PMID 40721204 · Publisher ↗
Childhood maltreatment increases the risk of psychiatric disorders with impulsive aggression. Post-weaning social isolation (PWSI) also increases impulsive aggression in adult rats, suggesting value as a model for elucid...
Childhood maltreatment increases the risk of psychiatric disorders with impulsive aggression. Post-weaning social isolation (PWSI) also increases impulsive aggression in adult rats, suggesting value as a model for elucidating the underlying neurodevelopmental mechanisms and for screening potential therapies. An enriched environment (EE) has been shown to increase social interaction, serotonergic transmission, and brain-derived neurotrophic factor level, and to reactivate developmental plasticity after the critical period. In this study, we show that the PWSI until adulthood increases shock-induced impulsive aggression in male Sprague-Dawley rats, and that housing in a long-term EE for 53 days (but not a short-term EE for 11 days) attenuates this increased aggression. However, this increased aggression re-emerged soon after return to standard housing. These results suggest that long-term EE is effective but not curative for PWSI-induced impulsive aggression.
Paeonol facilitates the repair of neuronal damage in the mPFC caused by chronic stress via the Rho GTPases-cofilin1 signaling pathway.
Zhu X, Zhang Y, Yan X … +7 more , Zhao Y, Shi L, Sun Z, Meng K, Zong Y, Li Q, Xu Z
Neurosci Lett · 2025 Oct · PMID 40721203 · Publisher ↗
BACKGROUND: The Rho GTPases-cofilin1 signalling axis preserves neuronal morphology and synaptic plasticity by modulating actin homeostasis. However, the potential role of paeonol-a bioactive compound derived from Paeonia...
BACKGROUND: The Rho GTPases-cofilin1 signalling axis preserves neuronal morphology and synaptic plasticity by modulating actin homeostasis. However, the potential role of paeonol-a bioactive compound derived from Paeonia suffruticosa-in mitigating CUMS-induced neuronal injury via this pathway remains unelucidated. OBJECTIVE: This study investigates the neuroprotective mechanisms of paeonol against CUMS-associated neuronal injury in the medial prefrontal cortex (mPFC), focusing on the Rho GTPases-cofilin1 signalling axis. METHODS: 60 male Sprague-Dawley rats were divided into five groups: Control, CUMS, Fluoxetine-treated (Flu), low-dose paeonol (LDP, 25 mg/kg), and high-dose paeonol (HDP, 80 mg/kg). Depressive-like phenotypes were induced via a 4-week CUMS paradigm, followed by daily gavage of fluoxetine or paeonol. Behavioral assessments quantified depressive-like phenotypes. Histology used HE and Nissl staining; dendritic morphology was assessed via Golgi impregnation. Protein levels of Rac1, Cdc42, RhoA, Cofilin1, and p-Cofilin1 in mPFC were quantified by Western blot. RESULTS: CUMS-exposed rats displayed prolonged immobility duration and delayed feeding initiation; paeonol and fluoxetine attenuated these deficits. Golgi analysis showed CUMS reduced total dendritic length, apical dendrite extension, branching complexity and mature dendritic spines (mushroom/branched), while increasing filopodial protrusions in mPFC pyramidal neurons. Both treatments rescued these alterations. Western blot showed CUMS decreased p-cofilin1 levels and downregulated Rac1 and Cdc42 expression, while increasing cofilin1. Paeonol normalized p-cofilin1 phosphorylation, restored Rac1 and Cdc42 expression and reduced cofilin1 levels. CONCLUSION: Paeonol alleviates CUMS-induced behavioural impairments, potentially through modulating the Rho GTPases-cofilin1 signaling axis.
Deep-layer neurons compensate for the loss of layer 4 sensory recipient cells in the developing neocortex.
Hou PS, Hanashima C
Neurosci Lett · 2025 Oct · PMID 40716697 · Publisher ↗
Layer 4 cortical neurons are key sensory recipients of thalamocortical inputs, facilitating higher-order information processing. Layer 4 cell fate is determined by intrinsic transcriptional programs and extrinsic cues, y...
