Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Altered regulation of oligodendrocytes associated with parvalbumin neurons in the ventral hippocampus underlies fear generalization in male mice

Neuropsychopharmacology (2023)Cite this article

Subjects

Abstract

Fear generalization is a neurobiological process by which an organism interprets a novel stimulus as threatening because of its similarity to previously learned fear-inducing stimuli. Because recent studies have suggested that the communication between oligodendrocyte precursor cells (OPCs) and parvalbumin (PV)-expressing GABAergic neurons (PV neurons) may play critical roles in stress-related disorders, we examined the involvement of these cells in fear generalization. We first tested the behavioral characteristics of mouse models for conventional fear conditioning (cFC) and modified FC (mFC) with severe electric foot shocks and found that fear generalization was observed in mice treated with mFC but not in mice treated with cFC. The expression levels of genes related to OPCs, oligodendrocytes (OLs), and myelin in the ventral hippocampus were lower in mFC mice than in cFC mice. The densities of OPCs and OLs were decreased in the ventral hippocampus of mFC mice compared to cFC mice. The myelination ratios of PV neurons in the ventral hippocampus were lower in mFC mice than in cFC mice. The chemogenetic activation of PV neurons in the ventral hippocampus of mFC mice reduced fear generalization. The expression levels of genes related to OPCs, OLs, and myelin were recovered following the activation of PV neurons. Finally, the myelination ratios of PV neurons were increased after the activation of PV neurons. Our results suggest that altered regulation of OLs specifically associated with axons of PV neurons in the ventral hippocampus may underlie the generalization of remote fear memory following severe stress exposure.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Learn more

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Decrease in myelin-related gene expression in the hippocampus of male mice exhibiting fear generalization.
Fig. 2: Decrease in OPCs and OLs in the hippocampus of male mice exhibiting fear generalization.
Fig. 3: Decrease in axonal myelination of PV neurons in the hippocampus of male mice exhibiting fear generalization.
Fig. 4: Behavioral and gene expression changes following chemogenetic activation of PV neurons in the hippocampus of male mice.
Fig. 5: OPCs, OLs, and axonal myelination increase following chemogenetic activation of PV neurons in the hippocampus of male mice.

Data availability

The dataset generated and/or analyzed during the current study is available from the corresponding authors upon reasonable request.

References

  1. Dunsmoor JE, Mitroff SR, Labar KS. Generalization of conditioned fear along a dimension of increasing fear intensity. Learn Mem. 2009;16:460–69.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Dymond S, Dunsmoor JE, Vervliet B, Roche B, Hermans D. Fear generalization in humans: systematic review and implications for anxiety disorder research. Behavior Therapy. 2015;46:561–82.

    Article  PubMed  Google Scholar 

  3. Berg H, Ma Y, Rueter A, Kaczkurkin A, Burton PC, DeYoung CG, et al. Salience and central executive networks track overgeneralization of conditioned-fear in posttraumatic stress disorder. Psychol Med. 2021;51:2610–19.

    Article  PubMed  Google Scholar 

  4. Asok A, Kandel ER, Rayman JB. The neurobiology of fear generalization. Front Behav Neurosci. 2018;12:329.

    Article  PubMed  Google Scholar 

  5. Bonnefil V, Dietz K, Amatruda M, Wentling M, Aubry AV, Dupree JL, et al. Region-specific myelin differences define behavioral consequences of chronic social defeat stress in mice. eLife. 2019;8:e408558.

  6. O’Doherty DCM, Ryder W, Paquola C, Tickell A, Chan C, Hermens DF, et al. White matter integrity alterations in posttraumatic stress disorder. Hum Brain Mapp. 2018;39:1327–38.

    Article  PubMed  Google Scholar 

  7. Liu J, Likhtik E, Shereen AD, Dennis-Tiwary TA, Casaccia P. White matter plasticity in anxiety: disruption of neural network synchronization during threat-safety discrimination. Front Cell Neurosci. 2020;14:587053.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Mazuir E, Fricker D, Sol-Foulon N. Neuron–oligodendrocyte communication in myelination of cortical GABAergic cells. Life. 2021;11:216.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Jinno S, Klausberger T, Marton LF, Dalezios Y, Roberts JD, Fuentealba P, et al. Neuronal diversity in GABAergic long-range projections from the hippocampus. J Neurosci. 2007;27:8790–804.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Zonouzi M, Berger D, Jokhi V, Kedaigle A, Lichtman J, Arlotta P. Individual oligodendrocytes show bias for inhibitory axons in the neocortex. Cell Reports. 2019;27:2799–808.e3.

