Skip to content
2000
image of Exposure to Stress or an Enriched Environment in Youth Modulates Prenatal Inflammation-Induced Cognitive Deficits in Mice and Is Associated with Hippocampal SNAP-25 Expression Levels

Abstract

Introduction

Brain aging can promote neuronal damage, contributing to aging-associated memory impairments (AAMI), a phenomenon characteristic of normal aging. However, it remains unclear whether and how exposure to stress or an enriched environment (S/E) during youth influences AAMI induced by prenatal inflammation. Therefore, SNAP-25, a key presynaptic membrane protein closely related to cognitive function, was selected as the primary molecular target. This project aimed to investigate the effects and underlying mechanisms of youth stress (S) and enriched environment (E) on the AAMI induced by prenatal inflammation.

Methods

Lipopolysaccharide (LPS) injection was used to establish an animal model of prenatal inflammation. Two experimental techniques, including S and E, were applied. The male offspring mice were randomly divided into four groups: LPS+S, LPS+E, LPS, and NS. Cognitive function was assessed using the Morris water maze test, while hippocampal synaptosomal-associated protein 25 (SNAP-25) expression was examined using Western blot and RNA hybridization (RNAscope) techniques.

Results and Discussion

Young mice (3 months old) exhibited better cognitive function and lower SNAP-25 expression compared with middle-aged mice (15 months old), indicating that the middle-aged mice displayed the expected impairment in spatial cognitive ability. Furthermore, LPS significantly impaired memory performance and increased SNAP-25 expression, whereas exposure to stress or an enriched environment (S/E) alleviated AAMI. In addition, a significant correlation was observed between SNAP-25 expression and cognitive performance.

Conclusion

Youth exposure to stress or an enriched environment (S/E) at 2 months of age modulated the expression level of hippocampal SNAP-25 induced by prenatal inflammation. Moreover, increased SNAP-25 expression was associated with memory impairment.

© 2025 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/cmm/10.2174/0115665240435677251020092938
2025-11-18
2026-01-30

