Importance of breastfeeding is well recognized, since it supports the survival of mammalian infants. The mammary papilla, a specialized skin region for breastfeeding, acts as a vital interface between mother and infant: perceiving the suckling to trigger the milk ejection reflex in mother and transporting milk from mother to infants. Despite its crucial roles in breastfeeding, the histological and cellular changes in the mammary papilla during lactation remain poorly understood. In this study, we focused on the sensory afferent projection mediating somatosensory perception. Our observation revealed that the mammary papilla is innervated by non-peptidergic C-fibers, which engage in the mechanical nociception. Moreover, we found that these sensory afferents are eliminated in the mammary papilla of lactating females. These results propose the lactation-associated elimination of sensory afferents in the mammary papilla as a novel mechanism adaptive for the breastfeeding.
{"title":"Sensory afferents in the mammary papilla are eliminated during the lactation","authors":"Kei Nakayama , Kotoko Suzuki , Yukiko Marunaka , Mari Kondo , Yuji Yokouchi , Naoki Takeda , Kenichi Yamamura , Hiroshi Hasegawa","doi":"10.1016/j.neulet.2025.138441","DOIUrl":"10.1016/j.neulet.2025.138441","url":null,"abstract":"<div><div>Importance of breastfeeding is well recognized, since it supports the survival of mammalian infants. The mammary papilla, a specialized skin region for breastfeeding, acts as a vital interface between mother and infant: perceiving the suckling to trigger the milk ejection reflex in mother and transporting milk from mother to infants. Despite its crucial roles in breastfeeding, the histological and cellular changes in the mammary papilla during lactation remain poorly understood. In this study, we focused on the sensory afferent projection mediating somatosensory perception. Our observation revealed that the mammary papilla is innervated by non-peptidergic C-fibers, which engage in the mechanical nociception. Moreover, we found that these sensory afferents are eliminated in the mammary papilla of lactating females. These results propose the lactation-associated elimination of sensory afferents in the mammary papilla as a novel mechanism adaptive for the breastfeeding.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"870 ","pages":"Article 138441"},"PeriodicalIF":2.0,"publicationDate":"2025-11-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145452453","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 : 2025-11-03DOI: 10.1016/j.neulet.2025.138440
TianYu Ge , Xi Chen , Chang Liu , SaiSai Huang
Chronic postsurgical pain (CPSP) is a global concern associated with significant health and economic issues for patients. We investigated the effects of C-X-C motif chemokine receptor 2 (CXCR2) related signal transduction mechanisms on CPSP in a rat skin muscle incision and retraction (SMIR) model. Following model establishment, glial cells in the spinal dorsal horn were activated, and the expression of inflammatory factors (tumor necrosis factor (TNF)-α and interleukin (IL)-1β increased. The SMIR group demonstrated elevated expression of CXCR2, phosphorylated ERK (p-ERK), and phosphorylated p38 (p-p38) in the spinal dorsal horn. After intrathecal injection of the CXCR2 antagonist SB225002, the rats’ pain threshold increased, accompanied by reduced expression of inflammatory factors and reversal of glial cell activation. Additionally, primary microglial cells induced by lipopolysaccharide were used as an in vitro model. Transfection with si-CXCR2 led to decreased expression of p-ERK and p-p38 in microglial cells, along with lower TNF-α and IL-1β levels in the cell supernatant. These results indicate that CXCR2 activates spinal glial cells via the ERK/p38 pathway, promoting neuroinflammation, and CPSP, whereas CXCR2 inhibition counteracts these effects and alleviates CPSP.
