Huang H, Shi H, Sun J
… +6 more, Song X, Yu Y, Yan L, Shi F, Wang W, Zhang Y
Neurosci Lett
· 2026 May · PMID 41935604
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Lead (Pb) is a pervasive environmental hazard that impairs cognitive function. However, the underlying mechanisms and non-pharmacological interventions need to be further investigated. Here, Pb-induced senescence in the...Lead (Pb) is a pervasive environmental hazard that impairs cognitive function. However, the underlying mechanisms and non-pharmacological interventions need to be further investigated. Here, Pb-induced senescence in the prefrontal cortex was associated with cognitive impairment. We found that exercise and exercise serum ameliorated Pb-induced prefrontal cortex senescence and cognitive impairment in mice. Further analyses revealed that exercise-derived irisin alleviated cellular senescence by regulating the SIRT3 signaling pathway. Meanwhile, irisin also mediated the association between blood Pb levels and MoCA scores in humans. Together, these findings suggest that exercise alleviates Pb-induced cognitive impairment via the irisin-SIRT3 pathway and identify irisin as a potential therapeutic target.
Neurosci Lett
· 2026 May · PMID 41933605
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Spatial learning and memory are reliant on activation of N-methyl-D-aspartate receptors (NMDARs) at excitatory synapses in the hippocampus. NMDARs at immature synapses contain mostly GluN2B subunits while at mature synap...Spatial learning and memory are reliant on activation of N-methyl-D-aspartate receptors (NMDARs) at excitatory synapses in the hippocampus. NMDARs at immature synapses contain mostly GluN2B subunits while at mature synapses, more NMDARs contain GluN2A subunits. A hippocampal NMDAR GluN2B to GluN2A subunit shift occurs in rodents during the third postnatal week, permitting rapid and detailed contextual encoding and memory retrieval without a reminder. Adult transgenic mice expressing chimeric GluN2 subunits (carboxy terminal domains swapped between GluN2A and GluN2B, GluN2A-B or GluN2B-A) have implicated GluN2A-type ionotropic signaling in spatial context encoding and GluN2B-type carboxy terminal domain (CTD) signaling in memory retrieval. However, the individual contributions of GluN2A and GluN2B subunit ionotropic and CTD signaling to the maturation of spatial learning and memory have not been defined. By increasing GluN2A-type ionotropic signaling in preweanling mice via expression of chimeric GluN2 subunits, we found improved long-term memory in a massed training version of the Morris water maze. These findings suggest that increased GluN2A-type ionotropic signaling enables encoding of spatial context in a manner that permits more mature long-term memory retrieval. These findings support unique contributions from GluN2A- and GluN2B-containing NMDARs that combine to optimize spatial learning and memory.
Swain C, Pokharel D, Peshattiwar V
… +4 more, Le K, Kennedy I, Venkiteswaran K, Subramanian T
Neurosci Lett
· 2026 May · PMID 41932383
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Recent studies have identified a "body-first" subtype of Parkinson's disease (PD) that is associated with more rapid progression to Parkinson's disease dementia (PDD). It is currently unknown whether chronic levodopa, th...Recent studies have identified a "body-first" subtype of Parkinson's disease (PD) that is associated with more rapid progression to Parkinson's disease dementia (PDD). It is currently unknown whether chronic levodopa, the primary treatment in PD, contributes to the progression of disease in the "body-first" subtype of PD. We investigated whether chronic levodopa affects motor or cognitive function in the paraquat and lectin (P + L) rat model of PD, a model which recapitulates the "body-first" subtype of PD. Rats (n = 9) were administered 7 days of P + L (1 mg/kg P + 0.05% L in 1% sucrose solution, oral gavage) with injection of cholecystokinin (3 μg/kg CCK, ip) to induce parkinsonism. At 15 weeks post-P + L treatment, rats with bilateral forelimb motor deficit (n = 6) were administered 60 days of twice daily levodopa (4 mg/kg) + benserazide (15 mg/kg) ip injections. Motor and cognitive behavioral testing were done pre-levodopa, on levodopa, and post-levodopa washout. Rats were euthanized and brains stained for tyrosine hydroxylase (TH), choline acetyltransferase (ChAT) and phosphorylated-S-α-synuclein (pSyn) to investigate the effects of chronic levodopa on neurodegeneration and pathology in the nigrostriatal pathways and basal forebrain nuclei. We show no long-term effects of chronic levodopa treatment on the progression of parkinsonian motor deficits, visuospatial working memory, dopaminergic nigral degeneration, or cholinergic medial septal nucleus - vertical nucleus of diagonal band of Broca complex degeneration in the P + L rat model of PD. This study provides important preclinical evidence that chronic levodopa therapy does not cause progression of neurodegeneration in this rat model which recapitulates the "body-first" subtype of PD.
