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Evidence for thyroid hormone regulation of amygdala-dependent fear-relevant memory and plasticity

Molecular Psychiatry (2024)Cite this article

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Abstract

The amygdala is an established site for fear memory formation, and clinical studies suggest involvement of hormone signaling cascades in development of trauma-related disorders. While an association of thyroid hormone (TH) status and mood disorders is established, the related brain-based mechanisms and the role of TH in anxiety disorders are unknown. Here we examine the role that TH receptor (TR, a nuclear transcriptional repressor when unbound and a transcriptional activator when bound to TH) may have in mediating the initial formation of fear memories in the amygdala. We identified mRNA levels of TR and other TH pathway regulatory genes, including thyrotropin-releasing hormone (Trh), transthyretin (Ttr), thyrotropin-releasing hormone receptor (Trhr), type 2 iodothyronine deiodinase (Dio2), mediator complex subunit 12 (Med12/Trap230) and retinoid X receptor gamma (Rxrg) to be altered in the amygdala following Pavlovian fear conditioning. Using TH agonist and antagonist infusion into the amygdala, we demonstrated that this pathway is both necessary and sufficient for fear memory consolidation. Inhibition of TH signaling with the TR antagonist 1-850 decreased fear memory consolidation; while activation of TR with T3 (triiodothyronine) resulted in increased memory formation. Using a systemic hypothyroid mouse model, we found that intra-amygdala infusions of T3 were sufficient to rescue deficits in fear memory. Finally, we demonstrated that T3 was sufficient to activate TR-specific gene pathways in the amygdala. These findings on the role of activity-dependent TR modulation support a model in which local TH is a critical regulator of fear memory-related plasticity in the amygdala.

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Fig. 1: Regulation of thyroid hormone relevant gene transcription in the amygdala by auditory fear conditioning.
Fig. 2: In situ validation of Trhr and Trha alterations in the amygdala after auditory fear conditioning.
Fig. 3: Intra-amygdala pharmacological manipulation of TH signaling alters fear- relevant memory consolidation in a temporally graded manner.
Fig. 4: Intra-amygdala pharmacological manipulation of TH signaling alters fear-relevant transcriptional processes.
Fig. 5: Local-amygdala replacement of T3 in hypothyroid mice is necessary and sufficient to rescue fear-memory deficit.

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Data availability

Data from this study, including raw images and GraphPad files, are available from the corresponding author upon reasonable request.

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Acknowledgements

Support was provided by NIH (P50-MH115874, R01-MH108665, K08-MH130802), a gift from the World Heritage Foundation, and the McLean Frazier Fund. The authors would also like to acknowledge the members of the Ressler lab at McLean for their support and the animal care staff at McLean Hospital.

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Author notes

  1. These authors contributed equally: Stephanie A. Maddox, Olga Y. Ponomareva.

Authors and Affiliations

  1. Neurobiology of Fear Laboratory, Basic Neuroscience Division, McLean Hospital, Belmont, MA, USA

    Stephanie A. Maddox, Olga Y. Ponomareva, Cole E. Zaleski, Michelle X. Chen, Claudia Klengel & Kerry J. Ressler

  2. Department of Psychiatry, Harvard Medical School, Boston, MA, USA

    Stephanie A. Maddox, Olga Y. Ponomareva & Kerry J. Ressler

  3. Northeastern University, Boston, MA, USA

    Cole E. Zaleski

  4. University of Iowa, Iowa City, IA, USA

    Michelle X. Chen

  5. Joan and Sanford I. Weill Department of Medicine, Division of Endocrinology, Diabetes and Metabolism, Weill Cornell Medicine, New York, NY, USA

    Kristen R. Vella & Anthony N. Hollenberg

  6. Weill Center for Metabolic Health, Weill Cornell Medicine, New York, NY, USA

    Kristen R. Vella & Anthony N. Hollenberg

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Contributions

SAM and OYP contributed equally. SAM designed and performed the qPCR experiments, stereotaxic surgeries and in vivo drug infusions, fear conditioning, and open field experiments, analyzed data, prepared figures, and wrote the initial draft of the paper. OYP designed and performed RNAscope validation experiments, fear conditioning experiments, quantified image data, reanalyzed behavioral data, prepared figures, and significantly revised the final manuscript. CEZ assisted with fear conditioning and RNAscope validation experiments and analyzed data. MXC assisted with fear conditioning and qPCR experiments and analyzed data. KRV and ANH provided resources and contributed to experimental design. CK assisted with analysis of qPCR data. KJR obtained funding and provided material support, assisted with experimental design, interpretation of data, writing, and revising the manuscript.

Corresponding author

Correspondence to Kerry J. Ressler.

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KJR has performed scientific consultation for Acer, Bionomics, and Jazz Pharma; serves on Scientific Advisory Boards for Sage, Boehringer Ingelheim, Senseye, Brain and Behavior Research Foundation, and the Brain Research Foundation, and he has received sponsored research support from Alto Neuroscience. The remaining authors declare no conflict of interest, financial or otherwise.

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Maddox, S.A., Ponomareva, O.Y., Zaleski, C.E. et al. Evidence for thyroid hormone regulation of amygdala-dependent fear-relevant memory and plasticity. Mol Psychiatry (2024). https://doi.org/10.1038/s41380-024-02679-2

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