{"title":"Involvement of CXCR2 in chronic postsurgical pain occurrence through ERK/p38 activation","authors":"TianYu Ge , Xi Chen , Chang Liu , SaiSai Huang","doi":"10.1016/j.neulet.2025.138440","DOIUrl":"10.1016/j.neulet.2025.138440","url":null,"abstract":"<div><div>Chronic postsurgical pain (CPSP) is a global concern associated with significant health and economic issues for patients. We investigated the effects of C-X-C motif chemokine receptor 2 (CXCR2) related signal transduction mechanisms on CPSP in a rat skin muscle incision and retraction (SMIR) model. Following model establishment, glial cells in the spinal dorsal horn were activated, and the expression of inflammatory factors (tumor necrosis factor (TNF)-α and interleukin (IL)-1β increased. The SMIR group demonstrated elevated expression of CXCR2, phosphorylated ERK (p-ERK), and phosphorylated p38 (p-p38) in the spinal dorsal horn. After intrathecal injection of the CXCR2 antagonist SB225002, the rats’ pain threshold increased, accompanied by reduced expression of inflammatory factors and reversal of glial cell activation. Additionally, primary microglial cells induced by lipopolysaccharide were used as an in vitro model. Transfection with si-CXCR2 led to decreased expression of p-ERK and p-p38 in microglial cells, along with lower TNF-α and IL-1β levels in the cell supernatant. These results indicate that CXCR2 activates spinal glial cells via the ERK/p38 pathway, promoting neuroinflammation, and CPSP, whereas CXCR2 inhibition counteracts these effects and alleviates CPSP.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"870 ","pages":"Article 138440"},"PeriodicalIF":2.0,"publicationDate":"2025-11-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145452462","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 : 2025-11-01DOI: 10.1016/j.neulet.2025.138411
Maria Elide Vanutelli , Mirella Manfredi
{"title":"Laughing your… brain off. New insights on the adaptive meaning of humour","authors":"Maria Elide Vanutelli , Mirella Manfredi","doi":"10.1016/j.neulet.2025.138411","DOIUrl":"10.1016/j.neulet.2025.138411","url":null,"abstract":"","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"867 ","pages":"Article 138411"},"PeriodicalIF":2.0,"publicationDate":"2025-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145275476","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 : 2025-10-31DOI: 10.1016/j.neulet.2025.138430
Federico Ferro , Veronica Fontebasso , Magali Basille-Dugay , David Vaudry , Karl Ebner
Vasoactive intestinal peptide (VIP) is a highly abundant neuropeptide in the central nervous system, implicated in the regulation of numerous behavioral and physiological functions, including the central stress response. Notably, VIP and its cognate receptors, VPAC1 and VPAC2, are widely expressed in brain areas implicated in stress and anxiety regulation such as the amygdala. However, the exact role of VIP in stress function is not fully understood. The present study therefore examined how acute or chronic stress affect VIP and VPAC receptor gene expression in specific limbic brain regions of Sprague-Dawley rats using quantitative real-time PCR. Acute stress via forced swim exposure significantly increased VIP expression in the central amygdala (CeA) by 200 %, and in the medial amygdala (MeA) by 350 %. It also elevated VPAC1 receptor expression in the hypothalamic paraventricular nucleus (PVN), basolateral amygdala (BLA), and CeA, and VPAC2 receptor expression in the bed nucleus of the stria terminalis (BNST) and BLA. Chronic unpredictable stress induced both overlapping and distinct patterns, including upregulation of the VPAC1 receptor expression in the PVN by 120 % and the VPAC2 receptor in the CeA by 280 %, accompanied by slight downregulation of VIP in the CeA. These findings highlight a stress-duration-dependent and region-specific regulation of the VIP/VPAC receptor system and its potential role in modulating stress-related neural circuits.
