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. 2021 Jul:95:269-286.
doi: 10.1016/j.bbi.2021.03.025. Epub 2021 Mar 30.

Maternal allergic inflammation in rats impacts the offspring perinatal neuroimmune milieu and the development of social play, locomotor behavior, and cognitive flexibility

Michaela R Breach  1 , Courtney N Dye  1 , Aarohi Joshi  2 , Steven Platko  2 , Rachel A Gilfarb  1 , Annemarie R Krug  2 , Dominic V Franceschelli  2 , Anabel Galan  2 , Claire M Dodson  2 , Kathryn M Lenz  3
Affiliations

Maternal allergic inflammation in rats impacts the offspring perinatal neuroimmune milieu and the development of social play, locomotor behavior, and cognitive flexibility

Michaela R Breach et al. Brain Behav Immun. 2021 Jul.

Abstract

Maternal systemic inflammation increases risk for neurodevelopmental disorders like autism, ADHD, and schizophrenia in offspring. Notably, these disorders are male-biased. Studies have implicated immune system dysfunction in the etiology of these disorders, and rodent models of maternal immune activation provide useful tools to examine mechanisms of sex-dependent effects on brain development, immunity, and behavior. Here, we employed an allergen-induced model of maternal inflammation in rats to characterize levels of mast cells and microglia in the perinatal period in male and female offspring, as well as social, emotional, and cognitive behaviors throughout the lifespan. Adult female rats were sensitized to ovalbumin (OVA), bred, and challenged intranasally on gestational day 15 of pregnancy with OVA or saline. Allergic inflammation upregulated microglia in the fetal brain, increased mast cell number in the hippocampus on the day of birth, and conferred region-, time- and sex- specific changes in microglia measures. Additionally, offspring of OVA-exposed mothers subsequently exhibited abnormal social behavior, hyperlocomotion, and reduced cognitive flexibility. These data demonstrate the long-term effects of maternal allergic challenge on offspring development and provide a basis for understanding neurodevelopmental disorders linked to maternal systemic inflammation in humans.

Keywords: Behavior; Immunology; Mast cells; Maternal immune activation; Microglia; Social play.

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Conflict of interest statement

Conflict of Interest Statement: The authors declare no competing financial interests.

