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Molecular architects of memory: BDNF/TrkB signaling and trafficking in neuronal plasticity and memory

Molecular Psychiatry (2026)Cite this article

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Abstract

Brain-derived neurotrophic factor (BDNF) has been firmly implicated in the synaptic plasticity of neurons in the central nervous system (CNS), which make BDNF as an important regulator of memory and emotion. In this review we will discuss our knowledge about the multiple intracellular signaling pathways activated by BDNF, and the regulation of intracellular trafficking of BDNF/TrkB in synaptic plasticity, memory and emotion. Alternations in BDNF/TrkB trafficking has been shown to be involved in memory deficits and mood disorders. Future studies could explore targeting the regulation of BDNF/TrkB trafficking to devise BDNF-based therapeutics for human memory and mood disorders.

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Fig. 1: Integrated mechanisms of BDNF/TrkB bidirectional trafficking.
Fig. 2: Mechanistic insights into BDNF–TrkB dysfunction in Rett syndrome and its pharmacological modulation by antidepressants and psychedelics.
Fig. 3: BDNF–TrkB signaling in memory formation and stage-specific interregional BDNF dynamics.
Fig. 4: BDNF-TrkB Signaling Dynamics in LTP.

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References

  1. Murer MG, Yan Q, Raisman-Vozari R. Brain-derived neurotrophic factor in the control human brain, and in Alzheimer’s disease and Parkinson’s disease. Prog Neurobiol. 2001;63:71–124.

    Article  CAS  PubMed  Google Scholar 

  2. Lessmann V, Gottmann K, Malcangio M. Neurotrophin secretion: current facts and future prospects. Prog Neurobiol. 2003;69:341–74.

    Article  CAS  Google Scholar 

  3. Dieni S, Matsumoto T, Dekkers M, Rauskolb S, Ionescu MS, Deogracias R, et al. BDNF and its pro-peptide are stored in presynaptic dense core vesicles in brain neurons. J Cell Biol. 2012;196:775–88.

    Article  CAS  PubMed Central  Google Scholar 

  4. Chen ZY, Ieraci A, Teng H, Dall H, Meng CX, Herrera DG, et al. Sortilin controls intracellular sorting of brain-derived neurotrophic factor to the regulated secretory pathway. J Neurosci. 2005;25:6156–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Lou H, Kim SK, Zaitsev E, Snell CR, Lu B, Loh YP. Sorting and activity-dependent secretion of BDNF require interaction of a specific motif with the sorting receptor carboxypeptidase e. Neuron. 2005;45:245–55.

    Article  CAS  PubMed  Google Scholar 

  6. Grigoriev I, Splinter D, Keijzer N, Wulf PS, Demmers J, Ohtsuka T, et al. Rab6 regulates transport and targeting of exocytotic carriers. Dev Cell. 2007;13:305–14.

    Article  CAS  PubMed  Google Scholar 

  7. Egan MF, Kojima M, Callicott JH, Goldberg TE, Kolachana BS, Bertolino A, et al. The BDNF val66met polymorphism affects activity-dependent secretion of BDNF and human memory and hippocampal function. Cell. 2003;112:257–69.

    Article  CAS  Google Scholar 

  8. Chen ZY, Patel PD, Sant G, Meng CX, Teng KK, Hempstead BL, et al. Variant brain-derived neurotrophic factor (BDNF) (Met66) alters the intracellular trafficking and activity-dependent secretion of wild-type BDNF in neurosecretory cells and cortical neurons. J Neurosci. 2004;24:4401–11.

    Article  CAS  PubMed Central  Google Scholar 

  9. Teng HK, Teng KK, Lee R, Wright S, Tevar S, Almeida RD, et al. ProBDNF induces neuronal apoptosis via activation of a receptor complex of p75NTR and sortilin. J Neurosci. 2005;25:5455–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Segal RA. Selectivity in neurotrophin signaling: theme and variations. Annu Rev Neurosci. 2003;26:299–330.

    Article  CAS  PubMed  Google Scholar 

  11. Wang CS, Kavalali ET, Monteggia LM. BDNF signaling in context: From synaptic regulation to psychiatric disorders. Cell. 2022;185:62–76.

    Article  CAS  PubMed  Google Scholar 

  12. Jovanovic JN, Czernik AJ, Fienberg AA, Greengard P, Sihra TS. Synapsins as mediators of BDNF-enhanced neurotransmitter release. Nat Neurosci. 2000;3:323–9.

    Article  CAS  PubMed  Google Scholar 

  13. Rose CR, Blum R, Kafitz KW, Kovalchuk Y, Konnerth A. From modulator to mediator: rapid effects of BDNF on ion channels. Bioessays. 2004;26:1185–94.

    Article  CAS  PubMed  Google Scholar 

  14. Itami C, Kimura F, Kohno T, Matsuoka M, Ichikawa M, Tsumoto T, et al. Brain-derived neurotrophic factor-dependent unmasking of “silent” synapses in the developing mouse barrel cortex. Proc Natl Acad Sci USA. 2003;100:13069–74.

    Article  CAS  PubMed Central  Google Scholar 

  15. Li W, Keifer J. BDNF-induced synaptic delivery of AMPAR subunits is differentially dependent on NMDA receptors and requires ERK. Neurobiol Learn Mem. 2009;91:243–9.

    Article  CAS  PubMed  Google Scholar 

  16. Yin Y, Edelman GM, Vanderklish PW. The brain-derived neurotrophic factor enhances synthesis of Arc in synaptoneurosomes. Proc Natl Acad Sci USA. 2002;99:2368–73.

    Article  CAS  Google Scholar 

  17. Bramham CR, Worley PF, Moore MJ, Guzowski JF. The immediate early gene arc/arg3.1: regulation, mechanisms, and function. J Neurosci. 2008;28:11760–7.

    Article  CAS  PubMed  Google Scholar 

  18. Elmariah SB, Crumling MA, Parsons TD, Balice-Gordon RJ. Postsynaptic TrkB-mediated signaling modulates excitatory and inhibitory neurotransmitter receptor clustering at hippocampal synapses. J Neurosci. 2004;24:2380–93.

    Article  CAS  PubMed Central  Google Scholar 

  19. Li HS, Xu XZ, Montell C. Activation of a TRPC3-dependent cation current through the neurotrophin BDNF. Neuron. 1999;24:261–73.

    Article  CAS  PubMed  Google Scholar 

  20. Blum R, Kafitz KW, Konnerth A. Neurotrophin-evoked depolarization requires the sodium channel Na(V)1.9. Nature. 2002;419:687–93.

    Article  CAS  PubMed  Google Scholar 

  21. Tucker K, Fadool DA. Neurotrophin modulation of voltage-gated potassium channels in rat through TrkB receptors is time and sensory experience dependent. J Physiol. 2002;542:413–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Ippolito DL, Temkin PA, Rogalski SL, Chavkin C. N-terminal tyrosine residues within the potassium channel Kir3 modulate GTPase activity of Galphai. J Biol Chem. 2002;277:32692–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Marshak S, Nikolakopoulou AM, Dirks R, Martens GJ, Cohen-Cory S. Cell-autonomous TrkB signaling in presynaptic retinal ganglion cells mediates axon arbor growth and synapse maturation during the establishment of retinotectal synaptic connectivity. J Neurosci. 2007;27:2444–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Dean C, Liu H, Dunning FM, Chang PY, Jackson MB, Chapman ER. Synaptotagmin-IV modulates synaptic function and long-term potentiation by regulating BDNF release. Nat Neurosci. 2009;12:767–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Danzer SC, Kotloski RJ, Walter C, Hughes M, McNamara JO. Altered morphology of hippocampal dentate granule cell presynaptic and postsynaptic terminals following conditional deletion of TrkB. Hippocampus. 2008;18:668–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Sala C, Segal M. Dendritic spines: the locus of structural and functional plasticity. Physiol Rev. 2014;94:141–88.

    Article  CAS  PubMed  Google Scholar 

  27. Gottmann K, Mittmann T, Lessmann V. BDNF signaling in the formation, maturation and plasticity of glutamatergic and GABAergic synapses. Exp Brain Res. 2009;199:203–34.

    Article  CAS  PubMed  Google Scholar 

  28. Zagrebelsky M, Korte M. Form follows function: BDNF and its involvement in sculpting the function and structure of synapses. Neuropharmacology. 2014;76:628–38.

    Article  CAS  PubMed  Google Scholar 

  29. Amaral MD, Pozzo-Miller L. TRPC3 channels are necessary for brain-derived neurotrophic factor to activate a nonselective cationic current and to induce dendritic spine formation. J Neurosci. 2007;27:5179–89.

    Article  CAS  PubMed  Google Scholar 

  30. Alonso M, Medina JH, Pozzo-Miller L. ERK1/2 activation is necessary for BDNF to increase dendritic spine density in hippocampal CA1 pyramidal neurons. Learn Mem. 2004;11:172–8.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Kellner Y, Godecke N, Dierkes T, Thieme N, Zagrebelsky M, Korte M. The BDNF effects on dendritic spines of mature hippocampal neurons depend on neuronal activity. Front Synaptic Neurosci. 2014;6:5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Zagrebelsky M, Godecke N, Remus A, Korte M. Cell type-specific effects of BDNF in modulating dendritic architecture of hippocampal neurons. Brain Struct Funct. 2018;223:3689–709.

    Article  CAS  PubMed  Google Scholar 

  33. Rauskolb S, Zagrebelsky M, Dreznjak A, Deogracias R, Matsumoto T, Wiese S, et al. Global deprivation of brain-derived neurotrophic factor in the CNS reveals an area-specific requirement for dendritic growth. J Neurosci. 2010;30:1739–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Rex CS, Lin CY, Kramar EA, Chen LY, Gall CM, Lynch G. Brain-derived neurotrophic factor promotes long-term potentiation-related cytoskeletal changes in adult hippocampus. J Neurosci. 2007;27:3017–29.

