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.

  • Hot Topics
  • Published:

Therapeutic effects of extinction require hippocampal input and BDNF signaling in IL

Neuropsychopharmacology volume 50, pages 355–356 (2025)Cite this article

Subjects

A Correction to this article was published on 19 March 2025

This article has been updated

Access through your institution
Buy or subscribe

Patients with stress-related psychiatric disorders exhibit impairments in cognitive flexibility, a form of executive function mediated by the medial prefrontal cortex (mPFC). Chronic stress in rodents impairs cognitive flexibility performance [1]. Exposure therapy in humans can reverse cognitive deficits and improve several mPFC-mediated symptoms. In rats, extinction of a cued fear conditioning memory reverses chronic stress-induced deficits in cognitive flexibility on the attentional set-shifting test (AST). The set-shifting stage of the AST evaluates animals’ ability to shift attention between perceptual stimuli to successfully retrieve a food reward [2].

Our previous work demonstrated that the therapeutic effects of extinction are dependent on the activity of pyramidal neurons in the infralimbic cortex (IL), a subregion of the mPFC that is integral to extinction memory consolidation. Brain-derived neurotrophic factor (BDNF) signaling in the IL during extinction is also necessary to reverse stress-induced cognitive flexibility impairments [1]. However, the circuit mechanisms underlying BDNF-mediated plasticity in the IL during extinction are poorly understood. The ventral hippocampus (vHipp) is vital for extinction memory consolidation, and infusion of BDNF in the vHipp is sufficient to mimic extinction in fear-conditioned rats [3,4,5]. We investigated the role of vHipp input to the IL for the effects of extinction in reversing stress-induced cognitive deficits. Excitatory vHipp input to the IL was silenced using Gi-Designer Receptors Exclusively Activated by Designer Drugs (DREADD) via local infusion of clozapine-N-oxide (CNO) into IL before extinction. 24 h later, stressed and control rats were tested for cognitive flexibility performance on the AST. Stressed rats exhibited impaired performance, and extinction reversed this effect. Inhibition of vHipp terminals in the IL prevented the beneficial effects of extinction. We previously reported that extinction induces the phosphorylation of the BDNF receptor TrkB at the Y515 site in the IL [1]. This same site is dephosphorylated when vHipp terminals in IL are chemogenetically inhibited during extinction, suggesting that vHipp input to the IL contributes to BDNF signaling during extinction. Therefore, we investigated whether activation of vHipp terminals in the IL (with Gq-DREADDs) is sufficient to reverse stress-induced deficits on cognitive flexibility. Stressed rats received a CNO microinjection in the IL in lieu of extinction, and were tested on the AST 24 h later. Indeed, chemogenetic activation of vHipp terminals in the IL was sufficient to reverse stress-induced cognitive deficits. Finally, we demonstrated that the beneficial effects of vHipp-IL activation were blocked with a local infusion of a neutralizing anti-BDNF antibody in the IL. Our studies suggest that extinction learning in the IL engages long-lasting plasticity processes that reverse the deleterious effects of stress, such as formation of de novo dendritic spines, translation of BDNF-associated proteins, and enhancement of neuronal connectivity. These data demonstrate that the vHipp is not only encoding contextual information during extinction but is modulating IL plasticity that counteracts the effects of chronic stress. Our work denotes the therapeutic potential of enhancing vHipp-IL plasticity for the treatment of stress-related psychiatric illnesses.

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

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

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

Change history

References

  1. Paredes D, Knippenberg AR, Morilak DA. Infralimbic BDNF signaling is necessary for the beneficial effects of extinction on set shifting in stressed rats. Neuropsychopharmacology. 2021;47:507–15.

  2. Birrell JM, Brown VJ. Medial frontal cortex mediates perceptual attentional set shifting in the rat. J Neurosci. 2000;20:4320–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Sierra-Mercado D, Padilla-Coreano N, Quirk GJ. Dissociable roles of prelimbic and infralimbic cortices, ventral hippocampus, and basolateral amygdala in the expression and extinction of conditioned fear. Neuropsychopharmacology. 2011;36:529–38.

    Article  PubMed  Google Scholar 

  4. 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  PubMed  PubMed Central  Google Scholar 

  5. 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 

  6. Paredes D, Morilak DA. Ventral hippocampal input to infralimbic cortex is necessary for the therapeutic-like effects of extinction in stressed rats. Int J Neuropsychopharmacol. 2023;26:529–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This work was supported by research grant MH053851 from the National Institute of Mental Health, National Institutes of Health; by Merit Award 1I01BX003512 from the U.S. Department of Veterans Affairs Biomedical Laboratory Research and Development Program.

Author information

Authors and Affiliations

  1. Department of Pharmacology and Center for Biomedical Neuroscience, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA

    Denisse Paredes & David A. Morilak

  2. South Texas Veterans Health Care System, San Antonio, TX, USA

    David A. Morilak

Authors
  1. Denisse Paredes
    View author publications

    Search author on:PubMed Google Scholar

  2. David A. Morilak
    View author publications

    Search author on:PubMed Google Scholar

Contributions

Denisse Paredes performed data collection, analysis, and interpretation, and wrote and edited the manuscript. David Morilak contributed to experimental design and conception, data interpretation, editing, and final approval of the manuscript. Original data by Paredes and Morilak [6].

Corresponding author

Correspondence to Denisse Paredes.

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.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Paredes, D., Morilak, D.A. Therapeutic effects of extinction require hippocampal input and BDNF signaling in IL. Neuropsychopharmacol. 50, 355–356 (2025). https://doi.org/10.1038/s41386-024-01948-6

Download citation

  • Published:

  • Issue date:

  • DOI: https://doi.org/10.1038/s41386-024-01948-6

Search

Advanced search

Quick links