Pub Date : 2025-01-31DOI: 10.1016/j.neulet.2025.138145
Li-Min Mao , Tayyibah Mahmood , John Q. Wang
Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase expressed in neurons of the developing and adult brain in addition to non-neuronal cells. Activation of FAK is initiated by autophosphorylation of the kinase at tyrosine 397 (Y397). Active FAK transmits extracellular signals inside neurons to integrate cytoskeletal rearrangements and modulate synaptic transmission and plasticity. Here we investigated roles of dopamine receptors, i.e., Gαs/olf-coupled D1 and Gαi/o-coupled D2 subtypes, in regulation of FAK autophosphorylation in two major dopamine-innervated areas of the mouse brain in vivo. We found that acute systemic administration of a dopamine D1 or D2 receptor agonist had no effect on basal FAK autophosphorylation at Y397 in the striatum and medial prefrontal cortex (mPFC). Similarly, a D1 receptor antagonist did not alter striatal and cortical Y397 phosphorylation. However, acute injection of a D2 receptor antagonist (eticlopride or haloperidol) induced a marked increase in Y397 phosphorylation in the striatum and mPFC. The eticlopride-induced Y397 phosphorylation can be seen in the two striatal subdivisions, the caudate putamen and nucleus accumbens, and was induced at two effective doses (0.1 and 0.5 mg/kg). All drug treatments caused insignificant changes in cellular FAK protein expression. These results reveal an existence of a tonic inhibitory tone of dopamine D2 receptors over basal FAK autophosphorylation in the mouse striatum and mPFC.
{"title":"Dopamine D2 receptor antagonists alter autophosphorylation of focal adhesion kinases in the mouse forebrain in vivo","authors":"Li-Min Mao , Tayyibah Mahmood , John Q. Wang","doi":"10.1016/j.neulet.2025.138145","DOIUrl":"10.1016/j.neulet.2025.138145","url":null,"abstract":"<div><div>Focal adhesion kinase (FAK) is a non-receptor tyrosine kinase expressed in neurons of the developing and adult brain in addition to non-neuronal cells. Activation of FAK is initiated by autophosphorylation of the kinase at tyrosine 397 (Y397). Active FAK transmits extracellular signals inside neurons to integrate cytoskeletal rearrangements and modulate synaptic transmission and plasticity. Here we investigated roles of dopamine receptors, i.e., G<sub>αs/olf</sub>-coupled D<sub>1</sub> and G<sub>αi/o</sub>-coupled D<sub>2</sub> subtypes, in regulation of FAK autophosphorylation in two major dopamine-innervated areas of the mouse brain <em>in vivo</em>. We found that acute systemic administration of a dopamine D<sub>1</sub> or D<sub>2</sub> receptor agonist had no effect on basal FAK autophosphorylation at Y397 in the striatum and medial prefrontal cortex (mPFC). Similarly, a D<sub>1</sub> receptor antagonist did not alter striatal and cortical Y397 phosphorylation. However, acute injection of a D<sub>2</sub> receptor antagonist (eticlopride or haloperidol) induced a marked increase in Y397 phosphorylation in the striatum and mPFC. The eticlopride-induced Y397 phosphorylation can be seen in the two striatal subdivisions, the caudate putamen and nucleus accumbens, and was induced at two effective doses (0.1 and 0.5 mg/kg). All drug treatments caused insignificant changes in cellular FAK protein expression. These results reveal an existence of a tonic inhibitory tone of dopamine D<sub>2</sub> receptors over basal FAK autophosphorylation in the mouse striatum and mPFC.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"850 ","pages":"Article 138145"},"PeriodicalIF":2.5,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143080727","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-31DOI: 10.1016/j.neulet.2025.138146
Jisu Elsa Jacob , Sreejith Chandrasekharan , Thomas Iype , Ajith Cherian
EEG signals exhibit spatio-temporal characteristics due to the neural activity dispersion in space over the brain and the dynamic temporal patterns of electrical activity in neurons. This study tries to effectively utilize the spatio-temporal nature of EEG signals for diagnosing encephalopathy using a combination of novel locality preserving feature extraction using Local Binary Patterns (LBP) and a custom fine-tuned Long Short-Term Memory (LSTM) neural network. A carefully curated primary EEG dataset is used to assess the effectiveness of the technique for treatment of encephalopathies. EEG signals of all electrodes are mapped onto a spatial matrix from which the custom feature extraction method isolates spatial features of the signals. These spatial features are further given to the neural network, which learns to combine the spatial information with temporal dynamics summarizing pertinent details from the raw EEG data. Such a unified representation is key to perform reliable disease classification at the output layer of the neural network, leading to a robust classification system, potentially providing improved diagnosis and treatment. The proposed method shows promising potential for enhancing the automated diagnosis of encephalopathy, with a remarkable accuracy rate of 90.5%. To the best of our knowledge, this is the first attempt to compress and represent both spatial and temporal features into a single vector for encephalopathy detection, simplifying visual diagnosis and providing a robust feature for automated predictions. This advancement holds significant promise for ensuring early detection and intervention strategies in the clinical environment, which in turn enhances patient care.
