Maternal immune activation in nonhuman primates alters social attention in juvenile offspring

Abstract

Background: Sickness during pregnancy is associated with an increased risk of offspring neurodevelopmental disorders. Rodent models have played a critical role in establishing causal relationships and identifying mechanisms of altered brain and behavior development in pups prenatally exposed to maternal immune activation (MIA). We recently developed a novel nonhuman primate model to bridge the gap between human epidemiological studies and rodent models of prenatal immune challenge. Our initial results demonstrated that rhesus monkeys given the viral mimic synthetic double-stranded RNA (polyinosinic:polycytidylic acid stabilized with poly-l-lysine) during pregnancy produce offspring with abnormal repetitive behaviors, altered communication, and atypical social interactions.

Methods: We utilized noninvasive infrared eye tracking to further evaluate social processing capabilities in a subset of the first trimester MIA-exposed offspring (n = 4) and control animals (n = 4) from our previous study.

Results: As juveniles, the MIA offspring differed from control animals on several measures of social attention, particularly when viewing macaque faces depicting the fear grimace facial expression. Compared with control animals, MIA offspring had a longer latency before fixating on the eyes, had fewer fixations directed at the eyes, and spent less total time fixating on the eyes of the fear grimace images.

Conclusions: In the rhesus monkey model, exposure to MIA at the end of the first trimester results in abnormal gaze patterns to salient social information. The use of noninvasive eye tracking extends the findings from rodent MIA models to more human-like behaviors resembling those in both autism spectrum disorder and schizophrenia.

Keywords: Autism spectrum disorders; Immunology; Macaque; Nonhuman primate; Poly IC; Schizophrenia; Social attention.

Figure 1.

Schematic of a typical testing trial (A). A 5-second black screen preceded and followed each face stimulus. Animals were also required to fixate a center and peripheral pulsating star target for >500 msec to receive a juice reward and proceed to the next trial. Examples of the four face stimulus categories (neutral, lipsmack, fear grimace, and open-mouth threat) are also shown (B).

Figure 2.

Four examples of visual stimuli used for experiment 2 are shown. Each background was downloaded from the internet and a neutral, lipsmack, fear grimace, or open-mouth threat facial expression was added at a pseudorandom spatial location (balanced across all stimuli) using Adobe Photoshop software.

Figure 3.

The average fixation duration directed at the face area of interest for control (CON) and offspring of dams treated with poly ICLC at the end of the first trimester (MIA¹) animals, regardless of facial expression (i.e., all expressions averaged). MIA¹ showed a significant decrease between day 1 and day 2 and then remained generally constant after that. Average fixation duration for CON animals remained constant until a significant decrease between day 4 and day 5. *p < .05.

Figure 4.

The total frequency (A) and duration (B) of fixations directed at the eyes area of interest of fear grimace expressions. Offspring of dams treated with poly ICLC at the end of the first trimester (MIA¹) directed fewer fixations at the eyes and those fixations totaled less time than control (CON) animals. *p < .05.

Figure 5.

The average latency from the start of a trial until the first fixation was registered in the eyes area of interest (A) or the mouth area of interest (B) for fear grimace expressions. The offspring of dams treated with poly ICLC at the end of the first trimester (MIA¹) animals showed a significantly longer latency before fixating on the eyes and significantly shorter latency before fixating the mouth relative to control (CON) animals. *p < .05.

Figure 6.

Each image shown is a composite of the 10 fear grimace facial expressions included in experiment 1. The 10 images were made semi-transparent and then overlaid on each other. The point of gaze for all offspring of dams treated with poly ICLC at the end of the first trimester (MIA¹) or control (CON) animals on days 1 through 5 were then mapped onto these images at 0 msec, 500 msec, 1000 msec, and 1500 msec to show the general distribution of gaze for the two groups when viewing fear grimaces. Notice that CON animals largely direct their gaze at the eyes by 500 msec into the presentation. During the next 1000 msec, their gaze is split between the eyes and the mouth. By contrast, MIA¹ animals largely direct their gaze at the nose at 500 msec, and their gaze generally disperses to many different parts of the face and background by 1500 msec into the presentation. A supplemental video is available online showing a comparison between the CON and MIA¹ animals for the entire 5-second presentation of the fear grimace composite image.