  • From This Site

    /content/journals/cmm/10.2174/0115665240435677251020092938
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. Keymoradzadeh A. Hedayati Ch.M. Abedinzade M. Gazor R. Rostampour M. Taleghani B.K. Enriched environment effect on lipopolysaccharide-induced spatial learning, memory impairment and hippocampal inflammatory cytokine levels in male rats. Behav. Brain Res. 2020 394 112814 10.1016/j.bbr.2020.112814 32707137
    [Google Scholar]
  2. Zhao J. Bi W. Xiao S. Neuroinflammation induced by lipopolysaccharide causes cognitive impairment in mice. Sci. Rep. 2019 9 1 5790 10.1038/s41598‑019‑42286‑8 30962497
    [Google Scholar]
  3. Manickavasagam D. Lin L. Oyewumi M.O. Nose-to-brain co-delivery of repurposed simvastatin and BDNF synergistically attenuates LPS-induced neuroinflammation. Nanomedicine 2020 23 102107 10.1016/j.nano.2019.102107 31655202
    [Google Scholar]
  4. Goeden N. Velasquez J. Arnold K.A. Maternal inflammation disrupts fetal neurodevelopment via increased placental output of serotonin to the fetal brain. J. Neurosci. 2016 36 22 6041 6049 10.1523/JNEUROSCI.2534‑15.2016 27251625
    [Google Scholar]
  5. Batista C.R.A. Gomes G.F. Candelario-Jalil E. Fiebich B.L. de Oliveira A.C.P. Lipopolysaccharide-induced neuro-inflammation as a bridge to understand neurodegeneration. Int. J. Mol. Sci. 2019 20 9 2293 10.3390/ijms20092293 31075861
    [Google Scholar]
  6. Zhang Z.Z. Zhuang Z.Q. Sun S.Y. Effects of prenatal exposure to inflammation coupled with stress exposure during adolescence on cognition and synaptic protein levels in aged CD-1 mice. Front. Aging Neurosci. 2020 12 157 10.3389/fnagi.2020.00157 32774299
    [Google Scholar]
  7. Wu Z.X. Cao L. Li X.W. Accelerated deficits of spatial learning and memory resulting from prenatal inflammatory insult are correlated with abnormal phosphorylation and methylation of histone 3 in CD-1 mice. Front. Aging Neurosci. 2019 11 114 10.3389/fnagi.2019.00114 31156421
    [Google Scholar]
  8. Bhagya V.R. Srikumar B.N. Veena J. Shankaranarayana Rao B.S. Short‐term exposure to enriched environment rescues chronic stress‐induced impaired hippocampal synaptic plasticity, anxiety, and memory deficits. J. Neurosci. Res. 2017 95 8 1602 1610 10.1002/jnr.23992 27862185
    [Google Scholar]
  9. Wu Y. Mitra R. Prefrontal-hippocampus plasticity reinstated by an enriched environment during stress. Neurosci. Res. 2021 170 360 363 10.1016/j.neures.2020.07.004 32710912
    [Google Scholar]
  10. Dang R. Guo Y. Zhang K. Jiang P. Zhao M. Predictable chronic mild stress promotes recovery from LPS-induced depression. Mol. Brain 2019 12 1 42 10.1186/s13041‑019‑0463‑2 31053149
    [Google Scholar]
  11. Han B. Yu L. Geng Y. Chronic stress aggravates cognitive impairment and suppresses insulin associated signaling pathway in APP/PS1 mice. J. Alzheimers Dis. 2016 53 4 1539 1552 10.3233/JAD‑160189 27392857
    [Google Scholar]
  12. Shen J. Li Y. Qu C. Xu L. Sun H. Zhang J. The enriched environment ameliorates chronic unpredictable mild stress-induced depressive-like behaviors and cognitive impairment by activating the SIRT1/miR-134 signaling pathway in hippocampus. J. Affect. Disord. 2019 248 81 90 10.1016/j.jad.2019.01.031 30716615
    [Google Scholar]
  13. Wu Y. Liu T. Wang X. Enriched environment enhances histone acetylation of NMDA receptor in the hippocampus and improves cognitive dysfunction in aged mice. Neural Regen. Res. 2020 15 12 2327 2334 10.4103/1673‑5374.285005 32594057
    [Google Scholar]
  14. Wu Y. Wang C-J. Zhang Q. Yu K.W. Wang Y.Y. An enriched environment promotes synaptic plasticity and cognitive recovery after permanent middle cerebral artery occlusion in mice. Neural Regen. Res. 2019 14 3 462 469 10.4103/1673‑5374.245470 30539814