    Article  CAS  Google Scholar 

  35. Hedrick NG, Harward SC, Hall CE, Murakoshi H, McNamara JO, Yasuda R. Rho GTPase complementation underlies BDNF-dependent homo- and heterosynaptic plasticity. Nature. 2016;538:104–8.

    Article  CAS  Google Scholar 

  36. Takei N, Inamura N, Kawamura M, Namba H, Hara K, Yonezawa K, et al. Brain-derived neurotrophic factor induces mammalian target of rapamycin-dependent local activation of translation machinery and protein synthesis in neuronal dendrites. J Neurosci. 2004;24:9760–9.

    Article  CAS  Google Scholar 

  37. Schratt GM, Nigh EA, Chen WG, Hu L, Greenberg ME. BDNF regulates the translation of a select group of mRNAs by a mammalian target of rapamycin-phosphatidylinositol 3-kinase-dependent pathway during neuronal development. J Neurosci. 2004;24:7366–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Tanaka J, Horiike Y, Matsuzaki M, Miyazaki T, Ellis-Davies GC, Kasai H. Protein synthesis and neurotrophin-dependent structural plasticity of single dendritic spines. Science. 2008;319:1683–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Harward SC, Hedrick NG, Hall CE, Parra-Bueno P, Milner TA, Pan E, et al. Autocrine BDNF-TrkB signalling within a single dendritic spine. Nature. 2016;538:99–103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Yang J, Harte-Hargrove LC, Siao CJ, Marinic T, Clarke R, Ma Q, et al. proBDNF negatively regulates neuronal remodeling, synaptic transmission, and synaptic plasticity in hippocampus. Cell Rep. 2014;7:796–806.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Winnubst J, Cheyne JE, Niculescu D, Lohmann C. Spontaneous activity drives local synaptic plasticity in vivo. Neuron. 2015;87:399–410.

    Article  CAS  Google Scholar 

  42. Matsumoto T, Rauskolb S, Polack M, Klose J, Kolbeck R, Korte M, et al. Biosynthesis and processing of endogenous BDNF: CNS neurons store and secrete BDNF, not pro-BDNF. Nat Neurosci. 2008;11:131–3.

    Article  CAS  Google Scholar 

  43. Yang J, Siao CJ, Nagappan G, Marinic T, Jing D, McGrath K, et al. Neuronal release of proBDNF. Nat Neurosci. 2009;12:113–5.

    Article  PubMed  PubMed Central  Google Scholar 

  44. Leal G, Comprido D, Duarte CB. BDNF-induced local protein synthesis and synaptic plasticity. Neuropharmacology. 2014;76:639–56.

    Article  CAS  PubMed  Google Scholar 

  45. Kang H, Welcher AA, Shelton D, Schuman EM. Neurotrophins and time: different roles for TrkB signaling in hippocampal long-term potentiation. Neuron. 1997;19:653–64.

    Article  CAS  PubMed  Google Scholar 

  46. Korte M, Carroll P, Wolf E, Brem G, Thoenen H, Bonhoeffer T. Hippocampal long-term potentiation is impaired in mice lacking brain-derived neurotrophic factor. Proc Natl Acad Sci USA. 1995;92:8856–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Bartoletti A, Cancedda L, Reid SW, Tessarollo L, Porciatti V, Pizzorusso T, et al. Heterozygous knock-out mice for brain-derived neurotrophic factor show a pathway-specific impairment of long-term potentiation but normal critical period for monocular deprivation. J Neurosci. 2002;22:10072–7.

    Article  CAS  PubMed  Google Scholar 

  48. Patterson SL, Abel T, Deuel TA, Martin KC, Rose JC, Kandel ER. Recombinant BDNF rescues deficits in basal synaptic transmission and hippocampal LTP in BDNF knockout mice. Neuron. 1996;16:1137–45.

    Article  CAS  Google Scholar 

  49. Pozzo-Miller LD, Gottschalk W, Zhang L, McDermott K, Du J, Gopalakrishnan R, et al. Impairments in high-frequency transmission, synaptic vesicle docking, and synaptic protein distribution in the hippocampus of BDNF knockout mice. J Neurosci. 1999;19:4972–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Korte M, Kang H, Bonhoeffer T, Schuman E. A role for BDNF in the late-phase of hippocampal long-term potentiation. Neuropharmacology. 1998;37:553–9.

    Article  CAS  PubMed  Google Scholar 

  51. Pang PT, Teng HK, Zaitsev E, Woo NT, Sakata K, Zhen S, et al. Cleavage of proBDNF by tPA/plasmin is essential for long-term hippocampal plasticity. Science. 2004;306:487–91.

    Article  CAS  PubMed  Google Scholar 

  52. Lin PY, Kavalali ET, Monteggia LM. Genetic dissection of presynaptic and postsynaptic BDNF-TrkB signaling in synaptic efficacy of CA3-CA1 synapses. Cell Rep. 2018;24:1550–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Jia Y, Gall CM, Lynch G. Presynaptic BDNF promotes postsynaptic long-term potentiation in the dorsal striatum. J Neurosci. 2010;30:14440–5.

    Article  CAS  PubMed Central  Google Scholar 

  54. Glerup S, Bolcho U, Molgaard S, Boggild S, Vaegter CB, Smith AH, et al. SorCS2 is required for BDNF-dependent plasticity in the hippocampus. Mol Psychiatry. 2016;21:1740–51.

    Article  CAS  PubMed  Google Scholar 

  55. Patterson SL, Pittenger C, Morozov A, Martin KC, Scanlin H, Drake C, et al. Some forms of cAMP-mediated long-lasting potentiation are associated with release of BDNF and nuclear translocation of phospho-MAP kinase. Neuron. 2001;32:123–40.

    Article  CAS  PubMed  Google Scholar 

  56. Woo NH, Teng HK, Siao CJ, Chiaruttini C, Pang PT, Milner TA, et al. Activation of p75NTR by proBDNF facilitates hippocampal long-term depression. Nat Neurosci. 2005;8:1069–77.

    Article  CAS  Google Scholar 

  57. Ma X, Vuyyuru H, Munsch T, Endres T, Lessmann V, Meis S. ProBDNF dependence of LTD and fear extinction learning in the amygdala of adult mice. Cereb Cortex. 2022;32:1350–64.

    Article  PubMed  Google Scholar 

  58. Martinowich K, Schloesser RJ, Lu Y, Jimenez DV, Paredes D, Greene JS, et al. Roles of p75(NTR), long-term depression, and cholinergic transmission in anxiety and acute stress coping. Biol Psychiatry. 2012;71:75–83.

    Article  CAS  Google Scholar 

  59. Zagrebelsky M, Holz A, Dechant G, Barde YA, Bonhoeffer T, Korte M. The p75 neurotrophin receptor negatively modulates dendrite complexity and spine density in hippocampal neurons. J Neurosci. 2005;25:9989–99.

    Article  CAS  PubMed Central  Google Scholar 

  60. Moya-Alvarado G, Guerra MV, Tiburcio R, Bravo E, Bronfman FC. The Rab11-regulated endocytic pathway and BDNF/TrkB signaling: Roles in plasticity changes and neurodegenerative diseases. Neurobiol Dis. 2022;171:105796.

    Article  CAS  PubMed  Google Scholar 

  61. Villarroel-Campos D, Schiavo G, Lazo OM. The many disguises of the signalling endosome. FEBS Lett. 2018;592:3615–32.

    Article  CAS  Google Scholar 

  62. Bronfman FC, Lazo OM, Flores C, Escudero CA. Spatiotemporal intracellular dynamics of neurotrophin and its receptors. Implications for neurotrophin signaling and neuronal function. Handb Exp Pharmacol. 2014;220:33–65.

    Article  CAS  Google Scholar 

  63. Zheng J, Shen WH, Lu TJ, Zhou Y, Chen Q, Wang Z, et al. Clathrin-dependent endocytosis is required for TrkB-dependent Akt-mediated neuronal protection and dendritic growth. J Biol Chem. 2008;283:13280–8.

    Article  CAS  Google Scholar 

  64. Liu XH, Geng Z, Yan J, Li T, Chen Q, Zhang QY, et al. Blocking GSK3beta-mediated dynamin1 phosphorylation enhances BDNF-dependent TrkB endocytosis and the protective effects of BDNF in neuronal and mouse models of Alzheimer’s disease. Neurobiol Dis. 2015;74:377–91.

    Article  CAS  PubMed  Google Scholar 

  65. Philippidou P, Valdez G, Akmentin W, Bowers WJ, Federoff HJ, Halegoua S. Trk retrograde signaling requires persistent, Pincher-directed endosomes. Proc Natl Acad Sci USA. 2011;108:852–7.

    Article  CAS  PubMed  Google Scholar 

  66. Xu C, Fu X, Zhu S, Liu JJ. Retrolinkin recruits the WAVE1 protein complex to facilitate BDNF-induced TrkB endocytosis and dendrite outgrowth. Mol Biol Cell. 2016;27:3342–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Du J, Feng L, Yang F, Lu B. Activity- and Ca(2+)-dependent modulation of surface expression of brain-derived neurotrophic factor receptors in hippocampal neurons. J Cell Biol. 2000;150:1423–34.

    Article  CAS  PubMed  Google Scholar 

  68. Zhou P, Porcionatto M, Pilapil M, Chen Y, Choi Y, Tolias KF, et al. Polarized signaling endosomes coordinate BDNF-induced chemotaxis of cerebellar precursors. Neuron. 2007;55:53–68.