Layer 4 cortical neurons are key sensory recipients of thalamocortical inputs, facilitating higher-order information processing. Layer 4 cell fate is determined by intrinsic transcriptional programs and extrinsic cues, yet the extent to which layer 4 cell identity is fixed remains unclear. Here, we investigate cortical fate plasticity using a tamoxifen-inducible conditional ablation to selectively eliminate layer 4-destined neurons at their earliest postmitotic stage. We found that, despite the depletion of these cells, the overall layer 4 neuron population remains intact, suggesting a compensatory mechanism. Birthdate labeling and molecular analysis revealed that earlier-born deep-layer neurons, rather than later-born upper-layer neurons, adopt a layer 4 identity in response to this loss. This fate shift is associated with altered Foxg1 downregulation and Nr2f1 upregulation, suggesting a molecular switch governing adaptive neurogenesis. Collectively, these findings provide new insights into the temporal and spatial constraints of cortical fate determination and reveal a compensatory mechanism that preserves cortical circuit formation despite early neuronal loss.
Neuronal dysfunction in the amygdala is involved in anxiety-like behaviors accompanying ulcerative colitis.
Takahashi K, Kurokawa K, Miyagawa K … +3 more , Mochida-Saito A, Takeda H, Tsuji M
Neurosci Lett · 2025 Sep · PMID 40701269 · Publisher ↗
Ulcerative colitis (UC) is a refractory inflammatory bowel disease that causes high rates of psychiatric disorders, such as anxiety and depression. In fact, dextran sodium sulfate (DSS)-treated mice, which are commonly u...
Ulcerative colitis (UC) is a refractory inflammatory bowel disease that causes high rates of psychiatric disorders, such as anxiety and depression. In fact, dextran sodium sulfate (DSS)-treated mice, which are commonly used as a model for UC, exhibit depression- and anxiety-like behaviors. However, the pathogeneses of these psychiatric disorders remain unclear. Acute stress increases immediate-early gene (IEG), including c-fos, expression in the various brain regions. To examine changes in neural activity during acute mild stress exposure in DSS-treated mice, we quantified c-Fos expression after behavioral tests. In the study, samples were collected 1 h after the behavioral test in the stress group, while samples were collected without behavioral tests in the control group. Treatment with 2 % DSS for 7 days induced UC-like symptoms and anxiety-like behaviors in the hole-board and elevated plus-maze tests. Furthermore, the c-Fos expression levels in the prefrontal cortex were significantly elevated in DSS-treated mice in the stress group compared to in those in the control group. Compared to water-treated mice, DSS-treated mice, both with and without stress exposure, showed significantly decreased c-Fos expression level and GluN1 phosphorylation in the amygdala. We found a correlation between DSS-induced anxiety-like behaviors and c-Fos expression in the amygdala. The elevated ERK1/2 phosphorylation levels in the amygdala observed in the water-treated mice exposed to mild acute stress were not exhibited in DSS-treated mice. Moreover, DSS-treated mice showed decreased synaptophysin expression in the amygdala. The neuronal dysfunction in the amygdala may be associated with the onset of anxiety related to UC.
Analysis of social interaction and proximity preferences in mice exposed to valproic acid prenatally.
Sugiyama R, Komada M
Neurosci Lett · 2025 Sep · PMID 40684842 · Publisher ↗
It is established that exposure to the antiepileptic drug valproic acid (VPA) during the prenatal period increases the risk of neurodevelopmental disorders, including autism spectrum disorders (ASD). In this study, a mul...