    [Google Scholar]
  15. Wang C. Zhang Q. Yu K. Shen X. Wu Y. Wu J. Enriched environment promoted cognitive function via bilateral synaptic remodeling after cerebral ischemia. Front. Neurol. 2019 10 1189 10.3389/fneur.2019.01189 31781025
    [Google Scholar]
  16. Santos T.C. Wierda K. Broeke J.H. Toonen R.F. Verhage M. Early Golgi Abnormalities and Neurodegeneration upon Loss of Presynaptic Proteins Munc18-1, Syntaxin-1, or SNAP-25. J. Neurosci. 2017 37 17 4525 4539 10.1523/JNEUROSCI.3352‑16.2017 28348137
    [Google Scholar]
  17. Sun S.Y. Li X.Y. Ge H.H. Effects of gestational inflammation with postpartum enriched environment on age-related changes in cognition and hippocampal synaptic plasticity-related proteins. Neural Plast. 2020 2020 5 1 11 10.1155/2020/9082945
    [Google Scholar]
  18. Agostini S. Mancuso R. Liuzzo G. Serum miRNAs expression and SNAP-25 genotype in Alzheimer’s disease. Front. Aging Neurosci. 2019 11 52 10.3389/fnagi.2019.00052 30914946
    [Google Scholar]
  19. Antonucci F. Corradini I. Fossati G. Tomasoni R. Menna E. Matteoli M. SNAP-25, a known presynaptic protein with emerging postsynaptic functions. Front. Synaptic Neurosci. 2016 8 7 10.3389/fnsyn.2016.00007 27047369
    [Google Scholar]
  20. Zhang H. Therriault J. Kang M.S. Cerebrospinal fluid synaptosomal-associated protein 25 is a key player in synaptic degeneration in mild cognitive impairment and Alzheimer’s disease. Alzheimers Res. Ther. 2018 10 1 80 10.1186/s13195‑018‑0407‑6 30115118
    [Google Scholar]
  21. Cao L. Wang F. Yang Q.G. Reduced thyroid hormones with increased hippocampal SNAP-25 and Munc18-1 might involve cognitive impairment during aging. Behav. Brain Res. 2012 229 1 131 137 10.1016/j.bbr.2012.01.014 22261019
    [Google Scholar]
  22. Li X.Y. Wang F. Chen G.H. Inflammatory insult during pregnancy accelerates age-related behavioral and neurobiochemical changes in CD-1 mice. Age 2016 38 3 59 10.1007/s11357‑016‑9920‑3 27194408
    [Google Scholar]
  23. Kaptan Z. Dar K.A. Kapucu A. Bulut H. Üzüm G. Effect of enriched environment and predictable chronic stress on spatial memory in adolescent rats: Predominant expression of BDNF, nNOS, and interestingly malondialdehyde in the right hippocampus. Brain Res. 2019 1721 146326 10.1016/j.brainres.2019.146326 31299186
    [Google Scholar]
  24. Wu Y.F. Zhang Y.M. Ge H.H. Effects of embryonic inflammation and adolescent psychosocial environment on cognition and hippocampal staufen in middle-aged mice. Front. Aging Neurosci. 2020 12 578719 10.3389/fnagi.2020.578719 33024434
    [Google Scholar]
  25. Ohline SM Abraham WC Environmental enrichment effects on synaptic and cellular physiology of hippocampal neurons. Neuropharmacology 2019 145 Pt A 2 12 10.1016/j.neuropharm.2018.04.007 29634984
    [Google Scholar]
  26. Kim J. Seo Y.H. Kim J. Casticin ameliorates scopolamine-induced cognitive dysfunction in mice. J. Ethnopharmacol. 2020 259 112843 10.1016/j.jep.2020.112843 32380246
    [Google Scholar]
  27. Cheng J. Zhao H. NEK7 induces lactylation in Alzheimer’s disease to promote pyroptosis in BV-2 cells. Mol. Brain 2024 17 1 81 10.1186/s13041‑024‑01156‑9 39563448
    [Google Scholar]
  28. Wang F. Xu W.H. Wang C. Huang D.W. Chen G.H. Can outbred mice be used as a mouse model of mild cognitive impairment? Neural Regen. Res. 2010 5 1650 1656
    [Google Scholar]
  29. Lapmanee S. Charoenphandhu J. Teerapornpuntakit J. Krishnamra N. Charoenphandhu N. Agomelatine, venlafaxine, and running exercise effectively prevent anxiety- and depression-like behaviors and memory impairment in restraint stressed rats. PLoS One 2017 12 11 0187671 10.1371/journal.pone.0187671 29099859
    [Google Scholar]