{"title":"Unveiling encephalopathy signatures: A deep learning approach with locality-preserving features and hybrid neural network for EEG analysis","authors":"Jisu Elsa Jacob , Sreejith Chandrasekharan , Thomas Iype , Ajith Cherian","doi":"10.1016/j.neulet.2025.138146","DOIUrl":"10.1016/j.neulet.2025.138146","url":null,"abstract":"<div><div>EEG signals exhibit spatio-temporal characteristics due to the neural activity dispersion in space over the brain and the dynamic temporal patterns of electrical activity in neurons. This study tries to effectively utilize the spatio-temporal nature of EEG signals for diagnosing encephalopathy using a combination of novel locality preserving feature extraction using Local Binary Patterns (LBP) and a custom fine-tuned Long Short-Term Memory (LSTM) neural network. A carefully curated primary EEG dataset is used to assess the effectiveness of the technique for treatment of encephalopathies. EEG signals of all electrodes are mapped onto a spatial matrix from which the custom feature extraction method isolates spatial features of the signals. These spatial features are further given to the neural network, which learns to combine the spatial information with temporal dynamics summarizing pertinent details from the raw EEG data. Such a unified representation is key to perform reliable disease classification at the output layer of the neural network, leading to a robust classification system, potentially providing improved diagnosis and treatment. The proposed method shows promising potential for enhancing the automated diagnosis of encephalopathy, with a remarkable accuracy rate of 90.5%. To the best of our knowledge, this is the first attempt to compress and represent both spatial and temporal features into a single vector for encephalopathy detection, simplifying visual diagnosis and providing a robust feature for automated predictions. This advancement holds significant promise for ensuring early detection and intervention strategies in the clinical environment, which in turn enhances patient care.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"849 ","pages":"Article 138146"},"PeriodicalIF":2.5,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143080692","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-31DOI: 10.1016/j.neulet.2024.138099
Marina Recatalá , Pablo Hidalgo , Juan Nàcher , José Miguel Blasco-Ibáñez , Carlos Crespo , Emilio Varea
Neuronal structural plasticity gives the adult brain the capacity to adapt to internal or external factors by structural and molecular changes. These plastic processes seem to be mediated, among others, by the action of the neurotransmitter serotonin through specific receptors (5-HTRs). Previous studies have shown that the maturation of granule cells in the hippocampus is mediated by 5-HT3. In the present study, we wanted to check if the neural maturation in layer II piriform cortex is also mediated by 5-HT3. In the piriform cortex, in contrast to the hippocampus, there is no postnatal neurogenesis. All immature neurons (PSA-NCAM immunoreactive) were originated prenatally. Immature cells in this area begin as small cells (type I cells) that then mature to larger cells (type II cells), and finally, mature to principal cells (PSA-NCAM immunonegative). To study the role of 5HT3 in this population, we first demonstrated the presence of 5HT3 receptors on both type I and II cells. Then we increased serotonin concentration using chronic fluoxetine administration, producing a reduction in the number of type I cells and an increment of type II cells but not an induction in the final stage of maturation to principal cells, as shown by the higher number of immature cells than in controls. This effect was blocked by ondansetron (a 5 HT3 antagonist). In conclusion, serotonin induces the progression from type I cells to type II cells but not from the later to mature PSA-NCAM immunonegative neurons. This effect is mediated by 5-HT3 receptors present in the immature cells.