    Article  CAS  PubMed  Google Scholar 

  11. Klausberger T, Somogyi P. Neuronal diversity and temporal dynamics: the unity of hippocampal circuit operations. Science. 2008;321:53–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Perlman G, Tanti A, Mechawar N. Parvalbumin interneuron alterations in stress-related mood disorders: a systematic review. Neurobiol Stress. 2021;15:100380.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Rossetti AC, Paladini MS, Colombo M, Gruca P, Lason-Tyburkiewicz M, Tota-Glowczyk K, et al. Chronic stress exposure reduces parvalbumin expression in the rat hippocampus through an imbalance of redox mechanisms: restorative effect of the antipsychotic lurasidone. Int J Neuropsychopharmacol. 2018;21:883–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Poggi G, Wennström M, Müller MB, Treccani G. NG2-glia: rising stars in stress-related mental disorders? Mol Psychiatry. 2023;28:518–20.

  15. Huckleberry KA, Ferguson LB, Drew MR. Behavioral mechanisms of context fear generalization in mice. Learn Mem. 2016;23:703–09.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Keiser AA, Turnbull LM, Darian MA, Feldman DE, Song I, Tronson NC. Sex differences in context fear generalization and recruitment of hippocampus and amygdala during retrieval. Neuropsychopharmacology. 2017;42:397–407.

    Article  PubMed  Google Scholar 

  17. Sims-Robinson C, Bakeman A, Bruno E, Jackson S, Glasser R, Murphy GG, et al. Dietary reversal ameliorates short- and long-term memory deficits induced by high-fat diet early in life. PLoS ONE. 2016;11:e0163883.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Yamada J, Nadanaka S, Kitagawa H, Takeuchi K, Jinno S. Increased synthesis of chondroitin sulfate proteoglycan promotes adult hippocampal neurogenesis in response to enriched environment. J Neurosci. 2018;38:8496–513.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Yamada J, Sato C, Konno K, Watanabe M, Jinno S. PSA-NCAM colocalized with cholecystokinin-expressing cells in the hippocampus is involved in mediating antidepressant efficacy. J Neurosci. 2020;40:825–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Maeda S, Yamada J, Iinuma KM, Nadanaka S, Kitagawa H, Jinno S. Chondroitin sulfate proteoglycan is a potential target of memantine to improve cognitive function via the promotion of adult neurogenesis. Br J Pharmacol. 2022;179:4857–77.

    Article  CAS  PubMed  Google Scholar 

  21. Meuth P, Gaburro S, Lesting J, Legler A, Herty M, Budde T, et al. Standardizing the analysis of conditioned fear in rodents: a multidimensional software approach. Genes Brain Behav. 2013;12:583–92.

    Article  CAS  PubMed  Google Scholar 

  22. Bin JM, Harris SN, Kennedy TE. The oligodendrocyte-specific antibody ‘CC1’ binds Quaking 7. J Neurochem. 2016;139:181–86.

    Article  CAS  PubMed  Google Scholar 

  23. Deshmukh VA, Tardif V, Lyssiotis CA, Green CC, Kerman B, Kim HJ, et al. A regenerative approach to the treatment of multiple sclerosis. Nature. 2013;502:327–32.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Çaliskan G, Müller I, Semtner M, Winkelmann A, Raza AS, Hollnagel JO, et al. Identification of parvalbumin interneurons as cellular substrate of fear memory persistence. Cereb Cortex. 2016;26:2325–40.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Jones DN, Erwin JM, Sherwood CC, Hof PR, Raghanti MA. A comparison of cell density and serotonergic innervation of the amygdala among four macaque species. J Comp Neurol. 2021;529:1659–68.

    Article  CAS  PubMed  Google Scholar 

  26. Lesuis SL, Brosens N, Immerzeel N, Van Der Loo RJ, Mitrić M, Bielefeld P, et al. Glucocorticoids promote fear generalization by increasing the size of a dentate gyrus engram cell population. Biol Psychiatry. 2021;90:494–504.

    Article  CAS  PubMed  Google Scholar 

  27. Choi EH, Blasiak A, Lee J, Yang IH. Modulation of neural activity for myelination in the central nervous system. Front Neurosci. 2019;13:952.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Deng S, Shu S, Zhai L, Xia S, Cao X, Li H, et al. Optogenetic stimulation of mPFC alleviates white matter injury-related cognitive decline after chronic ischemia through adaptive myelination. Adv Sci. 2023;10:e2202976.

    Article  Google Scholar 

  29. Rau V, DeCola JP, Fanselow MS. Stress-induced enhancement of fear learning: an animal model of posttraumatic stress disorder. Neurosci Biobehav Rev. 2005;29:1207–23.

    Article  PubMed  Google Scholar 

  30. Baldi E, Lorenzini CA, Bucherelli C. Footshock intensity and generalization in contextual and auditory-cued fear conditioning in the rat. Neurobiol Learn Mem. 2004;81:162–6.

