Skip to main content
SpringerLink
Log in

TrkB-BDNF Signalling and Arc/Arg3.1 Immediate Early Genes in the Anterior Cingulate Cortex and Hippocampus: Insights into Novel Memory Milestones Through Behavioural Tagging

  • Original Article
  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

In recent years, there has been a surge in interest in investigating the mechanisms underlying memory consolidation. However, our understanding of the behavioural tagging (BT) model and its establishment in diverse brain regions remains limited. This study elucidates the contributions of the anterior cingulate cortex (ACC) and hippocampus in the formation of long-term memory (LTM) employing behaviour tagging as a model for studying the underlying mechanism of LTM formation in rats. Existing knowledge highlights a protein synthesis–dependent phase as imperative for LTM. Brain-derived neurotrophic factor (BDNF) stands as a pivotal plasticity-related protein (PRP) in mediating molecular alterations crucial for long-term synaptic plasticity and memory consolidation. Our study offers evidence suggesting that tropomyosin receptor kinase B (TrkB), the receptor of BDNF, may act as a combined “behavioural tag/PRP”. Interfering with the expression of these molecules resulted in impaired LTM after 24 h. Furthermore, augmenting BDNF expression led to an elevation in Arc protein levels in both the ACC and hippocampus regions. Introducing novelty around weak inhibitory avoidance (IA) training resulted in heightened step-down latencies and expression of these molecules, respectively. We also demonstrate that the increase in Arc expression relies on BDNF synthesis, which is vital for the memory consolidation process. Additionally, inhibiting BDNF using an anti-BDNF function-blocking antibody impacted Arc expression in both the ACC and hippocampus regions, disrupting the transformations from labile to robust memory. These findings mark the initial identification of a “behavioural tag/PRP” combination and underscore the involvement of the TrkB-BDNF-Arc cascade in the behavioural tagging model of learning and memory.

Graphical Abstract

Synaptic plasticity induced by behavioural tagging phenomenon: Schematic representation orchestrating cellular level changes in synaptic plasticity induced by behavioural level transitions via behavioural tagging (BT) phenomenon. BT was achieved by incorporating open-field (OF) exploration with novel object recognition (NOR) and inhibitory avoidance test (IAT) paradigm. Exposing the animals to weak events through the NOR and IAT paradigms could only result in transient form of learning (short-term memory) by forming learning tags, whereas exposing the animals to a novel environment through OF resulted in a more stable form of memory (long-term memory) by capturing plasticity-related proteins in a restricted critical time window only. After a weak training, novelty exposure to OF works as a stimulant of pre-synaptic terminal and promotes the escape of stored glutamate into the synaptic cleft which is taken up by postsynaptic terminal’s glutamatergic receptors α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) and N-methyl-d-aspartate (NMDA) receptors causing AMPA receptors to open and allowing Na+ ion influx into the postsynaptic neuron causing positive change in the membrane potential leading to a shift in electrical charge called depolarisation. The elevated build-up of influxed Na+ ions unplugs the Mg2+ ions from the pockets of NMDAR, making way for even more Na+ ion influx, facilitating Ca2+ ion influx into the postsynaptic neuron, which leads to a secondary signalling cascade and activation of kinase proteins, resulting in plasticity changes that strengthen the synapse. This cascade eventually upregulates BDNF transcription, which activates TrkB receptors present on postsynaptic neuron, further enhancing expression of another PRP Arc protein in the novelty-exposed group of animals. Thus, this figure underscores the effect of behavioural tagging on the intricate interplay between cellular level changes involving TrkB, BDNF and Arc in maintaining long-term memory in the hippocampus and anterior cingulate cortex region.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

Data Availability

The datasets supporting the findings of this study are included within the article.