{"title":"Stress-type specific changes of VIP signaling in limbic regions of the rat brain","authors":"Federico Ferro , Veronica Fontebasso , Magali Basille-Dugay , David Vaudry , Karl Ebner","doi":"10.1016/j.neulet.2025.138430","DOIUrl":"10.1016/j.neulet.2025.138430","url":null,"abstract":"<div><div>Vasoactive intestinal peptide (VIP) is a highly abundant neuropeptide in the central nervous system, implicated in the regulation of numerous behavioral and physiological functions, including the central stress response. Notably, VIP and its cognate receptors, VPAC1 and VPAC2, are widely expressed in brain areas implicated in stress and anxiety regulation such as the amygdala. However, the exact role of VIP in stress function is not fully understood. The present study therefore examined how acute or chronic stress affect VIP and VPAC receptor gene expression in specific limbic brain regions of Sprague-Dawley rats using quantitative real-time PCR. Acute stress via forced swim exposure significantly increased VIP expression in the central amygdala (CeA) by 200 %, and in the medial amygdala (MeA) by 350 %. It also elevated VPAC1 receptor expression in the hypothalamic paraventricular nucleus (PVN), basolateral amygdala (BLA), and CeA, and VPAC2 receptor expression in the bed nucleus of the stria terminalis (BNST) and BLA. Chronic unpredictable stress induced both overlapping and distinct patterns, including upregulation of the VPAC1 receptor expression in the PVN by 120 % and the VPAC2 receptor in the CeA by 280 %, accompanied by slight downregulation of VIP in the CeA. These findings highlight a stress-duration-dependent and region-specific regulation of the VIP/VPAC receptor system and its potential role in modulating stress-related neural circuits.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"870 ","pages":"Article 138430"},"PeriodicalIF":2.0,"publicationDate":"2025-10-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145431320","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 : 2025-10-28DOI: 10.1016/j.neulet.2025.138429
Jiang Wu , Lijin Zhou , Chao Lang
Ziziphi Spinosae Semen (Suan Zao Ren) is a traditional Chinese medicine with the functions of nourishing the heart and liver, calming the mind, and stopping sweating. Swertisin, one of the main active ingredients in Ziziphi Spinosae Semen, has a wide range of pharmacological effects such as anti-inflammation, anti-oxidation, and enhancement of learning and memory. Based on the Aβ cascade and the neuroinflammatory theory, combined with the anti-inflammatory neuroprotective effect of endocannabinoid 2-AG, this work integrated modern biochemical technology methods such as liquid chromatography-mass spectrometry, Western blot, and electrophysiological technique to explore the neuroprotective effects and potential mechanism of swertisin on the Alzheimer’s disease (AD) model induced by Aβ25-35. The results showed that swertisin relieved impairment of learning and memory caused by Aβ25-35 on hippocampus slice by decreasing COX-2 expression and inhibiting COX-2 activity to up-regulate the endogenous 2-AG, and suppressing neuroinflammation and neuronal apoptosis via CB1R-dependent NF-κB pathway. It was further discovered that swertisin protected the primary hippocampal neurons, reduced over-expression of COX-2, and relieved the neuroinflammatory against Aβ25-35 through the CB1R-dependent NF-κB signaling pathway. Finally, it was confirmed that swertisin alleviated BV-2 cell apoptosis induced by Aβ25-35. These results help us understand the mechanism of swertisin against AD and promote the development of related drugs and healthy products.
{"title":"Neuro-protection of swertisin against impairment induced by Aβ25-35 by acting on COX-2 to up-regulate 2-AG and suppressing neuroinflammation","authors":"Jiang Wu , Lijin Zhou , Chao Lang","doi":"10.1016/j.neulet.2025.138429","DOIUrl":"10.1016/j.neulet.2025.138429","url":null,"abstract":"<div><div>Ziziphi Spinosae Semen (Suan Zao Ren) is a traditional Chinese medicine with the functions of nourishing the heart and liver, calming the mind, and stopping sweating. Swertisin, one of the main active ingredients in Ziziphi Spinosae Semen, has a wide range of pharmacological effects such as anti-inflammation, anti-oxidation, and enhancement of learning and memory. Based on the Aβ cascade and the neuroinflammatory theory, combined with the anti-inflammatory neuroprotective effect of endocannabinoid 2-AG, this work integrated modern biochemical technology methods such as liquid chromatography-mass spectrometry, Western blot, and electrophysiological technique to explore the neuroprotective effects and potential mechanism of swertisin