{"title":"Ondansetron blocks fluoxetine effects in immature neurons in the adult rat piriform cortex layer II","authors":"Marina Recatalá , Pablo Hidalgo , Juan Nàcher , José Miguel Blasco-Ibáñez , Carlos Crespo , Emilio Varea","doi":"10.1016/j.neulet.2024.138099","DOIUrl":"10.1016/j.neulet.2024.138099","url":null,"abstract":"<div><div>Neuronal structural plasticity gives the adult brain the capacity to adapt to internal or external factors by structural and molecular changes. These plastic processes seem to be mediated, among others, by the action of the neurotransmitter serotonin through specific receptors (5-HTRs). Previous studies have shown that the maturation of granule cells in the hippocampus is mediated by 5-HT3. In the present study, we wanted to check if the neural maturation in layer II piriform cortex is also mediated by 5-HT3. In the piriform cortex, in contrast to the hippocampus, there is no postnatal neurogenesis. All immature neurons (PSA-NCAM immunoreactive) were originated prenatally. Immature cells in this area begin as small cells (type I cells) that then mature to larger cells (type II cells), and finally, mature to principal cells (PSA-NCAM immunonegative). To study the role of 5HT3 in this population, we first demonstrated the presence of 5HT3 receptors on both type I and II cells. Then we increased serotonin concentration using chronic fluoxetine administration, producing a reduction in the number of type I cells and an increment of type II cells but not an induction in the final stage of maturation to principal cells, as shown by the higher number of immature cells than in controls. This effect was blocked by ondansetron (a 5 HT3 antagonist). In conclusion, serotonin induces the progression from type I cells to type II cells but not from the later to mature PSA-NCAM immunonegative neurons. This effect is mediated by 5-HT3 receptors present in the immature cells.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"847 ","pages":"Article 138099"},"PeriodicalIF":2.5,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142896278","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-31DOI: 10.1016/j.neulet.2024.138095
Jun Fan , Jumian Feng , Lin Yang , Qin Zhang , Huaqiu Li
Sleep loss becomes a major problem in modern life and increases the incidence of anxiety disorders. Benzodiazepines are the most commonly used anxiolytic medications. Remimazolam is an ultra-short-acting benzodiazepine, which has been shown to reduce the preoperative anxiety levels in patients. However, the effects on anxiety-like behaviors caused by chronic sleep deprivation (CSD) and the underlying molecular mechanisms remain unclear. Here, we found that administration of remimazolam can effectively alleviate anxiety-like behaviors induced by CSD. Furthermore, remimazolam can significantly preserve the sleep deprivation-induced deficits in neuronal calcium activity in CA1 of the hippocampus. In addition, stimulator of interferon genes (STING) was activated in CA1 after CSD, while remimazolam was sufficient to block the activation of the STING pathway. Further study showed that inhibiting the activation of STING also effectively alleviates the anxiety symptoms induced by CSD. Overall, our research offers new insight and a promising therapeutic agent for the anxiety disorders caused by sleep deprivation.
{"title":"Remimazolam alleviates sleep deprivation induced anxiety-like behaviors via regulating the STING pathway","authors":"Jun Fan , Jumian Feng , Lin Yang , Qin Zhang , Huaqiu Li","doi":"10.1016/j.neulet.2024.138095","DOIUrl":"10.1016/j.neulet.2024.138095","url":null,"abstract":"<div><div>Sleep loss becomes a major problem in modern life and increases the incidence of anxiety disorders. Benzodiazepines are the most commonly used anxiolytic medications. Remimazolam is an ultra-short-acting benzodiazepine, which has been shown to reduce the preoperative anxiety levels in patients. However, the effects on anxiety-like behaviors caused by chronic sleep deprivation (CSD) and the underlying molecular mechanisms remain unclear. Here, we found that administration of remimazolam can effectively alleviate anxiety-like behaviors induced by CSD. Furthermore, remimazolam can significantly preserve the sleep deprivation-induced deficits in neuronal calcium activity in CA1 of the hippocampus. In addition, stimulator of interferon genes (STING) was activated in CA1 after CSD, while remimazolam was sufficient to block the activation of the STING pathway. Further study showed that inhibiting the activation of STING also effectively alleviates the anxiety symptoms induced by CSD. Overall, our research offers new insight and a promising therapeutic agent for the anxiety disorders caused by sleep deprivation.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"847 ","pages":"Article 138095"},"PeriodicalIF":2.5,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142896282","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-31DOI: 10.1016/j.neulet.2024.138100
C. Berryman , G.L. Moseley , T.R. Stanton , B. Hordacre , F. Di Pietro
Background
Complex regional pain syndrome (CRPS) is characterised by sensorimotor disturbances in the painful limb, coupled with neuroimaging evidence of functional changes in the primary somatosensory cortex (S1). However, the interaction between S1 in both hemispheres is unknown; altered interhemispheric interaction may contribute to this disorder.