References

  1. Liu Y, Lin W, Liu C et al (2016) Memory consolidation reconfigures neural pathways involved in the suppression of emotional memories. Nat Commun 7:. https://doi.org/10.1038/ncomms13375

  2. Bin Ibrahim MZ, Benoy A, Sajikumar S (2022) Long-term plasticity in the hippocampus: maintaining within and “tagging” between synapses. The FEBS journal 289(8):2176–2201. https://doi.org/10.1111/febs.16065

    Article  CAS  PubMed  Google Scholar 

  3. Tonegawa S, Morrissey MD, Kitamura T (2018) The role of engram cells in the systems consolidation of memory. Nat Rev Neurosci 19(8):485–498. https://doi.org/10.1038/s41583-018-0031-2

    Article  CAS  PubMed  Google Scholar 

  4. Goto A (2022) Synaptic plasticity during systems memory consolidation. Neurosci Res 183:1–6. https://doi.org/10.1016/j.neures.2022.05.008

    Article  PubMed  Google Scholar 

  5. Shrestha P, Ayata P, Herrero-Vidal P et al (2020) Cell-type-specific drug-inducible protein synthesis inhibition demonstrates that memory consolidation requires rapid neuronal translation. Nat Neurosci 23. https://doi.org/10.1038/s41593-019-0568-z

  6. Moncada D, Ballarini F, Viola H (2015) Behavioral tagging: a translation of the synaptic tagging and capture hypothesis. Neural Plast 2015:650780. https://doi.org/10.1155/2015/650780

  7. Viola H, Ballarini F, Martínez MC, Moncada D (2014) The tagging and capture hypothesis from synapse to memory. Prog Mol Biol Transl Sci 122:391–423. https://doi.org/10.1016/B978-0-12-420170-5.00013-1

  8. Naseem M, Tabassum H, Parvez S (2019) PKM-ζ expression is important in consolidation of memory in prelimbic cortex formed by the process of behavioral tagging. Neuroscience 410. https://doi.org/10.1016/j.neuroscience.2019.03.060

  9. Lu Y, Christian K, Lu B (2008) BDNF: A key regulator for protein synthesis-dependent LTP and long-term memory? Neurobiol Learn Mem 89. https://doi.org/10.1016/j.nlm.2007.08.018

  10. Leal G, Bramham CR, Duarte CB (2017) BDNF and Hippocampal synaptic plasticity. Vitam Horm 104:153–195. https://doi.org/10.1016/bs.vh.2016.10.004

  11. Aarse J, Herlitze S, Manahan-Vaughan D (2016) The requirement of BDNF for hippocampal synaptic plasticity is experience-dependent. Hippocampus 26. https://doi.org/10.1002/hipo.22555

  12. Sajikumar S, Korte M (2011) Metaplasticity governs compartmentalization of synaptic tagging and capture through brain-derived neurotrophic factor (BDNF) and protein kinase Mζ (PKMζ). Proc Natl Acad Sci U S A 108. https://doi.org/10.1073/pnas.1016849108

  13. Harward SC, Hedrick NG, Hall CE et al (2016) Autocrine BDNF-TrkB signalling within a single dendritic spine. Nature 538. https://doi.org/10.1038/nature19766

  14. Lu Y, Ji Y, Ganesan S et al (2011) TrkB as a potential synaptic and behavioral tag. J Neurosci 31. https://doi.org/10.1523/JNEUROSCI.2707-11.2011

  15. Okuda K, Højgaard K, Privitera L, et al (2021) Initial memory consolidation and the synaptic tagging and capture hypothesis. Eur J Neurosci 54. https://doi.org/10.1111/ejn.14902

  16. Mergiya TF, Gundersen JET, Kanhema T et al (2023) Detection of Arc/Arg3.1 oligomers in rat brain: constitutive and synaptic activity-evoked dimer expression in vivo. Front Mol Neurosci 16. https://doi.org/10.3389/fnmol.2023.1142361

  17. Benekareddy M, Nair AR, Dias BG et al (2013) Induction of the plasticity-associated immediate early gene Arc by stress and hallucinogens: role of brain-derived neurotrophic factor. Int J Neuropsychopharmacol 16. https://doi.org/10.1017/S1461145712000168

  18. Minatohara K, Akiyoshi M, Okuno H (2016) Role of immediate-early genes in synaptic plasticity and neuronal ensembles underlying the memory trace. Front Mol Neurosci 8. https://doi.org/10.3389/fnmol.2015.00078

  19. Nakayama D, Iwata H, Teshirogi C et al (2015) Long-delayed expression of the immediate early gene Arc/Arg3.1 refines neuronal circuits to perpetuate fear memory. J Neurosci 35. https://doi.org/10.1523/JNEUROSCI.2525-14.2015

  20. Paolantoni C, Ricciardi S, de Paolis V et al (2018) Arc 3ʹ UTR splicing leads to dual and antagonistic effects in fine-tuning arc expression upon BDNF signaling. Front Mol Neurosci 11. https://doi.org/10.3389/fnmol.2018.00145