on the Alzheimer’s disease (AD) model induced by Aβ<sub>25-35</sub>. The results showed that swertisin relieved impairment of learning and memory caused by Aβ<sub>25-35</sub> on hippocampus slice by decreasing COX-2 expression and inhibiting COX-2 activity to up-regulate the endogenous 2-AG, and suppressing neuroinflammation and neuronal apoptosis <em>via</em> CB1R-dependent NF-κB pathway. It was further discovered that swertisin protected the primary hippocampal neurons, reduced over-expression of COX-2, and relieved the neuroinflammatory against Aβ<sub>25-35</sub> through the CB1R-dependent NF-κB signaling pathway. Finally, it was confirmed that swertisin alleviated BV-2 cell apoptosis induced by Aβ<sub>25-35.</sub> These results help us understand the mechanism of swertisin against AD and promote the development of related drugs and healthy products.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"870 ","pages":"Article 138429"},"PeriodicalIF":2.0,"publicationDate":"2025-10-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145409674","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 : 2025-10-26DOI: 10.1016/j.neulet.2025.138428
Mi Ran Choi , Chaeeun Park , Jihun Kim , Jeong-Hyeon Heo , Seok Hwan Chang , Han-Na Kim , Yeung Bae Jin , Sang-Rae Lee
Cannabidiol (CBD) is increasingly consumed via vaping, but its acute molecular impact on the striatum, a critical hub for motor control and reward processing that is highly sensitive to cannabinoid modulation, remains poorly understood. This study investigated differential expression of long noncoding RNAs (lncRNAs) and mRNAs in the striatum after acute exposure to vaporized CBD. Male ICR mice (n = 5 per group) were exposed to vaporized CBD oil (50 mg) and striatal tissues were collected 24 h later. Differentially expressed mRNAs and lncRNAs were identified using total RNA sequencing and mRNA–lncRNA co-expression networks were constructed. Selected transcripts were validated using qRT-PCR and discriminative capacity was assessed by ROC analysis. CBD exposure altered the expression of 931 mRNAs and 229 lncRNAs. GO and KEGG analyses revealed bidirectional regulation of pathways involved in neural development and synaptic transmission, including both up- and downregulated genes in categories such as glutamatergic synapse. Ion transport genes (Trpm2, Tmem63a, Tmem175, Glrb) were robustly upregulated, while genes involved in excitatory synaptic structure (Dlgap2, Shisa9, Tac1) and dopaminergic-associated pathways (Drd3, Oxt) were downregulated. mRNA–lncRNA network analysis highlighted regulatory hubs including NONMMUT114016.1 and NONMMUT057055.2, and ROC analysis identified strong biomarker candidates such as Tmem175, Ptprd, NONMMUT042895.2, and NONMMUT151847.1. These findings indicate that acute CBD vaping induces widespread transcriptomic remodeling in the striatum, enhancing ion transport and inhibitory signaling while suppressing excitatory and dopaminergic pathways. This study provides the first comprehensive striatal transcriptome profiling of coding and noncoding RNAs in response to vaporized CBD.
{"title":"Acute exposure to vaporized cannabidiol remodels coding and noncoding transcriptomes in the mouse striatum","authors":"Mi Ran Choi , Chaeeun Park , Jihun Kim , Jeong-Hyeon Heo , Seok Hwan Chang , Han-Na Kim , Yeung Bae Jin , Sang-Rae Lee","doi":"10.1016/j.neulet.2025.138428","DOIUrl":"10.1016/j.neulet.2025.138428","url":null,"abstract":"<div><div>Cannabidiol (CBD) is increasingly consumed via vaping, but its acute molecular impact on the striatum, a critical hub for motor control and reward processing that is highly sensitive to cannabinoid modulation, remains poorly understood. This study investigated differential expression of long noncoding RNAs (lncRNAs) and mRNAs in the striatum after acute exposure to vaporized CBD. Male ICR mice (n = 5 per group) were exposed to vaporized CBD oil (50 mg) and striatal tissues were collected 24 h later. Differentially expressed mRNAs and lncRNAs were identified using total RNA sequencing and mRNA–lncRNA co-expression networks were constructed. Selected transcripts were validated using qRT-PCR and discriminative capacity was assessed by ROC analysis. CBD exposure altered the expression of 931 mRNAs and 229 lncRNAs. GO and KEGG analyses revealed bidirectional regulation of pathways involved in neural development and synaptic transmission, including both up- and downregulated genes in categories such as glutamatergic synapse. Ion transport genes (<em>Trpm2, Tmem63a, Tmem175, Glrb</em>) were robustly upregulated, while genes involved in excitatory synaptic structure (<em>Dlgap2, Shisa9, Tac1</em>) and dopaminergic-associated pathways (<em>Drd3, Oxt</em>) were downregulated. mRNA–lncRNA network analysis highlighted regulatory hubs including <em>NONMMUT114016.1</em> and <em>NONMMUT057055.2</em>, and ROC analysis identified strong biomarker candidates such as <em>Tmem175, Ptprd, NONMMUT042895.2,</em> and <em>NONMMUT151847.1</em>. These findings indicate that acute CBD vaping induces widespread transcriptomic remodeling in the striatum, enhancing ion transport and inhibitory signaling while suppressing excitatory and dopaminergic pathways. This study provides the first comprehensive striatal transcriptome profiling of coding and noncoding RNAs in response to vaporized CBD.