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Examining sex differences in responses to footshock stress and the role of the metabotropic glutamate receptor 5: an [18F]FPEB and positron emission tomography study in rats

Neuropsychopharmacology volume 48, pages 489–497 (2023)Cite this article

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Abstract

Clinical investigations suggest involvement of the metabotropic glutamate receptor 5 (mGluR5) in the pathophysiology of fear learning that underlies trauma-related disorders. Here, we utilized a 4-day fear learning paradigm combined with positron emission tomography (PET) to examine the relationship between mGluR5 availability and differences in the response of rats to repeated footshock exposure (FE). Specifically, on day 1, male (n = 16) and female (n = 12) rats received 15 footshocks and were compared with control rats who did not receive footshocks (n = 7 male; n = 4 female). FE rats were classified as low responders (LR) or high responders (HR) based on freezing to the context the following day (day 2). PET with [18F]FPEB was used to calculate regional mGluR5 binding potential (BPND) at two timepoints: prior to FE (i.e., baseline), and post-behavioral testing. Additionally, we used an unbiased proteomics approach to assess group and sex differences in prefrontal cortex (PFC) protein expression. Post-behavioral testing we observed decreased BPND in LR females, but increased BPND in HR males relative to baseline. Further, individuals displaying the greatest freezing during the FE context memory test had the largest increases in PFC BPND. Males and females displayed unique post-test molecular profiles: in males, the greatest differences were between FE and CON, including upregulation of mGluR5 and related molecular networks in FE, whereas the greatest differences among females were between the LR and HR groups. These findings suggest greater mGluR5 availability increases following footshock exposure may be related to greater contextual fear memory. Results additionally reveal sex differences in the molecular response to footshock, including differential involvement of mGluR5-related molecular networks.

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Fig. 1: Variability in the behavioral response to footshock exposure in male and female rats.
Fig. 2: Using differences in day 2 freezing to identify low and high responding FE rats.
Fig. 3: Relationships between changes in mGluR5 availability and freezing behavior.
Fig. 4: Footshock exposure results in unique protein expression profiles in males and females.

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Acknowledgements

The authors would like to thank TuKiet Lam, Weiwei Wang, Florine Collin and the Yale Keck Biotechnology Resourse Loboratory for their assistance in the preparation and processing of samples for LC–MS/MS proteiomics.

Funding

This work was funded in part by the United States Department of Veterans Affairs National Center for PTSD. Additional support was provided by the Biological Sciences Training Program (BSTP) in Psychiatry (T32 MH014276) and the State of Connecticut, Department of Mental Health and Addiction Services. This publication does not express the views of the United States Department of Veterans Affairs, Department of Mental Health and Addiction Services, or the State of Connecticut. The views and opinions expressed are those of the authors.

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Authors and Affiliations

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

    Ruth H. Asch, Santosh Pothula, Ralph J. DiLeone, Jane R. Taylor & Irina Esterlis

  2. Department of Radiology & Biomedical Imaging, Yale University School of Medicine, New Haven, CT, USA

    Takuya Toyonaga & Krista Fowles

  3. Department of Neuroscience, University of Minnesota Medical School, Minneapolis, MN, USA

    Stephanie M. Groman

  4. Bioinformatics Support Program, Cushing/Whitney Medical Library, Yale University School of Medicine, New Haven, CT, USA

    Rolando Garcia-Milian

  5. Yale University, Department of Psychology, New Haven, CT, USA

    Jane R. Taylor & Irina Esterlis

  6. US Department of Veterans Affairs National Center for Posttraumatic Stress Disorder, VA Connecticut Healthcare System, West Haven, CT, USA

    Irina Esterlis

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Contributions

Experiments were designed by RHA, SMG, and IE. Data collection was performed by RHA, SP, and KF and analyzed by RHA, TT, and RG-M. Additional research support and recourses were provided by RJD. This manuscript was drafted by RHA, with the oversight and mentorship of SMG, RJD, JRT and IE. IE agreed to be held accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

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Correspondence to Ruth H. Asch.

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Asch, R.H., Pothula, S., Toyonaga, T. et al. Examining sex differences in responses to footshock stress and the role of the metabotropic glutamate receptor 5: an [18F]FPEB and positron emission tomography study in rats. Neuropsychopharmacol. 48, 489–497 (2023). https://doi.org/10.1038/s41386-022-01441-y

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