Objective
We conducted the first study of sensory interhemispheric interaction in CRPS, specifically S1. This is also the first study to compare S1 interhemispheric inhibition in both directions in healthy controls.
Methods
Somatosensory evoked potentials were read with electroencephalography following paired median nerve stimulation at interstimulus intervals of 20, 25 and 30 ms.
Results
There was an inhibitory effect of the non-dominant on the dominant hemisphere in controls (ß = −0.308, SE 0.089, [CI −0.535, −0.081], t (914.9) = -3.49, p = 0.003), driven by changes in the N20/P25 SEP (i.e. S1). Importantly, this pattern of interhemispheric interaction was not seen in CRPS; in the CRPS group there was no evidence of interhemispheric inhibition – in either direction.
Conclusion
Given the difference in interhemispheric inhibition between CRPS and control groups, the role of S1 interhemispheric inhibition in CRPS needs further investigation. This may shed light on the sensorimotor disturbances characteristic of this disorder.
{"title":"Exploring interhemispheric interaction in complex regional pain syndrome","authors":"C. Berryman , G.L. Moseley , T.R. Stanton , B. Hordacre , F. Di Pietro","doi":"10.1016/j.neulet.2024.138100","DOIUrl":"10.1016/j.neulet.2024.138100","url":null,"abstract":"<div><h3>Background</h3><div>Complex regional pain syndrome (CRPS) is characterised by sensorimotor disturbances in the painful limb, coupled with neuroimaging evidence of functional changes in the primary somatosensory cortex (S1). However, the interaction between S1 in both hemispheres is unknown; altered interhemispheric interaction may contribute to this disorder.</div></div><div><h3>Objective</h3><div>We conducted the first study of sensory interhemispheric interaction in CRPS, specifically S1. This is also the first study to compare S1 interhemispheric inhibition in both directions in healthy controls.</div></div><div><h3>Methods</h3><div>Somatosensory evoked potentials were read with electroencephalography following paired median nerve stimulation at interstimulus intervals of 20, 25 and 30 ms.</div></div><div><h3>Results</h3><div>There was an inhibitory effect of the non-dominant on the dominant hemisphere in controls (ß = −0.308, SE 0.089, [CI −0.535, −0.081], t (914.9) = -3.49, p = 0.003), driven by changes in the N20/P25 SEP (i.e. S1). Importantly, this pattern of interhemispheric interaction was not seen in CRPS; in the CRPS group there was no evidence of interhemispheric inhibition – in either direction.</div></div><div><h3>Conclusion</h3><div>Given the difference in interhemispheric inhibition between CRPS and control groups, the role of S1 interhemispheric inhibition in CRPS needs further investigation. This may shed light on the sensorimotor disturbances characteristic of this disorder.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"847 ","pages":"Article 138100"},"PeriodicalIF":2.5,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143143587","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Major Depressive Disorder (MDD) directly impacts the lives of countless individuals worldwide, yet its causes remain incompletely understood. However, it is recognized that a deficiency in monoamines, including dopamine, may contribute to this disorder. N-(3-((3-(trifluoromethyl)phenyl)selenyl)prop-2-yn-1-yl) (CF3SePB) is an organoselenium compound that presented antidepressant-like effect in mice related to modulation of serotonergic, but not noradrenergic system. To expand the knowledge about CF3SePB mechanisms of action, this study aimed to evaluate the involvement of dopaminergic system in its antidepressant-like effect. Male Swiss mice were pre-treated with the haloperidol (0.05 mg/kg, i.p., a non-selective D2 receptor antagonist), SCH 23390 (0.01 mg/kg, s.c., a D1 receptor antagonist), and sulpiride (50 mg/kg, i.p., a D2 receptor antagonist) 15 min before CF3SePB (50 mg/kg, i.g.), and after 30 min of CF3SePB administration the forced swimming test (FST) was performed. CF3SePB presented an anti-immobility effect in the FST, demonstrated by increase in the latency to first episode of immobility and reduction of total immobility of mice, and the pre-treatment of mice with haloperidol, SCH 23390 and sulpiride prevented these effects, showing that the antidepressant-like effect of CF3SePB is related to the modulation of the dopaminergic system, specifically the D1 and D2 receptors. In addition, in silico pharmacokinetic profiling of CF3SePB predicted its low likelihood of inducing adverse effects and potential to cross the blood–brain barrier. These results expand the understanding of CF3SePB mechanisms for its antidepressant-like effect, reinforcing the potential of this organonoselenium compound for developing new antidepressants.