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"869 ","pages":"Article 138428"},"PeriodicalIF":2.0,"publicationDate":"2025-10-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145391290","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 : 2025-10-21DOI: 10.1016/j.neulet.2025.138426
Cem Süer, Burak Tan, Nurcan Dursun, Bilal Koşar, Ercan Babur
This study examined the role of MAPKs in Tau phosphorylation and synaptic plasticity at perforant pathway–dentate gyrus (PP–DG) synapses following high-frequency stimulation (HFS). In vivo experiments were conducted on adult male Wistar rats under urethane anesthesia. Field potentials (fEPSP and PS) were recorded in the DG granule cell layer in response to PP stimulation. Western blotting assessed total and phosphorylated levels of Tau, ERK1/2, JNK, and P38 MAPK in HFS-induced hippocampus. MAPK inhibition disrupted early somatic potentiation when applied during induction, and JNK inhibition alone impaired late potentiation. Reduced somatic activity correlated with decreased MAPK phosphorylation and Tau phosphorylation at Ser422. Findings suggest that ERK1/2, JNK, and P38 are essential for Tau phosphorylation at Ser422 in HFS-induced hippocampal synapses.
{"title":"Site-Specific Regulation of Tau phosphorylation by MAPK pathways during HFS-Induced synaptic plasticity in the Rat hippocampus","authors":"Cem Süer, Burak Tan, Nurcan Dursun, Bilal Koşar, Ercan Babur","doi":"10.1016/j.neulet.2025.138426","DOIUrl":"10.1016/j.neulet.2025.138426","url":null,"abstract":"<div><div>This study examined the role of MAPKs in Tau phosphorylation and synaptic plasticity at perforant pathway–dentate gyrus (PP–DG) synapses following high-frequency stimulation (HFS). In vivo experiments were conducted on adult male Wistar rats under urethane anesthesia. Field potentials (fEPSP and PS) were recorded in the DG granule cell layer in response to PP stimulation. Western blotting assessed total and phosphorylated levels of Tau, ERK1/2, JNK, and P38 MAPK in HFS-induced hippocampus. MAPK inhibition disrupted early somatic potentiation when applied during induction, and JNK inhibition alone impaired late potentiation. Reduced somatic activity correlated with decreased MAPK phosphorylation and Tau phosphorylation at Ser422. Findings suggest that ERK1/2, JNK, and P38 are essential for Tau phosphorylation at Ser422 in HFS-induced hippocampal synapses.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"869 ","pages":"Article 138426"},"PeriodicalIF":2.0,"publicationDate":"2025-10-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145355586","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 : 2025-10-20DOI: 10.1016/j.neulet.2025.138427
Shin-Young Park
Hippocalcin (HPCA), a neuronal Ca2+ sensor protein in the EF-hand superfamily, plays a key role in calcium signaling and neurological function in the central nervous system. This review highlights HPCA’s structure–function relationships and clinical significance. Through Ca2+-dependent conformational changes and a unique calcium-myristoyl switch, HPCA dynamically associates with membranes, acting as both sensor and effector. It modulates neuronal excitability, synaptic plasticity, neurodevelopment, and neuroprotection. Notably, HPCA is critical in mediating slow afterhyperpolarization, a key mechanism for adjusting neuronal firing patterns and maintaining excitability homeostasis. It also influences neural stem cell fate by promoting neuronal differentiation and suppressing astrocytic differentiation. HPCA maintains mitochondrial calcium homeostasis and activates survival pathways, protecting against apoptosis and oxidative stress. Its dysregulation is implicated in Alzheimer’s and Parkinson’s diseases, epilepsy, depression, schizophrenia, and dystonia. Given its restricted expression in the brain and multifaceted functional roles, further elucidation of HPCA-mediated signaling mechanisms is warranted to advance the development of targeted therapeutic strategies for a broad spectrum of neurological disorders.
