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PET imaging evidence of HDAC6 suppression in the amygdala across species in PTSD

Molecular Psychiatry (2025)Cite this article

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Abstract

Histone deacetylases (HDACs), typically known for regulating gene expression, also play a major role in protein regulation outside of histone modification. Emerging evidence suggests the HDACs may be novel pharmacologic targets in complex disorders such as posttraumatic stress disorder (PTSD). Histone deacetylase 6 (HDAC6) regulates microtubule function and plays a role in stress-related cortisol signaling in serotonergic regions of the brain by maintaining the nuclear translocation of glucocorticoid receptors. Here, we report results of a translational positron emission tomography brain imaging study using a novel HDAC6-selective radiotracer, [18F]Bavarostat. In humans, we demonstrate significantly lower availability of HDAC6 in the amygdala of individuals with PTSD compared to non-trauma exposed controls. These proof-of-concept human findings are supported by rodent findings of reduced HDAC6 availability both in case-control groups and within-subject longitudinal analysis using a single prolonged stress model. Together, our translational findings demonstrate a potential role for HDAC6 in the pathophysiology of PTSD.

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Fig. 1: [18F]Bavarostat VT values for the primary ROI in three groups, non-trauma exposed control (n = 10), trauma exposed control (n = 10), and PTSD (n = 8).
Fig. 2: Behavior testing results for SPS animals.
Fig. 3: Rodent SPS model demonstrates lower HDAC6 on PET imaging.
Fig. 4: Rodent HDAC6 PET imaging results.

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Data availability

Due to the sensitive nature of human participant information, data are available upon reasonable request by contacting the corresponding author.

Code availability

Computer codes are written and property of Yale PET Center and can be accessed upon request.

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Acknowledgements

We are grateful for the expertise of the staff at the Yale PET Center and Yale PET animal facility, for their support of radiochemistry and imaging, particularly Dr. Takuya Toyonaga and Krista Fowles. We thank Alexa-Nicole Leverington, Rosemarie Terwilliger, and the animal staff at the Yale Animal Facilities and Charles Rivers. Additionally, we thank the Veterans Affairs National Center for PTSD for significant support of this work. We are thankful for our funding from the National Institute of Mental Health grants 5T32MH019961-24, the Veterans Affairs National Center for PTSD (KPC, MJG), and the Thomas P. Detre Award for Neurosciences (REB). This work was supported with resources and use of facilities at the VA Connecticut Health Care System, West Haven, CT and the National Center for PTSD, U.S. Department of Veterans Affairs. This work was funded in part by the State of Connecticut, Department of Mental Health and Addiction Services. The views expressed here are those of the authors and do not necessarily reflect the position or policy of the US Department of Veterans Affairs (VA) or the U.S. government or the views of the Department of Mental Health and Addiction Services or the State of Connecticut.

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Author notes

  1. These authors contributed equally: Matthew J. Girgenti, Kelly P. Cosgrove.

Authors and Affiliations

  1. Yale University Department of Psychiatry, New Haven, CT, 06511, USA

    Robin E. Bonomi, Delaney McRiley, Brittany LeVasseur, Catharine Duman, David Matuskey, Robert H. Pietrzak, Matthew J. Girgenti & Kelly P. Cosgrove

  2. Yale PET Center, Yale University, New Haven, CT, 06511, USA

    Mika Naganawa, Takuya Toyonaga, Yiyun Huang, David Matuskey & Richard E. Carson

  3. Yale University Department of Radiology and Biomedical Imaging, New Haven, CT, 06511, USA

    Mika Naganawa, Takuya Toyonaga, Yiyun Huang, David Matuskey & Richard E. Carson

  4. National Center for PTSD, Clinical Neuroscience Division, US Department of Veterans Affairs, New Haven, CT, 06511, USA

    Matthew J. Girgenti

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Contributions

REB, KPC, and MJG conceived and designed the study. REB and DM conducted human subjects’ recruitment, medical clearance, characterization, and oversight. REB conducted all animal studies and behavior analysis. REB and MN analyzed the PET data with input from REC and RP REB performed animal studies and CD performed immunohistochemistry with oversight from MJG REB analyzed rodent and human PET, and rodent behavior. REB, MJG, RP, and KPC wrote the manuscript. All authors edited and contributed comments and intellectual content to the manuscript.

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Correspondence to Matthew J. Girgenti or Kelly P. Cosgrove.

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Bonomi, R.E., Naganawa, M., McRiley, D. et al. PET imaging evidence of HDAC6 suppression in the amygdala across species in PTSD. Mol Psychiatry (2025). https://doi.org/10.1038/s41380-025-03124-8

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