Neves NA, Gallas-Lopes M, Patelli-Alves A
… +5 more, Müller DV, Bastos LM, Stahlhofer-Buss T, Herrmann AP, Piato A
Neurosci Lett
· 2026 May · PMID 41903864
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Stress-related disorders encompass diverse behavioral alterations, including impaired social functioning. The zebrafish (Danio rerio) is a valuable model for studying these phenomena, particularly because of its robust a...Stress-related disorders encompass diverse behavioral alterations, including impaired social functioning. The zebrafish (Danio rerio) is a valuable model for studying these phenomena, particularly because of its robust and ethologically conserved social behaviors. Unpredictable chronic stress (UCS) produces behavioral, physiological, and molecular changes in zebrafish that parallel core features of human anxiety and depressive disorders; however, its impact on social outcomes remains unclear. Here, we examined whether a 14-day UCS protocol alters social behavior in adult zebrafish using two complementary assays: the social preference test and the shoal cohesion test. Across two independent experiments, UCS did not elicit detectable changes in individual social approach or group-level cohesion. In contrast, UCS induced clear anxiety-like behavior in the novel tank test, validating the stress manipulation, with stressed fish displaying reduced vertical exploration and decreased time in the upper zone. Distance-based shoal dispersion measures increased over time in both groups, indicating reduced shoal cohesion, consistent with habituation to the testing environment rather than a stress-specific effect. Together, these results suggest that social behavior in adult zebrafish is relatively resilient to UCS under the conditions tested, whereas anxiety-like responses are markedly affected. Future work should investigate whether factors such as stressor intensity, developmental stage, sex composition, or social hierarchy modulate the sensitivity of social behavior to chronic stress.
Zhuikova NS, Mikheeva IB, Antonova OY
… +3 more, Kobyakova MI, Pavlik LL, Arkhipov VI
Neurosci Lett
· 2026 May · PMID 41871823
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Dysfunction of the vestibular nuclei, which can arise from various causes, is a common problem, affecting more than a third of people over 40. Its characteristic symptom is vestibular vertigo. This dysfunction is also as...Dysfunction of the vestibular nuclei, which can arise from various causes, is a common problem, affecting more than a third of people over 40. Its characteristic symptom is vestibular vertigo. This dysfunction is also associated with neurodegenerative diseases. To model vestibular disorders, mice were subjected to rotation for eight hours. They were then given two doses of betahistine (200 mg/kg), one and 24 h after stimulation. Results showed that this treatment affected the animals' open-field behavior, as well as the structure of Deiters' nucleus. One hour after stimulation, significant mitochondrial changes were detected in Deiters' neurons, including an increase in mitochondrial area, disruption of cristae structure, and the presence of mitophagosomes. Betahistine treatment mitigated these effects, reducing both mitochondrial damage and mitophagosome formation, and induced the formation of a special donut-shaped mitochondria, promoting the preservation of membrane potential. Furthermore, betahistine attenuated neuroinflammation, as evidenced by the state of microglia and astrocytes. These results clarify the mechanism of vestibular-induced damage to the Deiters nucleus and identify betahistine as a potential therapeutic agent for neurodegenerative diseases and ischemia.