    Article  CAS  PubMed  Google Scholar 

  69. Burk K, Murdoch JD, Freytag S, Koenig M, Bharat V, Markworth R, et al. EndophilinAs regulate endosomal sorting of BDNF-TrkB to mediate survival signaling in hippocampal neurons. Sci Rep. 2017;7:2149.

    Article  PubMed  PubMed Central  Google Scholar 

  70. Moya-Alvarado G, Gonzalez A, Stuardo N, Bronfman FC. Brain-Derived Neurotrophic Factor (BDNF) regulates Rab5-Positive early endosomes in hippocampal neurons to induce dendritic branching. Front Cell Neurosci. 2018;12:493.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Andres-Alonso M, Ammar MR, Butnaru I, Gomes GM, Acuna Sanhueza G, Raman R, et al. SIPA1L2 controls trafficking and local signaling of TrkB-containing amphisomes at presynaptic terminals. Nat Commun. 2019;10:5448.

    Article  PubMed  PubMed Central  Google Scholar 

  72. von Zastrow M, Sorkin A. Mechanisms for regulating and organizing receptor signaling by endocytosis. Annu Rev Biochem. 2021;90:709–37.

    Article  Google Scholar 

  73. Murray SS, Wong AW, Yang J, Li Y, Putz U, Tan SS, et al. Ubiquitin regulation of trk receptor trafficking and degradation. Mol Neurobiol. 2019;56:1628–36.

    Article  CAS  Google Scholar 

  74. Jadhav T, Geetha T, Jiang J, Wooten MW. Identification of a consensus site for TRAF6/p62 polyubiquitination. Biochem Biophys Res Commun. 2008;371:521–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Arevalo JC, Waite J, Rajagopal R, Beyna M, Chen ZY, Lee FS, et al. Cell survival through Trk neurotrophin receptors is differentially regulated by ubiquitination. Neuron. 2006;50:549–59.

    Article  CAS  PubMed  Google Scholar 

  76. Martin-Rodriguez C, Song M, Anta B, Gonzalez-Calvo FJ, Deogracias R, Jing D, et al. TrkB deubiquitylation by USP8 regulates receptor levels and BDNF-dependent neuronal differentiation. J Cell Sci. 2020;133:jcs247841.

    Article  CAS  PubMed Central  Google Scholar 

  77. Guo YY, Lu Y, Zheng Y, Chen XR, Dong JL, Yuan RR, et al. Ubiquitin C-Terminal Hydrolase L1 (UCH-L1) Promotes Hippocampus-Dependent Memory via Its Deubiquitinating Effect on TrkB. J Neurosci. 2017;37:5978–95.

    Article  CAS  PubMed Central  Google Scholar 

  78. Budzinska MI, Villarroel-Campos D, Golding M, Weston A, Collinson L, Snijders AP, et al. PTPN23 binds the dynein adaptor BICD1 and is required for endocytic sorting of neurotrophin receptors. J Cell Sci. 2020;133:jcs242412.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Zamani A, Xiao J, Turnley AM, Murray SS. Tropomyosin-Related Kinase B (TrkB) regulates neurite outgrowth via a novel interaction with suppressor of cytokine signalling 2 (SOCS2). Mol Neurobiol. 2019;56:1262–75.

    Article  CAS  PubMed  Google Scholar 

  80. Huang SH, Zhao L, Sun ZP, Li XZ, Geng Z, Zhang KD, et al. Essential role of Hrs in endocytic recycling of full-length TrkB receptor but not its isoform TrkB.T1. J Biol Chem. 2009;284:15126–36.

    Article  CAS  PubMed Central  Google Scholar 

  81. Yano H, Ninan I, Zhang H, Milner TA, Arancio O, Chao MV. BDNF-mediated neurotransmission relies upon a myosin VI motor complex. Nat Neurosci. 2006;9:1009–18.

    Article  CAS  PubMed  Google Scholar 

  82. Huang SH, Wang J, Sui WH, Chen B, Zhang XY, Yan J, et al. BDNF-dependent recycling facilitates TrkB translocation to postsynaptic density during LTP via a Rab11-dependent pathway. J Neurosci. 2013;33:9214–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Sui WH, Huang SH, Wang J, Chen Q, Liu T, Chen ZY. Myosin Va mediates BDNF-induced postendocytic recycling of full-length TrkB and its translocation into dendritic spines. J Cell Sci. 2015;128:1108–22.

    CAS  PubMed  Google Scholar 

  84. Santi S, Cappello S, Riccio M, Bergami M, Aicardi G, Schenk U, et al. Hippocampal neurons recycle BDNF for activity-dependent secretion and LTP maintenance. EMBO J. 2006;25:4372–80.

    Article  CAS  PubMed Central  Google Scholar 

  85. Gonzalez-Gutierrez A, Lazo OM, Bronfman FC. The Rab5-Rab11 Endosomal Pathway is Required for BDNF-Induced CREB Transcriptional Regulation in Hippocampal Neurons. J Neurosci. 2020;40:8042–54.

    Article  CAS  PubMed Central  Google Scholar 

  86. Lazo OM, Gonzalez A, Ascano M, Kuruvilla R, Couve A, Bronfman FC. BDNF regulates Rab11-mediated recycling endosome dynamics to induce dendritic branching. J Neurosci. 2013;33:6112–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Song M, Giza J, Proenca CC, Jing D, Elliott M, Dincheva I, et al. Slitrk5 Mediates BDNF-Dependent TrkB receptor trafficking and signaling. Dev Cell. 2015;33:690–702.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Barford K, Deppmann C, Winckler B. The neurotrophin receptor signaling endosome: Where trafficking meets signaling. Dev Neurobiol. 2017;77:405–18.

    Article  CAS  PubMed Central  Google Scholar 

  89. Harrington AW, Ginty DD. Long-distance retrograde neurotrophic factor signalling in neurons. Nat Rev Neurosci. 2013;14:177–87.

    Article  CAS  PubMed  Google Scholar 

  90. Howe CL, Mobley WC. Long-distance retrograde neurotrophic signaling. Curr Opin Neurobiol. 2005;15:40–48.

    Article  CAS  Google Scholar 

  91. Moya-Alvarado G, Tiburcio-Felix R, Ibanez MR, Aguirre-Soto AA, Guerra MV, Wu C, et al. BDNF/TrkB signaling endosomes in axons coordinate CREB/mTOR activation and protein synthesis in the cell body to induce dendritic growth in cortical neurons. Elife. 2023;12:e77455.

    Article  CAS  PubMed  Google Scholar 

  92. Wang T, Martin S, Nguyen TH, Harper CB, Gormal RS, Martinez-Marmol R, et al. Flux of signalling endosomes undergoing axonal retrograde transport is encoded by presynaptic activity and TrkB. Nat Commun. 2016;7:12976.

    Article  CAS  PubMed Central  Google Scholar 

  93. Cohen MS, Bas Orth C, Kim HJ, Jeon NL, Jaffrey SR. Neurotrophin-mediated dendrite-to-nucleus signaling revealed by microfluidic compartmentalization of dendrites. Proc Natl Acad Sci USA. 2011;108:11246–51.

    Article  CAS  Google Scholar 

  94. Yano H, Lee FS, Kong H, Chuang J, Arevalo J, Perez P, et al. Association of Trk neurotrophin receptors with components of the cytoplasmic dynein motor. J Neurosci. 2001;21:RC125.

    Article  CAS  Google Scholar 

  95. Mitchell DJ, Blasier KR, Jeffery ED, Ross MW, Pullikuth AK, Suo D, et al. Trk activation of the ERK1/2 kinase pathway stimulates intermediate chain phosphorylation and recruits cytoplasmic dynein to signaling endosomes for retrograde axonal transport. J Neurosci. 2012;32:15495–510.

    Article  CAS  PubMed Central  Google Scholar 

  96. Olenick MA, Dominguez R, Holzbaur ELF. Dynein activator Hook1 is required for trafficking of BDNF-signaling endosomes in neurons. J Cell Biol. 2019;218:220–33.

    Article  CAS  Google Scholar 

  97. Lazo OM, Schiavo G. Rab10 regulates the sorting of internalised TrkB for retrograde axonal transport. Elife. 2023;12:e81532.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Zhou B, Cai Q, Xie Y, Sheng ZH. Snapin recruits dynein to BDNF-TrkB signaling endosomes for retrograde axonal transport and is essential for dendrite growth of cortical neurons. Cell Rep. 2012;2:42–51.

    Article  CAS  PubMed  Google Scholar 

  99. Scaramuzzino C, Cuoc EC, Pla P, Humbert S, Saudou F. Calcineurin and huntingtin form a calcium-sensing machinery that directs neurotrophic signals to the nucleus. Sci Adv. 2022;8:eabj8812.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Cheng PL, Song AH, Wong YH, Wang S, Zhang X, Poo MM. Self-amplifying autocrine actions of BDNF in axon development. Proc Natl Acad Sci USA. 2011;108:18430–5.

    Article  CAS  Google Scholar 

  101. Zhao X, Chen XQ, Han E, Hu Y, Paik P, Ding Z, et al. TRiC subunits enhance BDNF axonal transport and rescue striatal atrophy in Huntington’s disease. Proc Natl Acad Sci USA. 2016;113:E5655–5664.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Puehringer D, Orel N, Luningschror P, Subramanian N, Herrmann T, Chao MV, et al. EGF transactivation of Trk receptors regulates the migration of newborn cortical neurons. Nat Neurosci. 2013;16:407–15.

