Neuropeptides最新文献

{"title":"Bioactive peptides as multipotent molecules bespoke and designed for Alzheimer's disease","authors":"Ana Mesias,&nbsp;Sandra Borges,&nbsp;Manuela Pintado,&nbsp;Sara Baptista-Silva","doi":"10.1016/j.npep.2025.102515","DOIUrl":"10.1016/j.npep.2025.102515","url":null,"abstract":"<div><div>In an increasingly aging world where neurodegenerative diseases (NDs) are exponentially rising, research into more effective and innovative treatments seems paramount. Bioactive peptides (BPs) emerge as promising compounds with revolutionary potential in the treatment of NDs, particularly in well-known conditions like Alzheimer's disease (AD). The biological potential of these compounds is primarily attributed to their drug development advantages such as enhanced penetration, low toxicity, and rapid clearance, as well as, their antioxidant, and anti-inflammatory properties bio-linked to the neuroprotective effect, able to attenuate the multifactorial pathologies of AD. BPs can be sourced from common dietary origins, like animals, plants, marine, and from emerging sources like edible insects. However, to isolate an active BP with beneficial biological effects it must first be released from its parent protein, followed by a synthesis-flow. While <em>in silico</em> approaches can predict a BP's potential bioactivity and structural characteristics, <em>in vitro</em>, cell-based, and <em>in vivo</em> assays should be conducted to ensure these properties. The blood-brain-barrier (BBB) microenvironment and permeability in health or disease state are key factors to consider since they can limit the ability of circulating therapeutical agents, including BPs, to reach the brain. This review focuses on the bioactivity properties of BPs from different dietary protein sources and explores their beneficial effect and neuroprotective activity in AD, unraveling new paths of treatment.</div></div>","PeriodicalId":19254,"journal":{"name":"Neuropeptides","volume":"111 ","pages":"Article 102515"},"PeriodicalIF":2.5,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143563444","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"BDNF-mediated depressor response by direct baroreceptor activation benefits for prevention and control of hypertension in high-latitude cold region","authors":"Yan Feng ,&nbsp;Lei Yin ,&nbsp;Ying Li","doi":"10.1016/j.npep.2025.102506","DOIUrl":"10.1016/j.npep.2025.102506","url":null,"abstract":"<div><div>Brian-derived neurotrophic factor (BDNF)-tyrosine kinase B (TrkB) signaling impacts on neuronal and cardiovascular physiology; however, its role in neurocontrol of circulation via baroreflex afferent pathway is largely unknown. Gene and protein expression of BDNF/TrkB were detected in the nodose (NG) and nucleus of tractus solitary (NTS) and expression levels were higher in male compared with female rats, which is relevant well with the blood pressure (BP, males &gt; females in average). Microinjection of BDNF into NG dose-dependently reduced BP and this reduction was more dramatic in shamed control vs. renovascular hypertension (RVH) model rats, which partially inhibited in the presence of TrkB inhibitor K252a, indicating that BDNF-TrkB tends to lower BP under physiological and hypertensive conditions due presumably to a negative feed-back control by BP or compensatory mechanism. To answer this question, expression profiles for BDNF-TrkB were tested in the tissue of NG and NTS collected from RVH model rats. Consistently, the expression of both BDNF-TrkB were significantly up-regulated in RVH model alone with the elevation of BP. Taken these data together, our observation provides direct evidence showing the fundamental role of BDNF-TrkB signaling in autonomic control of BP regulation through baroreflex afferent function, potentially dominant role of BDNF-TrkB-mediated BP reduction in vivo baroreceptor activation due to distinct cellular mechanism compared with their role in the NTS, which extends our understanding of activity-dependent or compensatory mechanism of BDNF-TrkB in response to BP change, and sheds new light of BDNF-TrkB as potential target in prevention and control of hypertension in cold-region.