Male and female impairments in odor span are observed in a rat model of PTSD

Abstract

Posttraumatic stress disorder (PTSD) is associated with neural and behavioral alterations in response to trauma exposure, including working memory impairments. Rodent models of PTSD have not fully investigated chronic or reactive working memory deficits, despite clinical relevance. The present study uses footshock to induce a posttraumatic stress state in male and female rats and evaluates the effect of footshock and trauma-paired odor cues on working memory performance in the odor span task. Results demonstrate the emergence of chronic deficits in working memory among animals exposed to footshock by 3 wk after traumatic stress. The presentation of a trauma-paired odor cue was associated with further decrement in working memory performance for male animals. Furthermore, anxiety-like behaviors associated with the PTSD-like phenotype could predict the degree of working memory impairment in response to the trauma-paired odor cue. This study enhances validation of an existing rodent model of PTSD through replication of the clinical observations of working memory deficits associated with PTSD and provides novel insight into effects in female rodents. This will facilitate work to probe underlying mechanistic dysregulation of working memory following footshock trauma exposure and future development of novel treatment strategies.

Figure 1.

Experimental procedures and counterbalancing measures. (A) Experimental time line. (B) Depiction of sample odor span session. (C) Group assignments show balanced pretest elevated zero maze performance, as assessed by open zone time, although females spent greater time in the open zones of the maze than males. (*) P < 0.05, male versus female. (D) Prefootshock DNMS performance, calculated as the average proportion of correct responses on the most recent three training sessions, did not differ between the groups. (DNMS) Delayed non-match to sample, (FST) footshock trauma, (ITI) intertrial interval. N = 8 per group.

Figure 2.

Delayed non-match to sample following acute stress. Acute stress did not significantly impact DNMS performance, expressed as a change score calculated as percent change from DNMS performance prestress. (FST) Footshock trauma. N = 8 per group.

Figure 3.

Footshock trauma history impacted training performance in the odor span test. (A) Maximum span, calculated as the average maximum odor span across the final 5 d of training, was significantly lower in males and FST animals. Maximum span is indicated by the dashed line. (*) P < 0.05, male versus female and FST versus control. (B) Summed trial escape omissions from the final 5 d of training did not differ between groups. (FST) Footshock trauma. N = 8 per group.

Figure 4.

Footshock trauma history and trauma-paired odor impacted performance in the odor span test. (A,B) Maximum span on baseline and TPO sessions. Span did not differ by sex or condition, but a significant interaction was present, suggesting male FST animals displayed greater odor span deficits in response to the TPO compared with same-sex controls. (C,D) Log-transformed latency to respond on non-TPO trials, calculated as the average latency per sampled cup on choice trials 1–3, compared with TPO trial 4. Latency was significantly greater for FST animals, regardless of sex. (*) P < 0.05, control versus FST. (E,F) Log-transformed latency to dig on the TPO trial correlated with span impairment, calculated as percent change in TPO span compared with baseline span, only for male FST animals. (*) P < 0.05, male FST. (FST) Footshock trauma, (TPO) trauma-paired odor. N = 7–8 per group.

Figure 5.

Behavioral profiling to assess PTSD-like phenotype. (A) Elevated zero maze open zone time did not differ between groups. (B) Open zone entries in zero maze were more numerous for females, indicating greater locomotor activity. (*) P < 0.05, male versus female. (C) Open field time in the center zone did not differ between groups. (D) Total distance traveled in the open field test did not differ between groups. (E) Time spent engaged in nonsocial, prosocial, and antisocial behaviors in the social interaction test differed by sex. (F) Correlation between normalized change in span and antisocial interaction was significant only for FST animals. Lines indicate group correlation slopes. (**) P < 0.01 FST group. (FST) Footshock trauma. N = 7–8 per group.

Figure 6.

Multiple linear regression covariance matrices. In accordance with assumptions for multiple linear regression, no regression parameters significantly covaried for control animals (A) or FST animals (B).