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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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.
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.
The authors declare no competing interests.
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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