    Article  CAS  PubMed  Google Scholar 

  103. Bartkowska K, Paquin A, Gauthier AS, Kaplan DR, Miller FD. Trk signaling regulates neural precursor cell proliferation and differentiation during cortical development. Development. 2007;134:4369–80.

    Article  CAS  Google Scholar 

  104. Butowt R, von Bartheld CS. Conventional kinesin-I motors participate in the anterograde axonal transport of neurotrophins in the visual system. J Neurosci Res. 2007;85:2546–56.

    Article  CAS  PubMed  Google Scholar 

  105. Arimura N, Kimura T, Nakamuta S, Taya S, Funahashi Y, Hattori A, et al. Anterograde transport of TrkB in axons is mediated by direct interaction with Slp1 and Rab27. Dev Cell. 2009;16:675–86.

    Article  CAS  Google Scholar 

  106. Huang SH, Duan S, Sun T, Wang J, Zhao L, Geng Z, et al. JIP3 mediates TrkB axonal anterograde transport and enhances BDNF signaling by directly bridging TrkB with kinesin-1. J Neurosci. 2011;31:10602–14.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Sun T, Li Y, Li T, Ma H, Guo Y, Jiang X, et al. JIP1 and JIP3 cooperate to mediate TrkB anterograde axonal transport by activating kinesin-1. Cell Mol Life Sci. 2017;74:4027–44.

    Article  CAS  PubMed  Google Scholar 

  108. Vaegter CB, Jansen P, Fjorback AW, Glerup S, Skeldal S, Kjolby M, et al. Sortilin associates with Trk receptors to enhance anterograde transport and neurotrophin signaling. Nat Neurosci. 2011;14:54–61.

    Article  CAS  PubMed  Google Scholar 

  109. Xiang J, Yang H, Zhao T, Sun M, Xu X, Zhou XF, et al. Huntingtin-associated protein 1 regulates postnatal neurogenesis and neurotrophin receptor sorting. J Clin Invest. 2014;124:85–98.

    Article  CAS  PubMed  Google Scholar 

  110. Zahavi EE, Hummel JJA, Han Y, Bar C, Stucchi R, Altelaar M, et al. Combined kinesin-1 and kinesin-3 activity drives axonal trafficking of TrkB receptors in Rab6 carriers. Dev Cell. 2021;56:494–508 e497.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Wu C, Cui B, He L, Chen L, Mobley WC. The coming of age of axonal neurotrophin signaling endosomes. J Proteomics. 2009;72:46–55.

    Article  CAS  PubMed  Google Scholar 

  112. Villarroel-Campos D, Rhymes ER, Tosolini AP, Malik B, Vagnoni A, Schiavo G, et al. Processivity and BDNF-dependent modulation of signalling endosome axonal transport are impaired in mice with advanced age. Neurobiol Aging. 2025;153:1–9.

    Article  CAS  Google Scholar 

  113. Poon WW, Blurton-Jones M, Tu CH, Feinberg LM, Chabrier MA, Harris JW, et al. beta-Amyloid impairs axonal BDNF retrograde trafficking. Neurobiol Aging. 2011;32:821–33.

    Article  CAS  PubMed  Google Scholar 

  114. Ye X, Tai W, Zhang D. The early events of Alzheimer’s disease pathology: from mitochondrial dysfunction to BDNF axonal transport deficits. Neurobiol Aging. 2012;33:1122 e1121–1110.

    Article  Google Scholar 

  115. Ramser EM, Gan KJ, Decker H, Fan EY, Suzuki MM, Ferreira ST, et al. Amyloid-beta oligomers induce tau-independent disruption of BDNF axonal transport via calcineurin activation in cultured hippocampal neurons. Mol Biol Cell. 2013;24:2494–505.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Pensalfini A, Kim S, Subbanna S, Bleiwas C, Goulbourne CN, Stavrides PH, et al. Endosomal dysfunction induced by directly overactivating Rab5 recapitulates prodromal and neurodegenerative features of Alzheimer’s disease. Cell Rep. 2020;33:108420.

    Article  CAS  PubMed Central  Google Scholar 

  117. Meyer-Franke A, Wilkinson GA, Kruttgen A, Hu M, Munro E, Hanson MG Jr., et al. Depolarization and cAMP elevation rapidly recruit TrkB to the plasma membrane of CNS neurons. Neuron. 1998;21:681–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Zhao L, Sheng AL, Huang SH, Yin YX, Chen B, Li XZ, et al. Mechanism underlying activity-dependent insertion of TrkB into the neuronal surface. J Cell Sci. 2009;122:3123–36.

    Article  CAS  PubMed  Google Scholar 

  119. Li N, Teng SW, Zhao L, Li JR, Xu JL, Li N, et al. Carboxypeptidase E regulates activity-dependent TrkB neuronal surface insertion and hippocampal memory. J Neurosci. 2021;41:6987–7002.

    Article  CAS  PubMed  Google Scholar 

  120. Andreska T, Luningschror P, Wolf D, McFleder RL, Ayon-Olivas M, Rattka M, et al. DRD1 signaling modulates TrkB turnover and BDNF sensitivity in direct pathway striatal medium spiny neurons. Cell Rep. 2023;42:112575.

    Article  CAS  PubMed  Google Scholar 

  121. Zampieri N, Chao MV. Mechanisms of neurotrophin receptor signalling. Biochem Soc Trans. 2006;34:607–11.

    Article  CAS  PubMed  Google Scholar 

  122. Lee FS, Chao MV. Activation of Trk neurotrophin receptors in the absence of neurotrophins. Proc Natl Acad Sci USA. 2001;98:3555–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Mitre M, Saadipour K, Williams K, Khatri L, Froemke RC, Chao MV. Transactivation of TrkB receptors by oxytocin and its G protein-coupled receptor. Front Mol Neurosci. 2022;15:891537.

    Article  CAS  PubMed  Google Scholar 

  124. Simonato M, Bregola G, Armellin M, Del Piccolo P, Rodi D, Zucchini S, et al. Dendritic targeting of mRNAs for plasticity genes in experimental models of temporal lobe epilepsy. Epilepsia. 2002;43:153–8.

    Article  CAS  PubMed  Google Scholar 

  125. Tongiorgi E, Righi M, Cattaneo A. Activity-dependent dendritic targeting of BDNF and TrkB mRNAs in hippocampal neurons. J Neurosci. 1997;17:9492–505.

    Article  CAS  PubMed Central  Google Scholar 

  126. Orefice LL, Waterhouse EG, Partridge JG, Lalchandani RR, Vicini S, Xu B. Distinct roles for somatically and dendritically synthesized brain-derived neurotrophic factor in morphogenesis of dendritic spines. J Neurosci. 2013;33:11618–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. An JJ, Gharami K, Liao GY, Woo NH, Lau AG, Vanevski F, et al. Distinct role of long 3’ UTR BDNF mRNA in spine morphology and synaptic plasticity in hippocampal neurons. Cell. 2008;134:175–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Chiaruttini C, Vicario A, Li Z, Baj G, Braiuca P, Wu Y, et al. Dendritic trafficking of BDNF mRNA is mediated by translin and blocked by the G196A (Val66Met) mutation. Proc Natl Acad Sci USA. 2009;106:16481–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Castren E, Monteggia LM. Brain-Derived neurotrophic factor signaling in depression and antidepressant action. Biol Psychiatry. 2021;90:128–36.

    Article  CAS  Google Scholar 

  130. Thompson Ray M, Weickert CS, Wyatt E, Webster MJ. Decreased BDNF, trkB-TK+ and GAD67 mRNA expression in the hippocampus of individuals with schizophrenia and mood disorders. J Psychiatry Neurosci. 2011;36:195–203.

    Article  PubMed  Google Scholar 

  131. Ray MT, Shannon Weickert C, Webster MJ. Decreased BDNF and TrkB mRNA expression in multiple cortical areas of patients with schizophrenia and mood disorders. Transl Psychiatry. 2014;4:e389.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Pandey GN, Dwivedi Y, Rizavi HS, Ren X, Zhang H, Pavuluri MN. Brain-derived neurotrophic factor gene and protein expression in pediatric and adult depressed subjects. Prog Neuropsychopharmacol Biol Psychiatry. 2010;34:645–51.

    Article  CAS  Google Scholar 

  133. Chen B, Dowlatshahi D, MacQueen GM, Wang JF, Young LT. Increased hippocampal BDNF immunoreactivity in subjects treated with antidepressant medication. Biol Psychiatry. 2001;50:260–5.

    Article  CAS  PubMed  Google Scholar 

  134. Berton O, Nestler EJ. New approaches to antidepressant drug discovery: beyond monoamines. Nat Rev Neurosci. 2006;7:137–51.

    Article  CAS  PubMed  Google Scholar 

  135. Martis LS, Wiborg O, Holmes MC, Harris AP. BDNF(+/-) rats exhibit depressive phenotype and altered expression of genes relevant in mood disorders. Genes Brain Behav. 2019;18:e12546.

    Article  PubMed  Google Scholar 

  136. Smith MA, Makino S, Kvetnansky R, Post RM. Stress and glucocorticoids affect the expression of brain-derived neurotrophic factor and neurotrophin-3 mRNAs in the hippocampus. J Neurosci. 1995;15:1768–77.

    Article  CAS  PubMed Central  Google Scholar 

  137. Hosang GM, Shiles C, Tansey KE, McGuffin P, Uher R. Interaction between stress and the BDNF Val66Met polymorphism in depression: a systematic review and meta-analysis. BMC Med. 2014;12:7.

