Prenatal exposure to a viral mimetic alters behavioural flexibility in male, but not female, rats

Abstract

Current understanding of the etiology of neurodevelopmental disorders is limited; however, recent epidemiological studies demonstrate a strong correlation between prenatal infection during pregnancy and the development of schizophrenia in adult offspring. In particular, schizophrenia patients subjected to prenatal infection exhibit impairments in executive functions greater than schizophrenia patients not exposed to an infection while in utero. Acute prenatal treatment of rodents with the viral mimetic polyinosinic-polycytidylic acid (PolyI:C) induces behavioural and neuropathological alterations in the adult offspring similar to schizophrenia. However, impairments on tasks of executive function that involve the prefrontal cortex (PFC) have been rarely examined for the prenatal infection model. Hence, we investigated the effects of acute prenatal injection of PolyI:C (4.0 mg/kg, i.v., gestational day 15) on strategy set-shifting and reversal learning in an operant-based task. Our results show male, but not female, PolyI:C-treated adult offspring require more trials to reach criterion and perseverate during set-shifting. An opposite pattern was seen on the reversal day where the PolyI:C-treated male rats made fewer regressive errors. Females took more pre-training days and were slower to respond during the trials when compared to males regardless of prenatal treatment. The present findings validate the utility of the prenatal infection model for examining alterations of executive function, one of the most prominent cognitive symptoms of schizophrenia.

Fig. 1

A. Effects of prenatal treatment on weight of pregnant dams (gestational day 15; Saline: n = 9; PolyI:C: n = 11). Weight change is expressed as a percentage of baseline weight at 0 h immediately prior to treatment. Dams treated with saline gained significantly more weight than those treated with PolyI:C at the 24 and 48 h time points. B. Effects of treatment on rectal temperature of dams. PolyI:C significantly increased rectal temperature of the dams 8, but not 24 or 48 h after treatment. All values are means ± SEM. * denotes p < 0.05.

Fig. 2

Performance of rats in the PolyI:C or saline-treated groups on the visual-cue discrimination day. A. Trials to criterion (TTC). B. Total errors. C. Average response latencies (ARL’s) to press a lever. Female rats had significantly increased ARL’s regardless of treatment. Saline: n = 11 males, 10 females; PolyI:C: n = 11 males, 12 females. * denotes p < 0.05.

Fig. 3

Effects of prenatal PolyI:C or saline treatment on set-shifting from a visual to response based strategy. A. Effects of prenatal PolyI:C treatment on trials to criterion (TTC). B. Total errors committed during set-shifting. Male offspring prenatally treated with PolyI:C took significantly more trials to reach criterion and made significantly more total errors than saline-treated offspring. C. Error subtypes committed by the males. The impairment in set-shifting for the PolyI:C-treated males was due to a significant increase in perseverative errors. D. Error subtypes committed by the females. * denotes p < 0.05.

Fig. 4

Effects of prenatal PolyI:C or saline treatment reversal learning. A. Effects of prenatal PolyI:C treatment on trials to criterion (TTC). B. Analysis of the subtypes of errors made by the male animals. Male PolyI:C-treated offspring made significantly more regressive errors during the reversal learning phase of the task. C. Subtypes of errors made by the females. * denotes p < 0.05.