Sex-dependent neurobiological and metabolic dysfunction in an aged rat model of post-traumatic stress disorder

The neurobiological underpinnings of post-traumatic stress disorder (PTSD) in the elderly remain poorly characterized, particularly regarding sex-dependent vulnerabilities. This study systematically investigated sex-specific behavioral and metabolic alterations in 15-month-old rats using a single prolonged stress and footshock (SPS + FS) paradigm. A multimodal approach integrating behavioral analysis, 2-deoxy-2-[¹⁸F]fluoro-D-glucose positron emission tomography (FDG-PET) imaging, plasma endocrine profiling, and brain transcriptomics was employed to assess PTSD-related dysfunction. Behavioral assessments revealed that female rats exhibited more severe PTSD-like manifestations, indicating a higher susceptibility compared to males. Macroscopically, FDG-PET imaging identified prominent sex-specific alterations in glucose metabolism within the core fear circuitry, including the prefrontal cortex (PFC), hippocampus (Hipp), and amygdala (Amyg). In females, these metabolic shifts were more pronounced and strongly correlated with behavioral phenotypes. Dynamic PET further confirmed a general decline in the cerebral metabolic rate of glucose (CMRglu) across PTSD groups. Transcriptomic analysis validated these observations, revealing a systemic reprogramming of central metabolic networks in core brain regions. These neuroenergetic shifts appeared potentially associated with the dysregulation of key metabolic signaling networks, primarily the insulin and AMPK pathways, which exhibited notable sex-dependent spatial heterogeneity. These findings elucidate sex-specific metabolic and molecular abnormalities in aged PTSD models, advancing our understanding of elderly pathophysiology.