    Article  PubMed Central  Google Scholar 

  138. Zhao M, Chen L, Yang J, Han D, Fang D, Qiu X, et al. BDNF Val66Met polymorphism, life stress and depression: A meta-analysis of gene-environment interaction. J Affect Disord. 2018;227:226–35.

    Article  CAS  PubMed  Google Scholar 

  139. Yu H, Wang DD, Wang Y, Liu T, Lee FS, Chen ZY. Variant brain-derived neurotrophic factor Val66Met polymorphism alters vulnerability to stress and response to antidepressants. J Neurosci. 2012;32:4092–101.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Casarotto PC, Girych M, Fred SM, Kovaleva V, Moliner R, Enkavi G, et al. Antidepressant drugs act by directly binding to TRKB neurotrophin receptors. Cell. 2021;184:1299–313 e1219.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Moliner R, Girych M, Brunello CA, Kovaleva V, Biojone C, Enkavi G, et al. Psychedelics promote plasticity by directly binding to BDNF receptor TrkB. Nat Neurosci. 2023;26:1032–41.

    Article  PubMed Central  Google Scholar 

  142. Brunello CA, Cannarozzo C, Castren E. Rethinking the role of TRKB in the action of antidepressants and psychedelics. Trends Neurosci. 2024;47:865–74.

    Article  CAS  Google Scholar 

  143. Shi X, Zhou XZ, Chen G, Luo WF, Zhou C, He TJ, et al. Targeting the postsynaptic scaffolding protein PSD-95 enhances BDNF signaling to mitigate depression-like behaviors in mice. Sci Signal. 2024;17:eadn4556.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Chen WJ, Zhu BL, Qian JJ, Zhao J, Zhang F, Jiang B, et al. Hippocampal SorCS2 overexpression represses chronic stress-induced depressive-like behaviors by promoting the BDNF-TrkB system. Pharmacol Biochem Behav. 2024;242:173820.

    Article  CAS  Google Scholar 

  145. Lin PY, Ma ZZ, Mahgoub M, Kavalali ET, Monteggia LM. A synaptic locus for TrkB signaling underlying ketamine rapid antidepressant action. Cell Rep. 2021;36:109513.

    Article  CAS  PubMed Central  Google Scholar 

  146. Li HY, Zhu MZ, Yuan XR, Guo ZX, Pan YD, Li YQ, et al. A thalamic-primary auditory cortex circuit mediates resilience to stress. Cell. 2023;186:1352–68 e1318.

    Article  CAS  PubMed  Google Scholar 

  147. Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U, Zoghbi HY. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet. 1999;23:185–8.

    Article  CAS  Google Scholar 

  148. Chang Q, Khare G, Dani V, Nelson S, Jaenisch R. The disease progression of Mecp2 mutant mice is affected by the level of BDNF expression. Neuron. 2006;49:341–8.

    Article  CAS  PubMed  Google Scholar 

  149. Zhou Z, Hong EJ, Cohen S, Zhao WN, Ho HY, Schmidt L, et al. Brain-specific phosphorylation of MeCP2 regulates activity-dependent Bdnf transcription, dendritic growth, and spine maturation. Neuron. 2006;52:255–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Cohen S, Greenberg ME. Communication between the synapse and the nucleus in neuronal development, plasticity, and disease. Annu Rev Cell Dev Biol. 2008;24:183–209.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Ebert DH, Gabel HW, Robinson ND, Kastan NR, Hu LS, Cohen S, et al. Activity-dependent phosphorylation of MeCP2 threonine 308 regulates interaction with NCoR. Nature. 2013;499:341–5.

    Article  CAS  Google Scholar 

  152. Sampathkumar C, Wu YJ, Vadhvani M, Trimbuch T, Eickholt B, Rosenmund C. Loss of MeCP2 disrupts cell autonomous and autocrine BDNF signaling in mouse glutamatergic neurons. Elife. 2016;5:e19374.

    Article  PubMed Central  Google Scholar 

  153. Medeiros D, Ayala-Baylon K, Egido-Betancourt H, Miller E, Chapleau C, Robinson H, et al. A small-molecule TrkB ligand improves dendritic spine phenotypes and atypical behaviors in female Rett syndrome mice. Dis Model Mech. 2024;17:050612.

  154. Larimore JL, Chapleau CA, Kudo S, Theibert A, Percy AK, Pozzo-Miller L. Bdnf overexpression in hippocampal neurons prevents dendritic atrophy caused by Rett-associated MECP2 mutations. Neurobiol Dis. 2009;34:199–211.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Miranda-Lourenco C, Duarte ST, Palminha C, Gaspar C, Rodrigues TM, Magalhaes-Cardoso T, et al. Impairment of adenosinergic system in Rett syndrome: Novel therapeutic target to boost BDNF signalling. Neurobiol Dis. 2020;145:105043.

    Article  CAS  PubMed  Google Scholar 

  156. Zeev BB, Bebbington A, Ho G, Leonard H, de Klerk N, Gak E, et al. The common BDNF polymorphism may be a modifier of disease severity in Rett syndrome. Neurology. 2009;72:1242–7.

    Article  PubMed  PubMed Central  Google Scholar 

  157. Xu X, Garcia J, Ewalt R, Nason S, Pozzo-Miller L. The BDNF val-66-met polymorphism affects neuronal morphology and synaptic transmission in cultured hippocampal neurons from rett syndrome mice. Front Cell Neurosci. 2017;11:203.

    Article  Google Scholar 

  158. Barde YA. The physiopathology of brain-derived neurotrophic factor. Physiol Rev. 2025;105:2073–140.

    CAS  PubMed  Google Scholar 

  159. Jaberi S, Fahnestock M. Mechanisms of the beneficial effects of exercise on brain-derived neurotrophic factor expression in Alzheimer’s disease. Biomolecules. 2023;13:1577.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Umemori J, Winkel F, Didio G, Llach Pou M, Castren E. iPlasticity: Induced juvenile-like plasticity in the adult brain as a mechanism of antidepressants. Psychiatry Clin Neurosci. 2018;72:633–53.

    Article  PubMed  PubMed Central  Google Scholar 

  161. Bramham CR, Messaoudi E. BDNF function in adult synaptic plasticity: the synaptic consolidation hypothesis. Prog Neurobiol. 2005;76:99–125.

    Article  CAS  PubMed  Google Scholar 

  162. Baxby K, Johnson RW. Prediction of kidney viability before transplantation. Br J Surg. 1975;62:810–2.

    Article  CAS  Google Scholar 

  163. Alonso M, Vianna MR, Depino AM, Mello e Souza T, Pereira P, Szapiro G, et al. BDNF-triggered events in the rat hippocampus are required for both short- and long-term memory formation. Hippocampus. 2002;12:551–60.

    Article  CAS  PubMed  Google Scholar 

  164. Lee JL, Everitt BJ, Thomas KL. Independent cellular processes for hippocampal memory consolidation and reconsolidation. Science. 2004;304:839–43.

    Article  CAS  PubMed  Google Scholar 

  165. Linnarsson S, Bjorklund A, Ernfors P. Learning deficit in BDNF mutant mice. Eur J Neurosci. 1997;9:2581–7.

    Article  CAS  PubMed  Google Scholar 

  166. Alonso M, Vianna MR, Izquierdo I, Medina JH. Signaling mechanisms mediating BDNF modulation of memory formation in vivo in the hippocampus. Cell Mol Neurobiol. 2002;22:663–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Johnston AN, Rose SP. Memory consolidation in day-old chicks requires BDNF but not NGF or NT-3; an antisense study. Brain Res Mol Brain Res. 2001;88:26–36.

    Article  CAS  PubMed  Google Scholar 

  168. Ma YL, Wang HL, Wu HC, Wei CL, Lee EH. Brain-derived neurotrophic factor antisense oligonucleotide impairs memory retention and inhibits long-term potentiation in rats. Neuroscience. 1998;82:957–67.

    Article  CAS  PubMed  Google Scholar 

  169. Heldt SA, Stanek L, Chhatwal JP, Ressler KJ. Hippocampus-specific deletion of BDNF in adult mice impairs spatial memory and extinction of aversive memories. Mol Psychiatry. 2007;12:656–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Ou LC, Gean PW. Regulation of amygdala-dependent learning by brain-derived neurotrophic factor is mediated by extracellular signal-regulated kinase and phosphatidylinositol-3-kinase. Neuropsychopharmacology. 2006;31:287–96.

    Article  CAS  PubMed  Google Scholar 

  171. Rattiner LM, Davis M, Ressler KJ. Brain-derived neurotrophic factor in amygdala-dependent learning. Neuroscientist. 2005;11:323–33.

    Article  CAS  PubMed  Google Scholar 

  172. Mizuno M, Yamada K, Olariu A, Nawa H, Nabeshima T. Involvement of brain-derived neurotrophic factor in spatial memory formation and maintenance in a radial arm maze test in rats. J Neurosci. 2000;20:7116–21.

    Article  CAS  Google Scholar 

  173. Miskowiak K, O’Sullivan U, Harmer CJ. Erythropoietin enhances hippocampal response during memory retrieval in humans. J Neurosci. 2007;27:2788–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. McGaugh JL. Time-dependent processes in memory storage. Science. 1966;153:1351–8.

    Article  CAS  PubMed  Google Scholar 

  175. Dudai Y, Eisenberg M. Rites of passage of the engram: reconsolidation and the lingering consolidation hypothesis. Neuron. 2004;44:93–100.

    Article  CAS  PubMed  Google Scholar 

  176. Kandel ER. The molecular biology of memory storage: a dialogue between genes and synapses. Science. 2001;294:1030–8.