</div></div>","PeriodicalId":19254,"journal":{"name":"Neuropeptides","volume":"111 ","pages":"Article 102506"},"PeriodicalIF":2.5,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143534406","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular mechanisms of GDNF/GFRA1/RET and PI3K/AKT/ERK signaling interplay in neuroprotection: Therapeutic strategies for treating neurological disorders","authors":"MD Nasiruddin Khan ,&nbsp;Divya Choudhary ,&nbsp;Sidharth Mehan ,&nbsp;Zuber Khan ,&nbsp;Ghanshyam Das Gupta ,&nbsp;Acharan S. Narula","doi":"10.1016/j.npep.2025.102516","DOIUrl":"10.1016/j.npep.2025.102516","url":null,"abstract":"<div><div>Neurological disorders, marked by progressive neuronal degeneration, impair essential cognitive functions like memory and motor coordination… This manuscript explores the significant roles of glial cell line-derived neurotrophic factor (GDNF), its co-receptors (GFRA1), and the receptor tyrosine kinase (RET) in mediating neuronal survival and function in various neurodegenerative conditions. The interplay between pivotal signaling pathways—PI3K/AKT and ERK1/2—facilitated by GDNF/GFRA1/RET, is emphasized for its neuroprotective effects. Dysregulation of these pathways is implicated in neurodegenerative and neuropsychiatric processes, with overactivation of GSK3β contributing to neuronal damage and apoptosis. Experimental evidence supports that activation of the RET receptor by GDNF enhances AKT signaling, promoting cell survival by inhibiting apoptotic pathways—therapeutic strategies incorporating GDNF delivery and RET activation present promising neuronal protection and regeneration options. Furthermore, inhibition of GSK3β demonstrates potential in ameliorating tau-related pathologies, while small molecule RET agonists may enhance therapeutic efficacy. This review explores the knowledge of GDNF/GFRA1/RET and PI3K/AKT/ERK1/2 associated signaling cascades, underscoring their significance in neuroprotection and therapeutic targeting to combat neurodegenerative diseases. Emerging approaches such as gene therapy and small-molecule RET agonists may offer novel avenues for treatment, although challenges like targeted delivery across the blood-brain barrier remain pertinent.</div></div>","PeriodicalId":19254,"journal":{"name":"Neuropeptides","volume":"111 ","pages":"Article 102516"},"PeriodicalIF":2.5,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143637309","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Netrin-3 enhances recovery and reduces inflammation following spinal cord injury via suppressing NLRP1 inflammasome activation","authors":"Zhe Li ,&nbsp;Xinghua Song ,&nbsp;Jialai Song","doi":"10.1016/j.npep.2025.102521","DOIUrl":"10.1016/j.npep.2025.102521","url":null,"abstract":"<div><div>Spinal cord injury (SCI) represents a significant challenge in the field of neurology due to its complex pathology and the limited efficacy of current treatments. The search for effective therapeutic strategies has led to investigations into molecules that can promote neural repair and functional recovery. Netrin-3, previously known for its roles in axonal guidance and development, emerges as a potential candidate for enhancing recovery post-SCI. Hereby, we used gene therapy to increase Netrin-3 expression in SCI mouse models and evaluated neurological recovery through behavioral tests, histological assessments, and biochemical analyses. Additionally, we examined the activation of the NOD-like receptor family pyrin domain containing 1 (NLRP1) inflammasome and production of interleukin-1β (IL-1β) and IL-18, and confirmed the dependency of Netrin-3's neuroprotective effects on the Adenosine Monophosphate-activated Protein Kinase (AMPK) pathway using an AMPK inhibitor. Our results explores the impact of Netrin-3 on neurological recovery following SCI. It was observed that Netrin-3 expression markedly decreased at both mRNA and protein levels after injury. Enhancing Netrin-3 levels through gene therapy improved neurological outcomes, including locomotor function, reduced lesion size, and normalized spinal cord water content compared to untreated injured mice. Furthermore, Netrin-3 administration mitigated oxidative stress by modulating malondialdehyde (MDA) levels and superoxide dismutase (SOD) activity, and inhibited NLRP1 inflammasome activation, resulting in suppressed IL-1β and IL-18 production. The AMPK pathway was activated by Netrin-3 post-injury, suggesting a mechanism underlying its neuroprotective effects. However, these beneficial impacts were abolished by an AMPK inhibitor, indicating the dependency of Netrin-3's protective actions on the AMPK pathway. Collectively, these findings highlight Netrin-3 as a promising target for developing novel therapies aimed at improving restoration from SCI.