The neuroinflammatory and behavioral response to recurrent psychosocial stress: An [¹¹C]PBR28 PET imaging study in stress-sensitized aged rats

Introduction:Neuroinflammation plays an important role in the relationship between psychosocial stress and depressive-like behavior. However, it is still unknown if prior exposure to psychosocial stress has long-term influences in the response to a recurrence of the stressful stimulus later in life. The present study aimed to evaluate the behavioral and neuroinflammatory profile after repeated social defeat (RSD) in stress-sensitized and stress-naïve aged rats.Methods:Fourteen months old stress-sensitized Wistar rats (n=10), exposed during adolescence to 5-days of RSD, underwent the same RSD protocol after one year. Stress-naïve age-matched rats (n=8) were subjected to RSD without previous adolescent RSD exposure. The RSD protocol was performed by introducing the experimental rat (intruder) inside the home cage of a dominant Long Evans (resident) rat for a total of 60 min each day (experimental days 0-4). The protocol was considered successful when the intruder indicated defeat by adopting a submissive posture for at least 3 sec. Anhedonic behavior was assessed through the sucrose preference test on day -2 and 5. On day -1 and 11, neuroinflammation was measured by a 30-min static PET scan, performed 45 min after injection of 11C-PBR28.Results:Decreased sucrose preference (-25%, p=0.003) was observed in stress-sensitized rats only on day 5, while no difference was found in stress naïve rats after RSD. On day 11, within-group comparison demonstrated that stress-naïve rats showed an increased 11C-PBR28 uptake in the frontal cortex association (+16%, p=0.035), cingulated cortex (+21%, p=0.008), orbitofrontal cortex (+20%, p<0.001), and medial/prefrontal cortex (+27%, p<0.001), while stress sensitized rats had a decreased 11C-PBR28 uptake in the cerebellum (-9%, p=0.004), frontal cortex association (-12%, p<0.001), medial/prefrontal cortex (-12%, p=0.002), and orbitofrontal cortex (-13%, p<0.001). Notably, the between-group comparison on day -1 showed a significant increased 11C-PBR28 uptake in stress-sensitized rats for the cingulate cortex (25%, p=0.022), frontal cortex association (33%, p=0.001), orbitofrontal cortex (45%, p<0.001) and medial/prefrontal cortex (47%, p<0.001). No differences between groups were observed on day 11.Conclusion:Rats that were stress-sensitized at adolescence showed higher neuroinflammatory levels in areas associated with depression at old age than stress-naïve rats. RSD exposure at old age provoked anhedonic-like behavior and decreased microglia activation in stress-sensitized rats. In contrast, stress-naïve rats demonstrated an increased neuroinflammatory profile in the same areas after RSD exposure at old age, but without anhedonic symptoms. This distinctive neuroinflammatory and behavioral response to psychosocial stress warrants further research into the longterm effects of early-life stress exposure