It is established that exposure to the antiepileptic drug valproic acid (VPA) during the prenatal period increases the risk of neurodevelopmental disorders, including autism spectrum disorders (ASD). In this study, a multi-animal positioning system (MAPS) was utilized to ICR male mice as control (CT) and prenatal VPA-treated male mice in a shared environment, with the objective of investigating the effects of VPA on social interaction and social proximity. The results of the behavioral analysis indicated that the frequency, duration, and number of contacts were reduced in mice treated with VPA compared to the control group. Additionally, while there was no effect on inter-individual distance, the time spent at a distance was reduced. While no effects were observed on spontaneous locomotion or psychomotor activity, mice treated with VPA demonstrated behavioral abnormalities, characterized by increased social proximity but decreased social interaction. This finding underscores the utility of the MAPS in assessing natural group behavior and highlights the main behavioral differences associated with autism spectrum disorders due to prenatal VPA exposure. The results of this study offer valuable insights into the behavioral consequences of altered neurodevelopment and encourage further research to elucidate the underlying mechanisms.
Brain biomarker profiles vary with semi-synthetic and grain-based diets in healthy and mTBI mice.
Anderson ED, Augustin DV, Georges AP … +2 more , Issadore DA, Meaney DF
Neurosci Lett · 2025 Sep · PMID 40669803 · Publisher ↗
Across a range of neurological disorders, there is a growing appreciation for how the gut influences brain health, but few ways of monitoring its effects. Although nutrition influences traumatic brain injury (TBI) recove...
Across a range of neurological disorders, there is a growing appreciation for how the gut influences brain health, but few ways of monitoring its effects. Although nutrition influences traumatic brain injury (TBI) recovery, its influence on biomarkers-whether as an intervention or confounder-is poorly understood. Beyond specialized diets, standard rodent diets may also affect brain function. Neuron-derived extracellular vesicles (NDEVs) offer a brain-specific complement to circulating biomarkers, but their sensitivity to diet is unknown. In this study, we isolated miRNAs from NDEVs from the serum of healthy and mild TBI (mTBI) mice fed a semi-synthetic or grain-based diet. NDEV miRNAs encoded dietary differences based on injury condition, suggesting that NDEVs are sensitive to dietary changes and may be able to track diet's effect on TBI recovery. Additionally, we found that diet influenced injury biomarkers, underscoring diet as a confounding variable for NDEV miRNA biomarkers. Together, these findings highlight NDEVs as a promising tool for monitoring the effects of subtle dietary differences on brain health and the importance of diet reporting to improve study reproducibility.
Neuro-compensatory changes in face recognition in older adults: evidence from evoked and oscillatory responses of event-related potentials.
Matsufuji K, Yamada E, Nakazono H … +1 more , Tobimatsu S
Neurosci Lett · 2025 Sep · PMID 40664308 · Publisher ↗
Although face recognition is an essential function for human social interaction, face identification, memory retention, and processing speed decline with age. Recent event-related potential studies suggest that aging eff...
Although face recognition is an essential function for human social interaction, face identification, memory retention, and processing speed decline with age. Recent event-related potential studies suggest that aging effects occur at relatively early perceptual stages; age-related increases in amplitude and latency and reduced hemispheric lateralization of the N170 component have been noted. However, studies into the P100 component have been sparse and yielded inconsistent findings. Here, we measured event-related potentials during face stimulus presentation in young (n = 22) and older (n = 22) adults. We focused on neuronal transients (P100 and N170) that are phase-locked to the stimulus, thereby reflecting changes in neuronal input. We also analyzed the oscillatory activities of P100 and N170, whose latencies fluctuate from trial to trial; this signaled the coupling mechanisms of each trial. We observed significant age-related differences in both P100 and N170. Notably, although older adults did not exhibit the characteristic right hemispheric predominance observed in young adults, they still demonstrated the preserved face inversion effect. Intertrial phase coherence analysis revealed lower phase synchronization in the older adults than in the young adults. Our findings suggest that age-related functional changes in the primary visual cortex influence the P100 component, and that the reduced right hemispheric predominance of N170 may be attributed to neural compensation. Thus, neural specificity for face recognition appears to be preserved in older adults, counterbalancing the aging effect. Moreover, intertrial phase coherence measurements indicate that the age-related decline in face recognition may be explained by asynchronous phase-locking neural activity in the face-specific area.
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