    Article  CAS  PubMed  Google Scholar 

  177. Frankland PW, Ding HK, Takahashi E, Suzuki A, Kida S, Silva AJ. Stability of recent and remote contextual fear memory. Learn Mem. 2006;13:451–7.

    Article  PubMed Central  Google Scholar 

  178. Furini CR, Rossato JI, Bitencourt LL, Medina JH, Izquierdo I, Cammarota M. Beta-adrenergic receptors link NO/sGC/PKG signaling to BDNF expression during the consolidation of object recognition long-term memory. Hippocampus. 2010;20:672–83.

    Article  CAS  PubMed  Google Scholar 

  179. Lubin FD, Roth TL, Sweatt JD. Epigenetic regulation of BDNF gene transcription in the consolidation of fear memory. J Neurosci. 2008;28:10576–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Lubin FD. Epigenetic gene regulation in the adult mammalian brain: multiple roles in memory formation. Neurobiol Learn Mem. 2011;96:68–78.

    Article  CAS  Google Scholar 

  181. Mahan AL, Ressler KJ. Fear conditioning, synaptic plasticity and the amygdala: implications for posttraumatic stress disorder. Trends Neurosci. 2012;35:24–35.

    Article  CAS  PubMed  Google Scholar 

  182. Ma L, Wang DD, Zhang TY, Yu H, Wang Y, Huang SH, et al. Region-specific involvement of BDNF secretion and synthesis in conditioned taste aversion memory formation. J Neurosci. 2011;31:2079–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Kang H, Schuman EM. Long-lasting neurotrophin-induced enhancement of synaptic transmission in the adult hippocampus. Science. 1995;267:1658–62.

    Article  CAS  Google Scholar 

  184. Ying SW, Futter M, Rosenblum K, Webber MJ, Hunt SP, Bliss TV, et al. Brain-derived neurotrophic factor induces long-term potentiation in intact adult hippocampus: requirement for ERK activation coupled to CREB and upregulation of Arc synthesis. J Neurosci. 2002;22:1532–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Bekinschtein P, Cammarota M, Igaz LM, Bevilaqua LR, Izquierdo I, Medina JH. Persistence of long-term memory storage requires a late protein synthesis- and BDNF- dependent phase in the hippocampus. Neuron. 2007;53:261–77.

    Article  CAS  PubMed  Google Scholar 

  186. Slipczuk L, Bekinschtein P, Katche C, Cammarota M, Izquierdo I, Medina JH. BDNF activates mTOR to regulate GluR1 expression required for memory formation. PLoS One. 2009;4:e6007.

    Article  PubMed  PubMed Central  Google Scholar 

  187. Mei F, Nagappan G, Ke Y, Sacktor TC, Lu B. BDNF facilitates L-LTP maintenance in the absence of protein synthesis through PKMzeta. PLoS One. 2011;6:e21568.

    Article  CAS  PubMed  Google Scholar 

  188. Adasme T, Haeger P, Paula-Lima AC, Espinoza I, Casas-Alarcon MM, Carrasco MA, et al. Involvement of ryanodine receptors in neurotrophin-induced hippocampal synaptic plasticity and spatial memory formation. Proc Natl Acad Sci USA. 2011;108:3029–34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Lee AM, Kanter BR, Wang D, Lim JP, Zou ME, Qiu C, et al. Prkcz null mice show normal learning and memory. Nature. 2013;493:416–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Volk LJ, Bachman JL, Johnson R, Yu Y, Huganir RL. PKM-zeta is not required for hippocampal synaptic plasticity, learning and memory. Nature. 2013;493:420–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Choi DC, Maguschak KA, Ye K, Jang SW, Myers KM, Ressler KJ. Prelimbic cortical BDNF is required for memory of learned fear but not extinction or innate fear. Proc Natl Acad Sci USA. 2010;107:2675–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Seoane A, Tinsley CJ, Brown MW. Interfering with perirhinal brain-derived neurotrophic factor expression impairs recognition memory in rats. Hippocampus. 2011;21:121–6.

    Article  PubMed  Google Scholar 

  193. Castillo DV, Escobar ML. A role for MAPK and PI-3K signaling pathways in brain-derived neurotrophic factor modification of conditioned taste aversion retention. Behav Brain Res. 2011;217:248–52.

    Article  CAS  PubMed  Google Scholar 

  194. Moguel-Gonzalez M, Gomez-Palacio-Schjetnan A, Escobar ML. BDNF reverses the CTA memory deficits produced by inhibition of protein synthesis. Neurobiol Learn Mem. 2008;90:584–7.

    Article  CAS  PubMed  Google Scholar 

  195. Kleim JA, Chan S, Pringle E, Schallert K, Procaccio V, Jimenez R, et al. BDNF val66met polymorphism is associated with modified experience-dependent plasticity in human motor cortex. Nat Neurosci. 2006;9:735–7.

    Article  CAS  Google Scholar 

  196. Fritsch B, Reis J, Martinowich K, Schambra HM, Ji Y, Cohen LG, et al. Direct current stimulation promotes BDNF-dependent synaptic plasticity: potential implications for motor learning. Neuron. 2010;66:198–204.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Frankland PW, Bontempi B. The organization of recent and remote memories. Nat Rev Neurosci. 2005;6:119–30.

    Article  CAS  Google Scholar 

  198. Zola-Morgan SM, Squire LR. The primate hippocampal formation: evidence for a time-limited role in memory storage. Science. 1990;250:288–90.

    Article  CAS  PubMed  Google Scholar 

  199. Bekinschtein P, Cammarota M, Katche C, Slipczuk L, Rossato JI, Goldin A, et al. BDNF is essential to promote persistence of long-term memory storage. Proc Natl Acad Sci USA. 2008;105:2711–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Rossato JI, Bevilaqua LR, Izquierdo I, Medina JH, Cammarota M. Dopamine controls persistence of long-term memory storage. Science. 2009;325:1017–20.

    Article  CAS  Google Scholar 

  201. Karpova NN, Pickenhagen A, Lindholm J, Tiraboschi E, Kulesskaya N, Agustsdottir A, et al. Fear erasure in mice requires synergy between antidepressant drugs and extinction training. Science. 2011;334:1731–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Psotta L, Lessmann V, Endres T. Impaired fear extinction learning in adult heterozygous BDNF knock-out mice. Neurobiol Learn Mem. 2013;103:34–38.

    Article  CAS  PubMed  Google Scholar 

  203. Peters J, Dieppa-Perea LM, Melendez LM, Quirk GJ. Induction of fear extinction with hippocampal-infralimbic BDNF. Science. 2010;328:1288–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Hoover WB, Vertes RP. Anatomical analysis of afferent projections to the medial prefrontal cortex in the rat. Brain Struct Funct. 2007;212:149–79.

    Article  PubMed  Google Scholar 

  205. Rosas-Vidal LE, Do-Monte FH, Sotres-Bayon F, Quirk GJ. Hippocampal–prefrontal BDNF and memory for fear extinction. Neuropsychopharmacology. 2014;39:2161–9.

    Article  CAS  Google Scholar 

  206. Fanselow MS, Dong HW. Are the dorsal and ventral hippocampus functionally distinct structures? Neuron. 2010;65:7–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Giza JI, Kim J, Meyer HC, Anastasia A, Dincheva I, Zheng CI, et al. The BDNF Val66Met prodomain disassembles dendritic spines altering fear extinction circuitry and behavior. Neuron. 2018;99:1356.

    Article  CAS  PubMed  Google Scholar 

  208. Sakata K, Martinowich K, Woo NH, Schloesser RJ, Jimenez DV, Ji Y, et al. Role of activity-dependent BDNF expression in hippocampal-prefrontal cortical regulation of behavioral perseverance. Proc Natl Acad Sci USA. 2013;110:15103–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. Xin J, Ma L, Zhang TY, Yu H, Wang Y, Kong L, et al. Involvement of BDNF signaling transmission from basolateral amygdala to infralimbic prefrontal cortex in conditioned taste aversion extinction. J Neurosci. 2014;34:7302–13.

    Article  CAS  PubMed Central  Google Scholar 

  210. Li Y, Wang D, Li Y, Chu H, Zhang L, Hou M, et al. Pre-synaptic TrkB in basolateral amygdala neurons mediates BDNF signaling transmission in memory extinction. Cell Death Dis. 2017;8:e2959.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Bredy TW, Wu H, Crego C, Zellhoefer J, Sun YE, Barad M. Histone modifications around individual BDNF gene promoters in prefrontal cortex are associated with extinction of conditioned fear. Learn Mem. 2007;14:268–76.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. Ehinger Y, Soneja D, Phamluong K, Salvi A, Ron D. Identification of novel BDNF-Specific corticostriatal circuitries. eNeuro. 2023;10:0238–21.

  213. Andreska T, Rauskolb S, Schukraft N, Luningschror P, Sasi M, Signoret-Genest J, et al. Induction of BDNF expression in Layer II/III and layer V neurons of the motor cortex is essential for motor learning. J Neurosci. 2020;40:6289–308.

    Article  CAS  PubMed Central  Google Scholar 

  214. Lin K, Coutellier L. Evidence for the involvement of a fronto-striatal pathway in the processing of social reward. Prog Neurobiol. 2025;254:102834.

    Article  CAS  Google Scholar 

  215. Brida KL, Day JJ. Molecular and genetic mechanisms of plasticity in addiction. Curr Opin Neurobiol. 2025;93:103032.

    Article  CAS  PubMed Central  Google Scholar 

  216. Vieitas-Gaspar N, Soares-Cunha C, Rodrigues AJ. From valence encoding to motivated behavior: A focus on the nucleus accumbens circuitry. Neurosci Biobehav Rev. 2025;172:106125.