    Article  PubMed  Google Scholar 

  31. Akay LA, Effenberger AH, Tsai L-H. Cell of all trades: oligodendrocyte precursor cells in synaptic, vascular, and immune function. Genes Dev. 2021;35:180–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Ruediger S, Vittori C, Bednarek E, Genoud C, Strata P, Sacchetti B, et al. Learning-related feedforward inhibitory connectivity growth required for memory precision. Nature. 2011;473:514–18.

    Article  CAS  PubMed  Google Scholar 

  33. Xia F, Richards BA, Tran MM, Josselyn SA, Takehara-Nishiuchi K, Frankland PW. Parvalbumin-positive interneurons mediate neocortical-hippocampal interactions that are necessary for memory consolidation. eLife. 2017;6:e27868.

  34. Strange BA, Witter MP, Lein ES, Moser EI. Functional organization of the hippocampal longitudinal axis. Nat Rev Neurosci. 2014;15:655–69.

    Article  CAS  PubMed  Google Scholar 

  35. Bian XL, Qin C, Cai CY, Zhou Y, Tao Y, Lin YH, et al. Anterior cingulate cortex to ventral hippocampus circuit mediates contextual fear generalization. J Neurosci. 2019;39:5728–39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Benamer N, Vidal M, Balia M, Angulo MC. Myelination of parvalbumin interneurons shapes the function of cortical sensory inhibitory circuits. Nat Commun. 2020;11:5151.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Ognjanovski N, Schaeffer S, Wu J, Mofakham S, Maruyama D, Zochowski M, et al. Parvalbumin-expressing interneurons coordinate hippocampal network dynamics required for memory consolidation. Nat Commun. 2017;8:15039.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Picard M, Prather AA, Puterman E, Cuillerier A, Coccia M, Aschbacher K, et al. A mitochondrial health index sensitive to mood and caregiving stress. Biol Psychiatry. 2018;84:9–17.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Bergaglio T, Luchicchi A, Schenk GJ. Engine failure in axo-myelinic signaling: a potential key player in the pathogenesis of multiple sclerosis. Front Cell Neurosci. 2021;15:610295.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Kraus KL, Chordia AP, Drake AW, Herman JP, Danzer SC. Hippocampal interneurons are direct targets for circulating glucocorticoids. J Comp Neurol. 2022;530:2100–12.

    Article  CAS  PubMed  Google Scholar 

  41. Hu W, Zhang M, Czéh B, Flügge G, Zhang W. Stress impairs GABAergic network function in the hippocampus by activating nongenomic glucocorticoid receptors and affecting the integrity of the parvalbumin-expressing neuronal network. Neuropsychopharmacology. 2010;35:1693–707.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Mei L, Zhou Y, Sun Y, Liu H, Zhang D, Liu P, et al. Acetylcholine muscarinic receptors in ventral hippocampus modulate stress-induced anxiety-like behaviors in mice. Front Mol Neurosci. 2020;13:598811.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Leaderbrand K, Chen HJ, Corcoran KA, Guedea AL, Jovasevic V, Wess J, et al. Muscarinic acetylcholine receptors act in synergy to facilitate learning and memory. Learn Mem. 2016;23:631–38.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank Ms. Saki Kanegae for her technical assistance and Editage (www.editage.jp) for English language editing. We also appreciate the technical assistance from the Research Support Center, Research Center for Human Disease Modeling, Kyushu University Graduate School of Medical Sciences.

Funding

This work was supported in part by JSPS KAKENHI (grant numbers JP19K06924 [to JY], JP22K06459 [to JY], JP19H05022 [to SJ], JP19K22812 [to SJ] 20H04105 [to SJ], JP21H05630 [to SJ], and JP22K19713 [to SJ]).

Author information

Authors and Affiliations

  1. Department of Anatomy and Neuroscience, Graduate School of Medical Sciences, Kyushu University, Fukuoka, 812-8582, Japan

    Jun Yamada, Shoichiro Maeda, Miori Tojo, Miyuki Hayashida, Kyoko M. Iinuma & Shozo Jinno

Authors
  1. Jun Yamada
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shoichiro Maeda
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Miori Tojo
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Miyuki Hayashida
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kyoko M. Iinuma
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Shozo Jinno
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

JY contributed to all aspects of the study; SM, MT, and MH performed experiments with the help of JY and KMI; KMI performed RT-qPCR; SJ conceptualized, designed, and supervised the project and edited the manuscript with input from all authors. All authors have approved the final version of the manuscript.

Corresponding authors

Correspondence to Jun Yamada or Shozo Jinno.

Ethics declarations

Competing interests

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.

Supplementary information

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

Yamada, J., Maeda, S., Tojo, M. et al. Altered regulation of oligodendrocytes associated with parvalbumin neurons in the ventral hippocampus underlies fear generalization in male mice. Neuropsychopharmacol. (2023). https://doi.org/10.1038/s41386-023-01611-6

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1038/s41386-023-01611-6

Search

Advanced search

Quick links