  30. Guan S. Fu Y. Zhao F. The mechanism of enriched environment repairing the learning and memory impairment in offspring of prenatal stress by regulating the expression of activity-regulated cytoskeletal-associated and insulin-like growth factor-2 in hippocampus. Environ. Health Prev. Med. 2021 26 1 8 10.1186/s12199‑020‑00929‑7 33451279
    [Google Scholar]
  31. Domi E. Caputi F.F. Romualdi P. Activation of PPARγ attenuates the expression of physical and affective nicotine withdrawal symptoms through mechanisms involving amygdala and hippocampus neurotransmission. J. Neurosci. 2019 39 49 9864 9875 10.1523/JNEUROSCI.1922‑19.2019 31685649
    [Google Scholar]
  32. Gavini C.K. Cook T.M. Rademacher D.J. Mansuy-Aubert V. Hypothalamic C2-domain protein involved in MC4R trafficking and control of energy balance. Metabolism 2020 102 153990 10.1016/j.metabol.2019.153990 31666192
    [Google Scholar]
  33. D’Amato A. Di Cesare Mannelli L. Lucarini E. Faecal microbiota transplant from aged donor mice affects spatial learning and memory via modulating hippocampal synaptic plasticity- and neurotransmission-related proteins in young recipients. Microbiome 2020 8 1 140 10.1186/s40168‑020‑00914‑w 33004079
    [Google Scholar]
  34. Luo W. Yan Y. Cao Y. Zhang Y. Zhang Z. The effects of GPER on age-associated memory impairment induced by decreased estrogen levels. Front. Mol. Biosci. 2023 10 1097018 10.3389/fmolb.2023.1097018 37021109
    [Google Scholar]
  35. Zou M. Li D. Yang Y. The memory- and cognition-facilitating effects of spermidine in aging and aging-related disorders. Ageing Res. Rev. 2025 109 102787 10.1016/j.arr.2025.102787 40447058
    [Google Scholar]
  36. Boa Sorte Silva N.C. Barha C.K. Erickson K.I. Kramer A.F. Liu-Ambrose T. Physical exercise, cognition, and brain health in aging. Trends Neurosci. 2024 47 6 402 417 10.1016/j.tins.2024.04.004 38811309
    [Google Scholar]
  37. Zhuang Z.Q. Zhang Z.Z. Zhang Y.M. A long-term enriched environment ameliorates the accelerated age-related memory impairment induced by gestational adminis-tration of lipopolysaccharide: Role of plastic mitochondrial quality control. Front. Cell. Neurosci. 2021 14 559182 10.3389/fncel.2020.559182 33613195
    [Google Scholar]
  38. Pike M.R. Lipner E. O’Brien K.J. Prenatal maternal Inflammation, childhood cognition and adolescent depressive symptoms. Brain Behav. Immun. 2024 119 908 918 10.1016/j.bbi.2024.05.012 38761818
    [Google Scholar]
  39. Serdar M. Walther K.A. Gallert M. Prenatal inflammation exacerbates hyperoxia-induced neonatal brain injury. J. Neuroinflammation 2025 22 1 57 10.1186/s12974‑025‑03389‑4 40022130
    [Google Scholar]
  40. Ma Y. Zhang Y. He Q. Vitamin D regulates microflora and ameliorates LPS-induced placental inflammation in rats. Physiol. Genomics 2023 55 7 286 296 10.1152/physiolgenomics.00004.2023 37092745
    [Google Scholar]
  41. Namvarpour Z. Azhdari S. Lotfi R. Impact of mild prenatal LPS-induced inflammation and postnatal stress on synaptic plasticity and neuroimmune responses in the prefrontal cortex of adult male mice. Tissue Cell 2025 96 103007 10.1016/j.tice.2025.103007 40482402
    [Google Scholar]
  42. Lotan A. Lifschytz T. Wolf G. Differential effects of chronic stress in young-adult and old female mice: Cognitive-behavioral manifestations and neurobiological correlates. Mol. Psychiatry 2018 23 6 1432 1445 10.1038/mp.2017.237 29257131
    [Google Scholar]
  43. Sanguino-Gómez J. Huijgens S. den Hartog M. Neural correlates of learning and memory are altered by early-life stress. Neurobiol. Learn. Mem. 2024 213 107952 10.1016/j.nlm.2024.107952 38906243
    [Google Scholar]
  44. Wang L. Cao M. Pu T. Huang H. Marshall C. Xiao M. Enriched physical environment attenuates spatial and social memory impairments of aged socially isolated mice. Int. J. Neuropsychopharmacol. 2018 21 12 1114 1127 10.1093/ijnp/pyy084 30247630