    Article  CAS  PubMed  Google Scholar 

  217. Goodpaster CM, Christensen CR, Alturki MB, DeNardo LA. Prefrontal cortex development and its implications in mental illness. Neuropsychopharmacology. 2026;51:114–28.

    Article  PubMed  Google Scholar 

  218. Zhao D, Zhang X, Bai J. Medial prefrontal cortex circuit dynamics involved in stage-specific addiction. Brain Struct Funct. 2025;230:185.

    Article  CAS  Google Scholar 

  219. Krishnan V, Han MH, Graham DL, Berton O, Renthal W, Russo SJ, et al. Molecular adaptations underlying susceptibility and resistance to social defeat in brain reward regions. Cell. 2007;131:391–404.

    Article  CAS  PubMed  Google Scholar 

  220. Eisch AJ, Bolanos CA, de Wit J, Simonak RD, Pudiak CM, Barrot M, et al. Brain-derived neurotrophic factor in the ventral midbrain-nucleus accumbens pathway: a role in depression. Biol Psychiatry. 2003;54:994–1005.

    Article  CAS  PubMed  Google Scholar 

  221. Malberg JE, Blendy JA. Antidepressant action: to the nucleus and beyond. Trends Pharmacol Sci. 2005;26:631–8.

    Article  CAS  PubMed  Google Scholar 

  222. Pliakas AM, Carlson RR, Neve RL, Konradi C, Nestler EJ, Carlezon WA Jr. Altered responsiveness to cocaine and increased immobility in the forced swim test associated with elevated cAMP response element-binding protein expression in nucleus accumbens. J Neurosci. 2001;21:7397–403.

    Article  CAS  PubMed Central  Google Scholar 

  223. Walsh JJ, Friedman AK, Sun H, Heller EA, Ku SM, Juarez B, et al. Stress and CRF gate neural activation of BDNF in the mesolimbic reward pathway. Nat Neurosci. 2014;17:27–29.

    Article  CAS  PubMed  Google Scholar 

  224. Wook Koo J, Labonte B, Engmann O, Calipari ES, Juarez B, Lorsch Z, et al. Essential role of mesolimbic brain-derived neurotrophic factor in chronic social stress-induced depressive behaviors. Biol Psychiatry. 2016;80:469–78.

    Article  PubMed  Google Scholar 

  225. Stein G, Aly JS, Lange L, Manzolillo A, Riege K, Brancato A, et al. Npbwr1 signaling mediates fast antidepressant action. Mol Psychiatry. 2025;30:1828–35.

    Article  CAS  PubMed  Google Scholar 

  226. Li WQ, Liu SN, Yang SC, Lin X, Zhang ZJ. Nitrous oxide exerts rewarding effect via regulating D1 receptor and BDNF pathway in ventral tegmental area-nucleus accumbens dopamine circuit. Transl Psychiatry. 2025;15:34.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  227. Ren Q, Ma M, Yang C, Zhang JC, Yao W, Hashimoto K. BDNF-TrkB signaling in the nucleus accumbens shell of mice has key role in methamphetamine withdrawal symptoms. Transl Psychiatry. 2015;5:e666.

    Article  CAS  PubMed Central  Google Scholar 

  228. Koo JW, Mazei-Robison MS, Chaudhury D, Juarez B, LaPlant Q, Ferguson D, et al. BDNF is a negative modulator of morphine action. Science. 2012;338:124–8.

    Article  CAS  PubMed  Google Scholar 

  229. Davis MI. Ethanol-BDNF interactions: still more questions than answers. Pharmacol Ther. 2008;118:36–57.

    Article  CAS  PubMed  Google Scholar 

  230. Carelli RM. Nucleus accumbens cell firing during goal-directed behaviors for cocaine vs. ‘natural’ reinforcement. Physiol Behav. 2002;76:379–87.

    Article  CAS  PubMed  Google Scholar 

  231. Nicola SM, Taha SA, Kim SW, Fields HL. Nucleus accumbens dopamine release is necessary and sufficient to promote the behavioral response to reward-predictive cues. Neuroscience. 2005;135:1025–33.

    Article  CAS  PubMed  Google Scholar 

  232. Taha SA, Fields HL. Encoding of palatability and appetitive behaviors by distinct neuronal populations in the nucleus accumbens. J Neurosci. 2005;25:1193–202.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  233. Jorjani H, Joneidi M, Vafaei AA, Rashidy-Pour A, Sameni H, Bandegi AR, et al. Microinjection of the BDNF receptor antagonist ANA-12 into the nucleus accumbens and medial-prefrontal cortex attenuates morphine-induced reward memory, and alterations of BDNF levels and apoptotic cells in rats. Pharmacol Biochem Behav. 2021;201:173111.

    Article  CAS  PubMed  Google Scholar 

  234. Chen ZY, Jing D, Bath KG, Ieraci A, Khan T, Siao CJ, et al. Genetic variant BDNF (Val66Met) polymorphism alters anxiety-related behavior. Science. 2006;314:140–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  235. Cao L, Dhilla A, Mukai J, Blazeski R, Lodovichi C, Mason CA, et al. Genetic modulation of BDNF signaling affects the outcome of axonal competition in vivo. Curr Biol. 2007;17:911–21.

    Article  CAS  PubMed Central  Google Scholar 

  236. Pattwell SS, Bath KG, Perez-Castro R, Lee FS, Chao MV, Ninan I. The BDNF Val66Met polymorphism impairs synaptic transmission and plasticity in the infralimbic medial prefrontal cortex. J Neurosci. 2012;32:2410–21.

    Article  CAS  PubMed  Google Scholar 

  237. Yu H, Wang Y, Pattwell S, Jing D, Liu T, Zhang Y, et al. Variant BDNF Val66Met polymorphism affects extinction of conditioned aversive memory. J Neurosci. 2009;29:4056–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  238. Soliman F, Glatt CE, Bath KG, Levita L, Jones RM, Pattwell SS, et al. A genetic variant BDNF polymorphism alters extinction learning in both mouse and human. Science. 2010;327:863–6.

    Article  CAS  PubMed  Google Scholar 

  239. Giza JI, Kim J, Meyer HC, Anastasia A, Dincheva I, Zheng CI, et al. The BDNF Val66Met prodomain disassembles dendritic spines altering fear extinction circuitry and behavior. Neuron. 2018;99:163–78.e166.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  240. Marek R, Xu L, Sullivan RKP, Sah P. Excitatory connections between the prelimbic and infralimbic medial prefrontal cortex show a role for the prelimbic cortex in fear extinction. Nat Neurosci. 2018;21:654–8.

    Article  CAS  PubMed  Google Scholar 

  241. Vasquez JH, Leong KC, Gagliardi CM, Harland B, Apicella AJ, Muzzio IA. Pathway specific activation of ventral hippocampal cells projecting to the prelimbic cortex diminishes fear renewal. Neurobiol Learn Mem. 2019;161:63–71.

    Article  CAS  PubMed Central  Google Scholar 

  242. Siegel GJ, Chauhan NB. Neurotrophic factors in Alzheimer’s and Parkinson’s disease brain. Brain Res Brain Res Rev. 2000;33:199–227.

    Article  CAS  PubMed  Google Scholar 

  243. Gao L, Zhang Y, Sterling K, Song W. Brain-derived neurotrophic factor in Alzheimer’s disease and its pharmaceutical potential. Transl Neurodegener. 2022;11:4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  244. Phillips HS, Hains JM, Armanini M, Laramee GR, Johnson SA, Winslow JW. BDNF mRNA is decreased in the hippocampus of individuals with Alzheimer’s disease. Neuron. 1991;7:695–702.

    Article  CAS  Google Scholar 

  245. Laske C, Stransky E, Leyhe T, Eschweiler GW, Wittorf A, Richartz E, et al. Stage-dependent BDNF serum concentrations in Alzheimer’s disease. J Neural Transm (Vienna). 2006;113:1217–24.

    Article  CAS  PubMed  Google Scholar 

  246. Forlenza OV, Diniz BS, Gattaz WF. Diagnosis and biomarkers of predementia in Alzheimer’s disease. BMC Med. 2010;8:89.

    Article  PubMed  PubMed Central  Google Scholar 

  247. Yasutake C. Serum BDNF, TNF- alpha and IL-1beta levels in dementia patients. Eur Arch Psychiatry Clin Neurosci. 2006;256:406.

    Article  Google Scholar 

  248. Michalski B, Fahnestock M. Pro-brain-derived neurotrophic factor is decreased in parietal cortex in Alzheimer’s disease. Brain Res Mol Brain Res. 2003;111:148–54.

    Article  CAS  PubMed  Google Scholar 

  249. Komulainen P, Pedersen M, Hanninen T, Bruunsgaard H, Lakka TA, Kivipelto M, et al. BDNF is a novel marker of cognitive function in ageing women: the DR’s EXTRA Study. Neurobiol Learn Mem. 2008;90:596–603.

    Article  CAS  Google Scholar 

  250. Kunugi H, Ueki A, Otsuka M, Isse K, Hirasawa H, Kato N, et al. A novel polymorphism of the brain-derived neurotrophic factor (BDNF) gene associated with late-onset Alzheimer’s disease. Mol Psychiatry. 2001;6:83–6.

    Article  CAS  PubMed  Google Scholar 

  251. Tsai SJ, Hong CJ, Liu HC, Liu TY, Hsu LE, Lin CH. Association analysis of brain-derived neurotrophic factor Val66Met polymorphisms with Alzheimer’s disease and age of onset. Neuropsychobiology. 2004;49:10–2.