{"title":"Mini-review: “Hippocalcin: Molecular mechanisms and therapeutic potential in neuronal function”","authors":"Shin-Young Park","doi":"10.1016/j.neulet.2025.138427","DOIUrl":"10.1016/j.neulet.2025.138427","url":null,"abstract":"<div><div>Hippocalcin (HPCA), a neuronal Ca<sup>2+</sup> sensor protein in the EF-hand superfamily, plays a key role in calcium signaling and neurological function in the central nervous system. This review highlights HPCA’s structure–function relationships and clinical significance. Through Ca2<sup>+</sup>-dependent conformational changes and a unique calcium-myristoyl switch, HPCA dynamically associates with membranes, acting as both sensor and effector. It modulates neuronal excitability, synaptic plasticity, neurodevelopment, and neuroprotection. Notably, HPCA is critical in mediating slow afterhyperpolarization, a key mechanism for adjusting neuronal firing patterns and maintaining excitability homeostasis. It also influences neural stem cell fate by promoting neuronal differentiation and suppressing astrocytic differentiation. HPCA maintains mitochondrial calcium homeostasis and activates survival pathways, protecting against apoptosis and oxidative stress. Its dysregulation is implicated in Alzheimer’s and Parkinson’s diseases, epilepsy, depression, schizophrenia, and dystonia. Given its restricted expression in the brain and multifaceted functional roles, further elucidation of HPCA-mediated signaling mechanisms is warranted to advance the development of targeted therapeutic strategies for a broad spectrum of neurological disorders.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"869 ","pages":"Article 138427"},"PeriodicalIF":2.0,"publicationDate":"2025-10-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145337081","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 : 2025-10-18DOI: 10.1016/j.neulet.2025.138424
Jee Hyun Yi
Impairments in working memory and cognitive flexibility are early and consistent features of both Alzheimer’s disease (AD) and stress. These functions depend critically on prefrontal cortical (PFC) circuits, which are particularly vulnerable to neuromodulatory and pathological insults. Recent studies suggest that stress and AD do not simply act globally, but instead converge on specific molecular and cellular targets within distinct neural populations. Notably, both chronic stress and Alzheimer’s disease models exhibit dysregulation of synaptic signaling via NR2B-containing NMDA receptors and aberrant GSK-3β activation. These changes often emerge in a cell-type-specific manner, affecting excitatory pyramidal neurons and vulnerable interneuron subtypes such as SST+, PV+, and VIP + cells. The resulting imbalance in excitation and inhibition disrupts the integrity of prefrontal circuits, impairing adaptive behavior. This review synthesizes evidence across molecular, cellular, and circuit levels to outline a framework in which stress and AD pathology converge on shared vulnerable pathways. Understanding how specific cell populations mediate this vulnerability may lead to targeted strategies for enhancing cognitive resilience in neurodegenerative and stress-related disorders.