</div></div>","PeriodicalId":19254,"journal":{"name":"Neuropeptides","volume":"111 ","pages":"Article 102521"},"PeriodicalIF":2.5,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143937226","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Catestatin-like immunoreactivity in the skin and related sensory ganglia","authors":"Victoria Stöckl ,&nbsp;Georgios Blatsios ,&nbsp;Christian Humpel ,&nbsp;Zenon Pidsudko ,&nbsp;Vincenzo Provitera ,&nbsp;Germar-Michael Pinggera ,&nbsp;Teresa Rauchegger ,&nbsp;Josef Troger","doi":"10.1016/j.npep.2025.102520","DOIUrl":"10.1016/j.npep.2025.102520","url":null,"abstract":"<div><h3>Aim</h3><div>The chromogranin A-derived peptide catestatin has previously been shown to be a constituent of the sensory innervation of the eye and dental pulp. The antibody used in these studies not only recognizes authentic catestatin but also larger molecules containing the sequence of catestatin. Therefore, the authors now aimed to explore whether there are additional molecular forms present in the rat skin, rat trigeminal ganglion and rat dorsal root ganglia apart from free catestatin.</div></div><div><h3>Methods</h3><div>Western blot analysis was performed in these tissues and and double immunofluorescence techniques in rat dorsal root ganglia.</div></div><div><h3>Results</h3><div>A very prominent band was found at approximately 50 kDa in the skin representing a middle-sized fragment containing the sequence of this peptide. Recently, the same result has been obtained in the dental pulp indicating that this fragment might represent a main molecular form in various other tissues of the body. It is likely of sensory nature since the band was also present of weaker intensity both in the trigeminal ganglion and dorsal root ganglia and since abundant cells expressed catestatin-like immunoreactivity in rat dorsal root ganglia. Another small sized fragment of weaker intensity was found in these tissues as well. No band was observed in the position of intact chromogranin A in the Western blot.</div></div><div><h3>Conclusion</h3><div>Chromogranin A is proteolytically processed in sensory ganglia to at least two fragments containing the sequence of catestatin which are then anterogradely transported to the skin and the 50 kDa fragment obviously becomes aggregated there in nerve endings.</div></div>","PeriodicalId":19254,"journal":{"name":"Neuropeptides","volume":"111 ","pages":"Article 102520"},"PeriodicalIF":2.5,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143760430","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Luteolin ameliorates kainic acid-induced seizure by modulating GADD45B and reducing oxidative stress in hippocampal neurons","authors":"Can Luo,&nbsp;Zhi Wang,&nbsp;Junbao Liao,&nbsp;Chuanyi Fu,&nbsp;Fan Zhang,&nbsp;Jiannong Zhao","doi":"10.1016/j.npep.2025.102524","DOIUrl":"10.1016/j.npep.2025.102524","url":null,"abstract":"<div><div>Epilepsy is a prevalent neurological disorder impacting numerous people. However, existing anti-seizure medications frequently fall short of adequately managing seizures, highlighting the urgent need for the development of novel therapeutic interventions. This study investigates the neuroprotective effects of luteolin, which is a bioactive compound derived from the traditional Chinese medicine Danshen, on kainic acid (KA)-induced seizure in mice. Network pharmacology analysis identified GADD45B as a key target gene involved in acute epileptic seizure, which is modulated by luteolin. In vivo experiments demonstrated that luteolin significantly reduces seizure severity, frequency, and duration dose-dependently. Histological analyses revealed that luteolin preserves neuronal integrity and reduces hippocampal damage. Moreover, luteolin inhibited neuronal apoptosis and inflammation in KA-induced seizure mice by inhibiting MAPK and NF-κB signaling pathways. Furthermore, luteolin was shown to decrease oxidative stress and apoptosis in glutamate-induced HT22 hippocampal neuronal cells. Molecular docking showed that luteolin can bind with its target protein GADD45B in a good bond by intermolecular force. These neuroprotective effects of luteolin are mediated by the upregulation of GADD45B, which was further confirmed through knockdown experiments that GADD45B knockdown attenuated luteolin's protective actions. The findings suggest that luteolin exerts its therapeutic effects by modulating oxidative stress and apoptosis through GADD45B, offering potential as a novel neuroprotective strategy for seizures.