    Article  CAS  PubMed  Google Scholar 

  252. Tsai SJ, Hong CJ, Liu HC, Liu TY, Liou YJ. The brain-derived neurotrophic factor gene as a possible susceptibility candidate for Alzheimer’s disease in a chinese population. Dement Geriatr Cogn Disord. 2006;21:139–43.

    Article  CAS  PubMed  Google Scholar 

  253. Forlenza OV, Diniz BS, Teixeira AL, Ojopi EB, Talib LL, Mendonca VA, et al. Effect of brain-derived neurotrophic factor Val66Met polymorphism and serum levels on the progression of mild cognitive impairment. World J Biol Psychiatry. 2010;11:774–80.

    Article  Google Scholar 

  254. Fujimura H, Altar CA, Chen R, Nakamura T, Nakahashi T, Kambayashi J, et al. Brain-derived neurotrophic factor is stored in human platelets and released by agonist stimulation. Thromb Haemost. 2002;87:728–34.

    Article  CAS  PubMed  Google Scholar 

  255. Diniz BS, Teixeira AL. Brain-derived neurotrophic factor and Alzheimer’s disease: physiopathology and beyond. Neuromolecular Med. 2011;13:217–22.

    Article  CAS  Google Scholar 

  256. Jiao SS, Shen LL, Zhu C, Bu XL, Liu YH, Liu CH, et al. Brain-derived neurotrophic factor protects against tau-related neurodegeneration of Alzheimer’s disease. Transl Psychiatry. 2016;6:e907.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  257. Nagahara AH, Mateling M, Kovacs I, Wang L, Eggert S, Rockenstein E, et al. Early BDNF treatment ameliorates cell loss in the entorhinal cortex of APP transgenic mice. J Neurosci. 2013;33:15596–602.

    Article  CAS  PubMed Central  Google Scholar 

  258. Nagahara AH, Merrill DA, Coppola G, Tsukada S, Schroeder BE, Shaked GM, et al. Neuroprotective effects of brain-derived neurotrophic factor in rodent and primate models of Alzheimer’s disease. Nat Med. 2009;15:331–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  259. Barbereau C, Yehya A, Silhol M, Cubedo N, Verdier JM, Maurice T, et al. Neuroprotective brain-derived neurotrophic factor signaling in the TAU-P301L tauopathy zebrafish model. Pharmacol Res. 2020;158:104865.

    Article  CAS  PubMed  Google Scholar 

  260. Blurton-Jones M, Kitazawa M, Martinez-Coria H, Castello NA, Muller FJ, Loring JF, et al. Neural stem cells improve cognition via BDNF in a transgenic model of Alzheimer disease. Proc Natl Acad Sci USA. 2009;106:13594–9.

    Article  CAS  Google Scholar 

  261. Wang ZH, Xiang J, Liu X, Yu SP, Manfredsson FP, Sandoval IM, et al. Deficiency in BDNF/TrkB neurotrophic activity stimulates delta-secretase by upregulating C/EBPbeta in Alzheimer’s disease. Cell Rep. 2019;28:655–69.e655.

    Article  CAS  PubMed  Google Scholar 

  262. Jang SW, Liu X, Yepes M, Shepherd KR, Miller GW, Liu Y, et al. A selective TrkB agonist with potent neurotrophic activities by 7,8-dihydroxyflavone. Proc Natl Acad Sci USA. 2010;107:2687–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  263. Devi L, Ohno M. 7,8-dihydroxyflavone, a small-molecule TrkB agonist, reverses memory deficits and BACE1 elevation in a mouse model of Alzheimer’s disease. Neuropsychopharmacology. 2012;37:434–44.

    Article  CAS  PubMed  Google Scholar 

  264. Zhang Z, Liu X, Schroeder JP, Chan CB, Song M, Yu SP, et al. 7,8-dihydroxyflavone prevents synaptic loss and memory deficits in a mouse model of Alzheimer’s disease. Neuropsychopharmacology. 2014;39:638–50.

    Article  Google Scholar 

  265. Chen C, Wang Z, Zhang Z, Liu X, Kang SS, Zhang Y, et al. The prodrug of 7,8-dihydroxyflavone development and therapeutic efficacy for treating Alzheimer’s disease. Proc Natl Acad Sci USA. 2018;115:578–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  266. Dudai Y. The neurobiology of consolidations, or, how stable is the engram? Annu Rev Psychol. 2004;55:51–86.

    Article  PubMed  Google Scholar 

  267. Silva AJ, Kogan JH, Frankland PW, Kida S. CREB and memory. Annu Rev Neurosci. 1998;21:127–48.

    Article  CAS  PubMed  Google Scholar 

  268. Matsuo N, Reijmers L, Mayford M. Spine-type-specific recruitment of newly synthesized AMPA receptors with learning. Science. 2008;319:1104–7.

    Article  CAS  PubMed Central  Google Scholar 

  269. Foster DJ, Wilson MA. Reverse replay of behavioural sequences in hippocampal place cells during the awake state. Nature. 2006;440:680–3.

    Article  CAS  PubMed  Google Scholar 

  270. Silva AJ, Zhou Y, Rogerson T, Shobe J, Balaji J. Molecular and cellular approaches to memory allocation in neural circuits. Science. 2009;326:391–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  271. Zhou Y, Won J, Karlsson MG, Zhou M, Rogerson T, Balaji J, et al. CREB regulates excitability and the allocation of memory to subsets of neurons in the amygdala. Nat Neurosci. 2009;12:1438–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  272. Han JH, Kushner SA, Yiu AP, Hsiang HL, Buch T, Waisman A, et al. Selective erasure of a fear memory. Science. 2009;323:1492–6.

    Article  CAS  PubMed  Google Scholar 

  273. Park S, Kramer EE, Mercaldo V, Rashid AJ, Insel N, Frankland PW, et al. Neuronal allocation to a hippocampal engram. Neuropsychopharmacology. 2016;41:2987–93.

    Article  CAS  PubMed Central  Google Scholar 

  274. Park A, Jacob AD, Walters BJ, Park S, Rashid AJ, Jung JH, et al. A time-dependent role for the transcription factor CREB in neuronal allocation to an engram underlying a fear memory revealed using a novel in vivo optogenetic tool to modulate CREB function. Neuropsychopharmacology. 2020;45:916–24.

    Article  Google Scholar 

  275. Barco A, Patterson SL, Alarcon JM, Gromova P, Mata-Roig M, Morozov A, et al. Gene expression profiling of facilitated L-LTP in VP16-CREB mice reveals that BDNF is critical for the maintenance of LTP and its synaptic capture. Neuron. 2005;48:123–37.

    Article  CAS  PubMed  Google Scholar 

  276. Nabavi S, Fox R, Proulx CD, Lin JY, Tsien RY, Malinow R. Engineering a memory with LTD and LTP. Nature. 2014;511:348–52.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  277. Ye X, Kapeller-Libermann D, Travaglia A, Inda MC, Alberini CM. Direct dorsal hippocampal-prelimbic cortex connections strengthen fear memories. Nat Neurosci. 2017;20:52–61.

    Article  CAS  PubMed  Google Scholar 

  278. Kelleher RJ 3rd, Govindarajan A, Tonegawa S. Translational regulatory mechanisms in persistent forms of synaptic plasticity. Neuron. 2004;44:59–73.

    Article  CAS  PubMed  Google Scholar 

  279. Takeuchi T, Duszkiewicz AJ, Morris RG. The synaptic plasticity and memory hypothesis: encoding, storage and persistence. Philos Trans R Soc Lond B Biol Sci. 2014;369:20130288.

    Article  Google Scholar 

  280. Reijmers LG, Perkins BL, Matsuo N, Mayford M. Localization of a stable neural correlate of associative memory. Science. 2007;317:1230–3.

    Article  CAS  PubMed  Google Scholar 

  281. Ryan TJ, Roy DS, Pignatelli M, Arons A, Tonegawa S. Memory. Engram cells retain memory under retrograde amnesia. Science. 2015;348:1007–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  282. Poo MM, Pignatelli M, Ryan TJ, Tonegawa S, Bonhoeffer T, Martin KC, et al. What is memory? The present state of the engram. BMC Biol. 2016;14:40.

    Article  PubMed  Google Scholar 

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Acknowledgements

This review was supported by the STI2030 Major Projects (2021ZD0202804 to Zhe-Yu Chen), National Natural Science Foundation of China (No. 32471068 to Zhe-Yu Chen, 32400851 to Shuai-Wen Teng), the Key R&D Program of Shandong Province (2022ZLGX03 to Zhe-Yu Chen), a postdoctoral innovation project of Shandong Province (SDCX-ZG-202400143 to Shuai-Wen Teng).

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  1. Department of Anatomy and Neurobiology, Shandong Key Laboratory of Mental Disorders and Intelligent Control, School of Basic Medical Sciences and Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, P.R. China

    Shuai-Wen Teng, Xiao-Lin Chen & Zhe-Yu Chen

  2. Research Center for Basic Medical Sciences, Qilu Hospital of Shandong University, No.107 Wenhua Xi Road, Jinan, Shandong, 250012, P.R. China

    Shuai-Wen Teng, Xiao-Lin Chen & Zhe-Yu Chen

  3. State Key Laboratory for Innovation and Transformation of Luobing Theory, No.107 Wenhua Xi Road, Jinan, Shandong, 250012, P.R. China

    Zhe-Yu Chen

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Z.Y.C. and S.W.T. conceptualized, wrote, and revised the manuscript and figures. X.L.C. contribute to the figure art.

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Teng, SW., Chen, XL. & Chen, ZY. Molecular architects of memory: BDNF/TrkB signaling and trafficking in neuronal plasticity and memory. Mol Psychiatry (2026). https://doi.org/10.1038/s41380-026-03552-0

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