Figures

Figure 1.
Figure 1.
Experimental timeline. Female rats were sensitized to chicken egg ovalbumin, bred, and challenged on GD15. Offspring brains were collected, and brain mast cells and microglia were examined at three time points: two hours post-challenge, PN0, and PN4. Offspring social, emotional, and cognitive behaviors were also quantified. BG = basal ganglia, BNST = Bed Nucleus of the Stria Terminalis HYPO = hypothalamus, HPC = hippocampus, AMY = amygdala, mPFC = medial prefrontal cortex.
Figure 2.
Figure 2.
Representative images of mast cell and microglia staining in a female vehicle offspring on PN0. (A) Toluidine Blue-stained Mast cells in the perivascular area near the hippocampus. (B) DAB-stained Microglia in the lateral septum. Representative ameboid (B.1) and phagocytic (B.2) microglia are pictured.
Figure 3.
Figure 3.
Maternal allergic inflammation increases the number of mast cells in the perinatal hippocampus. (A) OVA and vehicle offspring have similar numbers of mast cells throughout the brain two hours post-challenge on GD15. N’s = 7/group. (B – D) Males had more total, granulated, and degranulated mast cells in and near the hippocampus compared to females. (B and C) Allergic challenge increased total and granulated mast cell numbers. N = 3/group/sex. HPC = hippocampus, MC = mast cells.
Figure 4.
Figure 4.
Maternal allergic inflammation acutely produces sex- and region- specific changes in fetal brain microglia. (A-C) In the basal ganglia, males had more total and phagocytic microglia than females, and maternal allergic inflammation increased ameboid microglia without changing ameboid tone. N’s = 8/group/sex. (D-F) Allergic inflammation increased microglial colonization of the hypothalamus, without changing the number of ameboid microglia or ameboid tone. N’s = 8/group/sex. (G-I) Allergic inflammation increased the number of ameboid microglia in the male hippocampus only, yet decreased ameboid tone in the female hippocampus. N’s = 8 MV, 6 FV, 8 MOVA, 8 FOVA. BG = basal ganglia, HYPO = hypothalamus, HPC = hippocampus.
Figure 5.
Figure 5.
Gestational allergic inflammation alters offspring microglia in a region-dependent manner on PN0. (A-C) OVA offspring had lower counts of total and phagocytic microglia, but no change in phagocytic tone in the mPFC. N’s = 8 MV, 9 FV, 8 MOVA, 13 FOVA. (D-F) OVA offspring had increased phagocytic microglia and thus an increase in phagocytic tone in the basal ganglia. N’s = 7 MVs, 10 FVs, 8 MOVAs, 14 FOVAs. (G-I) OVA offspring had fewer total and phagocytic microglia in the septum, and this contributed to a decrease in phagocytic tone that approached significance. Notably, an interaction approached significance whereby OVA males, but not OVA females had fewer phagocytic microglia. N’s = 7 MV, 10 FV, 7 MOVA, 14 FOVA. (J-L) As with the mPFC, OVA offspring had fewer total and phagocytic microglia in the amygdala, but there was no change in phagocytic tone. N’s = 9 MV, 11 FV, 15 MOVA, 20 FOVA. (M-O) OVA offspring displayed fewer total and phagocytic microglia in the hippocampus. A significant interaction found that Allergic inflammation also tended to decrease the phagocytic tone in the hippocampus of females, but not males. N’s = 9 MV, 8 FV, 11 MOVA, 16 FOVA. mPFC = medial prefrontal cortex, BG = basal ganglia, AMY = amygdala, HPC = hippocampus.
Figure 6.
Figure 6.
Gestational allergic inflammation alters offspring microglia in a region-dependent manner on PN4. (A-B) OVA offspring did not show changes in the number of microglia in the mPFC, but microglial staining was increased. Males tended to have increased staining relative to females. N’s = 5 MVs, 5 FVs, 4 MOVAs, 10 FOVAs for A, and N’s = 4 MVs, 10 FVs, 5 MOVAs, and 4 FOVAs for B. (C-D) OVA offspring had fewer microglia in the basal ganglia relative to vehicle offspring, and there was a trend for a decrease in microglial staining. N’s = 5/group/sex. (E-F) OVA offspring tended to have fewer microglia in the amygdala, and this was due to a significant decrease in microglia in the males. Conversely, allergic inflammation decreased microglial staining in the amygdala of male offspring and increased staining in females. N’s = 5/group/sex. (G-H) Allergic inflammation did not affect microglial number or staining in the P4 hippocampus. N’s = 2 MV, 4 FV, 3 MOVA, 3 FOVA. mPFC = medial prefrontal cortex, BG = basal ganglia, AMY = amygdala, HPC = hippocampus.
Figure 7.
Figure 7.
Gestational allergic inflammation alters juvenile and adult social behavior. (A) OVA offspring demonstrated fewer total play behaviors compared to vehicle. (B) Social chase was reduced in OVA offspring. (C) An interaction was found whereby allergic challenge tended to reduce rough and tumble play in females but not males. N’s = 6 MVs, 5 FVs, 10 MOVAs, 9 FOVAs. (D, E, F) display mean counts of each behavior. (G, H, I) display total amount of time (s) spent engaged in each behavior. Allergic challenge did not alter passive or active social investigation, but OVA offspring were less socially avoidant compared to vehicle offspring (F, I). N’s = 11 MVs, 13 FVs, 9 MOVAs, 12 FOVAs.
Figure 8.
Figure 8.
Gestational allergic inflammation increases locomotion in late adolescence/early adulthood. (A) Females spent more time in the center of the open field. OVA offspring spent more time in the center. N’s = 10 MVs, 13 FVs, 8 MOVAs, 12 FOVAs. (B) Females crossed more grids in the open field compared to males. OVA offspring crossed more grids compared to vehicle offspring. N’s = 8 MVs, 9 FVs, 6 MOVAS, 9 FOVAs. (C and D) Females spent more time in the open arms and had higher numbers of open arm entries. N’s = 11 MVs, 13 FVs, 9 MOVAs, 12 FOVAs.
Figure 9.
Figure 9.
Gestational allergic inflammation reduces adult cognitive flexibility in offspring. (A - C) OVA and vehicle offspring performed similarly on the simple discrimination, compound discrimination, and intradimensional shift tasks. (D). OVA offspring displayed worse performance in the reversal task, and this may have been driven by females. (E) OVA offspring displayed worse performance on the extradimensional shift task. N’s = 9 MVs, 6 FVs, 7 MOVAs, 5 FOVAs.
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