{"title":"Dopaminergic receptors involvement in the antidepressant-like effect of N-(3-((3-(trifluoromethyl)phenyl)selanyl)prop-2-yn-1-yl) benzamide in mice","authors":"Camila Simões Pires , Marcia Juciele da Rocha , Marcelo Heinemann Presa , Narryman Pinto Zuge , Evelyn Mianes Besckow , Kauane Nayara Bahr Ledebuhr , Natália Emanuele Biolosor Kuntz , Benhur Godoi , Cristiani Folharini Bortolatto , César Augusto Brüning","doi":"10.1016/j.neulet.2025.138144","DOIUrl":"10.1016/j.neulet.2025.138144","url":null,"abstract":"<div><div>Major Depressive Disorder (MDD) directly impacts the lives of countless individuals worldwide, yet its causes remain incompletely understood. However, it is recognized that a deficiency in monoamines, including dopamine, may contribute to this disorder. <em>N</em>-(3-((3-(trifluoromethyl)phenyl)selenyl)prop-2-yn-1-yl) (CF<sub>3</sub>SePB) is an organoselenium compound that presented antidepressant-like effect in mice related to modulation of serotonergic, but not noradrenergic system. To expand the knowledge about CF<sub>3</sub>SePB mechanisms of action, this study aimed to evaluate the involvement of dopaminergic system in its antidepressant-like effect. Male Swiss mice were pre-treated with the haloperidol (0.05 mg/kg, i.p., a non-selective D<sub>2</sub> receptor antagonist), SCH 23390 (0.01 mg/kg, s.c., a D<sub>1</sub> receptor antagonist), and sulpiride (50 mg/kg, i.p., a D<sub>2</sub> receptor antagonist) 15 min before CF<sub>3</sub>SePB (50 mg/kg, i.g.), and after 30 min of CF<sub>3</sub>SePB administration the forced swimming test (FST) was performed. CF<sub>3</sub>SePB presented an anti-immobility effect in the FST, demonstrated by increase in the latency to first episode of immobility and reduction of total immobility of mice, and the pre-treatment of mice with haloperidol, SCH 23390 and sulpiride prevented these effects, showing that the antidepressant-like effect of CF<sub>3</sub>SePB is related to the modulation of the dopaminergic system, specifically the D<sub>1</sub> and D<sub>2</sub> receptors. In addition, in silico pharmacokinetic profiling of CF<sub>3</sub>SePB predicted its low likelihood of inducing adverse effects and potential to cross the blood–brain barrier. These results expand the understanding of CF<sub>3</sub>SePB mechanisms for its antidepressant-like effect, reinforcing the potential of this organonoselenium compound for developing new antidepressants.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"849 ","pages":"Article 138144"},"PeriodicalIF":2.5,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143075160","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-28DOI: 10.1016/j.neulet.2025.138136
Ming-Yu Hao , Wei Su , Jun-Yi Xu , Zhong-Rui Chen , Lu He , Jing-Ying Guo , Ke Liu , Shu-Sheng Gong , Guo-Peng Wang
Hair cells (HCs) are essential for vestibular function, and irreversible damage to vestibular HCs in mammals is closely associated with vertigo. The stimulation of HC regeneration through exogenous gene delivery represents an ideal therapeutic approach for restoring vestibular function. Overexpression of Atoh1, Pou4f3, and Gfi1 (collectively referred to as APG) has demonstrated efficacy in promoting HC regeneration in the cochlea. However, the effects of APG on vestibular HC regeneration remain unclear. Here, we used adeno-associated virus-inner ear (AAVie) as a carrier to deliver APG to the utricles of neonatal mice and assessed the morphology and number of HCs and supporting cells (SCs) by immunofluorescence staining. GLASTCreERT;Rosa26tdTomato mouse line was used to trace SCs. The results showed that APG overexpression resulted in substantial SC transdifferentiation into HCs in the neonatal mouse utricle. Furthermore, APG overexpression maintained SC number by facilitating SC proliferation. Continuous Atoh1 overexpression caused stereocilia damage, which was alleviated by APG overexpression. This study highlights the potential of regulating multiple transcription factors to promote vestibular HC regeneration.