</div></div>","PeriodicalId":19254,"journal":{"name":"Neuropeptides","volume":"111 ","pages":"Article 102524"},"PeriodicalIF":2.5,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144166699","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PQK7: A novel peptide inhibitor targeting alpha-synuclein fibrillogenesis in Parkinson's disease","authors":"Maryam Motamedi ,&nbsp;Dina Morshedi ,&nbsp;Najaf Allahyari Fard","doi":"10.1016/j.npep.2025.102522","DOIUrl":"10.1016/j.npep.2025.102522","url":null,"abstract":"<div><div>The accumulation of alpha-synuclein (⍺-Syn) fibrils plays a central role in the progression of Parkinson's disease (PD) and related neurodegenerative disorders. In this context, the development of peptide inhibitors designed to inhibit ⍺-Syn through computational methods has emerged as a promising area of research. This study focused on developing a peptide inhibitor, PQK7, designed based on the key residues of NAC region of ⍺-Syn fibrils involved in its aggregation. Using molecular docking and dynamics simulations, PQK7 was shown to bind key residues in the NAC region of ⍺-Syn (Val-74, Ala-76, Val-77, Thr-81, Ser-87, Ile-88, and Ala-89), effectively disrupting the formation of fibrils. MD simulations indicated that the PQK7-⍺-Syn complex reaches a stable conformation, which showed increased fluctuations and reduced β-sheet content, suggests that PQK7 interferes with ⍺-Syn fibrillation at the molecular level. In vitro assays like ThT fluorescence assay, AFM imaging, CD specotroscopy, and SDS-PAGE analysis confirmed that PQK7 significantly reduces ⍺-Syn fibril formation, particularly at substoichiometric concentrations, while keeping ⍺-Syn monomers in a soluble state. Additionally, PQK7-⍺-Syn treatment in SH-SY5Y cells reduced the toxicity of ⍺-Syn aggregates, restoring normal cell cycle progression and reducing apoptosis and oxidative stress. Our findings suggest that PQK7 holds potential as a therapeutic agent for PD, acting as an anti-oligomeric inhibitor that targets early ⍺-Syn aggregates without affecting the protein's normal function.</div></div>","PeriodicalId":19254,"journal":{"name":"Neuropeptides","volume":"111 ","pages":"Article 102522"},"PeriodicalIF":2.5,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143916682","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ginsenoside Rg1 improves autophagy dysfunction to ameliorate Alzheimer's disease via targeting FGR proto-oncogene","authors":"Qiankun Quan ,&nbsp;Xinxin Ma ,&nbsp;JianJun Feng ,&nbsp;Wanni Li ,&nbsp;Xi Li","doi":"10.1016/j.npep.2025.102514","DOIUrl":"10.1016/j.npep.2025.102514","url":null,"abstract":"<div><div>Alzheimer's disease (AD) is a neurodegeneration driven by beta-amyloid (Aβ) deposits in the brain involving autophagy dysfunction. Ginsenoside Rg1, a pharmacologically active compound found in ginseng, has possible therapeutic effects for AD. This study discovered that FGR proto-oncogene (FGR) was a therapeutic target of Rg1 in AD and it was possibly involved in autophagy. C57BL/6 J mice were injected with 5 μL (1 μg/mL) Aβ_1–42 in the right lateral ventricle to establish an AD model. AD mouse hippocampus had high FGR expression. Intragastrically administered Rg1 (40 mg/kg) decreased FGR protein levels in AD mice's hippocampus and improved memory function in AD mice. Both sides of the mice hippocampal fissure were administered with 2 μL lentiviral particles (1 × 10⁷ TU) containing FGR overexpression plasmids. FGR overexpression rendered Rg1 ineffectual in restoring memory function and reducing hippocampal neuron damage. We injected 2 μL lentiviral particles (1 × 10⁷ TU) containing short hairpin RNA plasmids targeting FGR to the mice hippocampal fissures. FGR knockdown improved spatial memory function of AD mice, reduced hippocampal neuron apoptosis, and prevented Aβ accumulation. HT22 cells were transfected with small interfering RNA targeting FGR. FGR knockdown increased the viability of Aβ_1–42 treated HT22 cells. BACE1 and LC3II/I protein levels were decreased and p62 and SIRT1 were increased in AD mice and cells with FGR knockdown. LC3 was down-regulated after inhibiting FGR expression in Aβ_1–42 treated hippocampal neurons. In conclusion, Rg1 exerts anti-AD functions by targeting FGR and downregulating its expression.