    [Google Scholar]
  45. Druzian A.F. Melo J.A.O. Souza A.S. The influence of enriched environment on spatial memory in Swiss mice of different ages. Arq. Neuropsiquiatr. 2015 73 8 692 697 10.1590/0004‑282X20150089 26222362
    [Google Scholar]
  46. Gao W. Xie W. Xie W. Jiang C. Kang Z. Liu N. An enriched environment promotes cognitive recovery and cerebral blood flow in aged mice under sevoflurane anaesthesia. Folia Neuropathol. 2024 62 3 312 320 10.5114/fn.2024.136017 39165209
    [Google Scholar]
  47. Wang F. Zhang Z.Z. Cao L. Yang Q.G. Lu Q.F. Chen G.H. Lipopolysaccharide exposure during late embryogenesis triggers and drives Alzheimer‐like behavioral and neuropathological changes in CD‐1 mice. Brain Behav. 2020 10 3 01546 10.1002/brb3.1546 31997558
    [Google Scholar]
  48. Mota C Taipa R das Neves SP Structural and molecular correlates of cognitive aging in the rat. Sci. Rep. 2019 9 1 2005 10.1038/s41598‑019‑39645‑w 30765864
    [Google Scholar]
  49. Hamieh A.M. Camperos E. Hernier A.M. Castagné V. C57BL/6 mice as a preclinical model to study age-related cognitive deficits: Executive functions impairment and inter-individual differences. Brain Res. 2021 1751 147173 10.1016/j.brainres.2020.147173 33148432
    [Google Scholar]
  50. Hoang T.H.X. Ho D.V. Van Phan K. Le Q.V. Raal A. Nguyen H.T. Effects of Hippeastrum reticulatum on memory, spatial learning and object recognition in a scopolamine-induced animal model of Alzheimer’s disease. Pharm. Biol. 2020 58 1 1107 1113 10.1080/13880209.2020.1841810 33170051
    [Google Scholar]
  51. Yuan M. Wang Y. Wen J. Dietary salt disrupts tricarboxylic acid cycle and induces tau hyperphosphorylation and synapse dysfunction during aging. Aging Dis. 2022 13 5 1532 1545 10.14336/AD.2022.0220 36186135
    [Google Scholar]
  52. Yasuda R. Hayashi Y. Hell J.W. CaMKII: A central molecular organizer of synaptic plasticity, learning and memory. Nat. Rev. Neurosci. 2022 23 11 666 682 10.1038/s41583‑022‑00624‑2 36056211
    [Google Scholar]
  53. Chen Y. Wang X. Xiao B. Luo Z. Long H. Mechanisms and functions of activity-regulated cytoskeleton-associated protein in synaptic plasticity. Mol. Neurobiol. 2023 60 10 5738 5754 10.1007/s12035‑023‑03442‑4 37338805
    [Google Scholar]
  54. Araki Y. Rajkovich K.E. Gerber E.E. SynGAP regulates synaptic plasticity and cognition independently of its catalytic activity. Science 2024 383 6686 eadk1291 10.1126/science.adk1291 38422154
    [Google Scholar]
  55. Kádková A. Radecke J. Sørensen J.B. The SNAP-25 protein family. Neuroscience 2019 420 50 71 10.1016/j.neuroscience.2018.09.020 30267828
    [Google Scholar]
  56. Madrigal M.P. Portalés A. SanJuan M.P. Jurado S. Postsynaptic SNARE proteins: Role in synaptic transmission and plasticity. Neuroscience 2019 420 12 21 10.1016/j.neuroscience.2018.11.012 30458218
    [Google Scholar]
  57. Bin N.R. Huang M. Sugita S. Investigating the role of SNARE proteins in trafficking of postsynaptic receptors using conditional knockouts. Neuroscience 2019 420 22 31 10.1016/j.neuroscience.2018.11.027 30481567
    [Google Scholar]
  58. Canas P.M. Duarte J.M.N. Rodrigues R.J. Köfalvi A. Cunha R.A. Modification upon aging of the density of presynaptic modulation systems in the hippocampus. Neurobiol. Aging 2009 30 11 1877 1884 10.1016/j.neurobiolaging.2008.01.003 18304697
    [Google Scholar]
  59. Lapchak P.A. Araujo D.M. Beck K.D. Finch C.E. Johnson S.A. Hefti F. BDNF and trkB mRNA expression in the hippocampal formation of aging rats. Neurobiol. Aging 1993 14 2 121 126 10.1016/0197‑4580(93)90087‑R 8487914
    [Google Scholar]