Neurosci Lett
· 2026 May · PMID 41866020
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Long-term memory formation requires gene transcription followed by mRNA translation. Research in Aplysia has revealed that behavioral training, consisting of repeated exposure to aversive stimuli, induces a persisting tr...Long-term memory formation requires gene transcription followed by mRNA translation. Research in Aplysia has revealed that behavioral training, consisting of repeated exposure to aversive stimuli, induces a persisting transcription- and translation- dependent enhancement of defensive withdrawal responses, known as long-term sensitization. Transcription and translation are also necessary for the expression of the cellular correlates of long-term sensitization within the withdrawal neural circuits, including increased excitability of sensory neurons. Aversive training also induces long-term feeding suppression, which is sustained, at least in part, by decreased excitability of decision-making neuron B51 in the feeding neural circuit. However, it was unknown whether B51 decreased excitability depends on molecular processes analogous to those in the defensive circuits. Therefore, this project examined whether transcription and/or translation were required for this form of plasticity. Actinomycin D and anisomycin were utilized to selectively inhibit gene transcription and mRNA translation, respectively. Experiments were conducted in a reduced preparation in which in vitro aversive training co-induces sensory neuron increased excitability and B51 decreased excitability. Results indicate that actinomycin D and anisomycin blocked the expression of both forms of plasticity. These findings demonstrate that concurrent experience-dependent long-term cellular changes in defensive and appetitive circuits share the same transcription and translation requirements to ensure persistence over time.
Sensory inputs are integrated by interneurons to generate appropriate behavioural outputs. In the nematode Caenorhabditis elegans, the AIY interneuron receives major synaptic input from the salt-sensing ASE neurons, ASEL...Sensory inputs are integrated by interneurons to generate appropriate behavioural outputs. In the nematode Caenorhabditis elegans, the AIY interneuron receives major synaptic input from the salt-sensing ASE neurons, ASEL and ASER, which respond asymmetrically to increases and decreases in NaCl concentration. How these asymmetric signals are integrated downstream, however, remains unclear. Here, we conducted in vivo calcium imaging of AIY. In wild-type animals, AIY exhibited dynamic calcium responses to NaCl concentration changes, including concentration-dependent responses and stochastic spike-like events that appeared independent of salt levels. These responses were abolished in sensory-deficient mutants, indicating that ASE is essential for salt-dependent activation of AIY. In unc-13 mutants, stochastic events were markedly suppressed, and AIY activity remained largely static. The contribution of UNC-13-dependent classical synaptic transmission to NaCl-evoked AIY responses could not be clearly established, despite the many synaptic contacts from ASE neurons. In contrast, the exaggerated upshift responses observed in unc-31 mutants suggest that neuropeptides normally act to suppress AIY activation. Notably, responses persisted even in the background of decreased functional synaptic or peptidergic input, indicating the existence of alternative signalling mechanisms. These findings reveal the complexity of interneuronal activation in the state of sensory inputs and suggest that AIY integrates both excitatory and inhibitory inputs from ASE through synaptic and nonsynaptic pathways. Significance statement This study shows that a single interneuron integrates asymmetric sensory inputs via synaptic and non-synaptic mechanisms, highlighting complex circuit computation.
There is a pressing need for effective alternatives to opioid analgesics, the development of which requires the identification of novel anti-nociceptive drug targets. Here, we have further investigated the anti-nocicepti...There is a pressing need for effective alternatives to opioid analgesics, the development of which requires the identification of novel anti-nociceptive drug targets. Here, we have further investigated the anti-nociceptive properties of a GPR35 agonist, cromolyn, in an in vitro model of inflammatory sensitisation. We used ratiometric Ca imaging of cultured sensory neurons to examine the effect of cromolyn on prostaglandin E (PGE)-mediated sensitisation of the pro-nociceptive ion channel, transient receptor potential cation channel, subfamily V, member 1 (TRPV1). The sensitisation of TRPV1 by PGE was inhibited by cromolyn in a GPR35-dependent manner. These observations provide further evidence in support of an anti-nociceptive role for GPR35, highlighting the potential use of GPR35 agonists as analgesics.
