In Vivo PET Imaging of Preynaptic Density Reveals Stress-Associated Synaptic Deficits Related to Behavioral and Molecular Alterations in Rats.

Background: Preclinical research indicates chronic stress can induce synaptic loss in corticolimbic brain regions regulating mood and cognition. Presynaptic density can now be measured in vivo using radioligands targeting synaptic vesicle protein 2A and positron emission tomography (PET). We conducted a first in vivo PET study to investigate chronic stress-induced synaptic density changes in rats and examined correlates with behavior and protein expression.

Methods: Male and female Long-Evans rats were exposed to chronic unpredictable stress (CUS; n=24/sex) and compared with controls (n=12/sex). Sucrose preference and novel object recognition (NOR) were used to assess stress-related behavioral phenotypes. PET with [¹⁸F]SynVesT-1 was used to measure synaptic density in a subset of rats (n=8-9/group/sex). Prefrontal cortex (PFC) and hippocampal proteins were quantified via LC-MS/MS (n=5/group/sex), followed by pathway analysis and linear regression to examine molecular profiles associated with CUS and correlated with synaptic density as measured by PET.

Results: Synaptic density was lower in the PFC of CUS rats relative to controls (d=0.94, p=0.012) and correlated with sucrose preference (r=0.35, p=0.042). Synaptic density was also lower in hippocampus (d=0.55, p=0.017), which correlated with NOR (r=0.35 p=0.045). Differentially expressed proteins were enriched for transcriptional regulation and metabolic pathways. Proteins implicated in synaptogenesis and neurodegeneration were positively and negatively correlated, respectively, with synaptic density.

Conclusions: We demonstrate that [¹⁸F]SynVesT-1 PET can be used for in vivo quantification of synaptic density in a rodent model of chronic stress. This method can, therefore, facilitate translational research investigating synaptic mechanisms in stress-related pathology and treatment response.