毛细胞对前庭功能至关重要，哺乳动物前庭毛细胞的不可逆损伤与眩晕密切相关。通过外源基因递送刺激毛细胞再生是恢复前庭功能的理想治疗方法。过量表达 Atoh1、Pou4f3 和 Gfi1（统称为 APG）已被证明能有效促进耳蜗中 HC 的再生。然而，APG 对前庭 HC 再生的影响仍不清楚。在这里，我们使用腺相关病毒内耳（AAVie）作为载体，将APG送入新生小鼠的耳蜗，并通过免疫荧光染色评估了HCs和支持细胞（SCs）的形态和数量。GLASTCreERT;Rosa26tdTomato小鼠品系用于追踪SCs。结果表明，APG过表达会导致新生小鼠胞器中的SC大量转分化为HC。此外，APG过表达还能促进SC增殖，从而维持SC的数量。持续过表达 Atoh1 会造成立体纤毛损伤，而过表达 APG 则可减轻损伤。这项研究强调了调节多种转录因子促进前庭HC再生的潜力。
{"title":"Co-overexpression of Atoh1, Pou4f3, and Gfi1 enhances the transdifferentiation of supporting cells into hair cells in the neonatal mouse utricle","authors":"Ming-Yu Hao , Wei Su , Jun-Yi Xu , Zhong-Rui Chen , Lu He , Jing-Ying Guo , Ke Liu , Shu-Sheng Gong , Guo-Peng Wang","doi":"10.1016/j.neulet.2025.138136","DOIUrl":"10.1016/j.neulet.2025.138136","url":null,"abstract":"<div><div>Hair cells (HCs) are essential for vestibular function, and irreversible damage to vestibular HCs in mammals is closely associated with vertigo. The stimulation of HC regeneration through exogenous gene delivery represents an ideal therapeutic approach for restoring vestibular function. Overexpression of Atoh1, Pou4f3, and Gfi1 (collectively referred to as APG) has demonstrated efficacy in promoting HC regeneration in the cochlea. However, the effects of APG on vestibular HC regeneration remain unclear. Here, we used adeno-associated virus-inner ear (AAVie) as a carrier to deliver APG to the utricles of neonatal mice and assessed the morphology and number of HCs and supporting cells (SCs) by immunofluorescence staining. GLAST<sup>CreERT</sup>;Rosa26<sup>tdTomato</sup> mouse line was used to trace SCs. The results showed that APG overexpression resulted in substantial SC transdifferentiation into HCs in the neonatal mouse utricle. Furthermore, APG overexpression maintained SC number by facilitating SC proliferation. Continuous Atoh1 overexpression caused stereocilia damage, which was alleviated by APG overexpression. This study highlights the potential of regulating multiple transcription factors to promote vestibular HC regeneration.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"849 ","pages":"Article 138136"},"PeriodicalIF":2.5,"publicationDate":"2025-01-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143066465","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-27DOI: 10.1016/j.neulet.2025.138134
Yan Hua , Congqin Li , Anjing Zhang , Yuyuan Wang , Ying Xing , Zhanzhuang Tian , Jian Hu , Yulong Bai
The effect of Constraint-induced movement therapy (CIMT) or Intermittent theta-burst stimulation (iTBS) alone is limited in improving motor function after a stroke. In this study, we explored the efficacy and possible mechanisms in combination of CIMT and iTBS through behavioral evaluation, RNA sequencing, Golgi staining, transmission electronic microscope (TEM), high-performance liquid chromatography (HPLC), western blotting (WB) and immunofluorescence. Firstly, we observed that combination therapy is safe and effective, and it can significantly reduce the number of immature dendritic spines and increase the number of functional dendritic spines, the amount of glutamate (Glu) and the expression of Glu1 receptor (Glu1R). Meanwhile, we have found a significant reduction in neutrophil extracellular traps (NETs) in the combination group, and correlation analysis showed that the number of NETs is negatively correlated with the number of functional dendritic spines and the expression of Glu1R. After Cl-amidine ((S) - N - (1-amino-5- (2-chloroacetamiprid) -1-oxopentan-2-yl) benzamide 2,2,2-trifluoroacetate salt, PAD4 inhibitors) application, combined therapy did not further improve motor function and the expression of Glu1R. Our results proved that CIMT combined with iTBS therapy is a better therapeutic intervention. It improved motor function and synaptic plasticity after a stroke by promoting the transformation of functional dendritic spines and the expression of Glu1R in the ipsilateral primary motor cortex. The reduction of NETs generation is one of the key targets within it.