Tobin ER, Ofori E, McClure SM
… +2 more, Mehta SH, Peterson DS
Neurosci Lett
· 2026 May · PMID 41862073
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Reactive stepping is impaired in people with Parkinson's disease (PwPD) and can be trained through practice. However, these improvements are often variable across individuals. Identifying neurological predictors and pote...Reactive stepping is impaired in people with Parkinson's disease (PwPD) and can be trained through practice. However, these improvements are often variable across individuals. Identifying neurological predictors and potential mechanisms of this variability can improve the efficiency of rehabilitation. This study investigated the association between improvements in backward reactive stepping performance through training and resting-state functional magnetic resonance imaging (rs-fMRI) in PwPD. 16 PwPD underwent rs-fMRI and an eighteen-week multiple-baseline study, which included baseline assessments (B1 and B2, 2-weeks apart), a 2-week training protocol, and post-training assessments immediately after protocol (P1) and 2-months later (P2), in which we assessed anterior-posterior margin of stability (MOS) at first foot contact. Linear regression analyses assessed the relationship between functional connectivity, using a region of interest approach, and immediate (P1-B2) and retained (P2-B2) improvements in MOS during reactive stepping. Results showed that higher right thalamus-right amygdala connectivity was related to immediate MOS improvements (p < 0.05). Right thalamus-right amygdala, left caudate-left hippocampus, and left thalamus-left hippocampus connectivity were associated with better long-term retention of MOS (p's < 0.05). These findings suggest thalamo-limbic coupling may contribute to immediate and retained improvements in reactive balance in PwPD and could aid in identifying individuals who would benefit most from balance rehabilitation.
BACKGROUND: Approximately 50%-60% of anti-gamma-aminobutyric acid B receptor (anti-GABABR) encephalitis are associated with malignancy. Paraneoplastic anti-GABABR encephalitis patients have poorer prognosis than non-para...BACKGROUND: Approximately 50%-60% of anti-gamma-aminobutyric acid B receptor (anti-GABABR) encephalitis are associated with malignancy. Paraneoplastic anti-GABABR encephalitis patients have poorer prognosis than non-paraneoplastic cases. This study aimed to explore distinct cerebral metabolism patterns and network topologies that may underlie prognostic differences in paraneoplastic and non-paraneoplastic anti-GABABR encephalitis, using 18F-fluorodeoxyglucose positron emission tomography (F-FDG PET) imaging. METHODS: We retrospectively analyzed FDG PET images from 20 healthy controls, and 20 anti-GABABR encephalitis patients, including 7 patients with malignancy (paraneoplastic subgroup) and 13 patients without malignancy (non-paraneoplastic subgroup). Prognosis outcomes were assessed by comparing modified Rankin Scale scores at hospitalization and discharge between two patient subgroups. We employed voxel-wise statistical parametric mapping to identify cerebral metabolism patterns in each patient subgroup compared with controls. Graph theory analysis was utilized to evaluate topological parameters of metabolism network. RESULTS: The non-paraneoplastic subgroup showed significantly greater prognosis outcomes than the paraneoplastic subgroup. Both patient subgroups exhibited a similar hypermetabolism pattern in limbic system. However, paraneoplastic subgroup demonstrated more extensive hypometabolism across parieto-occipital regions. Furthermore, Paraneoplastic subgroup exhibited significantly higher assortativity than non-paraneoplastic subgroup and healthy controls, whereas no such difference was observed between non-paraneoplastic subgroup and controls. CONCLUSION: Compared with non-paraneoplastic subgroup, paraneoplastic subgroup exhibited more widespread hypometabolism patterns, and disruption of metabolic network stability measured by higher assortativity. These distinct metabolic characteristics may underlie prognosis differences in paraneoplastic and non-paraneoplastic cases. These findings may inform more effective treatment strategies, thereby improving the clinical management of anti-GABABR encephalitis.
The occurrence and development of amyotrophic lateral sclerosis (ALS) involve neuroinflammatory responses, in which microglial activation plays a critical role. IRF5, a key regulator of inflammatory responses, is implica...The occurrence and development of amyotrophic lateral sclerosis (ALS) involve neuroinflammatory responses, in which microglial activation plays a critical role. IRF5, a key regulator of inflammatory responses, is implicated in the disease mechanisms of various conditions. However, its mechanism in ALS remains unclear. This study found that IRF5 expression was significantly increased in hSOD1-G93A transgenic ALS mice and cell models, primarily localized in activated microglia. Silencing IRF5 altered microglial polarization, suppressed the release of inflammatory factors, enhanced phagocytic function, and reduced motor neuron apoptosis in a co-culture system. Mechanistic studies suggested that IRF5 may regulate microglial function through the NF-κB signaling pathway. This study reveals the key role of IRF5 in microglia-mediated neuroinflammation and neuronal damage in ALS, indicating that targeting IRF5 could represent a promising treatment strategy for this disease.
