Hidden talents: Poly (I:C)-induced maternal immune activation improves mouse visual discrimination performance and reversal learning in a sex-dependent manner

Abstract

While there is a strong focus on the negative consequences of maternal immune activation (MIA) on developing brains, very little attention is directed towards potential advantages of early life challenges. In this study, we utilized a polyinosine-polycytidylic acid (poly(I:C)) MIA model to test visual pairwise discrimination (PD) and reversal learning (RL) in mice using touchscreen technology. Significant sex differences emerged in that MIA reduced the latency for males to make a correct choice in the PD task while females reached criterion sooner, made fewer errors, and utilized fewer correction trials in RL compared to saline controls. These surprising improvements were accompanied by the sex-specific upregulation of several genes critical to cognitive functioning, indicative of compensatory plasticity in response to MIA. In contrast, when exposed to a 'two-hit' stress model (MIA + loss of the social component of environmental enrichment [EE]), mice did not display anhedonia but required an increased number of PD and RL correction trials. These animals also had significant reductions of CamK2a mRNA in the prefrontal cortex. Appropriate functioning of synaptic plasticity, via mediators such as this protein kinase and others, are critical for behavioral flexibility. Although EE has been implicated in, delaying the appearance of symptoms associated with certain brain disorders, these findings are in line with evidence that it also makes individuals more vulnerable to its loss. Overall, with the right 'dose', early life stress exposure can confer at least some functional advantages, which are lost when the number or magnitude of these exposures become too great.

Keywords: acetylcholine; cognitive flexibility; companion loss; compensatory mechanisms; fetal programming; hippocampus; parvalbumin; perineuronal nets; prefrontal cortex; prenatal immune activation; sex differences; social isolation; two-hit.

Figure 1.

Outline of experimental procedures.

Figure 2.

Visual pairwise discrimination learning in male (left) and female (right) MIA offspring. (A) Survival analysis of sessions to discrimination criterion (n = 8-13 litters represented per sex, MIA and housing group). (B) Total number of trials, errors, and correction trials completed by animals that met criterion during all discrimination sessions. (C) Latency (seconds) to respond for a correct choice, incorrect choice, and reward during all discrimination sessions. Data expressed as mean ± SEM, n=7-11 litters represented per sex, MIA, and housing group. ##p < 0.01, versus EE-poly (I:C); ^ap < 0.05, main effect of housing; ^bbp < 0.01, main effect of MIA.

Figure 3.

Reversal learning in male (left) and female (right) MIA offspring. (A) Survival analysis of sessions to reversal criterion. (B) Total number of trials, errors, and correction trials completed during all reversal sessions. (C) Latency (seconds) to respond for a correct choice, incorrect choice, and reward during all reversal sessions. Data expressed as mean ± SEM, n=7-11 litters represented per sex, MIA, and housing group. ***p < 0.001, versus SD-saline; #p < 0.05, ###p < 0.001, versus EE-poly (I:C); ^bbp < 0.01, main effect of MIA.

Figure 4.

Prefrontal cortex gene expression in male (left) and female (right) MIA offspring on postnatal day 85. Levels of (A) Grin1, (B) Grin2b, (C) Htr2a, (D) Slc18a3 (E) Chat, (F) Chrm1, (G) Camk2a, and (H) Prkca mRNA. Gene expression data are expressed as mean ± SEM, n=8 litters represented per sex, MIA, and housing group. *p < 0.05, **p < 0.01, versus SD-saline; ##p < 0.01, versus EE-poly (I:C).

Figure 5.

Expression of parvalbumin (PV+) and perineuronal net (PNN) density for male and female MIA offspring on postnatal day 85. (A) Representative brain plates for brain regions of interest such as prelimbic (PL), infralimbic (PL), medial orbital (MO) and the ventral medial (VO) cortices. (B) Representative depictions of PV+, PNN, and PV/PNN colocalization. Representative sections and associated data for (C) prelimbic, (D) infralimbic, (E) medial orbital and (F) ventral orbital cortex. Data are expressed as mean ± SEM; n=5-7 litters represented per sex, MIA, and housing group. Where there were no sex differences, male and female data were collapsed for visualization purposes. *p < 0.05, **p < 0.01, versus SD-saline; #p < 0.05, ##p < 0.01, versus EE-poly (I:C). ^ap < 0.05, main effect of housing; ^bp < 0.05, main effect of MIA.