  21. Kuipers SD, Trentani A, Tiron A et al (2016) BDNF-induced LTP is associated with rapid Arc/Arg3.1-dependent enhancement in adult hippocampal neurogenesis. Sci Rep 6. https://doi.org/10.1038/srep21222

  22. Zhang Y, Fukushima H, Kida S (2011) Induction and requirement of gene expression in the anterior cingulate cortex and medial prefrontal cortex for the consolidation of inhibitory avoidance memory. Mol Brain 4. https://doi.org/10.1186/1756-6606-4-4

  23. Broadbent NJ, Gaskin S, Squire LR, Clark RE (2010) Object recognition memory and the rodent hippocampus. Learn Mem 17. https://doi.org/10.1101/lm.1650110

  24. da Silva TR, Sohn JMB, Andreatini R, Stern CA (2020) The role of prelimbic and anterior cingulate cortices in fear memory reconsolidation and persistence depends on the memory age. Learn Mem 27. https://doi.org/10.1101/LM.051615.120

  25. Paxinos G, Watson C (2013) The rat brain in stereotaxic coordinates. Academic Press. http://books.google.ie/books?id=FuqGAwAAQBAJ&pg=PA19-IA76&dq=9780124157521&hl=&cd=4&source=gbs_ap

  26. Ghosal S, Bang E, Yue W et al (2018) Activity-dependent brain-derived neurotrophic factor release is required for the rapid antidepressant actions of scopolamine. Biol Psychiatry 83. https://doi.org/10.1016/j.biopsych.2017.06.017

  27. Zhou Q, Chen Y, Tang H et al (2023) Transcranial direct current stimulation alleviated ischemic stroke induced injury involving the BDNF-TrkB signaling axis in rats. Heliyon 9. https://doi.org/10.1016/j.heliyon.2023.e14946

  28. Guzowski JF, Lyford GL, Stevenson GD et al (2000) Inhibition of activity-dependent arc protein expression in the rat hippocampus impairs the maintenance of long-term potentiation and the consolidation of long-term memory. J Neurosci 20. https://doi.org/10.1523/jneurosci.20-11-03993.2000

  29. Moncada D, Viola H (2007) Induction of long-term memory by exposure to novelty requires protein synthesis: evidence for a behavioral tagging. J Neurosci 27. https://doi.org/10.1523/JNEUROSCI.1083-07.2007

  30. Sajikumar S, Frey JU (2004) Late-associativity, synaptic tagging, and the role of dopamine during LTP and LTD. Neurobiol Learn Mem 82. https://doi.org/10.1016/j.nlm.2004.03.003

  31. Lemon N, Manahan-Vaughan D (2006) Dopamine D1/D5 receptors gate the acquisition of novel information through hippocampal long-term potentiation and long-term depression. J Neurosci 26. https://doi.org/10.1523/JNEUROSCI.1454-06.2006

  32. Davis CD, Jones FL, Derrick BE (2004) Novel environments enhance the induction and maintenance of long-term potentiation in the dentate gyrus. J Neurosci 24. https://doi.org/10.1523/JNEUROSCI.4970-03.2004

  33. Schomaker J, van Bronkhorst MLV, Meeter M (2014) Exploring a novel environment improves motivation and promotes recall of words. Front Psychol 5. https://doi.org/10.3389/fpsyg.2014.00918

  34. Whitlock JR, Heynen AJ, Shuler MG, Bear MF (2006) Learning induces long-term potentiation in the hippocampus. Science (1979) 313. https://doi.org/10.1126/science.1128134

  35. Alonso M, Vianna MRM, Depino AM et al (2002) BDNF-triggered events in the rat hippocampus are required for both short- and long-term memory formation. Hippocampus 12. https://doi.org/10.1002/hipo.10035

  36. Lopes da Cunha P, Villar ME, Ballarini F et al (2019) Spatial object recognition memory formation under acute stress. Hippocampus 29. https://doi.org/10.1002/hipo.23037

  37. De Carvalho Myskiw J, Furini CRG, Benetti F, Izquierdo I (2014) Hippocampal molecular mechanisms involved in the enhancement of fear extinction caused by exposure to novelty. Proc Natl Acad Sci U S A 111. https://doi.org/10.1073/pnas.1400423111