Dorsal root ganglion (DRG) neurons serve as the first-order sensory neurons relaying peripheral inputs to the spinal cord. Studies have shown that dopaminergic signalling contributes to the modulation of DRG neurons exci...Dorsal root ganglion (DRG) neurons serve as the first-order sensory neurons relaying peripheral inputs to the spinal cord. Studies have shown that dopaminergic signalling contributes to the modulation of DRG neurons excitability and nociceptive transmission. In this study, we examined the effects of dopamine receptor subtypes on the excitability of small and large-sized DRG neurons using whole-cell patch-clamp recordings in acutely cultured rat DRG neurons. Activation of D1-like receptors by SKF38393 caused a depolarizing shift in the action potential threshold in small sized DRG neurons whereas an increase in spike width was observed in both small and large sized DRG neurons, suggesting reduced excitability likely mediated through modulation of sodium channel activity, whereas activation of D2-like receptors by ropinirole reduced the action potential amplitude and modulated the repolarization dynamics in small sized DRG neurons, indicating potential involvement of Gi-coupled mechanisms affecting sodium and potassium currents. Together, these findings demonstrate subtype-specific modulation of DRG neurons excitability by dopamine and highlight the peripheral dopaminergic system as a critical regulator of nociceptive signalling with potential implications for pain management.
Healthy aging is associated with changes in neural organization that may influence language production. Using task-based fNIRS, we examined cortical activation and functional connectivity during overt picture naming and...Healthy aging is associated with changes in neural organization that may influence language production. Using task-based fNIRS, we examined cortical activation and functional connectivity during overt picture naming and sentence repetition in Mandarin speakers. Seventeen right-handed adults (10 younger, mean age = 22.1; 7 older, mean age = 58.6) completed both tasks while HbO responses were recorded over fronto-temporo-parietal cortex. Block-averaged HbO activation did not differ reliably between groups in either task. In contrast, the primary task-epoch connectivity analysis indicated stronger dorsolateral prefrontal-temporo-parietal coupling in older adults during picture naming; however, this group difference was not statistically robust in a more conservative baseline-referenced contrast. No connections survived correction for multiple comparisons during sentence repetition. These results suggest that, under relatively low-demand overt speech production, age-related differences may be more evident in network-level interactions than in mean regional activation magnitude. Task-based fNIRS may be useful for probing age-related modulation of speech-related brain networks during overt language production.
Thoracic spinal cord stimulation (SCS) has been reported to facilitate swallowing, however the underlying brainstem mechanisms remain unclear. We developed a Gaussian-frequency, charge-imbalanced biphasic waveform design...Thoracic spinal cord stimulation (SCS) has been reported to facilitate swallowing, however the underlying brainstem mechanisms remain unclear. We developed a Gaussian-frequency, charge-imbalanced biphasic waveform designed to enhance sensory afferent drive to spinal circuits while maintaining safe charge delivery. Using an in situ perfused brainstem-spinal cord preparation of rats, which preserves intrinsic swallowing circuits and enables direct assessment of central pattern generator (CPG) outputs, we compared this waveform with a conventional fixed-frequency monophasic pulse used in clinical and experimental settings. Electrical stimulation was applied epidurally to the T8 spinal segment via a concentric electrode, and neural activity was recorded from the phrenic nerves, vagus nerves, and hypoglossal nerves under three conditions: no stimulation, monophasic stimulation, and Gaussian-frequency charge-imbalanced biphasic stimulation. Both stimulation types significantly increased swallow count, shortened the swallowing interburst interval, and enhanced swallow-related vagus nerve activity (VNA) and hypoglossal nerve activity (HNA) compared with no stimulation. However, the Gaussian-frequency waveform produced a significantly greater increase in swallow number than monophasic stimulation. Consistent with previous findings that stochastic stimulation can reduce sensory adaptation and improve detection of weak inputs, our results suggest that, once the swallowing CPG is engaged, stochastic stimulation does not primarily accelerate its rhythm but instead increases the likelihood and duration of CPG activation bouts.Thoracic SCS using this waveform may therefore provide a neuromodulatory strategy that may enhance the functional selectivity of cathodal activation within spinal circuits within spinal circuits and facilitates recruitment of brainstem swallowing networks.