  60. Santana M.M. Rosmaninho-Salgado J. Cortez V. Impaired adrenal medullary function in a mouse model of depression induced by unpredictable chronic stress. Eur. Neuropsychopharmacol. 2015 25 10 1753 1766 10.1016/j.euroneuro.2015.06.013 26187454
    [Google Scholar]
  61. Yang L. Shi L.J. Shen S.Y. Toward antifragility: Social defeat stress enhances learning and memory in young mice via hippocampal synaptosome associated protein 25. Psychol. Sci. 2023 34 5 616 632 10.1177/09567976231160098 37040450
    [Google Scholar]
  62. Arcego D.M. Toniazzo A.P. Krolow R. Impact of high-fat diet and early stress on depressive-like behavior and hippocampal plasticity in adult male rats. Mol. Neurobiol. 2018 55 4 2740 2753 10.1007/s12035‑017‑0538‑y 28451885
    [Google Scholar]
  63. Liu Y. Bian H. Xu S. Muscone ameliorates synaptic dysfunction and cognitive deficits in APP/PS1 mice. J. Alzheimers Dis. 2020 76 2 491 504 10.3233/JAD‑200188 32538849
    [Google Scholar]
  64. Nikolaienko O. Patil S. Eriksen M.S. Bramham C.R. Arc protein: A flexible hub for synaptic plasticity and cognition. Semin. Cell Dev. Biol. 2018 77 33 42 10.1016/j.semcdb.2017.09.006 28890419
    [Google Scholar]
  65. Araki Y. Hong I. Gamache T.R. SynGAP isoforms differentially regulate synaptic plasticity and dendritic development. eLife 2020 9 56273 10.7554/eLife.56273 32579114
    [Google Scholar]
  66. Wang W. Li Y. Ma F. Microglial repopulation reverses cognitive and synaptic deficits in an Alzheimer’s disease model by restoring BDNF signaling. Brain Behav. Immun. 2023 113 275 288 10.1016/j.bbi.2023.07.011 37482204
    [Google Scholar]
  67. Irfan M. Gopaul K.R. Miry O. Hökfelt T. Stanton P.K. Bark C. SNAP-25 isoforms differentially regulate synaptic transmission and long-term synaptic plasticity at central synapses. Sci. Rep. 2019 9 1 6403 10.1038/s41598‑019‑42833‑3 31024034
    [Google Scholar]
  68. McKee A.G. Loscher J.S. O’Sullivan N.C. AAV‐mediated chronic over‐expression of SNAP‐25 in adult rat dorsal hippocampus impairs memory‐associated synaptic plasticity. J. Neurochem. 2010 112 4 991 1004 10.1111/j.1471‑4159.2009.06516.x 20002519
    [Google Scholar]
  69. Zhang C. Xie S. Malek M. SNAP-25: A biomarker of synaptic loss in neurodegeneration. Clin. Chim. Acta 2025 571 120236 10.1016/j.cca.2025.120236 40058720
    [Google Scholar]
  70. Wolner S.H. Gleerup H.S. Musaeus C.S. Synaptosomal‐associated protein 25 kDA (SNAP‐25) levels in cerebrospinal fluid: Implications for Alzheimer’s disease diagnosis and monitoring. Synapse 2025 79 2 70010 10.1002/syn.70010 39912369
    [Google Scholar]
  71. Musunuri S. Khoonsari P.E. Mikus M. Increased levels of extracellular microvesicle markers and decreased levels of endocytic/exocytic proteins in the Alzheimer’s disease brain. J. Alzheimers Dis. 2016 54 4 1671 1686 10.3233/JAD‑160271 27636840
    [Google Scholar]
  72. Braida D. Guerini F.R. Ponzoni L. Association between SNAP-25 gene polymorphisms and cognition in autism: Functional consequences and potential therapeutic strategies. Transl. Psychiatry 2015 5 1 500 10.1038/tp.2014.136 25629685
    [Google Scholar]
/content/journals/cmm/10.2174/0115665240435677251020092938
Loading
Exposure to Stress or an Enriched Environment in Youth Modulates Prenatal Inflammation-Induced Cognitive Deficits in Mice and Is Associated with Hippocampal SNAP-25 Expression Levels
Bentham Science Publishers ; https://doi.org/10.2174/0115665240435677251020092938
/content/journals/cmm/10.2174/0115665240435677251020092938
/content/journals/cmm/10.2174/0115665240435677251020092938
Loading

Data & Media loading...


  • Article Type:     Research Article
Keywords: stress ; SNAP-25 ; Prenatal inflammation ; age-associated memory impairment ; the Morris water maze test ; enriched environment

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test