  38. Lipsky RH, Marini AM (2007) Brain-derived neurotrophic factor in neuronal survival and behavior-related plasticity. Ann N Y Acad Sci 1122:130–143. https://doi.org/10.1196/annals.1403.009

  39. Zagrebelsky M, Tacke C, Korte M (2020) BDNF signaling during the lifetime of dendritic spines. Cell Tissue Res 382(1):185–199. https://doi.org/10.1007/s00441-020-03226-5

    Article  PubMed  PubMed Central  Google Scholar 

  40. Bekinschtein P, Cammarota M, Igaz LM et al (2007) Persistence of long-term memory storage requires a late protein synthesis- and BDNF-dependent phase in the hippocampus. Neuron 53. https://doi.org/10.1016/j.neuron.2006.11.025

  41. Bekinschtein P, Cammarota M, Katche C et al (2008) BDNF is essential to promote persistence of long-term memory storage. Proc Natl Acad Sci U S A 105. https://doi.org/10.1073/pnas.0711863105

  42. Notaras M, van den Buuse M (2020) Neurobiology of BDNF in fear memory, sensitivity to stress, and stress-related disorders. Mol Psychiatry 25(10):2251–2274. https://doi.org/10.1038/s41380-019-0639-2

    Article  PubMed  Google Scholar 

  43. Sun YX, Su YA, Wang Q et al (2023) The causal involvement of the BDNF-TrkB pathway in dentate gyrus in early-life stress-induced cognitive deficits in male mice. Transl Psychiatry 13. https://doi.org/10.1038/s41398-023-02476-5

  44. Heldt SA, Zimmermann K, Parker K et al (2014) Bdnf deletion or TrkB impairment in amygdala inhibits both appetitive and aversive learning. J Neurosci 34. https://doi.org/10.1523/JNEUROSCI.4085-12.2014

  45. Pinho J, Marcut C, Fonseca R (2020) Actin remodeling, the synaptic tag and the maintenance of synaptic plasticity. IUBMB life 72(4):577–589. https://doi.org/10.1002/iub.2261

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We would like to acknowledge Sheeraj for his dedication to maintaining the animals throughout the duration of experimental period, all while adhering to ethical guidelines.

Funding

This research was supported by the Fund for Improvement of S&T Infrastructure (FIST) Grant No. SR/FST/LS-I/2017/05[C] to the Department of Toxicology and the Promotion of University Research and Scientific Excellence (PURSE) Grant No. SR/PURSE Phase 2/39[C] from the Department of Science and Technology (DST), Government of India (to Jamia Hamdard). This work was also supported by the DST Cognitive Science Research Initiative (CSRI) Grant DST/CSRI/2021/85[G] to Prof. Suhel Parvez. Dr. Mehar Naseem is grateful to University Grants Commission (UGC), for the Senior Research Fellowship (sanction no. MANF-2013–14-MUS-JHA-30114). Ms. Hiba Khan duly acknowledges the support of Junior Research Fellowship from UGC (UGC JRF ref. no. 210510555146).

Author information

Author notes

  1. Mehar Naseem and Hiba Khan contributed equally to the study.

Authors and Affiliations

  1. Department of Toxicology, School of Chemical and Life Sciences, Jamia Hamdard, New Delhi, 110062, India

    Mehar Naseem, Hiba Khan & Suhel Parvez

Authors
  1. Mehar Naseem
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hiba Khan
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Suhel Parvez
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

MN and SP designed research, MN performed research and analysed the data, HK designed the layouts of figures and MN and HK wrote the paper.

Corresponding author

Correspondence to Suhel Parvez.

Ethics declarations

Ethics Approval

The animal experiments were conducted in compliance with the established protocols of the Institutional Animal Ethics Committee (IAEC), which is officially recognised by the Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA) under Registration No. 173/GO/Re/2000/CPCSEA.

Consent to Participate

Not applicable.

Consent for Publication

Not applicable.

Competing Interest

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Naseem, M., Khan, H. & Parvez, S. TrkB-BDNF Signalling and Arc/Arg3.1 Immediate Early Genes in the Anterior Cingulate Cortex and Hippocampus: Insights into Novel Memory Milestones Through Behavioural Tagging. Mol Neurobiol (2024). https://doi.org/10.1007/s12035-024-04071-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s12035-024-04071-1

Keywords

Search

Navigation