{"title":"Constraint-induced movement therapy combined with intermittent theta-burst stimulation improve synaptic plasticity by inhibiting neutrophils extracellular traps formation in ipsilateral primary motor cortex of stroke rats","authors":"Yan Hua , Congqin Li , Anjing Zhang , Yuyuan Wang , Ying Xing , Zhanzhuang Tian , Jian Hu , Yulong Bai","doi":"10.1016/j.neulet.2025.138134","DOIUrl":"10.1016/j.neulet.2025.138134","url":null,"abstract":"<div><div>The effect of Constraint-induced movement therapy (CIMT) or Intermittent theta-burst stimulation (iTBS) alone is limited in improving motor function after a stroke. In this study, we explored the efficacy and possible mechanisms in combination of CIMT and iTBS through behavioral evaluation, RNA sequencing, Golgi staining, transmission electronic microscope (TEM), high-performance liquid chromatography (HPLC), western blotting (WB) and immunofluorescence. Firstly, we observed that combination therapy is safe and effective, and it can significantly reduce the number of immature dendritic spines and increase the number of functional dendritic spines, the amount of glutamate (Glu) and the expression of Glu1 receptor (Glu1R). Meanwhile, we have found a significant reduction in neutrophil extracellular traps (NETs) in the combination group, and correlation analysis showed that the number of NETs is negatively correlated with the number of functional dendritic spines and the expression of Glu1R. After Cl-amidine ((S) - N - (1-amino-5- (2-chloroacetamiprid) -1-oxopentan-2-yl) benzamide 2,2,2-trifluoroacetate salt, PAD4 inhibitors) application, combined therapy did not further improve motor function and the expression of Glu1R. Our results proved that CIMT combined with iTBS therapy is a better therapeutic intervention. It improved motor function and synaptic plasticity after a stroke by promoting the transformation of functional dendritic spines and the expression of Glu1R in the ipsilateral primary motor cortex. The reduction of NETs generation is one of the key targets within it.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"849 ","pages":"Article 138134"},"PeriodicalIF":2.5,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143066271","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-25DOI: 10.1016/j.neulet.2025.138132
Evdokia Skalnik, Natalia Ivlieva
Contemporary analyses of neurophysiological mechanisms of associative learning suggest that instrumental behavior can be controlled by separable action and habit processes. An increasingly broad range of human psychiatric and neurological disorders are now associated with maladaptive habit formation. The question of how the brain controls transitions into habit is thus relevant. Widely used training procedures that might differentially generate goal-directed actions or habits are variable schedules of reinforcement. Random interval schedules are known to generate habitual behavior compared with random ratio schedules Here, we report attempt to identify the behavioral characteristics of the bifurcation point of habitual and goal-directed behavior. We compared the time courses of learning in random ratio and random interval schedules with more common for neurophysiological researches parameters. Behavioral differences between schedules emerge early in learning. However, in outcome devaluation test we found that training in the random ratio schedule, but not in the random interval schedule, led to results interpreted as habitual behavior. This result is the opposite of what we expected based on previous research. We assume that the most commonly used variable schedules of reinforcement cannot serve as a reliable tool for analyzing neural mechanisms of habitual and goal-directed behavior.
