Altered object-in-place recognition memory, prepulse inhibition, and locomotor activity in the offspring of rats exposed to a viral mimetic during pregnancy

Abstract

Infection during pregnancy (i.e., prenatal infection) increases the risk of psychiatric illnesses such as schizophrenia and autism in the adult offspring. The present experiments examined the effects of prenatal immune challenge on behavior in three paradigms relevant to these disorders: prepulse inhibition (PPI) of the acoustic startle response, locomotor responses to an unfamiliar environment and the N-methyl-d-aspartate antagonist MK-801, and three forms of recognition memory. Pregnant Long-Evans rats were exposed to the viral mimetic polyinosinic-polycytidylic acid (PolyI:C; 4 mg/kg, i.v.) on gestational day 15. Offspring were tested for PPI and locomotor activity before puberty (postnatal days (PNDs)35 and 36) and during young adulthood (PNDs 56 and 57). Four prepulse-pulse intervals (30, 50, 80, and 140 ms) were employed in the PPI test. Recognition memory testing was performed using three different spontaneous novelty recognition tests (object, object location, and object-in-place recognition) after PND 60. Regardless of sex, offspring of PolyI:C-treated dams showed disrupted PPI at 50-, 80-, and 140-ms prepulse-pulse intervals. In the prepubescent rats, we observed prepulse facilitation for the 30-ms prepulse-pulse interval trials that was selectively retained in the adult PolyI:C-treated offspring. Locomotor responses to MK-801 were significantly reduced before puberty, whereas responses to an unfamiliar environment were increased in young adulthood. Both male and female PolyI:C-treated offspring showed intact object and object location recognition memory, whereas male PolyI:C-treated offspring displayed significantly impaired object-in-place recognition memory. Females were unable to perform the object-in-place test. The present results demonstrate that prenatal immune challenge during mid/late gestation disrupts PPI and locomotor behavior. In addition, the selective impairment of object-in-place recognition memory suggests tasks that depend on prefrontal cortex may be particularly vulnerable following prenatal immune challenge.

Fig. 1

The effects of PolyI:C treatment on maternal weight (A) and rectal temperature (B). Weight change is expressed as a percentage of baseline weight at 0 h immediately before treatment. Dams treated with PolyI:C (4 mg/kg, i.v.; n=14) gained significantly less weight than those treated with saline (n=18) at all time points.

Fig. 2

Effects of PolyI:C treatment on startle amplitude and prepulse inhibition (PPI) in prepubescent and young adult rats. Prepulse-pulse intervals of 50, 80, and 140 ms are shown. (A) Startle amplitudes (arbitrary units) of rats before puberty for the pulse-alone trials before, during, and after the PPI trials (saline-treated: males n=14 from 11 litters, females n=13 from 11 litters; PolyI:C-treated: males n=16 from 10 litters, females n=18 from 11 litters). (B) Startle amplitudes of young adult rats for the pulse-alone trials before, during, and after the PPI trials (saline-treated: males n=14 from 11 litters, females n=13 from 11 litters; PolyI:C-treated: males n=15 from 10 litters, females n=18 from 11 litters). Panels C and D show percent PPI for each prepulse-pulse interval (50, 80, and 140 ms) for the prepubescent and young adult rats, respectively. Panels E (before puberty) and F (young adulthood) depict percent PPI for each prepulse intensity (3, 6, 12 dB above background) averaged for trials with 50-, 80-, 140-ms prepulse-pulse intervals. Asterisks indicate a significant difference (P<0.05).

Fig. 3

Effects of PolyI:C treatment on PPI for trials with a 30-ms prepulse-pulse interval for rats before puberty (A) and in young adulthood (B). Note that a negative PPI score reflects an increase in startle responding on the trials with a prepulse (3, 6, or 12 dB above background). Groups are as described in Fig 2. Asterisks indicate a significant difference (P<0.05).

Fig. 4

Locomotor responses of the offspring of dams exposed to PolyI:C or saline on gestational day 15. Locomotor responses to an unfamiliar environment (30 min) and MK-801 (120 min) are depicted in panels A–D in 10-min bins. MK-801 was administered at 30 min (before puberty: all animals 0.2 mg/kg; after puberty: males 0.2 mg/kg, females 0.06 mg/kg, i.p.). Panels E and F depict the total locomotor activity of the animals for during exposure to the unfamiliar environment (E) and after MK-801 administration (F). Groups are composed of the following numbers of subjects: before puberty: spontaneous, saline-treated: males n=12 from 10 litters, females n=11 from nine litters; PolyI:C-treated: males n=11 from seven litters, females n=12 from eight litters; MK-801, saline-treated: males n=12 from 10 litters, females n=12 from 10 litters; PolyI:C-treated: males n=11 from seven litters, females n=11 from seven litters. Young adult: saline-treated: males n=15 from 12 litters, females n=20 from 14 litters; PolyI:C-treated: males n=15 from 10 litters, females n=15 from eight litters; MK-801, saline-treated: males n=15 from 11 litters, females n=8 from four litters; PolyI:C-treated males n=16 from 10 litters, females n=8 from three litters. Asterisks indicate a significant difference (P<0.05).

Fig. 5

Summary of the recognition memory tests and the effects of PolyI:C treatment on each type of memory for male and female subjects. (A) Object recognition. Rats explored two identical objects during a sample phase followed 24 h later by a test phase in which rats explored one copy of the sample object and one novel object. (B) Effect of PolyI:C on object recognition memory (saline-treated: male n=15 from 11 litters, female n=14 from 11 litters; PolyI:C-treated: male n=15 from 10 litters, female: n=16 from nine litters). (C) Object location recognition. Rats explored two identical objects during the sample phase. Following a 24-h delay, they explored two objects identical to the sample phase objects but with one object in a new location. (D) Prenatal PolyI:C treatment did not influence object location recognition memory, although female rats in both groups performed poorer than male rats (saline-treated: male n=15 from 12 litters, female n=13 from 10 litters; PolyI:C-treated: male n=16 from nine litters, female: n=17 from 11 litters). (E) Object-in-place recognition. During the sample phase, rats explored four different objects located in the corners of the box. One hour after the sample phase, rats again explored copies of the same four sample objects, but with two objects in displaced positions. Note the location of the black wall. (F) Effect of PolyI:C on object-in-place recognition memory (saline-treated: male n=17 from 10 litters, female n=17 from 10 litters; PolyI:C-treated: male n=14 from seven litters, female: n=16 from eight litters). Prenatal PolyI:C treatment significantly disrupted object-in-place memory in male rats. Female rats failed to show reliable memory. Asterisks indicate a significant difference (P<0.05).