Sudden unexpected death in epilepsy (SUDEP) poses a significant public health burden. Seizure-induced apnea has been identified as a major event leading to death after generalized seizures. Vanillin, an herbal compound,...Sudden unexpected death in epilepsy (SUDEP) poses a significant public health burden. Seizure-induced apnea has been identified as a major event leading to death after generalized seizures. Vanillin, an herbal compound, stimulates monoaminergic signaling. Given that enhancing the function of monoamines [serotonin (5-HT) and norepinephrine (NE)] reduces seizure-induced mortality in animal models of SUDEP, we hypothesized that vanillin prevents seizure-induced mortality in DBA/1 mice. DBA/1 mice of both sexes were primed by acoustic stimulation once daily for 3-4 days. Vanillin, ondansetron (a 5-HT receptor antagonist), ketanserin (a 5-HT antagonist), GR 125487 (a 5-HT antagonist), yohimbine (a α2 adrenoceptor antagonist), prazosin (a α1 antagonist), ICI 118,551 (a β2 antagonist), SB 366791 (a TRPV1 antagonist) or vehicle was administered intraperitoneally 30-60 min before acoustic stimulation, and the effects of each drug or drug combination (an antagonist + vanillin) on seizure-induced mortality, apnea or seizures were examined. The incidence of seizure-induced mortality was significantly reduced by vanillin at 300 and 400 mg/kg as compared with the vehicle control. Vanillin treatment was associated with reduced seizure-induced apnea and blockade of tonic seizures. Notably, the reduction in seizure-induced mortality by vanillin was not reversed by antagonists of monoaminergic receptors, despite their reported involvement in seizure-induced deaths, nor by an antagonist of TRPV1 receptors, a known direct target of vanillin. These findings demonstrate that vanillin suppresses seizure-induced mortality in DBA/1 mice, with associated effects on respiratory dysfunction and tonic seizures, and suggest that this protection is unlikely to be mediated by monoaminergic or TRPV1 pathways.
Proteinase activated receptors (PARs) are family of four G protein-coupled receptors that signal following enzymatic cleavage of their extracellular N-terminal domain. Activation of PAR-4 has been found to sensitize join...Proteinase activated receptors (PARs) are family of four G protein-coupled receptors that signal following enzymatic cleavage of their extracellular N-terminal domain. Activation of PAR-4 has been found to sensitize joint nociceptors leading to the generation of pain. The identity of the proteinases that activate PAR-4 in joints is unclear but may include the serine proteinase plasmin. The aim of this study was to determine whether plasmin signals joint pain via PAR-4 activation and whether the plasmin inhibitor neuroserpin could attenuate acute inflammatory joint pain. Either plasmin (0.04 - 04U) or vehicle (0.9% saline) were injected into the right knee joint of male rats and pain behaviour was assessed by von Frey hair mechanosensitivity or hindlimb dynamic weight bearing. Intra-articular injection of plasmin increased hindpaw mechanosensitivity and reduced the amount of weight borne on the ipsilateral hindlimb. These pain behaviours were attenuated by pre-treating the rats with the PAR-4 antagonist pepducin P4pal10 (100 μg i.p.) or the plasmin inhibitor neuroserpin (3 μg s.c.). In a group of animals with acute synovitis, prophylactic treatment with neuroserpin increased von Frey hair mechanical threshold but had no effect on weight bearing deficits. Taken together, these data show that plasmin produces joint pain by local activation of PAR-4 while blockade of plasmin bioactivity with neuroserpin can alleviate joint pain in an acute model of arthritis.