</div></div>","PeriodicalId":19254,"journal":{"name":"Neuropeptides","volume":"111 ","pages":"Article 102514"},"PeriodicalIF":2.5,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143592338","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transcranial pulsed current stimulation alleviates neuronal pyroptosis and neurological dysfunction following traumatic brain injury via the orexin-A/NLRP3 pathway","authors":"Peng Yao ,&nbsp;Qianhui Zhou ,&nbsp;Bingkai Ren ,&nbsp;Li Yang ,&nbsp;Yang Bai ,&nbsp;Zhen Feng","doi":"10.1016/j.npep.2025.102501","DOIUrl":"10.1016/j.npep.2025.102501","url":null,"abstract":"<div><div>Traumatic brain injury (TBI) is a life-threatening condition with high incidence and mortality rates. The current pharmacological interventions for TBI exhibit limited efficacy, underscoring the necessity to explore novel and effective therapeutic approaches to ameliorate its impact. Previous studies have indicated that transcranial pulsed current stimulation (tPCS) can improve neurofunctional deficits in patients by modulating brain neuroplasticity. However, the exact mechanism underlying this neuroprotective effect remains elusive. In this study, mice with TBI induced by controlled cortical impact were subjected to 30 min of daily tPCS for 5 consecutive days and intraperitoneally administered an orexin receptor type 1 (OX₁R) antagonist (SB334867). The neuroprotective effects of tPCS and its potential mechanisms were assessed through behavioral tests, histopathological examination, immunohistochemistry and Western blotting. In vitro experiments involved stimulating HT22 cells with LPS + ATP to assess the anti-neuroinflammatory effects of Orexin-A (OX-A) using CCK-8, Western blotting, and Flow cytometry. The results demonstrated that tPCS reduced the mNSS in TBI mice, ameliorated tissue damage, improved motor and cognitive deficits, and upregulated OX-A expression. Notably, SB334867 reversed the protective effects of tPCS. In vitro studies revealed that OX-A inhibited the formation and activation of NLRP3 inflammasomes, resulting in reduced levels of ROS and restoration of MMP. However, this effect could be reversed by the NLRP3 agonist BMS-986299. Our findings suggest that tPCS promotes the release of OX-A and modulates the OX₁R/NLRP3 pathway to mitigate the inflammatory response following TBI, thereby exerting neuroprotective effects.</div></div>","PeriodicalId":19254,"journal":{"name":"Neuropeptides","volume":"110 ","pages":"Article 102501"},"PeriodicalIF":2.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143137317","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Modulation of temporoammonic-CA1 synapses by neuropeptide Y is through Y1 receptors in mice","authors":"Mariana A. Cortes ,&nbsp;Aundrea F. Bartley ,&nbsp;Qin Li ,&nbsp;Taylor R. Davis ,&nbsp;Stephen E. Cunningham ,&nbsp;Mary Anne Garner ,&nbsp;Patric J. Perez ,&nbsp;Adela C. Harvey ,&nbsp;Alecia K. Gross ,&nbsp;Lynn E. Dobrunz","doi":"10.1016/j.npep.2025.102504","DOIUrl":"10.1016/j.npep.2025.102504","url":null,"abstract":"<div><div>Reduced levels of neuropeptide Y (NPY), an abundant neuromodulator in the brain, are linked to multiple neuropsychiatric disorders, including post-traumatic stress disorder (PTSD). The CA1 region of hippocampus is important for anxiety regulation and highly expresses NPY. Injecting NPY into CA1 is anxiolytic and alleviates behavioral symptoms in a model of traumatic stress; these anxiolytic effects are blocked by a Y1 receptor antagonist. However the location of Y1Rs that mediate NPY's anxiolytic effects in CA1 remains unclear. CA1 receives inputs from entorhinal cortex through the temporammonic pathway (TA), which is important for fear learning and sensitive to stress. Our lab previously showed that NPY reduces TA-evoked synaptic responses, however, the subtype of NPY receptor mediating this reduction is unknown. Here we demonstrate that in mice both exogenous (bath-applied) and endogenously-released NPY act through Y1 receptors in the TA pathway. This is the first demonstration of Y1 receptor-mediated effect on synaptic function in CA1. Interestingly, chronic overexpression of NPY (in NPY-expressing interneurons) impairs the sensitivity of the TA-evoked synaptic response to a Y1 receptor agonist. However, the long-known NPY Y2 receptor-mediated effect on the Schaffer collateral (SC) pathway is unaffected by NPY overexpression. Therefore, NPY can have a pathway-specific impact on synaptic transmission in CA1 based on the differential expression of NPY receptors and their response to overexpression of NPY. Our results demonstrating that NPY acts at Y1 receptors in the TA pathway are consistent with the idea that the TA pathway underlies the anxiolytic effects of NPY in CA1.</div></div>","PeriodicalId":19254,"journal":{"name":"Neuropeptides","volume":"110 ","pages":"Article 102504"},"PeriodicalIF":2.5,"publicationDate":"2025-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143402962","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}