{"title":"Variable schedules of reinforcement do not reliably distinguish habit from goal-directed behavior","authors":"Evdokia Skalnik, Natalia Ivlieva","doi":"10.1016/j.neulet.2025.138132","DOIUrl":"10.1016/j.neulet.2025.138132","url":null,"abstract":"<div><div>Contemporary analyses of neurophysiological mechanisms of associative learning suggest that instrumental behavior can be controlled by separable action and habit processes. An increasingly broad range of human psychiatric and neurological disorders are now associated with maladaptive habit formation. The question of how the brain controls transitions into habit is thus relevant. Widely used training procedures that might differentially generate goal-directed actions or habits are variable schedules of reinforcement. Random interval schedules are known to generate habitual behavior compared with random ratio schedules Here, we report attempt to identify the behavioral characteristics of the bifurcation point of habitual and goal-directed behavior. We compared the time courses of learning in random ratio and random interval schedules with more common for neurophysiological researches parameters. Behavioral differences between schedules emerge early in learning. However, in outcome devaluation test we found that training in the random ratio schedule, but not in the random interval schedule, led to results interpreted as habitual behavior. This result is the opposite of what we expected based on previous research. We assume that the most commonly used variable schedules of reinforcement cannot serve as a reliable tool for analyzing neural mechanisms of habitual and goal-directed behavior.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"849 ","pages":"Article 138132"},"PeriodicalIF":2.5,"publicationDate":"2025-01-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143053150","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2025-01-23DOI: 10.1016/j.neulet.2025.138120
Abigail E. Bower , Jae Woo Chung , Roxana G. Burciu
Aging has a significant impact on brain structure, demonstrated by numerous MRI studies using diffusion tensor imaging (DTI). While these studies reveal changes in fractional anisotropy (FA) across different brain regions, they tend to focus on white matter tracts and cognitive regions, often overlooking gray matter and motor areas. Additionally, traditional DTI metrics can be affected by partial volume effects. To address these limitations and gain a better understanding of microstructural changes across the whole brain, we utilized free water-corrected fractional anisotropy (FAt) to examine aging-related microstructural changes in a group of 20 young adults (YA) and 24 older adults (OA). A voxel-wise analysis revealed that YA had higher FAt values predominantly in white matter tracts associated with both motor and non-motor functions. In contrast, OA showed higher levels of FAt primarily in gray matter regions, including both subcortical and cortical motor areas, and occipital and temporal cortices. Complementing these cross-sectional results, correlation analyses within the OA group showed that many of these changes are further exacerbated with increasing age, underscoring the progressive nature of these microstructural alterations. In summary, the distinct patterns of FAt changes in gray versus white matter with aging suggest different underlying mechanisms. While white matter FAt values decrease, likely due to axonal degeneration, the increase in gray matter FAt could reflect either compensatory processes or pathological changes. Including behavioral data in future studies will be crucial for understanding the functional implications of these microstructural gray matter changes and their effects on cognitive and motor functions.
{"title":"Mapping the aging brain: Insights into microstructural changes from free water-corrected fractional anisotropy","authors":"Abigail E. Bower , Jae Woo Chung , Roxana G. Burciu","doi":"10.1016/j.neulet.2025.138120","DOIUrl":"10.1016/j.neulet.2025.138120","url":null,"abstract":"<div><div>Aging has a significant impact on brain structure, demonstrated by numerous MRI studies using diffusion tensor imaging (DTI). While these studies reveal changes in fractional anisotropy (FA) across different brain regions, they tend to focus on white matter tracts and cognitive regions, often overlooking gray matter and motor areas. Additionally, traditional DTI metrics can be affected by partial volume effects. To address these limitations and gain a better understanding of microstructural changes across the whole brain, we utilized free water-corrected fractional anisotropy (FAt) to examine aging-related microstructural changes in a group of 20 young adults (YA) and 24 older adults (OA). A voxel-wise analysis revealed that YA had higher FAt values predominantly in white matter tracts associated with both motor and non-motor functions. In contrast, OA showed higher levels of FAt primarily in gray matter regions, including both subcortical and cortical motor areas, and occipital and temporal cortices. Complementing these cross-sectional results, correlation analyses within the OA group showed that many of these changes are further exacerbated with increasing age, underscoring the progressive nature of these microstructural alterations. In summary, the distinct patterns of FAt changes in gray versus white matter with aging suggest different underlying mechanisms. While white matter FAt values decrease, likely due to axonal degeneration, the increase in gray matter FAt could reflect either compensatory processes or pathological changes. Including behavioral data in future studies will be crucial for understanding the functional implications of these microstructural gray matter changes and their effects on cognitive and motor functions.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"849 ","pages":"Article 138120"},"PeriodicalIF":2.5,"publicationDate":"2025-01-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143039184","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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