{"title":"From stress to Alzheimer’s: A circuit-based framework for prefrontal cognitive dysfunction","authors":"Jee Hyun Yi","doi":"10.1016/j.neulet.2025.138424","DOIUrl":"10.1016/j.neulet.2025.138424","url":null,"abstract":"<div><div>Impairments in working memory and cognitive flexibility are early and consistent features of both Alzheimer’s disease (AD) and stress. These functions depend critically on prefrontal cortical (PFC) circuits, which are particularly vulnerable to neuromodulatory and pathological insults. Recent studies suggest that stress and AD do not simply act globally, but instead converge on specific molecular and cellular targets within distinct neural populations. Notably, both chronic stress and Alzheimer’s disease models exhibit dysregulation of synaptic signaling via NR2B-containing NMDA receptors and aberrant GSK-3β activation. These changes often emerge in a cell-type-specific manner, affecting excitatory pyramidal neurons and vulnerable interneuron subtypes such as SST+, PV+, and VIP + cells. The resulting imbalance in excitation and inhibition disrupts the integrity of prefrontal circuits, impairing adaptive behavior. This review synthesizes evidence across molecular, cellular, and circuit levels to outline a framework in which stress and AD pathology converge on shared vulnerable pathways. Understanding how specific cell populations mediate this vulnerability may lead to targeted strategies for enhancing cognitive resilience in neurodegenerative and stress-related disorders.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"869 ","pages":"Article 138424"},"PeriodicalIF":2.0,"publicationDate":"2025-10-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145327029","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 : 2025-10-17DOI: 10.1016/j.neulet.2025.138425
Rubing Zhou, Dawei Song, Miao Li, Hua Gao
The role of neutrophils in spinal cord injury (SCI) remains incompletely understood due to the absence of effective intervention strategies. Some studies employing antibody-mediated neutrophil depletion (ND) in vivo have yielded various conclusions. However, the mechanism of ND remains unclear, and a comprehensive assessment of its effects was largely lacking prior to application. In this study, we aimed to evaluate neutrophil-related changes following ND in SCI. Hematological analysis revealed that ND attenuated the SCI-induced rise in neutrophil counts but had a negligible effect on baseline levels. The level of IL-1β and IL-8 increased in plasma and intact spinal cord after ND, but exhibited divergent changes post-SCI. Tissue concentrations of TNF-α were elevated in the intact spinal cord but declined following SCI with ND. Neutrophil elastase, a neutrophil cytoplasm-specific protein, increased in both intact and injured spinal cord following ND. Furthermore, ND did not markedly affect SCI-induced blood-spinal cord barrier (BSCB) leakage. These findings indicate that antibody-mediated ND produces complicated effects, rendering it a suboptimal approach for studying neutrophils’ contributions in SCI pathophysiology. Conclusions derived from this method should be interpreted with caution, and alternative strategies should be pursued to better elucidate the role of neutrophils in SCI.
{"title":"Limitations of antibody-mediated neutrophil depletion in understanding the role of neutrophils following spinal cord injury in mice","authors":"Rubing Zhou, Dawei Song, Miao Li, Hua Gao","doi":"10.1016/j.neulet.2025.138425","DOIUrl":"10.1016/j.neulet.2025.138425","url":null,"abstract":"<div><div>The role of neutrophils in spinal cord injury (SCI) remains incompletely understood due to the absence of effective intervention strategies. Some studies employing antibody-mediated neutrophil depletion (ND) in vivo have yielded various conclusions. However, the mechanism of ND remains unclear, and a comprehensive assessment of its effects was largely lacking prior to application. In this study, we aimed to evaluate neutrophil-related changes following ND in SCI. Hematological analysis revealed that ND attenuated the SCI-induced rise in neutrophil counts but had a negligible effect on baseline levels. The level of IL-1β and IL-8 increased in plasma and intact spinal cord after ND, but exhibited divergent changes post-SCI. Tissue concentrations of TNF-α were elevated in the intact spinal cord but declined following SCI with ND. Neutrophil elastase, a neutrophil cytoplasm-specific protein, increased in both intact and injured spinal cord following ND. Furthermore, ND did not markedly affect SCI-induced blood-spinal cord barrier (BSCB) leakage. These findings indicate that antibody-mediated ND produces complicated effects, rendering it a suboptimal approach for studying neutrophils’ contributions in SCI pathophysiology. Conclusions derived from this method should be interpreted with caution, and alternative strategies should be pursued to better elucidate the role of neutrophils in SCI.</div></div>","PeriodicalId":19290,"journal":{"name":"Neuroscience Letters","volume":"869 ","pages":"Article 138425"},"PeriodicalIF":2.0,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145329721","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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