Maternal Immune Activation during Pregnancy Alters the Behavior Profile of Female Offspring of Sprague Dawley Rats

Abstract

Sex differences are documented in psychiatric and neurological disorders, yet most preclinical animal research has been conducted in males only. There is a need to better understand of the nature of sex differences in brain disease in order to meet the needs of psychiatric patients. We present the behavior profile of adult female offspring produced using a maternal immune activation (MIA) model where pregnant rats receive an immune stimulant and the offspring typically show various abnormalities consistent with psychiatric illnesses such as schizophrenia and autism. The results in female offspring were compared to a previously published cohort of their male siblings (Lins et al., 2018). We examined prepulse inhibition (PPI), sociability, MK-801-induced locomotor activity, crossmodal object recognition (CMOR), and oddity discrimination; behaviors relevant to the positive, negative, and cognitive symptoms of schizophrenia. No between-treatment differences in PPI or locomotor activity were noted. Tactile memory was observed in the control and treated female offspring, visual recognition memory was deficient in the polyinosinic:polycytidylic acid (polyI:C) offspring only, and both groups lacked crossmodal recognition. PolyI:C offspring were impaired in oddity preference and had reduced preference for a stranger conspecific in a sociability assay. Systemic maternal CXCL1, IL-6, and TNF-a levels 3 h after polyI:C treatment were determined, but no relationship was found between these cytokines and the behavior seen in the adult female offspring. Overall, female offspring of polyI:C-treated dams display an array of behavior abnormalities relevant to psychiatric illnesses such as schizophrenia similar to those previously reported in male rats.

Keywords: behavior; prepulse inhibition; recognition memory; sex differences; sociability.

Figure 1.

A, Schematic detailing the time line of maternal treatment and initiation of offspring behavior testing. Schematic has been published previously (Lins et al., 2018). B, Flowchart depicting the order of the behavior test battery.

Figure 2.

A, Schematic illustrating a startle response to a 120 dB tone (top panel) versus the typical reduction in startle reactivity when a prepulse of 3, 6, or 12 dB precedes the startling tone (bottom panel). Schematic has been published previously (Lins et al., 2018). B, Startle reactivity decreased over the course of the PPI testing protocol and polyI:C offspring had significantly higher reactivity at the “after” time point (*p < 0.05). C, There were no differences between groups in %PPI for the short (30 ms) prepulse-pulse interval but %PPI increased with increasing prepulse intensity where the 12 dB prepulse had higher PPI than 2 or 6 dB prepulses. D, There were no differences between groups in %PPI for the long (80 ms) prepulse-pulse interval but %PPI increased with increasing prepulse intensity (3 dB < 6 dB < 12 dB; *p < 0.05).

Figure 3.

A, Schematic representing the black, three-chambered arena used to conduct the sociability task. The chambers on either side of the center start chamber contain identical holding cages, one of which would contain a social stimulus (an age, sex, and treatment matched stranger rat), while the test rat was free to explore. Schematic has been published previously (Henbid et al., 2017; Lins et al., 2018). B, When the exploration data are presented as a DR, both groups show significant preference for the stranger rat; however, polyI:C offspring show significantly less preference when compared to saline offspring. C, There was no significant difference between groups in total exploration or exploration of the social stimulus, although polyI:C rats spent more time exploring the non-social stimulus than saline rats. D, Schematic of the black, square arena where rats’ activity was monitored before and after administration of MK-801. Schematic has been published previously (Lins et al., 2018). E, Graph displaying locomotor activity as distance traveled per 10 min time bin. Both groups had elevated locomotor activity following MK-801 administration, but there was no effect of maternal treatment. *p < 0.05.

Figure 4.

A, The Y-maze assembled to conduct the tactile phase in red light conditions where the rat is able to explore objects via touch. B, both groups of offspring display robust novelty preference in the tactile phase with novel object exploration significantly greater than chance levels. C, The Y-maze assembled for the visual phase which is conducted in white light conditions with the addition of a clear, Plexiglas window to prevent tactile exploration of the objects, limiting the rats to visual observation. D, Saline offspring demonstrated visual memory with novel object exploration significantly greater than chance but polyI:C offspring did not perform above chance levels. E, The Y-maze assembled for the crossmodal phase which has a tactile sample phase and visual test phase. F, both groups failed to display crossmodal recognition memory as novel object exploration was equal to chance; # indicates significant difference from chance exploration (DR = 0, p < 0.05) in a single sample t test. Schematic has been published previously (Lins et al., 2018; Paylor et al., 2018).

Figure 5.

A, Schematic of the white square arena used to conduct the oddity discrimination task showing the arrangement of three identical objects and one different, or odd object. Schematic has been published previously (Lins et al., 2018). B, bar graph displaying the percentage of total object exploration spent examining the odd object. PolyI:C offspring displayed significantly less oddity preference than saline offspring (*p < 0.05).